Uroxatral (alfuzosin HCl)
Alpha-Blockers Oral Tablet, Extended Release 24 Hr
Last reviewed · Source: First Databank (FDB) drug data
Overview
Alfuzosin is an alpha1-adrenergic blocking agent that exhibits selectivity for alpha1-adrenergic receptors in the lower urinary tract (e.g., bladder base, bladder neck, prostate, prostatic capsule, prostatic urethra).
Alfuzosin hydrochloride, a quinazoline-derivative alpha1-adrenergic blocking agent, is structurally and pharmacologically related to doxazosin, prazosin, and terazosin and pharmacologically related to tamsulosin. Alfuzosin is a non-subtype-specific alpha1-adrenergic blocking agent that exhibits selectivity for alpha1-adrenergic receptors in the lower urinary tract (e.g., bladder base, bladder neck, prostate, prostatic capsule, prostatic urethra). Blockade of these adrenoreceptors can cause relaxation of smooth muscle in the bladder neck and prostate, resulting in improvement in urine flow and a reduction in symptoms of benign prostatic hyperplasia (BPH).
Such effects generally are achieved with alfuzosin hydrochloride dosages that do not have clinically important effects on blood pressure or heart rate.
Alfuzosin is extensively metabolized in the liver via oxidation, O-demethylation, and/or N-dealkylation, principally by the cytochrome P-450 (CYP) 3A4 isoenzyme, to form pharmacologically inactive metabolites. Alfuzosin is not an inhibitor of CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, or 3A4 nor an inducer of CYP isoenzymes 1A, 2A6, or 3A4.
USES: Alfuzosin is used by men to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia-BPH). It does not shrink the prostate, but it works by relaxing the muscles in the prostate and the bladder. This helps to relieve symptoms of BPH such as difficulty in beginning the flow of urine, weak stream, and the need to urinate often or urgently (including during the middle of the night).
Alfuzosin belongs to a class of drugs known as alpha blockers. Do not use this medication to treat high blood pressure.
Generic name: alfuzosin HCl
Pronunciation: (al-FUE-zoe-sin)
Drug class: Alpha-Blockers
Therapeutic class: Genitourinary Therapy
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Uroxatral
Indications
The following indications are listed for Uroxatral:
- Benign Prostatic Hyperplasia With Lower Urinary Tract Symptom
Also known as: Symptomatic Benign Prostatic Hyperplasia, Symptomatic Benign Prostatic Hypertrophy, Symptomatic Bph, Symptomatic Prostatic Hypertrophy.
Dosing
No dosing information is available for this tab.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Uroxatral 10 Mg Tablet | Maintenance | Take 1 tablet (10 mg) by oral route once daily. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Alfuzosin Hcl Er 10 Mg Tablet | Maintenance | Take 1 tablet (10 mg) by oral route once daily. |
Drug interactions
There is no enhanced messaging for this drug.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Alfuzosin/Iloperidone; Milsaperidone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Iloperidone and milsaperidone may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2) Concurrent use of iloperidone or milsaperidone and an alpha-blocker such as alfuzosin may result in additive or synergistic effects on blood pressure.(1,2)
CLINICAL EFFECTS: The concurrent use of milsaperidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2) Concurrent use of iloperidone or milsaperidone and an alpha-blocker may result in symptomatic hypotension.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and with concurrent use of inhibitors of CYP3A4 or CYP2D6, which metabolize milsaperidone.(1-3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of iloperidone and milsaperidone states that concurrent use of other drugs that are known to prolong the QTc interval or alpha-blockers should be avoided.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval is consistently above 500 msec, discontinue milsaperidone.(2)
DISCUSSION: Milsaperidone and iloperidone rapidly interconvert in vivo. In a study of 160 patients with psychiatric disorders, coadministration of paroxetine (20 mg daily) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1,2) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(1,2) Iloperidone and milsaperidone have alpha-blocking properties.(1,2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(4)
Alfuzosin/Selected Strong Cyp3a4 Inhibitors
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of alfuzosin.(1)
CLINICAL EFFECTS: Coadministration of strong CYP3A4 inhibitors may cause an increase in alfuzosin levels and effects, including severe hypotension and potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of alfuzosin states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that alfuzosin should not be administered until at least 2 weeks after itraconazole treatment.(3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Repeated administration of ketoconazole (400 mg, a strong inhibitor of CYP3A4) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and 3.2-fold, respectively.(1) Administration of ketoconazole (200 mg daily) increased the Cmax and AUC of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold, respectively.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, relacorilant, telaprevir, troleandomycin, and tucatinib.(4)
Alfuzosin/Strong Cyp3a4 Inhibitors That Prolong Qt
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong CYP3A4 inhibitors decrease the metabolism of alfuzosin. Concurrent use of alfuzosin with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: Coadministration of strong CYP3A4 inhibitors that prolong the QTc interval may cause an increase in alfuzosin levels and effects, including severe hypotension. Coadministration may lead to additive risk of potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of alfuzosin states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Repeated administration of ketoconazole (400 mg, a strong inhibitor of CYP3A4) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and 3.2-fold, respectively.(1) Administration of ketoconazole (200 mg daily) increased the Cmax and AUC of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold, respectively.(1) Strong inhibitors of CYP3A4 that prolong the QTc interval include: adagrasib, ceritinib, clarithromycin, lonafarnib, posaconazole, ribociclib, telithromycin, and voriconazole.(3)
Alfuzosin;Silodosin;Tamsulosin/Protease Inhibitors
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of alfuzosin,(1) silodosin,(2) and tamsulosin(3) by CYP3A4.
CLINICAL EFFECTS: Co-administration of a protease inhibitor may result in increased alfuzosin,(1) silodosin,(2) and tamsulosin(3) levels and serious effects such as hypotension.
PREDISPOSING FACTORS: In patients receiving tamsulosin, the interaction may be worse in patients who are CYP2D6 poor metabolizers because tamsulosin also undergoes metabolism by this pathway.(3)
PATIENT MANAGEMENT: The US manufacturers of alfuzosin(1) and silodosin(2) state that concurrent use of strong CYP3A4 inhibitors is contraindicated. The US manufacturer of tamsulosin states that tamsulosin should not be used with strong CYP3A4 inhibitors.(3) The US manufacturers of atazanavir,(4) darunavir,(5) ensitrelvir,(6) fosamprenavir,(7) indinavir,(8) lopinavir/ritonavir,(9) nelfinavir,(10), nirmatrelvir/ritonavir,(11) paritaprevir, (12) saquinavir,(13) and tipranavir(14) state that concurrent use of alfuzosin is contraindicated.
DISCUSSION: Administration of ketoconazole (400 mg daily), another inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and 3.2-fold, respectively.(1) Administration of ketoconazole (200 mg daily) increased the Cmax and AUC of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold, respectively.(1) Administration of ketoconazole (200 mg daily for 4 days), increased the Cmax and AUC of a single dose of silodosin (4 mg) by 3.7-fold and 2.9-fold, respectively.(2) Administration of ketoconazole (400 mg daily for 4 days) increased the Cmax and AUC of a single dose of silodosin (8 mg) by 3.8-fold and 3.2-fold, respectively.(2) In a study in 24 healthy subjects, administration of ketoconazole (400 mg daily for 5 days) increased the Cmax and AUC of a single dose of tamsulosin (0.4 mg) by 2.2-fold and 2.8-fold, respectively.(3)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Possible Qt Prolonging Agents/Anagrelide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of anagrelide with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-4)
CLINICAL EFFECTS: The concurrent use of anagrelide with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-4)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(5)
PATIENT MANAGEMENT: The US manufacturer of anagrelide states that anagrelide should not be used in patients taking medications known to prolong the QT interval.(1) The Australian, Canadian, and UK manufacturers of anagrelide state use of anagrelide should be approached with caution in patients taking medications that can prolong the QTc interval.(2-4) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, dose-related QT changes were observed with anagrelide. The maximum mean change in QTcI (95% CI) in comparison to placebo was 7.0 (9.8) ms and 13.0 (15.7) msec following doses of 0.5 mg and 2.5mg, respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(6) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Artemether-Lumefantrine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of artemether-lumefantrine and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the use of artemether-lumefantrine in patients taking drugs that are known to prolong the QTc interval is contraindicated. These agents include class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some macrolides, fluoroquinolones, imidazole and triazole antifungals; terfenadine; astemizole; and cisapride.(1) The US manufacturer of artemether-lumefantrine states that the use of artemether-lumefantrine should be avoided in patients taking drugs that are known to prolong the QTc interval. These agents include class IA and III antiarrhythmics; neuroleptics; antidepressive agents; some macrolides, fluoroquinolones, imidazole and triazole antifungals; terfenadine; astemizole; and cisapride.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Bepridil
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bepridil has shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of bepridil with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Hypokalemia, the use of potassium wasting diuretics, and the presence of antecedent bradycardia may increase the risk of torsades de pointes.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypomagnesemia, hypocalcemia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of bepridil states that under contraindications that bepridil is contraindicated in patients taking other drugs that prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Cisapride
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Torsades de pointes has been reported with cisapride. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of cisapride with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The Australian manufacturer of cisapride states that concurrent use of agents known to prolong the QTc interval with cisapride is contraindicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Disopyramide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of disopyramide and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The Australian manufacturer of disopyramide states that concurrent use with agents liable to produce torsades de pointes, including tricyclic or tetracyclic antidepressants, erythromycin, vincamine, and sultopride, is contraindicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Domperidone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of domperidone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of domperidone patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or female gender.(2) The elderly and patients taking dosages of domperidone greater than 30 mg may also be at increased risk. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of domperidone and agents known to prolong the QT interval is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Treatment with domperidone has been associated with increased risk of sudden cardiac death.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Possible Qt Prolonging Agents/Dronedarone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of dronedarone and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration of dronedarone and QT prolonging agents may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of dronedarone states that the use of drugs or herbal products that are known to prolong the QTc interval is contraindicated. These agents include phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class IA and III antiarrhythmics.(1) When concurrent therapy of dronedarone and possible QT prolonging agents is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Droperidol
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Droperidol has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of droperidol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, age over 65 years, alcohol abuse, and the use of agents such as benzodiazepines, volatile anesthetics, and intravenous opiates may predispose patients to the development of prolonged QT syndrome.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypocalcemia, or female gender.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of droperidol states under precautions/drug interactions that drugs known to have the potential to prolong the QT interval should not be used together with droperidol.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Halofantrine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Halofantrine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of halofantrine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of halofantrine states in a black box warning that halofantrine is not recommended for use in combination with drugs known to prolong the QTc interval. Under precautions, drug interactions, the manufacturer states that halofantrine should not be administered with drugs known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Levomethadyl
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Levomethadyl has been shown to prolong the QTc interval and induce torsades de pointes. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of levomethadyl with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Congestive heart failure, bradycardia, diuretic use, cardiac hypertrophy, hypokalemia, or hypomagnesemia may increase the risk of torsades de pointes and/or sudden death.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypocalcemia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of levomethadyl states under contraindications that levomethadyl is contraindicated in patients being treated concomitantly with other drug products known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Pimozide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Pimozide has shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of pimozide with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of pimozide states that the use of pimozide is contraindicated in patients taking other drugs which prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Sertindole
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sertindole has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects of the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of sertindole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of sertindole state that sertindole is contraindicated in patients receiving drugs known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2)
Possible Qt Prolonging Agents/Sparfloxacin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sparfloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of sparfloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmics, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of sparfloxacin states under contraindications that sparfloxacin is contraindicated in patients being treated concomitantly with medications known to produce an increase in the QTc interval and/or torsades de pointes.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2)
Selected Qt Prolonging Agents/Ziprasidone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ziprasidone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ziprasidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1,3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QT interval such as dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.(1) It would be prudent to avoid the use of ziprasidone with medicines suspected of prolonging the QT interval. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Alfuzosin/Qt Prolonging Agents
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of alfuzosin with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of alfuzosin in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Approach the concurrent use of alfuzosin and other agents that are known to prolong the QTc interval with caution.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Alpha-Blockers/Cgmp Specific Pde Type-5 Inhibitors
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of avanafil,(1) sildenafil,(2-5) tadalafil,(6-9) or vardenafil(10-14) and an alpha-blocker may result in additive or synergistic effects on blood pressure.
CLINICAL EFFECTS: Concurrent use of avanafil,(1) sildenafil,(2-5) tadalafil,(6-9) or vardenafil(10-14)) and an alpha-blocker may result in symptomatic hypotension.
PREDISPOSING FACTORS: Patients who have a history of hemodynamic instability on alpha-blocker therapy prior to initiating avanafil, sildenafil, tadalafil, or vardenafil may be at an increased risk of symptomatic hypotension during concurrent therapy.
PATIENT MANAGEMENT: The US manufacturer of avanafil states that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning avanafil therapy. Avanafil should be initiated at the 50 mg dosage. In patients stabilized on avanafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(1) The US, Australian, Canadian, and UK manufacturers of sildenafil state that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning sildenafil therapy. Sildenafil should be initiated at the lowest possible dosage. In patients stabilized on sildenafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(2-5) The US manufacturer of tadalafil states that patients taking tadalafil for erectile dysfunction (ED) and alpha-blockers should be stabilized on their alpha-blocker prior to beginning tadalafil therapy. Tadalafil should be initiated at the lowest possible dosage. In patients stabilized on tadalafil therapy, alpha-blocker therapy should be initiated at the lowest possible dose. The combination of tadalafil and an alpha-blocker for treatment of benign prostatic hyperplasia (BPH) is not recommended. Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting tadalafil for once daily use for the treatment of BPH.(6) The Australian manufacturer of tadalafil states that tadalafil should be used with caution in patients taking alpha-blockers.(7) The Canadian manufacturer of tadalafil states that it may be used with tamsulosin and should be used with caution with other alpha-blockers.(8) The UK manufacturer of tadalafil states that concurrent use with alpha-blockers is not recommended.(9) The US, Canadian, and UK manufacturers of vardenafil state that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning vardenafil therapy. Vardenafil should be initiated at the lowest possible dosage. In patients stabilized on vardenafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(10-12) The UK manufacturer of vardenafil states that vardenafil may be give at any time in relation to tamsulosin; however, a dose separation period of 6 hour should be considered for other alpha-blockers.(12) The Australian manufacturer of vardenafil states that concurrent use with alpha-blockers is not recommended.(13) The US manufacturers of doxazosin,(14) prazosin(15) and terazosin(16) state that PDE-5 inhibitor therapy should be initiated at the lowest dose.
DISCUSSION: In a study in 24 subjects, concurrent use of avanafil (200 mg) with doxazosin (1 mg on Day 1, titrated to 8 mg for Days 8-18) resulted in 7 subjects experiencing potentially clinically significant changes in blood pressure.(1) In a study in 24 subjects, concurrent use of avanafil (200 mg) with tamsulosin (0.4 mg Days 1-11) resulted in 5 subjects experiencing potentially clinically significant changes in blood pressure.(1) Simultaneous administration of sildenafil (25 mg) and doxazosin (4 mg) resulted in mean additional reductions of supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic. When doxazosin (4 mg) was simultaneously administered with higher doses of sildenafil, there were reports of symptomatic postural hypotension within one to four hours.(2) In a study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving alfuzosin (10 mg daily) resulted in mean maximum decreases in standing and supine systolic blood pressure by 2.2 mmHg and 4.4 mmHg, respectively. There were no subjects with a decrease from baseline standing systolic blood pressure greater than 30 mmHg.(6) In a study, concurrent administration of a single dose of tadalafil (20 mg) to 18 healthy subjects receiving doxazosin (8 mg daily) resulted in significant augmentation of the blood-pressure lowering effects of doxazosin (by 9.8 mmHg). The number of subjects with a standing blood pressure of less than 85 mmHg was greater after concurrent doxazosin and tadalafil than when compared to doxazosin with placebo (28% versus 6%). One subject reported vertigo and another reported dizziness. No syncope was reported.(5,14) In a second study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving doxazosin (4-8 mg daily) also resulted in augmentation of the blood-pressure lowering affects of doxazosin. One subject reported symptomatic hypotension and another reported dizziness with concurrent therapy.(6) In a study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving tamsulosin (0.4 mg daily) resulted in no significant decreases in blood pressure.(6,17) Hypotension has been reported with concurrent use of terazosin and phosphodiesterase-5 inhibitors.(16) With simultaneous administration of vardenafil (10 mg) and terazosin (10 mg), 6 of 8 healthy subjects experienced a standing systolic blood pressure of less than 85 mmHg. With simultaneous vardenafil (20 mg) and terazosin (10 mg), 2 of 9 subjects experienced a standing systolic blood pressure of less than 85 mmHg. When vardenafil (20 mg) was administered 6 hours apart from terazosin (10 mg), 7 of 28 subjects experienced a standing systolic blood pressure of less than 85 mmHg.(10) With simultaneous administration of vardenafil (10 mg) and tamsulosin (0.4 mg), two of 16 subjects experienced a standing systolic blood pressure of less than 85 mmHg. When vardenafil (20 mg) was administered six hours apart from tamsulosin (0.4 mg), one of 24 subjects experienced a standing systolic blood pressure of less than 85 mmHg.(10) In a study in subjects with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy, simultaneous vardenafil (5 mg) and tamsulosin resulted in no effects on blood pressure. Simultaneous vardenafil (5 mg) with terazosin resulted in hypotension in some subjects. This effect did not occur when vardenafil and terazosin were separated by 6 hours.(12) In a placebo controlled, crossover study in 22 subjects with benign prostatic hyperplasia receiving tamsulosin, subjects received single doses of vardenafil (10 mg and 20 mg). No patients exhibited symptomatic hypotension. Three patients receiving 20 mg of vardenafil reported dizziness, but none had a systolic blood pressure of less than 95 mmHg.(18) In a placebo-controlled study in 24 health male subjects, administration of sildenafil (100 mg) or tadalafil (20 mg) with silodosin resulted in an increase in positive orthostatic tests in the 12 hours after concurrent administration when compared with the administration of silodosin alone. There were no reports of symptomatic orthostasis or dizziness.(19)
Possible Qt Prolonging Agents/Ajmaline
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ajmaline has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ajmaline with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: If possible, avoid the use of ajmaline with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Ajmaline has been associated with case reports of QT prolongation and torsades de pointes (TdP).(1,3-8) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(9)
Possible Qt Prolonging Agents/Amiodarone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Amiodarone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)
CLINICAL EFFECTS: The concurrent use of amiodarone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)
PATIENT MANAGEMENT: The Australian(1) and UK(2) manufacturers of amiodarone states that concurrent use of agents known to cause torsades de pointes is contraindicated. The US manufacturer of amiodarone states that the concurrent use of QT prolonging drugs should be avoided and that need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient.(3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: QTc prolongation has been reported during concurrent amiodarone and fluoroquinolones and macrolide antibiotics. Agents that are linked to this monograph may have been associated with Torsades de Pointes and/or QT prolongation but at this time lack substantial evidence for causing Torsades de Pointes.(4) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Arsenic
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Arsenic has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of arsenic with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, use of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia.(1) Risk may also be increased in patients with other cardiovascular disease (e.g. myocardial infarction, congenital long QT syndrome), hypocalcemia, bradycardia, female gender, or advanced age.(2) Higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of arsenic trioxide states that, if possible, drugs that are known to prolong the QT interval should be discontinued prior to therapy and caution is advised during coadministration.(1) In patients who reach a QTc interval value > 450 msec in men or >460 msec in women, withhold arsenic and any other QT prolonging agents. Monitor electrolytes and correct abnormalities. After the QTc normalizes, follow manufacturer instructions concerning restarting arsenic and escalation of dosing.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Aumolertinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)
DISCUSSION: A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Citalopram
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)
CLINICAL EFFECTS: The use of citalopram in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)
PREDISPOSING FACTORS: Higher doses of citalopram, especially doses greater than 40 mg, may increase the risk of QT prolongation. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: Concurrent use of citalopram with agents known to prolong the QT interval should be avoided. Due to the risk of QT prolongation, citalopram doses greater than 40 mg once daily are not recommended. Citalopram doses should be limited to 20 mg once daily in patients who are CYP2C19 poor metabolizers or patients receiving CYP2C19 inhibitors. If patients have a persistent QTc measurement > 500 ms, discontinue citalopram. If a patient develops symptoms including dizziness, palpitations, or syncope, further evaluation is warranted included cardiac monitoring. The manufacturer recommends ECG monitoring in patients for whom citalopram is not recommended, including those receiving concurrent therapy with agents known to prolong the QT interval. Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(1-2) Consider obtaining serum calcium, magnesium, and potassium levels at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Citalopram has been associated with dose-depended increases in the QTc interval. In healthy subjects, the maximum mean difference in QTc interval seen with 20 mg of citalopram and 60 mg of citalopram were 8.5 msec (90% CI = 6.2-10.8 msec) and 18.5 msec (90% CI = 16.0-21.0 msec), respectively. Based on extrapolation, a 40 mg dose of citalopram is expected to produce a mean increase in the QTc interval of 12.6 msec (90% CI = 10.9-14.3 msec).(1) In a clinical trial of use of citalopram for agitation in Alzheimer's disease, citalopram (30 mg daily) was associated with a mean increase in QTc of 18.1 msec.(5) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(6)
Possible Qt Prolonging Agents/Crizotinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of crizotinib in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Consider periodic electrocardiogram (ECG) and electrolyte monitoring (calcium, magnesium, and potassium levels at baseline and regular intervals) in patients receiving concurrent therapy with crizotinib and another agent that prolongs the QTc interval.(1) In patients who develop a QTc greater than 500 ms on at least 2 separate ECGs, withhold crizotinib until recovery to baseline or to a QTc less than 481 ms, then resume crizotinib at reduced dose.(1) In patients who develop a QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, permanently discontinue crizotinib.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Crizotinib is associated with concentration-dependent QTc interval prolongation. In a clinical trial 2.1% of patients were found to have a QTcF greater than or equal to 500 msec and 5% of patients had an increase in QTcF by greater than or equal to 60 msec.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received crizotinib, QTc prolongation was identified in 1 (50%) with 1 (100%) having Grade 1 (QTc 450-480 ms). No patients had a QTc change greater than or equal to 60 ms, ventricular tachycardia, sudden cardiac death, or TdP.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Possible Qt Prolonging Agents/Delamanid
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent use of delamanid in patients taking other medications that prolong the QT interval may result in additive QT prolongation. QT prolongation may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: If possible, avoid concurrent use of delamanid and other agents that prolong the QT interval. If concurrent use is necessary, frequently monitor ECGs (more frequently than the standard recommended monthly ECG during delamanid therapy). Discontinue delamanid if a QTcF greater than 500 msec is observed.(1) Serum albumin, calcium, magnesium, and potassium levels should be obtained at baseline and at regular intervals. Correct any electrolyte abnormalities. Discontinue delamanid if albumin falls below 2.8 g/DL. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: QT prolongation has been observed with delamanid and increases over the first 6-10 weeks of therapy. In a placebo controlled study in healthy subjects, the mean increase in QTcF from baseline during delamanid therapy was 7/6 msec at 1 month and 12.1 msec at 2 months. Three percent of patients experienced an increase of 60 msec or greater at some point during therapy. One patient had a QTcF greater than 500 msec. All patients with a QTcF greater than 60 msec were also taking a fluoroquinolone.(1)
Possible Qt Prolonging Agents/Dexmedetomidine Sublingual
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Dexmedetomidine sublingual has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of dexmedetomidine sublingual with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of dexmedetomidine sublingual states that concurrent use should be avoided with other agents known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a QT study, dexmedetomidine sublingual had a concentration dependent effect on the QT interval. The mean QTc (95% confidence interval) increased from baseline by 6 (7) msec with a 120 mcg single dose, 8 (9) msec with 120 mcg followed by 2 additional doses of 60 mcg (total 3 doses), 8 (11) msec with a single 180 mcg dose, and 11 (14) msec with 180 mcg followed by 2 additional doses of 90 mcg (total 3 doses), respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Dofetilide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Dofetilide has been shown to prolong the QTc interval in a dose-dependent fashion. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of dofetilide with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(1)
PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of dofetilide states that the use of dofetilide with other agents known to prolong the QTc interval is not recommended.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If dofetilide dose is increased or if dofetilide therapy is reinitiated after an interruption, the patient should be hospitalized for continuous ECG monitoring.(1)
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Dordaviprone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Dordaviprone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of dordaviprone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: If possible, avoid the use of dordaviprone with other agents known to prolong the QTc interval. If current use cannot be avoided, separate administration of dordaviprone and the QT-prolonging agent. The manufacturer does not provide details about how to separate administration and states that the exposure-response relationship and time course of pharmacodynamic response is not fully characterized. Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours (0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1) Baseline and periodic monitoring of ECG and electrolytes is recommended.(1) Increase the frequency of monitoring in patients with congenital long QT syndrome, existing QTc prolongation, history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or are taking strong or moderate CYP3A4 inhibitors.(1) If QTc interval prolongation occurs, dose modifications are warranted. If QTc is >500 msec or the change from baseline is >60 msec, interrupt dordaviprone therapy until QTc interval is <= 480 msec or returns to baseline. If the patient has Torsades de pointes, polymorphic ventricular tachycardia, or signs or symptoms of serious or life-threatening arrhythmia, permanently discontinue dordaviprone.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Dordaviprone causes concentration-dependent QTc prolongation.(1) In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8, 13.7) with dordaviprone (1.2 times the maximum recommended dose).(1) In a pooled safety analysis, out of 82 patients with baseline ECG, 6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had an increase in QTc >500 msec. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Encorafenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of encorafenib with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of encorafenib with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of encorafenib with medications that prolong the QT interval.(1) Recommended dosage modifications for encorafenib and QTc prolongation adverse reactions include: - QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline: Withhold encorafenib until QTcF less than or equal to 500 ms. Resume at reduced dose. If more than one recurrence, permanently discontinue encorafenib. - QTcF greater than 500 ms and greater than 60 ms increase from baseline: Permanently discontinue encorafenib.(1) See prescribing information for additional information regarding dose reductions.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Encorafenib has been associated with a dose-dependent QTc interval prolongation. Following administration of encorafenib in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms (14-22 ms), based on central tendency analysis.(1) Following administration of encorafenib in combination with cetuximab and mFOLFOX6, an increase of QTcF >500 ms was measured in 4% (9/226) of patients. Following administration of encorafenib with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Entrectinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of entrectinib with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of entrectinib with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of entrectinib with medications that prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications ---Interrupt entrectinib therapy for QTc interval greater than 500 ms. ---Follow labeling recommendations regarding restarting entrectinib.(1) If torsade de pointes, polymorphic ventricular tachycardia, and/or signs/symptoms of serious arrhythmia occur, permanently discontinue entrectinib.(1)
DISCUSSION: In clinical trials, 3.1% of patients with at least one post-baseline ECG experienced QTcF prolongation of greater than 60 msec after starting entrectinib..(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Eribulin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Eribulin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of eribulin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of eribulin states that patients receiving concurrent therapy with eribulin and other agents known to prolong the QT interval should receive ECG monitoring.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: QT prolongation, independent of eribulin concentration, was observed on Day 8 of therapy but not on Day 1 in an uncontrolled open-label ECG study in 26 patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Ezogabine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of ezogabine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsade de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of ezogabine with agents known to prolong the QT interval should be approached with caution. Patients receiving concurrent therapy with other QT prolongers, an electrocardiogram (ECG) should be performed prior to ezogabine initiation. In those patients with a corrected QT interval greater than 440 msec at baseline, a repeat ECG should be performed after reaching the maintenance dose of ezogabine.(1) Consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a study in healthy subjects, ezogabine titrated to 1200 mg/day increased the mean QTc interval by 6.7 msec (upper bound of 95% CI was 12.6 msec) within three hours of dosing.(1)
Possible Qt Prolonging Agents/Fexinidazole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Fexinidazole has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of fexinidazole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of fexinidazole states that fexinidazole should be avoided in patients receiving other drugs known to cause QT prolongation.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to prolong QTcF interval or to induce bradycardia do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Firmonertinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Firmonertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of firmonertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of firmonertinib states that firmonertinib should be avoided in patients with risk factors that may increase the risk of QTc interval prolongation or arrhythmic events, such as heart failure, hypokalemia, or congenital long QT syndrome.(1) Concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating firmonertinib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. The manufacturer of firmonertinib states patients with at least two independent ECG tests indicating a QTc > 500 ms should temporarily discontinue firmonertinib until QTc < 481 ms or returns to baseline levels (e.g., baseline QTc > or = 481 ms). Patients with QTc prolongation and severe arrhythmic symptoms or signs should permanently discontinue firmonertinib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical trials, among 446 patients treated with firmonertinib at a dose of 80 mg, 57 (12.8%) experienced QT interval prolongation on an ECG, of which 6 (1.3%) were grade 3 and the rest were grade 1-2. Of these, 7 (1.6%) experienced dose interruption, 5 (1.1%) experienced dose reduction, and 1 (0.2%) experienced permanent discontinuation of treatment.(1) In another study, QTc interval prolongation was reported as an adverse event in 6% of 130 patients (in 20 mg, 40 mg, 80 mg, and 160 mg groups; n=2 each). All were classified as grade 1 or grade 2 and assessed as possibly related to treatment. Two events (grade 2 at 80 mg, grade 2 at 160 mg) led to dose interruption before resolution. QT prolongation in the remaining patients was resolved without intervention, except for one event (grade 1) reported as worsening.(3)
Possible Qt Prolonging Agents/Gadofosveset
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: QT prolongation has been reported following gadofosveset administration. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of gadofosveset in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: In patients maintained on agents known to prolong the QT interval, consider a baseline ECG prior to administration of gadofosveset to asses the risk/benefit of gadofosveset. If gadofosveset is used, consider ECG monitoring for 72 hours until the majority of gadofosveset is eliminated. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Counsel patients to report any irregular heartbeat, dizziness, or fainting episodes during this time frame.(1)
DISCUSSION: In clinical trials, 6% of patients experienced an increase in QTc of 30 msec to 60 msec 45 minutes after the administration of gadofosveset and 0.4% of patients experienced a QTc increase of greater than 60 msec at 45 minutes post-administration.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Gepotidacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Gepotidacin may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of gepotidacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of gepotidacin states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating gepotidacin, during concomitant use, and as clinically indicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: The effect of gepotidacin on the QTc interval was evaluated in a randomized, active (moxifloxacin 400 mg) and placebo-controlled, double-blind cross-over trial in healthy subjects who received single intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and concentration-dependent QTc prolongation effect of gepotidacin was observed. The mean placebo-corrected change from baseline QTcF values around Tmax were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing regimens and route of administration). Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Givinostat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Givinostat may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of givinostat with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of givinostat states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating givinostat, during concomitant use, and as clinically indicated.(1) If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold givinostat therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a QT study, the largest mean increase in QTc interval of 13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after administration of givinostat 265.8 mg (approximately 5 times the recommended 53.2 mg dose in patients weighing 60 kg or more).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Glasdegib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of glasdegib with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of glasdegib with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of glasdegib with medications that prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications ---Interrupt glasdegib therapy for QTc interval greater than 500 ms. ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation ---Follow labeling recommendations regarding restarting glasdegib.(1)
DISCUSSION: In a randomized, single-dose, double-blind, 4-way cross-over, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects, the largest placebo and baseline-adjusted QTc interval change was 8 msec (90% CI: 6-10 msec) with a single 150 mg dose of glasdegib (The 150 mg single dose was used to achieve therapeutic plasma concentrations). With two-fold therapeutic plasma concentrations (achieved with a 300 mg single dose), the QTc change was 13 msec (90% CI: 11-16 msec).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Hydroquinidine; Quinidine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Hydroquinidine and quinidine have been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of hydroquinidine or quinidine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)
PATIENT MANAGEMENT: If possible, avoid the use of hydroquinidine or quinidine with other agents known to prolong the QT interval. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Possible Qt Prolonging Agents/Hydroxychloroquine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Hydroxychloroquine has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of hydroxychloroquine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of hydroxychloroquine states that hydroxychloroquine should not be administered with other agents that prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: The manufacturer states that hydroxychloroquine has been shown to prolong the QT interval;(1) however, conditions that hydroxychloroquine treats have also been associated with QT prolongation. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Hydroxyzine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of hydroxyzine with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-4)
CLINICAL EFFECTS: The concurrent use of hydroxyzine with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-4)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(5) Doses of hydroxyzine greater than 100 mg/day may also increase the risk.(1,2)
PATIENT MANAGEMENT: Concurrent use of hydroxyzine with agents known to prolong the QT interval is contraindicated in Canada(1,2) and the UK.(3) The US manufacturer states that concurrent use should be approached with caution.(4) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In vitro data indicates that hydroxyzine blocks the hERG channel, which results in the potential risk of QT interval prolongation.(6) In a placebo controlled, non-thorough QT study, 10 patients in the placebo group (n=152) had a change in QT interval from baseline between 30 ms and 60 ms and one patient presented a change from baseline higher than 60 ms. In the hydroxyzine group (n=148), 14 subjects had a change in QT interval from baseline between 30 and 60 ms and were considered to have a potential risk factor for risk of QT interval prolongation and TdP due to relevant medical history, concomitant medication potentially associated with the induction of prolongation of QT interval, and/or polymedication.(6) Health Canada reviewed 61 cases of QT interval prolongation or torsades de pointes with hydroxyzine. In a majority of cases, patients had additional risk factors for QT prolongation. Three reports provided enough data for a more detailed review. Hydroxyzine was found to be either "possible" or "probably" contribution to QT prolongation/torsades in these reports.(1) The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) reviewed 190 case reports found in a search of "torsade de pointes/QT prolongation with hydroxyzine". Forty-two non-fatality cases were subdivided into torsades (n=16), QT prolongation (n=21), and ventricular tachycardia (n=5). All included risk factors for QT interval prolongation and TdP (cardiac disorders, hypokalemia, long QT syndrome, bradycardia, concomitant drugs which are known to prolong the QT interval). Dosages ranged from <= 100 mg/day (n=10), > 100 mg/day to <=300 mg/day (n=4), > 300 mg/day (n=8), overdosages (n=11), and premedication (n=9). Twenty-one cases involving fatalities had at least one risk factor for QT prolongation. The PRAC concluded that post-marketing cases of QT interval prolongation, TdP and ventricular tachycardia confirm the findings of the hERG studies suggesting that hydroxyzine blocks hERG channels. No difference in the risk of QT interval prolongation could be observed based on the indication, age of the subject, or dose.(6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)
Possible Qt Prolonging Agents/Inotuzumab Ozogamicin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of inotuzumab ozogamicin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of inotuzumab ozogamicin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: When possible, discontinue QT prolonging agents prior to therapy with inotuzumab ozogamicin or use alternative agents during inotuzumab ozogamicin therapy.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy.(1) Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(1)
DISCUSSION: Inotuzumab ozogamicin was shown to prolong the QT interval in clinical trials. In the INO-VATE trial, 3% (4/162) of patients experienced an increase in QTc equal to or greater than 60 msec. No patients has QTc values greater than 500 msec. Grade 2 QT prolongation was reported in 1% (2/164) patients. There were no reports of Grade 3 QT prolongation or Torsade de Pointes.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Ivabradine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: QT prolongation may be exacerbated by ivabradine-induced reduction in heart rate.(1)
CLINICAL EFFECTS: Concurrent use of ivabradine and agents known to prolong the QT interval may exacerbate QT prolongation.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The UK, AU, and Canadian manufacturer of ivabradine states that concurrent use with cardiovascular and non-cardiovascular QT prolonging agents should be avoided.(1) The Canadian manufacturer states that if concurrent therapy is deemed necessary, close cardiac monitoring (12-lead ECG) is required. Depending on the ECG results, ivabradine dosing may need to be decreased or stopped.(4) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2)
Possible Qt Prolonging Agents/Ivosidenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of ivosidenib with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ivosidenib with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of ivosidenib with medications that prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications ---Interrupt ivosidenib therapy ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation ---Follow labeling recommendations regarding restarting ivosidenib.(1)
DISCUSSION: In clinical trials of ivosidenib, 9% of patients experienced a QTc interval greater than 500 msec and 14% of patients had an increased from baseline QTc interval of greater than 60 msec. Patients with a baseline QTc of equal to or greater than 450 msec without pre-existing bundle branch block, or with a history of long QT syndrome were excluded from this trial.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Lefamulin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of lefamulin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of lefamulin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of lefamulin with medications that prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, intravenous lefamulin increased the QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by 9.3 msec (90% CI = 10.9 msec).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Lenvatinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent use of lenvatinib in patients taking other medications that prolong the QT interval may result in additive QT prolongation. QT prolongation may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Monitor electrocardiograms during concurrent therapy with lenvatinib and agents that prolong the QT interval. In a clinical trial of patients with refractory, progressive thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients. Monitor and correct electrolyte abnormalities in all patients.(1) This is particularly important in lenvatinib patients as diarrhea, nausea, vomiting, and decreased appetite are common side effects which may increase the risk for electrolyte disturbances. Monitor ECG at baseline and at regular intervals. Lenvatinib dose must be withheld if the QTc exceeds 500 msec until QTc resolves to less than 480 msec or baseline. Lenvatinib must be resumed at reduced dose when QTc prolongation resolves to less than 480 msec or to baseline. Dose adjustments below are indication specific and are for patients with normal hepatic and renal function:(1) Dose Modifications in Differentiated Thyroid Cancer(DTC): - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 20 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 14 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 10 mg once daily Dose Modifications in Renal Cell Cancer (RCC): - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 14 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 10 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 8 mg once daily Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight 60 kg or greater: - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 8 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 4 mg every other day Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight less than 60 kg: - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg every other day - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline and discontinue lenvatinib (1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a clinical trial of patients with refractory, progressive thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients and 2% of placebo patients. The incidence of Grade 3 QT prolongation of > 500 msec was reported in 2% of lenvatinib patients compared with no reports in placebo patients.(1) In contrast, a single lenvatinib dose of 32 mg (1.3 times the recommended daily dose) did not prolong the QT/QTc interval in a thorough QT study performed in healthy subjects.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received lenvatinib, QTc prolongation was identified in 9 (42.9%) with 4 (44.4%) having Grade 1 (QTc 450-480 ms) and 3 (33.3%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 0 (0%) having QTc greater than or equal to 500 ms and 1 (11.1%) having QTc change greater than or equal to 60 ms. Ventricular tachycardia was seen in 1 (11.1%) patient.(3)
Possible Qt Prolonging Agents/Levomepromazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Levomepromazine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of levomepromazine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of levomepromazine states that levomepromazine is not recommended in patients receiving other drugs known to cause QT prolongation.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Case reports of QTc prolongation associated with levomepromazine have been reported.(1,3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Possible Qt Prolonging Agents/Levomethadone; Methadone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Levomethadone and methadone have been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)
CLINICAL EFFECTS: The concurrent use of levomethadone or methadone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Concurrent use of levomethadone or methadone with other agents known to prolong the QT interval should be approached with extreme caution.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Most cases of methadone-induced QT prolongation are associated with, but not limited to, higher dose treatment (greater than 200 mg daily) and most involve patients being treated for pain with large, multiple daily doses. Cases have been reported in patients treated with doses commonly used for maintenance treatment of opioid addiction.(2) Levomethadone should be used with caution in patients with a history of QT prolongation, advanced heart disease, concomitant CYP3A4 inhibitors, or electrolyte abnormalities. Cases of QT prolongation and torsades de pointes have been reported, most commonly with high doses.(1)
Possible Qt Prolonging Agents/Lofexidine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Lofexidine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)
CLINICAL EFFECTS: Concurrent use of lofexidine and agents known to prolong the QT interval may exacerbate QT prolongation.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age,(3) renal impairment, and/or hepatic impairment.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The UK manufacturer of lofexidine states that concurrent use of lofexidine and QT prolonging agents should be avoided.(1) The US manufacturer states that ECGs should be monitored in patients receiving concurrent therapy with lofexidine and agents that are known to prolong the QT interval.(2) Consider obtaining serum calcium, magnesium, and potassium levels at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a study of healthy volunteers, lofexidine 1.44 mg to 1.8 mg had a change from baseline in QTc of 14.4 msec and 13.6 msec, respectively.(2) In a dose response study, lofexidine had a mean QTc prolongation of 7.3 msec and 9.3 msec at doses of 2.16 mg/day and 2.88 mg/day, respectively.(2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(4)
Possible Qt Prolonging Agents/Macimorelin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of macimorelin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of macimorelin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of macimorelin with medications that prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study in 60 healthy subjects, a supra-therapeutic dose of macimorelin (2mg/kg, 4 times the recommended dosage) produced a mean change in QTc of 9.6 msec (upper 95% CI of 11.4 msec). Similar effects were seen in a single-ascending dose study which examined dosages of 1.5 mg/kg, 1 mg/kg, and 2 mg/kg, suggesting an absence of dose-dependent changes.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Mesoridazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Mesoridazine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of mesoridazine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of mesoridazine states under contraindications that the use of mesoridazine should be avoided in combination with other drugs that are known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Mobocertinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Mobocertinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of mobocertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of mobocertinib states that mobocertinib may cause life-threatening QTc prolongation, including torsades de pointes. Mobocertinib should be avoided in patients receiving other drugs known to cause QT prolongation.(1) If patients develop QTc prolongation during mobocertinib therapy, dose modifications are recommended: - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the same dose. - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60 msec from baseline) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 and recurrence: permanently discontinue mobocertinib. - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Increase the frequency of ECG monitoring in patients with risk factors for QTc prolongation, including congenital long QT syndrome, heart disease, or electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a clinical study, mobocertinib 160 mg once daily was associated with a concentration-dependent increase in QTc, with the largest mean increase in QTc of 23 msec.(1) In clinical studies, patients were excluded if baseline QTc was greater than 470 msec. In a subset of 250 patient with scheduled and unscheduled electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and 11% of patients had a change-from-baseline QTc interval >60 msec. Grade 4 Torsades de Pointes occurred in 1 patient (0.4%).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Moxifloxacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moxifloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of moxifloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of moxifloxacin states that moxifloxacin should be avoided in patients taking agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Possible Qt Prolonging Agents/Nilotinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Nilotinib prolongs the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,3)
CLINICAL EFFECTS: The concurrent use of nilotinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The US manufacturer of nilotinib states that the use of nilotinib should be avoided with other drugs that are known to prolong the QTc interval. Should treatment with a QT prolonging agent be required, interruption of nilotinib therapy should be considered. The UK manufacturer of nilotinib states that the use of nilotinib should be used with caution with other drugs that are known to prolong the QTc interval.(3) Patient monitoring recommendations: If concurrent therapy cannot be avoided, monitor patients closely for prolongation of the QT interval and follow recommended nilotinib dosage adjustments for QT prolongation.(1) Consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received nilotinib, QTc prolongation was identified in 29 (38.7%) with 1 (3.5%) having Grade 1 (QTc 450-480 ms) and 2 (7%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 9 (31%) having QTc greater than or equal to 500 ms and 17 (58.6%) having QTc change greater than or equal to 60 ms. No patients developed ventricular tachycardia, sudden cardiac death, or TdP.(5) Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(2)
Possible Qt Prolonging Agents/Ondansetron
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)
CLINICAL EFFECTS: The use of ondansetron in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or in the elderly (> or = 75 years of age).(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The risk for QT prolongation due to ondansetron is dose and route related. Intravenous (IV) doses lead to higher peak concentrations and systemic exposure and so have a greater risk for QT prolongation compared with the same dose given orally. Faster rates of IV infusion are also associated with a greater risk for QT prolongation.(5) If concomitant therapy is needed, correct electrolyte abnormalities prior to starting therapy. Monitor closely, particularly in patients with predisposing risk factors for QT prolongation (e.g. cardiac disease, female, elderly). Electrocardiogram (ECG) monitoring should be performed in patients receiving concurrent therapy.(1-3) The Canadian manufacturer of Zofran injection has specific recommendations for use of IV ondansetron in oncology patients greater than or equal to 75 years of age (5): - all IV doses must be diluted in 50 - 100 mL of compatible fluid and infused over at least 15 minutes - initial and repeat IV doses must not exceed 8 mg. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a double-blind, randomized, placebo and positive controlled cross-over study, an ondansetron intravenous (IV) dose of 32 mg increased the maximum mean QTcF by 19.6 msec (upper limit of 90% CI: 21.5). A dose of 8mg increased the QTcF by a maximum mean of 5.8 (upper limit of 90% CI: 7.8). A dose of 16 mg was predicted to have a mean increase in QTcF of 9.1 msec (upper limit of 90% CI: 11.2).(1) QT prolongation and torsades de pointes have been reported in post-marketing reports in patients receiving ondansetron.(2-3) In a review of published reports of QT prolongation associated with ondansetron administration, 67% of patients were also receiving another medication known to prolong the QT interval.(6) In a prospective, observational study, administration of a single ondansetron IV dose of 4 mg in the emergency department increased the mean and median QTc interval by 16.2 msec (95% CI 4.2-28.2 msec; p=0.01) and 12 msec (IQR 5.5-18 msec; p<0.01), respectively. Three patients had extreme QTc prolongation. With exclusion of those 3 patients, the median QTc prolongation was 10 msec (IQR 5-15 msec; p<0.01).(7) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(8)
Possible Qt Prolonging Agents/Osimertinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Osimertinib prolongs the QTc interval.(1) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2,3)
CLINICAL EFFECTS: The concurrent use of osimertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2,3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Osimertinib prolongs the QT interval. Premarket clinical trials excluded patients with a baseline QTc > or = 470 msec. In these trials 11 patients (2.7%) had increase in QTc greater than 60 msec.(1) Manufacturer recommendations: when feasible, avoid concurrent administrations of osimertinib with drugs known to prolong the QTc interval. Conduct baseline and periodic monitoring with ECGs in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities (e.g. serum calcium, magnesium, and potassium), or those taking medications known to prolong the QT interval.(1) Dose adjustments (1): - If QTc is greater than 500 msec on at least 2 separate ECGs, withhold osimertinib until QTc is < 481 msec or recovery to baseline (if baseline QTc was greater than or equal to 481 msec), then resume osimertinib at 40 mg per day. - For QTc prolongation with signs or symptoms of life threatening arrhythmia, permanently discontinue osimertinib. During concomitant therapy with another QT prolonging agent, monitor patients closely for prolongation of the QT interval.(1) Obtain serum calcium, magnesium, and potassium levels and monitoring ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received osimertinib, QTc prolongation was identified in 4 (25%) with 1 (25%) having Grade 1 (QTc 450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 1 (25%) having QTc greater than or equal to 500 ms and 1 (25%) having QTc change greater than or equal to 60 ms. No patients had ventricular tachycardia, sudden cardiac death, or TdP.(4) In clinical studies of 1813 patients treated with osimertinib monotherapy, 1.1% of patients were found to have a QTc interval greater than 500 ms and 4.3% of patients had an increase from baseline QTc > 60 ms.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Possible Qt Prolonging Agents/Oxaliplatin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of oxaliplatin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of oxaliplatin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the concurrent use of oxaliplatin in patients with congenital long QT syndrome. ECG monitoring is recommended if oxaliplatin therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Prescribing information for oxaliplatin states post-marketing cases of QT prolongation and ventricular arrhythmias, including fatal Torsades de Pointes, have been reported.(1) Case reports have documented QT prolongation in patients with varying cancer indications for oxaliplatin.(3-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)
Possible Qt Prolonging Agents/Pacritinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Pacritinib has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of pacritinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of pacritinib states concurrent use with agents known to prolong the QT interval should be avoided. Avoid the use of pacritinib in patients with a baseline QTc > 480 msec. Correct hypokalemia prior to initiation and during therapy with pacritinib.(1) If patients develop QTc prolongation >500 msec or >60 msec from baseline, hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline within 1 week, resume pacritinib at the same dose. If time to resolution of the QTc interval takes greater than 1 week to resolve, reduce the pacritinib dose.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a 24 week clinical study, patients treatment with pacritinib 200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1) Pacritinib has been associated with QTc interval prolongation. In clinical trials, patients with QTc prolongation >500 msec occurred in 1.4% of patients in the treatment arm compared to 1% in the control arm. The treatment arm had a greater incidence of an increase in QTc > 60 msec from baseline than the control arm (1.9% vs 1%, respectively). QTc prolongation adverse reactions were higher in the treatment arm than the control group (3.8% vs 2%, respectively).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Paliperidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Paliperidone has been shown to cause a modest increase in the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)
CLINICAL EFFECTS: The concurrent use of paliperidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The US manufacturer of paliperidone states that the use of paliperidone should be avoided with other drugs that are known to prolong the QTc interval, including Class IA and Class III antiarrhythmics, antipsychotics, antibiotics such as gatifloxacin and moxifloxacin, or any other class of medications known to prolong the QTc interval.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with torsades de pointes and/or QT prolongation but at this time lack substantial evidence for causing torsades de pointes.(3)
Possible Qt Prolonging Agents/Pazopanib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Pazopanib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of pazopanib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of pazopanib states that pazopanib should be avoided in patients receiving other drugs known to cause QT prolongation.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical studies, 2% (11/558) of patients receiving pazopanib experienced QT prolongation. Torsades de pointes occurred in less than 1% (2/977) of patients who received pazopanib in monotherapy studies. In a randomized clinical trial, 3 of 290 patients who received pazopanib had post-baseline QTc values between 500 and 549 msec. None of the patients receiving placebo had post-baseline QTc values greater than or equal to 500 msec.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received pazopanib, QTc prolongation was identified in 32 (19.4%) with 18 (56.3%) having Grade 1 (QTc 450-480 ms) and 4 (12.5%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 3 (9.3%) having QTc greater than or equal to 500 ms and 4 (12.5%) having QTc change greater than or equal to 60 ms. Ventricular tachycardia was seen in 2 (6.3%) of patients and 1 (3.1%) patient experienced sudden cardiac death.(4) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Possible Qt Prolonging Agents/Pimavanserin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Pimavanserin prolongs the QTc interval.(1) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2,3)
CLINICAL EFFECTS: The concurrent use of pimavanserin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2,3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Avoid the use of pimavanserin in patients receiving QT prolonging agents.(1) During concomitant therapy with another QT prolonging agent, monitor patients closely for prolongation of the QT interval.(1) Obtain serum calcium, magnesium, and potassium levels and monitoring ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In thorough-QT study, pimavanserin (at twice the therapeutic dose) found that the maximum mean change was 13.5 (16.6) msec. In placebo-controlled effectiveness studies, mean increases of 5-8 msec were observed with normal dosages of 37 mg daily. Sporadic QTcF values of equal to or greater than 500 msec and change from baseline values equal to or greater than 60 msec were observed at this dose as well.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Possible Qt Prolonging Agents/Propafenone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Propafenone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of propafenone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of propafenone states that the use of propafenone with other agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Possible Qt Prolonging Agents/Quetiapine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of quetiapine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of quetiapine states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Although quetiapine was not associated with QT or QTc changes in clinical trials, QT prolongation has been reported in post-marketing reports in conjunction with the use of other agents known to prolong the QT interval.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Possible Qt Prolonging Agents/Quinine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Quinine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of quinine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of quinine states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.
Possible Qt Prolonging Agents/Quizartinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Quizartinib has been shown to prolong the QTc interval in a dose- and concentration dependent manner. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)
CLINICAL EFFECTS: The concurrent use of quizartinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of quizartinib states that the concurrent use of QT prolonging agents should be avoided.(1) Quizartinib is only available through a restricted REMS program due to the serious risk of QT prolongation, torsades de pointes, and cardiac arrest. The manufacturer recommends monitoring as follows: -Initiate quizartinib only if the QTcF is less than or equal to 450 ms. -During induction and consolidation, monitor ECGs prior to initiation and then at minimum once weekly during treatment. -During maintenance, monitor ECGs prior to initiation and then at minimum once weekly for the first month following dose initiation and escalation and clinically therafter. Dose escalation may occur only if the QTcF is less than or equal to 450 ms. The manufacturer recommends the following dose modifications for adverse reactions: -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose. -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of quizartinib without interruption based on prescribing information. Resume the previous dose in the next cycle if the QTcF has decreased to less than 450 ms. -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib. Resume at a reduced dose based on prescribing information when the QTcF is less than 450 ms. Maintain the dose of 26.5 mg once daily during maintenance if the QTcF is greater than 500 ms during induction or consolidation. -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently discontinue quizartinib if QTcF is greater than 500 ms despite dose reduction and correction/elimination of other risk factors. -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of life-threatening arrhythmia occur (Grade 4) - Permanently discontinue quizartinib. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Quizartinib has been associated with QTc interval prolongation, Torsades de Pointes, ventricular arrhythmias, cardiac arrest, and sudden death. Quizartinib increased QTc in a dose- and concentration-dependent manner.(1) In an exposure-response analysis, quizartinib had a predicted concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of 2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg and 53 mg during maintenance therapy.(1) In patients administered quizartinib, 2.3% of 265 patients had a QTcF greater than 500 msec and 10% of patients had a increase from baseline QTcF greater than 60 msec.(1) In patients administered quizartinib during the induction phase, torsades de pointes occurred in approximately 0.2% of patients, cardiac arrest occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients experienced ventricular fibrillation.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Revumenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Revumenib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of revumenib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of revumenib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib, during concomitant use, and as clinically indicated.(1) If the QTc interval is greater than 480 ms, withhold revumenib therapy. Resume revumenib after the QTc interval drops to 480 msec or less.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical trials, QTc interval prolongation was reported as an adverse event in 29% of 135 patients treated with the recommended dosage of revumenib; 12% of patients had Grade 3 QTc prolongation. Revumenib increased the QTc interval in a concentration-dependent manner. At the mean steady-state Cmax using the highest approved recommended dosage of revumenib without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper bound of 90% confidence interval = 30 msec). At the steady-state Cmax using the highest approved recommended dosage of revumenib with CYP3A4 inhibitors, QTc increase was predicted to be 19 msec (upper bound of 90% confidence interval = 22 msec).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Romidepsin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Romidepsin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of romidepsin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of romidepsin states that appropriate cardiovascular monitoring, such as baseline and regular monitoring of ECG and obtaining serum calcium, magnesium, and potassium levels, should be performed if concurrent therapy with agents known to prolong the ECG is warranted.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In two clinical trials, discontinuation of romidepsin secondary to QT prolongation occurred in at least 2% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Selpercatinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Selpercatinib prolongs the QTc interval.(1) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2,3)
CLINICAL EFFECTS: The concurrent use of selpercatinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2,3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Selpercatinib prolongs the QT interval. An increase in QT interval to > 500 ms was measured in 6% of patients and increase in the QT interval of at least 60 ms over baseline was measured in 15% of patients. Monitor patients at significant risk of developing QT prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes, and TSH at baseline and periodically during treatment. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiation and during treatment. Dose adjustments (1): For grade 3 QT interval prolongation, withhold selpercatinib until recovery to baseline or grade 0 or 1. Resume at a reduced dose. -1st dose reduction: For patients weighing less than 50 kg: 80 mg twice daily. For patients weighing 50 kg or greater: 120 mg twice daily. -2nd dose reduction: For patients weighing less than 50 kg: 40 mg twice daily. For patients weighing 50 kg or greater: 80 mg twice daily. -3rd dose reduction: For patients weighing less than 50 kg: 40 mg once daily. For patients weighing 50 kg or greater: 40 mg twice daily. -For grade 4 QT prolongation, discontinue selpercatinib.
DISCUSSION: The effect of selpercatinib on the QT interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QT is predicted to be 10.6 ms (upper 90% confidence interval: 12.1 ms) at the mean steady state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QT was concentration-dependent. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Possible Qt Prolonging Agents/Sorafenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of sorafenib with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of sorafenib in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Patients receiving concurrent therapy with agents known to prolong the QTc interval should be monitored with electrocardiograms during treatment with sorafenib. Electrolytes (calcium, magnesium, and potassium) should also be monitored.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a non-randomized trial in 53 patients, sorafenib resulted in a mean change in QTc of 8.5 msec (upper bound of 90% CI: 13.3 msec).(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received sorafenib, QTc prolongation was identified in 13 (31.7%) with 5 (38.5%) having Grade 1 (QTc 450-480 ms) and 4 (30.7%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 2 (15.4%) having QTc greater than or equal to 500 ms and 2 (15.4%) having QTc change greater than or equal to 60 ms. No patients developed ventricular tachycardia, sudden cardiac death, or TdP.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Possible Qt Prolonging Agents/Sotalol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sotalol has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of sotalol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation may be increased by reduced creatinine clearance, female gender, larger doses of sotalol, and a history of cardiomegaly or congestive heart failure.(1) Risk may also be increased in patients with cardiovascular disease (e.g. myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of sotalol states that concurrent use with other agents known to prolong the QT interval is not recommended.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Possible Qt Prolonging Agents/Sulpiride
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sulpiride has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of sulpiride with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)
PATIENT MANAGEMENT: If possible, avoid the use of sulpiride with other agents known to prolong the QT interval. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Possible Qt Prolonging Agents/Taletrectinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Taletrectinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of taletrectinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Taletrectinib should be taken on an empty stomach. Administration with food may increase the risk of QT prolongation or torsade de pointes.
PATIENT MANAGEMENT: If possible, avoid the use of taletrectinib with other agents known to prolong the QT interval.(1) If concurrent therapy cannot be avoided, adjust the frequency of monitoring as recommended in the prescribing information. If QTc is >500 msec or the change from baseline is >60 msec, withhold taletrectinib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Taletrectinib causes concentration-dependent QTc prolongation. At steady state maximal concentration, taletrectinib (600 mg daily) increased the QTc interval by 12.8 msec (upper confidence interval 15.4 msec). At plasma concentrations achieved with taletrectinib (600 mg daily) with high fat food (1.5-fold higher than on an empty stomach), the predicted QTc interval increase is 20.5 (16.3, 24.7) msec.(1) In a clinical trial including 351 evaluable patients, 13% experienced an increase in QTcF of >60 msec compared to baseline and 2.6% had an increase in QTcF to >500 msec. Overall, 3.4% of patients had Grade 3 QTc interval prolongation. The median time from the first dose of taletrectinib to the onset of QT prolongation was 22 days (range: 1 day to 38.7 months). Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(9)
Possible Qt Prolonging Agents/Telavancin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Telavancin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of telavancin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of telavancin recommends against the use of telavancin with other drugs known to cause QT prolongation.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a randomized, double-blind, multiple-dose, positive-controlled, placebo-controlled, parallel study in healthy subjects, the mean maximum baseline-corrected, placebo-corrected QTc prolongation was 11.6 msec and 15.1 msec for telavancin at dosages of 7.5 mg/kg and 15 mg/kg, respectively. The estimated mean maximum baseline-corrected, placebo-corrected QTc prolongation for a telavancin dosage of 10 mg/kg is 12-15 msec.(1) In studies in patients, 21% of patients receiving telavancin (214 of 1029, 10 mg/kg) and 16% of patients receiving vancomycin (164 of 1033) received concurrent QT prolonging agents. The rate of QTc prolongation greater than 60 msec was 1.5% (15 patients) in the telavancin group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 telavancin subjects with QTc prolongation received concurrent QT prolongers, compared with 1 of the vancomycin patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Thioridazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Thioridazine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of thioridazine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Hypokalemia, bradycardia, the presence of congenital prolongation of the QT interval, or use of thioridazine in patients with reduced CYP2D6 activity (either through genetic predisposition or use of drugs that inhibit CYP2D6 activity) may increase the risk of torsades de pointes and/or sudden death in patients taking thioridazine.(1) The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes), hypomagnesemia, hypocalcemia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of thioridazine states under contraindications that the use of thioridazine should be avoided in combination with other drugs that are known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have been associated with Torsades de Pointes and/or QT prolongation but at this time lack substantial evidence for causing Torsades de Pointes.(4) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Toremifene
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Toremifene has been shown to prolong the QTc interval in a dose-related and concentration-related manner.(1) Concurrent use of toremifene and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1,2)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The US manufacturer of toremifene states that concurrent use should be avoided. If treatment with an agent known to prolong the QT interval is required, toremifene therapy should be interrupted. If it is not possible to interrupt toremifene therapy, electrocardiograms (ECGs) should be obtained and patients should be closely monitored for QT prolongation.(1) Additional monitoring when concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. The UK manufacturer of toremifene states that the use of other drugs that are known to prolong the QTc interval is contraindicated. These agents include class IA and III antiarrhythmics, astemizole, bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, haloperidol, mizolastine, moxifloxacin, pentamidine, phenothiazines, pimozide, sertindole, terfenadine, and vincamine IV.(2)
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Trazodone (< 100 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of trazodone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)
CLINICAL EFFECTS: The use of trazodone in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of trazodone states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Trazodone has been reported to prolong the QT interval.(1) A thorough QT study in 20 subjects evaluated the effects of trazodone at doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI 3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval by more than 5 ms. The study found a dose-dependent effect on QTc prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI 11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of 19.8 ms (95% CI 17.6-22.1).(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Possible Qt Prolonging Agents/Trazodone (>= 100 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of trazodone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)
CLINICAL EFFECTS: The use of trazodone in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of trazodone states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Trazodone has been reported to prolong the QT interval.(1) A thorough QT study in 20 subjects evaluated the effects of trazodone at doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI 3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval by more than 5 ms. The study found a dose-dependent effect on QTc prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI 11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of 19.8 ms (95% CI 17.6-22.1).(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Possible Qt Prolonging Agents/Vandetanib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Vandetanib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of vandetanib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of vandetanib states that the use of vandetanib with other agents known to prolong the QT interval should be avoided.(1) The manufacturer of vandetanib states therapy should be interrupted if Corrected QT interval, Fridericia (QTcF) is greater than 500 ms; resume at a reduced dose when the QTcF returns to less than 450 ms. Consult current prescribing information for further details.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Vandetanib has been shown to prolong the QTc interval in a dose-dependent manner. Vandetanib has a long half-life (19 days) and effects on the QTc interval may not resolve quickly following vandetanib discontinuation.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received vandetanib, QTc prolongation was identified in 4 (80%) with 0 (0%) having Grade 1 (QTc 450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 1 (25%) having QTc greater than or equal to 500 ms and 2 (50%) having QTc change greater than or equal to 60 ms. No patients had ventricular tachycardia, sudden cardiac death, or TdP.(4) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Possible Qt Prolonging Agents/Vemurafenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of vemurafenib in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Vemurafenib should not be initiated in patients taking medications known to prolong the QT interval, patients with a baseline QTc greater than 500 msec, uncorrectable electrolyte abnormalities, or known long QT syndrome is not recommended.(1) All patients receiving vemurafenib should undergo ECG testing at baseline, after 15 days of treatment, monthly during the first 3 months of treatment, and then every 3 months. If a patient's QTc exceeds 500 msec during treatment, vemurafenib should be discontinued and cardiac risk factors for QT prolongation should be controlled. Consider discontinuing other medications known to prolong the QT interval at this time. If the patient's QTc decreases below 500 msec, vemurafenib may be introduced at a lower dosage according to the current labeling recommendations. If the patient's QTc remains greater than 500 msec and increased >60 msec from pre-treatment values after controlling cardiac risk factors for prolongation, permanently discontinue vemurafenib.(1) Consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Vemurafenib is associated with concentration-dependent QTc interval prolongation. In the first month of treatment, the largest mean QTc change was 12.8 msec (upper boundary of 90% CI: 14.9 msec). In the first 6 months of treatment, the largest mean QTc change was 15.1 msec (upper boundary of 90% CI: 17.7 msec).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Possible Qt Prolonging Agents/Vepdegestrant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Vepdegestrant may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of vepdegestrant with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of vepdegestrant states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If concurrent therapy is warranted, monitor ECG when initiating vepdegestrant, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG monitoring. Do not initiate vepdegestrant in patients with a baseline QTc >470 ms. Withhold vepdegestrant if the QTc is >480 ms or the change from baseline is >60 ms.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Vepdegestrant 200 mg daily increased QTc by 12 ms (upper confidence interval = 15 ms) in patients with ESR1 mutation-positive breast cancer.(1) In VERITAC-2, QTc prolongation occurred in 10% of patients, with 1.6% of patients having Grade 3 events. QTc was >500 ms in 1.6% of patients and QTc increase from baseline of >60 ms occurred in 2.6% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Ziftomenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ziftomenib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ziftomenib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of ziftomenib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating ziftomenib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. Do not initiate ziftomenib if baseline QTcF > 480 ms.(1) Perform ECG at least once weekly for the first 4 weeks on treatment, then at least monthly thereafter. If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold ziftomenib therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In clinical trials, QTc interval prolongation was reported as an adverse event in 12% of 112 patients treated with the recommended dosage of ziftomenib. QTc was >500 ms in 9% of patients and the increase from baseline QTcF was >60 ms in 12% of patients. Ziftomenib increased the QTc interval in a concentration-dependent manner. At a dose of 600 mg daily, the largest mean increase in QTc was 7.7 ms (upper bound of confidence interval = 12.6 ms).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Possible Qt Prolonging Agents/Zuclopenthixol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Zuclopenthixol prolongs the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of zuclopenthixol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The UK manufacturer of zuclopenthixol states that the concurrent administration of other drugs that are known to prolong the QTc interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Amisulpride
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Amisulpride has been shown to prolong the QT interval. Concurrent use with QT prolonging agents may result in additive effects on the QT interval.(1)
CLINICAL EFFECTS: The concurrent use of amisulpride with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Use caution when using amisulpride concurrently with other agents that can prolong the QT interval. Amisulpride may cause a dose and concentration dependent increase in the QTc interval. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. ECG monitoring is recommended in patients with pre-existing arrhythmias or cardiac conduction disorders; electrolyte abnormalities; congestive heart failure; or in patients taking medications or with other medical conditions known to prolong the QT interval. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)
DISCUSSION: QT prolongation and torsades de pointes have been reported with amisulpride. In a study in 40 patients with post operative nausea and vomiting, amisulpride increased baseline QTcF by 5 msec after a 2-minute intravenous infusion of 5 mg and by 23.4 msec after an 8-minute intravenous infusion of 40 mg. Based on an exposure-response relationship, it is expected that a 10 mg intravenous infusion over 1 minute may increase the QTcF by 13.4 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Anamorelin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Anamorelin may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of anamorelin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of anamorelin states that the concurrent use of QT prolonging agents should be approached with caution, especially in the early stages (i.e., the first 3 weeks) of drug administration.(1,3) Obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. If abnormalities are found, take appropriate measures, including discontinuing anamorelin.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Anamorelin blocks sodium channels and may suppress cardiac conduction, resulting in prolongation of the QRS width or QT interval. A study of 7 healthy volunteers receiving single-dose anamorelin 400 mg found that 1 patient experienced QRS width prolongation. In 60 healthy adults recieving anamorelin, the maximum difference (upper limit of 95% one-sided confidence interval) in the change from baseline in QTcF interval compared to placebo was 6.16 (7.73) msec in patients on 100 mg and 7.38 (10.31) msec in patients on 300 mg.(1) The Japanese pharmacovigilance database was reviewed to evaluate disproportionality of conduction defects related to anamorelin. Out of 537 cases of adverse reactions, there were 51 cases of conduction defects (36 cases of prolonged QT, 5 cases of prolonged QRS complex, 2 cases of long QT syndrome). When adjusted for concomitant use of QT prolonging agents, the reporting odds ratio (ROR) of anamorelin-related conduction defects was 20.00 (95% CI 14.86-26.91).(3) There have been several case reports of widened QRS complexes following anamorelin exposure, usually accompanied by worsening hepatic function.(4-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)
Qt Prolonging Agents/Apomorphine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Apomorphine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of apomorphine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of apomorphine states that the use of apomorphine with other agents known to prolong the QT interval should be done with caution.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Bedaquiline
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of bedaquiline with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of bedaquiline patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Bedaquiline should be used with caution in patients receiving therapy with agents that prolong the QT interval. Patients should receive a baseline electrocardiogram (ECG) before initiation, 2 weeks after initiation, during treatment as clinically indicated, and at the expected time of maximum increase of the QT interval when receiving concurrent agents that prolong the QT interval. Bedaquiline and other QT prolonging agents should be discontinued if the patient develops a clinically significant ventricular arrhythmia or a QTcF of greater than 500 msec confirmed by repeat ECGs. If a patient develops syncope, perform an ECG.(1) Also consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a clinical trial, mean increases in QTc were greater in patients treated with bedaquiline than with placebo. At Week 1, bedaquiline increased QTc by an average of 9.9 msec, compared with 2.5 msec for placebo. At Week 24, bedaquiline increased QTc by an average of 15.7 msec, compared with 6.2 msec for placebo. In another clinical trial in which patients received bedaquiline with other QT prolonging agents, QT prolongation was additive and proportional to the number of QT prolonging drugs used. Patients receiving bedaquiline alone averaged a QTc increase of 23.7 msec over baseline, while patients receiving bedaquiline with at least one other QT prolonging agent averaged a QTc increase of 30.7 msec.(1) In a study, bedaquiline was coadministered with QTc prolonging agents clofazimine and levofloxacin. In the study, 5% of patients had a QTc >= 500 ms and 43% of patients had an increase in QTc >= 60 ms from baseline.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Catequentinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Catequentinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of catequentinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of catequentinib with other agents known to prolong the QTc interval should be monitored closely. Monitor ECG and electrolytes regularly (every 3-6 weeks) if catequentinib is administered with concurrent QTc prolonging drugs.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Catequentinib causes QTc prolongation. In clinical studies, QTc prolongation was reported as a very common adverse effect.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Ciprofloxacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ciprofloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of ciprofloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The US manufacturer of ciprofloxacin states that ciprofloxacin should be used with caution with other agents known to prolong the QT interval, especially in the elderly.(1) The UK manufacturer of ciprofloxacin states that ciprofloxacin should be used with caution in patients at risk for torsades.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Qt Prolonging Agents/Clofazimine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Clofazimine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of clofazimine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The concurrent use of clofazimine with other agents known to prolong the QTc interval should be approached with caution and monitored closely. Monitor ECG and electrolytes regularly if clofazimine is administered with concurrent QTc prolonging drugs.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Clofazimine has been reported to cause QTc prolongation and torsades de pointes when combined with medications that also prolong the QT interval.(1) In a pharmacovigilance analysis based on FAERS data from 2004-2025, a disproportionality analysis identified multiple serious and consistent safety signals associated with clofazimine. The most prominent safety signals included QT prolongation (ROR 37.61).(3) In an observational cohort of 321 patients with rifampin-resistant tuberculosis (RR-TB), the mean maximum increase of QTcF was 27.1 ms (IQR 13.8-42.4) for treatment with fluoroquinolones, 43.3 ms (IQR 31.3-65.9) for clofazimine, and 53.2 ms (IQR 36.2-73.2) for clofazimine with fluoroquinolone. Clofazimine was significantly associated with QTcF >=501 ms in multivariable analysis (adjusted HR 4.35, 95% CI 2.01-9.44).(4) A post-hoc analysis of an open label phase 2/3 randomized controlled trial compared QTcF associated with RR-TB therapies using bedaquiline/pretomanid/linezolid (BPaL), BPaL with clofazimine (BPaLC), or BPaL with moxifloxacin (BPaLM). Only 1 incidence of QTcF >500 ms occurred in the BPaLC arm. Peak QTcF values were higher in the BPaLC arm than in the BPaL or BPaLM arms (446.5 ms +/- 19.4 ms, 436 ms +/- 22.2 ms, 439.5 ms +/- 20.7 ms, respectively), but the differences were considered to be small and not clinically important.(5) An analysis of a phase 3 randomized controlled trial (STREAM) compared the effects of a short 9-month regimen (moxifloxacin + clofazimine) with a long 20-month regimen (moxifloxacin or levofloxacin) on the QT interval. The long regimen had a median maximum QTcF change of 30 ms (IQR 22-41) compared to 50 ms (IQR 36-65 ms) on the short regimen. Thirty-one patients (11%) on the short regimen had a maximum QTcF >=500 ms, compared to seven patients (5%) on the long regimen.(6) In a case report, a 66 year old male on clofazimine 300 mg daily for 11 days for leprosy developed torsades de pointe. Although his magnesium level was also low, it was believed that clofazimine alone or with the electrolyte disturbance was responsible for his arrhythmia.(7) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(8)
Qt Prolonging Agents/Clozapine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of clozapine with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of clozapine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Approach the concurrent use of clozapine and other agents that are known to prolong the QTc interval with caution.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Treatment with clozapine has been associated with QT prolongation as well as ventricular arrhythmia, Torsades de Pointes, cardiac arrest, and sudden death.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Dasatinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of dasatinib and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of dasatinib states that dasatinib should be used with caution when given with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received dasatinib, QTc prolongation was identified in 48 (41.7%) with 8 (16.7%) having Grade 1 (QTc 450-480 ms) and 15 (31.3%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 8 (16.7%) having QTc greater than or equal to 500 ms and 14 (29.2%) having QTc change greater than or equal to 60 ms. Ventricular tachycardia was seen in 2 (4.2%) of patients and 1 (2.1%) patient experienced TdP.(4) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Dolasetron
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Dolasetron has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of dolasetron with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1,3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of dolasetron states that dolasetron should be used with caution when given with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Efavirenz
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Efavirenz has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of efavirenz with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) CYP2B6 genotype may also increase the risk of this interaction. Patients who are most susceptible to this interaction are patients who are CYP2B6 poor metabolizers with CYP2B6 *6/*6 allele.(3)
PATIENT MANAGEMENT: The US manufacturer of efavirenz states alternatives should be considered when concurrent administration with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes. Limited information is available on the potential pharmacodynamic interaction between efavirenz and drugs that prolong the QT interval; however, QT prolongation has been observed with efavirenz.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: A thorough QT study was conducted in the general population in 120 healthy subjects receiving efavirenz 600 mg daily. Time-matched differences in QTc with efavirenz compared to placebo was evaluated on day 11, at 6 hours post dose. The mean change in QTc was 5.2 msec and no change in QTc was greater than 10 msec.(4) In addition to the thorough QT study, the effect of efavirenz on the QTc interval was evaluated in 58 healthy subjects based on CYP2B6 genotype. CYP2B6 polymorphism was evaluated for each patient and results were the following: 65% with *1/*1 or *1/*4 allele (wild-type metabolizers), 26% with *1/*6 allele (intermediate metabolizers) and 9% with *6/*6 allele (slow metabolizers). Subjects with 2 copies of the CYP2B6*6 allele had significantly higher efavirenz exposure at steady-state (p<0.05). At steady-state concentrations of efavirenz, patients with CYP2B6 *1/*1 or *1/*6 alleles had no change in the QTc interval (p>0.05). However, patients with CYP2B6 *6/*6 allele had an increase in QTc mean +/- SD from 406 +/- 16.4 to 423 +/- 11.8 msec (p=0.02).(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(5)
Qt Prolonging Agents/Escitalopram
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of multiple agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of multiple agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(1)
PATIENT MANAGEMENT: While the US FDA and manufacturer recommend no special precautions when escitalopram is used with QT prolonging agents,(2,3) Health Canada and the Canadian manufacturer of escitalopram discourage the concurrent use of agents known to prolong the QT interval(4,5) and the UK manufacturer states that concurrent use is contraindicated.(6) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(7) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Qt Prolonging Agents/Fingolimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. Initiation of fingolimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1-3) Fingolimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.(1-3)
CLINICAL EFFECTS: The heart rate lowering effect of fingolimod is biphasic with an initial decrease usually within 6 hours, followed by a second decrease 12 to 24 hours after the first dose. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment.(1-3)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to fingolimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to fingolimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: Patients with a baseline QTc interval greater than or equal to 500 milliseconds should not be started on fingolimod. Patients with pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, or a prolonged QTc interval prior to fingolimod initiation should receive cardiologist consultation to evaluate the risks of fingolimod therapy. In all patients, first dose monitoring is recommended to monitor for bradycardia for the first 6 hours. Check blood pressure and pulse hourly. ECG monitoring is recommended prior to dosing and at the end of the observation period. US monitoring recommendations include additional monitoring for the following patients:(1) If heart rate (HR) is less than 45 beats per minute (bpm), the heart rate 6 hours postdose is at the lowest value postdose, or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. Continuous overnight ECG monitoring is recommended in patients requiring pharmacologic intervention for symptomatic bradycardia, some preexisting heart and cerebrovascular conditions, prolonged QTc before dosing or during 6 hours observation, concurrent therapy with QT prolonging drugs, or concurrent therapy with drugs that slow heart rate or AV conduction. Consult the prescribing information for full monitoring recommendations. United Kingdom recommendations:(3) Obtain a 12-lead ECG prior to initiating fingolimod therapy. Consult a cardiologist for pretreatment risk-benefit assessment if patient has a resting heart rate less than 55 bpm, history of syncope, second degree or greater AV block, sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or other significant cardiovascular disease. Perform continuous ECG monitoring, measure blood pressure and heart rate every hour, and perform a 12-lead ECG 6 hours after the first dose. Monitoring should be extended beyond 6 hours if symptomatic bradycardia or new onset of second degree AV block, Mobitz Type II or third degree AV block has occurred at any time during the monitoring period. If heart rate 6 hours after the first dose is less than 40 bpm, has decreased more than 20 bpm compared with baseline, or if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists, then monitoring should also be continued. If fingolimod treatment is discontinued for more than two weeks, the effects on heart rate and conduction could recur. Thus, first dose monitoring precautions should be followed upon reintroduction of fingolimod. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: After the first dose of fingolimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 6 hours followed by a second decrease 12 to 24 hours after the first dose. The second dose may further decrease heart rate, but the magnitude of change is smaller than the first dose. With continued, chronic dosing, heart rate gradually returns to baseline in about one month.(1,2) In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper boundary of the 90% confidence interval (CI) of 14.0 msec. The cause of death in a patient who died within 24 hour after taking the first dose of fingolimod was not conclusive; however a link to fingolimod or a drug interaction with fingolimod could not be ruled out.(1)
Qt Prolonging Agents/Galantamine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Galantamine may reduce heart rate by increasing acetylcholine in the heart and increasing vagal tone. Bradycardia has been associated with increased risk of QTc interval prolongation.(1) Concurrent use of galantamine with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2)
CLINICAL EFFECTS: The use of galantamine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age or when receiving concomitant treatment with an inhibitor of CYP3A4.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The UK manufacturer of galantamine states that it should be used with caution in patients treated with drugs that affect the QTc interval.(2) If concurrent therapy is warranted, monitor ECG more frequently and consider obtaining serum calcium, magnesium, and potassium levels at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Therapeutic doses of galantamine have been reported to cause QTc prolongation in patients.(2) An 85 year old male with dementia was restarted on galantamine 8 mg daily after a 2-week treatment interruption due to a syncopal episode that occurred 3 months previously. During his prior syncopal episode, he was hypotensive and bradycardic, but QTc interval was normal. After restarting galantamine, he was found to be hypotension and bradycardiac again, and QTc interval was significantly prolonged to 503 msec, over 60 msec longer than when he was off galantamine. Galantamine was discontinued and his QTc interval returned to baseline.(4) A 47 year old schizophrenic male experienced prolongation of the QTc interval to 518 msec after galantamine was increased from 8 mg daily to 12 mg daily. Although he was also on quetiapine and metoprolol, he had been stable on his other medications. His QTc interval normalized after galantamine was stopped.(5) The European pharmacovigilance (Eudravigilance) database contains 14 reports of torsades de pointe in patients on galantamine as of October 2019.(1) A pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS) database found that, of a total of 33,626 cases of TdP/QT prolongation reported between January 2004 and September 2022, 54 cases occurred in patients on galantamine. The disproportionality analysis found a ROR = 5.12, 95% CI (3.92,6.68) and a PRR = 5.11, chi-square = 175.44.(6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(7)
Qt Prolonging Agents/Gatifloxacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Gatifloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of gatifloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes. congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of gatifloxacin states that gatifloxacin should be used with caution when given with other agents known to prolong the QT interval, including erythromycin, phenothiazines, and tricyclics.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Gemifloxacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Gemifloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of gemifloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of gemifloxacin states that gemifloxacin should be used with caution when given with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Gepirone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Gepirone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of gepirone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of gepirone states that gepirone should be used with caution and ECGs should be monitored more frequently when used with other agents known to prolong the QTc interval.(1) If QTcF is > 450 msec at baseline, do not initiate gepirone. If QTc increases to > 450 msec during treatment, monitor ECGs more frequently and do not increase the dose of gepirone.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, 100 mg per day of immediate-release gepirone increased the mean QTc 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and 16.1 msec (upper 90% CI = 20.7) on day 7. The dose of gepirone was 2-fold the exposure of the recommended maximum daily dose.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Gilteritinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of gilteritinib with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of gilteritinib with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(1)
PATIENT MANAGEMENT: When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Prior to initiation of therapy with gilteritinib, obtain baseline ECG and on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications For a QTc interval greater than 500 msec: ---Interrupt gilteritinib therapy ---Resume gilteritinib therapy at 80 mg when the QTc interval returns to within 30 msec of baseline or <= 480 msec. For QTc interval increased by > 30 msec on ECG on Day 8 of cycle 1: ---Confirm with ECG on Day 9 ---If confirmed, consider dose reduction to 80 mg.(2)
DISCUSSION: In the gilteritinib clinical trial, 1.4% of patients developed a QTc interval greater than 500 msec and 7% of patients had an increase QTc greater than 60 msec.(2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Haloperidol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Torsades de pointes has been reported with haloperidol. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)
CLINICAL EFFECTS: The concurrent use of haloperidol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation may be increased by: hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, use of multiple medications, intravenous haloperidol, or higher than recommended dosages of haloperidol. The risk of QT prolongation or torsade de pointes may also be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), bradycardia, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)
PATIENT MANAGEMENT: The Australian,(1) UK(2) and US(3) manufacturers of haloperidol state that haloperidol should be used with caution when given with other agents known to prolong the QT interval. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Sudden death, QT-prolongation, and torsades de pointes have been reported with haloperidol.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(4) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Qt Prolonging Agents/Lapatinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of lapatinib and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of lapatinib states that lapatinib should be used with caution when given with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Lapatinib is associated with concentration-dependent QTc interval prolongation. In a single-blind, placebo-controlled crossover study with lapatinib 2,000 mg every 12 hours for 3 doses, a maximum mean double delta QTcF of 8.75 ms was observed. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Levofloxacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of levofloxacin and agents known to prolong the QT interval may result in additive or synergistic effects on the QTc Interval.(1)
CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug know to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The U.S. manufacturer of levofloxacin states that levofloxacin should be used with caution when given with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Qt Prolonging Agents/Mavorixafor
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Mavorixafor has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of mavorixafor with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of mavorixafor states that concurrent use of mavorixafor with other agents known to prolong the QTc interval should be approached with caution. ECG monitoring is recommended prior to initiation, during concurrent therapy, and as clinically indicated with other agents known to prolong the QTc interval.(1) If QT prolongation occurs, a dose reduction or discontinuation of mavorixafor may be required.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, a dose of mavorixafor 800 mg increased the mean QTc 15.6 msec (upper 90% CI = 19.9 msec). The dose of mavorixafor was 2 times the recommended maximum daily dose.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Norfloxacin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Norfloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of norfloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of norfloxacin states that norfloxacin should be used with caution when given with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)
Qt Prolonging Agents/Osilodrostat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Osilodrostat has been shown to prolong the QT interval. Concurrent use with QT prolonging agents may result in additive effects on the QT interval.(1)
CLINICAL EFFECTS: The concurrent use of osilodrostat with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Use caution when using osilodrostat concurrently with other agents that can prolong the QT interval and consider more frequent ECG monitoring. A dose-dependent QT interval prolongation was noted in clinical studies. Prior to initiating therapy with osilodrostat, obtain a baseline ECG and monitor for QTc interval changes thereafter. Consider temporary discontinuation of therapy if the QTc interval increases > 480 msec. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)
DISCUSSION: QTc prolongation has been reported with osilodrostat. In a thorough QT study in 86 healthy patients, osilodrostat increased baseline QTcF by 1.73 msec at a 10 mg dose and 25.38 msec at a 150 mg dose (up to 2.5 times the maximum recommended dosage). The predicted mean placebo-corrected QTcF at the highest recommended dose in clinical practice (30 mg twice daily) was estimated as 5.3 msec.(1) In a clinical study, five patients (4%) were reported to have an event of QT prolongation, three patients (2%) had a QTcF increase of > 60 msec from baseline, and 18 patients (13%) had a new QTcF value of > 450 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Ozanimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator. Initiation of ozanimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1,2) Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.
CLINICAL EFFECTS: The initial heart rate lowering effect of ozanimod usually occurs within 5 hours. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ozanimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ozanimod.(1,2) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Prior to initiation of ozanimod, obtain an ECG to determine if preexisting conduction abnormalities are present. Patients with preexisting cardiac conditions, significant QT prolongation (QTc >450 msec in males, >470 msec in females), concurrent Class Ia or Class III antiarrhythmics, or receiving concurrent treatment with a QT prolonging agent at the time ozanimod is initiated or resumed should be referred to a cardiologist.(1) The US recommendations state: Dose titration is recommended with initiation of ozanimod due to transient decrease in heart rate and AV conduction delays.(1) United Kingdom recommendations:(2) Due to the risk of transient decreases in HR with the initiation of ozanimod, first dose, 6-hour monitoring for signs and symptoms of symptomatic bradycardia is recommended in patients with resting HR <55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction or heart failure. Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hour period. An ECG prior to and at the end of this 6-hour period is recommended. Additional monitoring after 6 hours is recommended in patients with: heart rate less than 45 bpm, heart rate at the lowest value post-dose (suggesting that the maximum decrease in HR may not have occurred yet), evidence of a new onset second-degree or higher AV block at the 6-hour post dose ECG, or QTc interval greater than 500 msec. In these cases, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2,3)
DISCUSSION: After the first dose of ozanimod heart rate decline is usually maximal at approximately 5 hours, returning to baseline at 6 hours. With continued, chronic dosing, maximum heart rate effect occurred on day 8.(1,2)
Qt Prolonging Agents/Pasireotide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of pasireotide with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of pasireotide patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Pasireotide should be used with caution in patients receiving therapy with agents that prolong the QT interval. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals.(1) Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In randomized, blinded, crossover study in healthy subjects, pasireotide (0.6 mg BID) increased the placebo-subtracted QTcI by 12.7 msec (95 upper CI: 14.7 msec). Supra-therapeutic doses of 1.95 mg BID increased the placebo-subtracted QTcI by 16.6 msec (95 upper CI: 18.6 msec).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(2)
Qt Prolonging Agents/Pitolisant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of pitolisant with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of pitolisant with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers or on concurrent use with CYP2D6 inhibitors are at increased risk for higher systemic exposure to pitolisant and may be at increased risk of QT prolongation.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)
DISCUSSION: In two dedicated QT prolongation studies, supra-therapeutic doses of pitolisant at 3-6 times the therapeutic dose (108-216 mg) were seen to cause mild to moderate QTc prolongation (10-13 ms). A study in patients who were CYP2D6 poor metabolizers had higher systemic exposure up to 3-fold compared to CYP2D6 extensive metabolizers.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Ponesimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator. Initiation of ponesimod has a negative chronotropic effect leading to a mean decrease in heart rate of 6 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1)
CLINICAL EFFECTS: After a dose of ponesimod, a decrease in heart rate typically begins within an hour and reaches its nadir within 2-4 hours. The heart rate typically recovers to baseline levels 4-5 hours after administration. All patients recovered from bradycardia. The conduction abnormalities typically were transient, asymptomatic, and resolved within 24 hours. Second- and third-degree AV blocks were not reported. With up-titration after Day 1, the post-dose decrease in heart rate is less pronounced. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ponesimod initiation, factors associated with QTc prolongation, or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ponesimod.(1) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Prior to initiation of ponesimod, obtain an ECG to determine if preexisting conduction abnormalities are present. Ponesimod is generally not recommended in patients who are receiving concurrent treatment with a QT prolonging agent, anti-arrhythmic drugs, or drugs that may decrease heart rate. Consultation with a cardiologist is recommended.(1) In patients with heart rate (HR) less than 55 beats per minute (bpm), first- or second-degree AV block, or history of myocardial infarction or heart failure, monitor patients for 4 hours after the first dose for signs and symptoms of bradycardia with a minimum of hourly pulse and blood pressure measurements. Obtain an ECG in these patients prior to dosing and at the end of the 4-hour observation period.(1) Additional US monitoring recommendations include: If HR is less than 45 bpm, the heart rate 4 hours post-dose is at the lowest value post-dose or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, second-degree or higher AV block, or QTc interval greater than or equal to 500 msec, perform continuous overnight ECG monitoring and repeat the first dose monitoring strategy for the second dose of ponesimod. Consult the prescribing information for full monitoring recommendations. If fewer than 4 consecutive doses are missed during titration: resume treatment with the first missed titration dose and resume the titration schedule at that dose and titration day. If fewer than 4 consecutive doses are missed during maintenance: resume treatment with the maintenance dosage. If 4 or more consecutive daily doses are missed during treatment initiation or maintenance treatment, reinitiate Day 1 of the dose titration (new starter pack) and follow first-dose monitoring recommendations. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: After the first dose of ponesimod, heart rate decrease may begin within the first hour. Decline is usually maximal at approximately 4 hours. With continued, chronic dosing, post-dose decrease in heart rate is less pronounced. Heart rate gradually returns to baseline in about 4-5 hours.(1)
Qt Prolonging Agents/Ranolazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ranolazine prolongs the QTc interval in a dose-related manner. Use with other agents that prolong the QTc interval may result in additive effects.(1)
CLINICAL EFFECTS: Concurrent use of ranolazine and agents known to prolong the QTc interval may result in prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The UK manufacturer of ranolazine states that concurrent use with agents known to prolong the QT interval should be approached with caution.(1) Patients should be instructed to inform their physician if they are receiving any drugs that prolong the QTc interval.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Ranolazine has been shown to prolong the QTc interval in a dose-related manner.(1,2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Qt Prolonging Agents/Savolitinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Savolitinib has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of savolitinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of savolitinib states concurrent use with agents known to prolong the QT interval should be used with caution.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, patients treatment with savolitinib 600 mg had a mean change in QTc from baseline of 11.93 msec at 3-6 hours postdose.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Qt Prolonging Agents/Sevoflurane
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of multiple agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of multiple agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(1)
PATIENT MANAGEMENT: Sevoflurane should be used with caution in patients taking agents known to prolong the QT interval.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Qt Prolonging Agents/Siponimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Initiation of siponimod has a negative chronotropic effect. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.(1,2)
CLINICAL EFFECTS: The heart rate lowering effect of siponimod starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. This leads to a mean decrease in heart rate of 5-6 beats per minute after the first dose. The first dose has also been associated with heart block. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. Symptomatic bradycardia has been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1)
PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to siponimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Prior to initiation of siponimod, obtain an ECG to determine if preexisting conduction abnormalities are present.(1) Advice from a cardiologist is recommended in patients with preexisting heart and cerebrovascular conditions, prolonged QTc interval before or during the 6 hour observation, risk factors for QT prolongation, concurrent therapy with QT prolonging drugs or drugs that slow the heart rate or AV conduction.(1) In patients with heart rate (HR) less than 55 beats per minute (bpm), first- or second-degree AV block, or history of myocardial infarction or heart failure, first dose monitoring is recommended with hourly pulse and blood pressure to monitor for bradycardia for the first 6 hours. ECG monitoring is recommended prior to dosing and at the end of the observation period.(1) Additional US monitoring recommendations include: If HR is less than 45 bpm, the heart rate 6 hours postdose is at the lowest value postdose or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, second-degree or higher AV block, or QTc interval greater than or equal to 500 msec, perform continuous overnight ECG monitoring. Repeat the first dose monitoring strategy for the second dose of siponimod. If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations. Patient will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods. Consult the prescribing information for full monitoring recommendations. United Kingdom recommendations:(3) In certain patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post-dose bradyarrhythmia or conduction-related symptoms occur or if ECG 6 hours post-dose shows new onset second-degree or higher AV block or QTc > 500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6-hour monitoring should be repeated after the second dose. During the first 6 days of treatment, if a titration dose is missed on one day, treatment needs to be re-initiated with a new titration pack. If there is a missed dose after day 6 the prescribed dose should be taken at the next scheduled time; the next dose should not be doubled. If maintenance treatment is interrupted for 4 or more consecutive daily doses, siponimod needs to be re-initiated with a new titration pack.(1,2)
DISCUSSION: After the first dose of siponimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 3-4 hours. With continued, chronic dosing, heart rate gradually returns to baseline in about 10 days.(1,2) A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of siponimod, which plateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detected at a higher incidence under siponimod treatment than placebo. AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions.(1)
Qt Prolonging Agents/Tolterodine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tolterodine has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)
CLINICAL EFFECTS: The concurrent use of tolterodine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)
PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers may be at increased risk.(1,2) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The manufacturer of tolterodine states concurrent use agents known to prolong the QT interval should be used with caution. Consider close observation in patients with a known history of QT prolongation or patients taking antiarrhythmic medications.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a study of the effect of tolterodine immediate release tablets, the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. Tolterodine 2 mg BID and tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and 11.84 msec (7.11-16.58 msec), respectively. The change in QT interval was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs).(1,2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)
Qt Prolonging Agents/Triclabendazole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Triclabendazole has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Triclabendazole is partially metabolized by CYP1A2. Ciprofloxacin, propafenone, and vemurafenib are CYP1A2 inhibitors and may inhibit the CYP1A2 mediated metabolism of triclabendazole.
CLINICAL EFFECTS: The concurrent use of triclabendazole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Hepatic impairment and concurrent use of CYP1A2 inhibitors may raise triclabendazole levels and increase the risk of QT prolongation.(1)
PATIENT MANAGEMENT: The manufacturer of triclabendazole states concurrent use with agents known to prolong the QT interval should be used with caution. Monitor ECG in patients with a history of QTc prolongation, symptoms of long QT interval, electrolyte imbalances, concurrent CYP1A2 inhibitors, or hepatic impairment. If signs of a cardiac arrhythmia develop, stop treatment with triclabendazole and monitor ECG.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a thorough QT study, a dose-dependent prolongation in the QTc interval was observed with triclabendazole. The largest placebo-corrected mean increase in QTc was 9.2 msec (upper limit of confidence interval (UCI): 12.2 msec) following oral administration of 10 mg/kg triclabendazole twice daily (at the recommended dose), and the largest placebo-corrected mean increase in QTc was 21.7 msec (UCI: 24.7 msec) following oral administration of 10 mg/kg triclabendazole twice daily for 3 days (3 times the approved recommended dosing duration).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Tucidinostat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of tucidinostat with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The use of tucidinostat in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Concurrent use of tucidinostat and other agents that are known to prolong the QTc interval should be used with caution. The manufacturer of tucidinostat recommends monitoring ECG and electrolytes every three weeks.(1) If the QTc interval exceeds 500 ms, tucidinostat should be suspended and the ECG should be monitored more frequently. After the QTc interval prolongation has resolved, tucidinostat may be restarted at a reduced dose.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)
Qt Prolonging Agents/Zidesamtinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Zidesamtinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)
CLINICAL EFFECTS: The concurrent use of zidesamtinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of zidesamtinib states that concurrent use of other drugs that are known to prolong the QTc interval should be monitored more frequently.(1) If concurrent use is warranted, monitor ECG and electrolytes when initiating zidesamtinib, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG and electrolyte monitoring. Withhold, then resume at same or reduced dose, or permanently discontinue zidesamtinib based on severity.(1) If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval 481-500 ms): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at same dose. - Grade 3 (QTc interval >= 501 ms or QTc interval increase of > 60 ms from baseline): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at reduced dose. - Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; or signs/symptoms of serious arrhythmia): Permanently discontinue zidesamtinib. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Zidesamtinib 100 mg once daily increased the QTc by 13 ms (upper confidence interval = 19 ms) in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors.(1) In a pooled safety study, QTc increase >60 ms occurred in 2% of patients and 0.2% of patients had an increase in QTcF > 500 ms.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)
Selected Alpha-Blockers/Selected Beta-Blockers
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Alpha-blockers may cause syncope with sudden loss of consciousness secondary to excessive postural hypotension. Following the first dose of an alpha-blocker, compensatory tachycardia helps to prevent or limit syncope. Beta-blockers may inhibit this tachycardia, thereby worsening alpha-blocker induced hypotension.
CLINICAL EFFECTS: The hypotensive effects of an alpha-blocker may be increased in patients on concurrent beta-blocker therapy.
PREDISPOSING FACTORS: Patients may be at increased risk of postural hypotension with concurrent diuretic therapy and those on low-sodium diets.
PATIENT MANAGEMENT: When starting alpha-blocker therapy in patients receiving beta-blockers, consider initiating treatment with a reduced dose of the alpha-blocker. If syncope occurs, provide supportive treatment as necessary. The adverse effect is self limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration with the alpha-blocker.
DISCUSSION: Beta-blockers increase the acute postural hypotension that frequently follows the first dose of an alpha-blocker. Initiation of beta-blocker therapy in patients that have started taking an alpha-blocker would not be expected to produce acute postural hypotension. Alpha-blockers linked to this interaction include alfuzosin, doxazosin, prazosin, and terazosin. Beta-blockers linked to this interaction include acebutolol, atenolol, betaxolol, bevantolol, levobunolol, metoprolol, nadolol, pindolol, pronethalol, propranolol, and timolol.
Selected Antihypertensive Agents/Selected Maois
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2)
CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension.
DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan.
Selected Qt Prolonging Agents/Fluconazole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of fluconazole with other agents that prolong the QTc interval may result in additive effects on the QTc interval.
CLINICAL EFFECTS: The use of fluconazole patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(1)
PATIENT MANAGEMENT: When concurrent therapy is warranted, approach the use of alfuzosin,(2) apomorphine,(3) clozapine,(4) dolasetron,(5) gemifloxacin,(6) maprotiline, norfloxacin,(7) and pasireotide(8) with other agents that are known to prolong the QTc interval with caution. For patients receiving concurrent therapy, consider monitoring calcium, magnesium, and potassium levels and monitoring electrocardiogram (ECG) at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.
Contraindications
Moderate or severe hepatic impairment (Child-Pugh class B or C).
Concomitant use with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., itraconazole, ketoconazole, ritonavir). (See Drug Interactions.)
Known hypersensitivity to alfuzosin hydrochloride or any ingredient in the formulation.
- Child-pugh class B hepatic impairment
- Child-pugh class C hepatic impairment
- Micturition syncope
- Angina
- Congenital long QT syndrome
- Disease of liver
- Prolonged QT interval
- Torsades de pointes
- Cataract surgery
- Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
- Intraoperative floppy iris syndrome
- Orthostatic hypotension
Adverse reactions
Adverse effects reported in 2% or more of patients receiving alfuzosin and at an incidence higher than that reported with placebo include dizziness, upper respiratory tract infection, headache, and fatigue.
More Frequent
- Upper respiratory infection
Rare or Very Rare
- Angioedema
- Atrial fibrillation
- Chest pain
- Cholestatic hepatitis
- Hepatocellular damage
- Intraoperative floppy iris syndrome
- Priapism
- Prolonged QT interval
- Tachycardia
- Thrombocytopenic disorder
- Toxic epidermal necrolysis
More Frequent
- Dizziness
- Fatigue
- Headache disorder
Less Frequent
- Acute abdominal pain
- Constipation
- Dyspepsia
- Erectile dysfunction
- Nausea
- Pain
Rare or Very Rare
- Accidental fall
- Diarrhea
- Edema
- Flushing
- Orthostatic hypotension
- Pharyngitis
- Pruritus of skin
- Rhinitis
- Sinusitis
- Skin rash
- Syncope
- Urticaria
- Vomiting
Precautions
No enhanced messaging available.
Alfuzosin is not intended for use in children.
Category B. (See Users Guide) Alfuzosin is not intended for use in women.
Alfuzosin is not intended for use in women.
When the total number of patients studied in clinical trials of alfuzosin is considered, 48% were 65 years of age or older, while 11% were 75 years of age or older. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.
ICD codes
| Code | Type | Description |
|---|---|---|
| Benign prostatic hyperplasia with lower urinary tract symptom | ||
| N40.1 | ICD10CM | Benign prostatic hyperplasia with lower urinary tract symptoms |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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