Vizimpro (dacomitinib)
Antineoplastic - Protein-Tyrosine Kinase Inhibitors Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Dacomitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an antineoplastic agent.
Dacomitinib, a selective and irreversible inhibitor of epidermal growth factor receptor (EGFR/human epidermal growth factor receptor type 1 (HER1)/ErbB1), HER2/ErbB2, HER4/ErbB4, and mutated EGFR (e.g., exon 19 deletion (del19), exon 21 substitution (L858R)) tyrosine kinases, is an antineoplastic agent. EGFR is expressed on the cell surface of many cancer cells, as well as many normal cells; activation of EGFR tyrosine kinase is thought to initiate a cascade of intracellular signaling events leading to cell proliferation and influencing processes critical to cell survival and tumor progression (e.g., angiogenesis, apoptosis, metastasis). Some EGFR-activating mutations, such asdel19 andL858R, contribute to increased cell proliferation and survival in non-small cell lung cancer (NSCLC) cells harboring these mutations.
Although first-generation (reversible) EGFR tyrosine kinase inhibitors (e.g., erlotinib, gefitinib) have demonstrated improved outcomes in patients with NSCLC harboring EGFR mutations (e.g.,del19,L858R substitution), secondary resistance to these agents eventually develops following 9-13 months of treatment. Clinical resistance to first-generation EGFR tyrosine kinase inhibitors has been attributed to several mechanisms, but development of the secondary T790M mutation in exon 20 appears to be the most common, occurring in 50-60% of patients who develop this resistance. This mutation results in production of a bulky methionine side chain in the receptor kinase domain of EGFR that is thought to sterically hinder the binding of first-generation EGFR tyrosine kinase inhibitors to EGFR.
It has been suggested that second-generation EGFR tyrosine kinase inhibitors (e.g., dacomitinib, afatinib) may theoretically delay or prevent the emergence of secondary resistance through their irreversible inhibition of EGFR, more complete blockade of the EGFR signaling pathway (i.e., inhibition of EGFR as well as HER2/ErbB2 and HER4/ErbB4), and inhibitory effects against tumors harboring the T790M mutation. Dacomitinib has demonstrated dose-dependent inhibition of phosphorylation of wild-type EGFR and HER2 and tumor growth in xenograft models of human NSCLC or ovarian cancer cell lines that harbored HER2 or EGFR (i.e., del19, L858R, T790M) mutations in mice. Dacomitinib also has demonstrated antitumor activity in xenograft models of human glioblastoma cells driven by EGFR gene amplifications, including EGFR variant III (EGFRvIII, EGFR exon 2-7 deletion (del2-7)), in mice.
In vitro, dacomitinib also has been shown to inhibit DDR1, DDR2, EPHA6, LCK, andMNK1 at clinically relevant concentrations.
Based on dose-exposure safety relationships, higher dacomitinib exposures at the recommended dacomitinib dosage have been associated with an increased incidence of grade 3 or greater adverse effects, particularly dermatologic toxicities (e.g., rash, dermatitis acneiform) and diarrhea. Maximum concentrations of dacomitinib had no large effect on QT interval corrected for rate (QTc). Dacomitinib exhibits dose-proportional pharmacokinetics over a dosage range of 2-60 mg once daily.
Steady-state concentrations of dacomitinib are achieved within 14 days of repeated dosing and the mean accumulation ratio is 5.7. Following oral administration of a single dose of dacomitinib 45 mg, the median time to peak plasma concentrations is approximately 6 hours (range: 2-24 hours); the mean absolute bioavailability of dacomitinib is 80%. Administration with a high-fat, high-calorie meal did not substantially alter the pharmacokinetics of dacomitinib.
Dacomitinib is approximately 98% bound to plasma proteins. Dacomitinib is principally metabolized by oxidation and glutathione conjugation. Cytochrome P-450 (CYP) isoenzyme 2D6 metabolizes dacomitinib to its major metabolite, O-desmethyldacomitinib, which has similar activity inhibiting EGFR tyrosine kinase as dacomitinib in vitro.
Pharmacokinetics of dacomitinib are not substantially different between poor and extensive metabolizers of CYP2D6. O-desmethyldacomitinib accounts for 7.4-19% of the total trough concentrations at steady state. The mean terminal half-lives of dacomitinib and O-desmethyldacomitinib are 70.3 and 72.8 hours, respectively.
Following oral administration of a radiolabeled dose of dacomitinib, 79% of the dose is recovered in feces (approximately 20% of the dose as unchanged drug) and 3% is recovered in urine (<1% of the dose as unchanged drug).
Analysis of population pharmacokinetic data indicates that age (range: 20-92 years), body weight, gender, race (Asian versus non-Asian), EGFR mutation status, and baseline albumin concentrations have no clinically important effects on clearance of dacomitinib.
USES: Dacomitinib is used to treat a certain type of lung cancer (non-small cell lung cancer). It works by slowing or stopping the growth of cancer cells.
Generic name: dacomitinib
Pronunciation: (DAK-oh-MI-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Vizimpro:
- Metastatic Non-Small Cell Lung Cancer With Egfr Exon 19 Deletion
- Metastatic Non-Small Cell Lung Cancer With Egfr Exon 21 L858r Substitution Mutation
Also known as: Egfr Exon 19 Deletion Mutation-Positive Metastatic Non-Small Cell Lung Cancer (Nsclc), Egfr L858r Substitution Mutation-Positive Metastatic Non-Small Cell Lung Cancer (Nsclc), Metastatic Non-Small Cell Lung Cancer With Egfr Exon 21 Leu858arg Substitution, Metastatic Nsclc With Egfr Ex19del.
Dosing
Avoid concomitant use of dacomitinib and proton-pump inhibitors. If therapy with an acid suppressive agent is necessary in a patient receiving dacomitinib, use a histamine H2-receptor antagonist or locally-acting antacid instead of a proton-pump inhibitor. Administer dacomitinib >=6 hours before or 10 hours after administration of a histamine H2-receptor antagonist.
Dosage interruption and/or reduction or discontinuance of dacomitinib therapy may be necessary based on type andseverity of adverse reactions. If dosage reduction from 45 mg once daily is necessary, the dosage should be reduced to 30 mg once daily. If the toxicity recurs at a dosage of 30 mg once daily, the dosage should be furtherreduced to 15 mg once daily.
Dacomitinib is administered orally once daily at approximately the same time each day; the drug can be taken without regard to meals.
If a dose of dacomitinib is missed or vomited, the prescribed dose should be taken at the next scheduled time; an additional dose should not be administered to replace the missed dose.
Store at 20-25degreesC (excursions permitted between 15-30degreesC).
| Drug label | Dosing type | Instructions |
|---|---|---|
| Vizimpro 15 Mg Tablet | Maintenance | Take 1 tablet (15 mg) by oral route once daily. |
| Vizimpro 30 Mg Tablet | Maintenance | Take 1 tablet (30 mg) by oral route once daily. |
| Vizimpro 45 Mg Tablet | Maintenance | Take 1 tablet (45 mg) by oral route once daily. |
No dosing information is available for this tab.
Drug interactions
Dacomitinib is principally metabolized by oxidation and glutathione conjugation. Dacomitinib also is metabolized by cytochrome P-450 (CYP)isoenzyme 2D6 to form its major metabolite,O-desmethyldacomitinib, and by CYP3A4 to form other minor oxidative metabolites.
In vitro studies indicate that dacomitinib is a potent inhibitor and substrate of CYP2D6; dacomitinib does not induce CYP isoenzymes 1A2, 2B6, or 3A4. In vitro studies show that dacomitinib and its principal active metabolite do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5. Dacomitinib also is an inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1, but does not inhibit UGT1A4, 1A6, 1A9, 2B7, or 2B15.
In vitro studies indicate that dacomitinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In vitro, dacomitinib is an inhibitor of P-gp, BCRP, and organic cation transporter (OCT) 1, but does not inhibit organic anion transporter (OAT) 1, OAT3, OCT2, organic anion transport protein (OATP) 1B1, or OATP1B3.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Selected Kinase Inhibitors/Vonoprazan
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 solubility of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib(8) is pH dependent. Changes in gastric pH from vonoprazan(9) may decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8)
CLINICAL EFFECTS: Use of vonoprazan may result in decreased levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the use of vonoprazan(9) in patients receiving treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8) Consider the use of short-acting antacids in these patients.(1-8) If antacids are used, separate the administration times by several hours(1-8) but at least 2 hours for bosutinib,(1) dasatinib,(3) and nilotinib,(7) 6 hours for gefitinib,(5) and 3 hours for neratinib.(6) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(2) If H2 antagonist therapy is required with gefitinib, administer gefitinib 6 hours before or after H2-antagonists or antacids.(5) If H2 antagonist therapy is required with erlotinib, neratinib, or nilotinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(4,6,7) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids.(14)
DISCUSSION: Vonoprazan decreases gastric acidity by suppressing gastric acid secretion and is characterized as a type of gastric proton-pump inhibitor.(9) In a pharmacodynamic study, a single 20 mg dose of vonoprazan, elevated the intragastric pH compared to placebo and was sustained for over 24-hours after dosing. The inhibitory effect of vonoprazan on acid secretion increased with repeated daily dosing and antisecretory effect reached steady state by Day 4 with a mean 24-hour intragastric pH of 6.0 following 20 mg once daily dose.(9) In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%, respectively.(3) In a study in 14 healthy subjects, administration of a single dose of dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state) decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(4) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(4) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(10) In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(5) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(6) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(7,11) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(7) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(7) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(7) In a study in 13 patients, esomeprazole (40 mg daily for 5 days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%, respectively, when compared to the administration of pazopanib alone.(12) In an open-label, crossover study in 17 evaluable patients, omeprazole (40 mg daily) had no significant effects on the pharmacokinetics, pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(13) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(14)
Selected Kinase Inhibitors/Vonoprazan-Clarithromycin
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 solubility of dacomitinib(1) and gefitinib(2) is pH dependent. Changes in gastric pH from proton pump inhibitors may decrease the absorption of dacomitinib(1) and gefitinib.(2)
CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of dacomitinib(1) and gefitinib.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with dacomitinib(1) and gefitinib.(2) Consider the use of short-acting antacids in these patients.(1,2) If antacids are used, separate the administration times by several hours(1,2) but at least 6 hours for gefitinib.(2) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(1) If PPIs are required with gefitinib, administer gefitinib 12 hours after the last dose or 12 hours before the next dose of the PPI. Administer gefitinib 6 hours before or after H2-antagonists or antacids.(2)
DISCUSSION: In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(2)
Selected Strong Cyp2d6 Inhibitors/Thioridazine
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 inhibitors of CYP2D6 may inhibit the metabolism of thioridazine.(1-4)
CLINICAL EFFECTS: The concurrent administration of strong CYP2D6 inhibitors with thioridazine may result in elevated levels of thioridazine.(1-4) Elevated levels of thioridazine may augment thioridazine-induced prolongation of the QTc interval, increasing the risk of serious, potentially fatal, cardiac arrhythmias such as torsades de pointes.(1)
PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. 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. co-administration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)
PATIENT MANAGEMENT: The concurrent use of thioridazine with CYP2D6 inhibitors is contraindicated.(1) Use an alternative agent, or change to another antipsychotic agent. If alternative treatments are not possible for either agent and concurrent therapy is deemed medically necessary, strongly 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. Thioridazine should not be initiated in patients with a QTc interval greater than 450 msec and should be discontinued in patients found to have a corrected QTc greater than 500 msec.(3)
DISCUSSION: A study in six slow and 13 rapid metabolizers of debrisoquin, a marker of CYP2D6 activity, showed that slow metabolizers of debrisoquin had 2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and area-under-curve (AUC), respectively, than rapid metabolizers.(4) A study in 9 healthy male subjects showed a thioridazine dose-related prolongation of the QTc interval. One subtherapeutic thioridazine 10 mg dose increased QTc 9 msec (range -1 to 19 msec), and a single low-therapeutic thioridazine dose of 50 mg increased QTc 22 msec (range 11 to 33 msec).(7) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib and terbinafine.(3)
Strong Cyp2d6 Inhibitors/Pimozide
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 CYP2D6 inhibitors may inhibit the metabolism of pimozide at CYP2D6.(1-6)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors that prolong QT may increase the levels and effects of pimozide including additive QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes. Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(8)
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.(7) 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).(7) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)
PATIENT MANAGEMENT: The concurrent use of pimozide with strong inhibitors of CYP2D6 is contraindicated.(1) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. 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 controlled study in healthy subjects, steady-state paroxetine (60 mg daily, a strong inhibitor of CYP2D6) increased the AUC and Cmax of a single dose of pimozide (2 mg) by 151% and 62%, respectively.(2-4) Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine, paroxetine, and terbinafine.(1,9) 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.
Strong Cyp2d6 Inhibitors/Sofpironium
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 inhibitors of CYP2D6 may inhibit the metabolism of sofpironium.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels and adverse effects of sofpironium, including increased risk of anticholinergic side effects.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of sofpironium and strong CYP2D6 inhibitors should be avoided.(1) If concurrent therapy is warranted with a strong CYP2D6 inhibitor, monitor patients closely for anticholinergic side effects.
DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with sofpironium increased the maximum concentration (Cmax) and area-under-the-curve (AUC) by approximately 2-fold compared to sofpironium administration alone.(1) Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)
Strong Cyp2d6 Inhibitors/Valbenazine (> 40 Mg)
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: Valbenazine's active metabolite (alpha-HTBZ) is metabolized by CYP2D6 and CYP3A4.(1) Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine are strong inhibitors of CYP2D6.(2,3)
CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine or terbinafine may result in elevated levels and adverse effects of valbenazine such as somnolence and QT prolongation.
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 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 own metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(2) Concurrent use of strong CYP3A4 inhibitors may further increase levels of valbenazine.(1)
PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP2D6 inhibitor.(1) During concomitant therapy with a strong CYP2D6 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine did not affect valbenazine maximum concentration (Cmax) or area-under-the-curve (AUC). However, Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold, respectively. Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Selected Kinase Inhibitors/Proton Pump Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The solubility of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib(8), and pexidartinib (9) is pH dependent. Changes in gastric pH from proton pump inhibitors may decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9)
CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) Consider the use of short-acting antacids in these patients.(1-9) If antacids are used, separate the administration times by several hours(1-9) but at least 2 hours for bosutinib,(1) dasatinib,(3) nilotinib,(7) and pexidartinib(9), 6 hours for gefitinib,(5) and 3 hours for neratinib.(6) If PPIs are required with gefitinib, administer gefitinib 12 hours after the last dose or 12 hours before the next dose of the PPI. Administer gefitinib 6 hours before or after H2-antagonists or antacids.(5) If H2 antagonist therapy is used with bosutinib, separate administration by at least 2 hours.(1) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(2) If H2 antagonist therapy is required with erlotinib, neratinib, nilotinib, or pexidartinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(4,6,7,9) If H2 antagonist therapy is required with gefitinib, gefitinib should be given at least 6 hours before or after the H2 antagonist.(5) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids.
DISCUSSION: In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%, respectively.(3) In a study in 14 healthy subjects, administration of a single dose of dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state) decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(4) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(4) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(9) In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(5) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(6) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(7,10) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(7) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(7) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(7) In a study in 13 patients, esomeprazole (40 mg daily for 5 days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%, respectively, when compared to the administration of pazopanib alone.(11) In an open-label, crossover study in 17 evaluable patients, omeprazole (40 mg daily) had no significant effects on the pharmacokinetics, pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(12) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%. (13) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant dasatinib pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(14)
Selected Strong Cyp2d6 Inhibitors/Nasal Metoclopramide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of metoclopramide.
CLINICAL EFFECTS: Concurrent use may result in elevated levels of metoclopramide, which may increase the risk of extrapyramidal symptoms such as tardive dyskinesia, which may be permanent. Tardive dyskinesia typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs. Concurrent use may also result in serotonin syndrome. Symptoms of serotonin syndrome include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death.
PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination.
PATIENT MANAGEMENT: The manufacturer of metoclopramide nasal spray states concurrent use with strong CYP2D6 inhibitors is not recommended. If concurrent therapy is warranted, patients should be monitored for extrapyramidal symptoms and signs and symptoms of serotonin syndrome. Instruct patients to report any abnormal/uncontrollable muscle movements, muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily, another strong CYP2D6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(1,2) There have been case reports of serotonin syndrome in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3) sertraline,(5-7) and venlafaxine.(7) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)
Selected Strong Cyp2d6 Inhibitors/Tamoxifen
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)
CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.
PREDISPOSING FACTORS: Concurrent use of strong CYP2D6 inhibitors in patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.
PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The Canadian and UK manufacturers of fluoxetine state that whenever possible co-administration with tamoxifen should be avoided.(14-15) The National Comprehensive Cancer Network's (NCCN) breast cancer guidelines advise caution when coadministering strong CYP2D6 inhibitors with tamoxifen. NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(16) Cancer Care Ontario breast cancer guidelines state concurrent use of strong CYP2D6 inhibitors should be avoided.(17) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(18) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient.
DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(19) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(20-21) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(22-24) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(25-29) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Strong inhibitors of CYP2D6 include bupropion, dacomitinib, fluoxetine, paroxetine, peruvian bark extract, and terbinafine.(30-31)
Slt Strong 2D6 Inhibitor/Aripiprazole Lauroxil Submicronized
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong 2D6 inhibitors such as dacomitinib, fluoxetine, paroxetine, and quinidine may inhibit the metabolism of aripiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1) Strong CYP2D6 inhibitors linked to this monograph are bupropion, dacomitinib, fluoxetine, paroxetine and quinidine.
PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)
PATIENT MANAGEMENT: The US manufacturer of the extended release aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding use of strong CYP2D6 inhibitors with Aristada Initio. Aristada Initio is only available in a single strength as a single-dose pre-filled syringe.
DISCUSSION: Drug interaction studies have not been conducted with Aristada Initio. Aristada Initio has a long half-life (15-18 days). The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1)
Strong & Moderate Cyp2d6 Inhibitors/Eliglustat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP3A4, eliglustat metabolism can be further inhibited.(1)
CLINICAL EFFECTS: Concurrent use of an agent that is a strong or moderate inhibitor of CYP2D6 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)
PREDISPOSING FACTORS: If the patient has hepatic impairment, is also taking an inhibitor of CYP3A4 and/or is an extensive or intermediate metabolizer of CYP2D6, eliglustat metabolism can be further inhibited.(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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate CYP2D6 metabolizers should be limited to 84 mg daily.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP2D6 in poor CYP2D6 metabolizers should be continued at 84 mg once daily.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in poor metabolizers of CYP2D6 should be avoided and is contraindicated in extensive and intermediate metabolizers of CYP2D6.(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. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(5)
DISCUSSION: Paroxetine (30 mg daily), a strong inhibitor of CYP2D6, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 7-fold and 8.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested paroxetine would increase eliglustat Cmax and AUC by 2.1-fold and 2.3-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested terbinafine, a moderate inhibitor of CYP2D6, would increase eliglustat Cmax and AUC by 3.8-fold and 4.5-fold, respectively, in extensive metabolizers and by 1.6-fold and 1.6-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(5) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(1,3,4) Moderate inhibitors of CYP2D6 include: abiraterone, asunaprevir, capivasertib, cinacalcet, duloxetine, escitalopram, levomepromazine, levomethadone, mirabegron, moclobemide, and rolapitant.(1,3,4)
Strong 2D6 Inhibitors/Atomoxetine; Vortioxetine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: FDA designates atomoxetine as a 'sensitive substrate' at CYP2D6. Sensitive substrates are drugs whose area-under-curve (AUC) increases 5-fold or higher when given a strong inhibitor of a particular enzyme.(1) Although metabolized via several CYP P-450 pathways, vortioxetine appears primarily metabolized via CYP2D6.(2-3) Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of CYP2D6.(1,4)
CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, or terbinafine may result in elevated levels and adverse effects of atomoxetine or vortioxetine. Atomoxetine adverse effects may include elevated blood pressure, tachycardia, insomnia, irritability, nausea/vomiting, or appetite suppression.(5,7) Vortioxetine adverse effects may include headache, nausea, vomiting, dizziness, or abnormal dreams.(2,3)
PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.
PATIENT MANAGEMENT: When a strong CYP2D6 inhibitor is added to existing atomoxetine therapy, exposure to atomoxetine may increase greater than 5-fold, depending upon the dosage and specific CYP2D6 inhibitor involved. The manufacturer of atomoxetine recommends downward dosage adjustments when patients receive concomitant treatment with strong CYP2D6 inhibitors.(5) When initiating atomoxetine in children and adolescents weighing up to 70 Kg who are already receiving strong CYP2D6 inhibitors, the atomoxetine dose should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.(5) When initiating atomoxetine in children and adolescents weighing over 70 Kg and adults who are receiving strong CYP2D6 inhibitors, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.(5) The manufacturer of vortioxetine recommends reducing vortioxetine dose by half when a strong CYP2D6 inhibitor is coadministered.(2)
DISCUSSION: In a single-blind study in 22 healthy subjects, the concurrent administration of paroxetine (20 mg twice daily in one arm, 20 mg one daily in another arm) with atomoxetine (20 mg twice daily) resulted in increases in the maximum concentration (Cmax), area-under-curve (AUC), and half-life of atomoxetine by 3.5-fold, 6.5-fold, and 2.5-fold, respectively. There were no changes in paroxetine pharmacokinetics.(4) In extensive metabolizers administered paroxetine(2,3) or fluoxetine(2) with atomoxetine, the AUC of atomoxetine is approximately 6-fold to 8-fold and the Cmax is about 3-fold to 4-fold greater than with atomoxetine alone. In vitro studies suggest that administration of CYP P-450 inhibitors to poor metabolizers would not increase plasma atomoxetine concentrations.(2) A drug interaction study conducted over 28 days evaluated the effect of bupropion 150 mg twice daily on the tolerance and steady-state kinetics of vortioxetine 10 mg daily in 28 healthy subjects. Vortioxetine AUC and Cmax increased by 2.3 and 2.1 fold respectively.(3) Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine are strong inhibitors of CYP2D6. Terbinafine is a moderate to strong inhibitors of CYP2D6.(1,4)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Select Strong Cyp2d6 Inhibitors/Aripiprazole Lauroxil
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)
PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor. Poor metabolizers of CYP2D6 are not expected to be affected by this interaction.(1)
PATIENT MANAGEMENT: The US manufacturer of aripiprazole lauroxil extended-release injection (Aristada) recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - Reduce the dose of aripiprazole lauroxil to the next lower strength. No dosage adjustment is necessary in patient taking the 441 mg dose, if tolerated. - For patients taking both a strong CYP2D6 and CYP3A4 inhibitor, avoid 662 mg, 882 mg, and 1,064 mg doses. No dose adjustment is necessary in patients taking the 441 mg dose, if tolerated. If the patient is a poor metabolizer of CYP2D6, no dose adjusment is required.(1)
DISCUSSION: The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold. (1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)
Selected Cyp2d6 Inhibitors/Metoprolol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2)
CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2)
PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6.(1,2)
PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2)
DISCUSSION: In an open-label, randomized, cross-over study in 12 healthy males, celecoxib (200 mg BID) increased the AUC of metoprolol (50 mg) by 64%. One subject experienced a 200% increase.(3) In a randomized, double-blind, cross-over study in 7 healthy subjects, hydroxychloroquine (400 mg) increased the AUC of a single dose of metoprolol by 65%.(4) In a study in 20 Chinese patients with chronic myelogenous leukemia, imatinib (400 mg BID) increased the AUC of metoprolol (100 mg single dose) by 23%. (5) In healthy subjects, ranolazine (750 mg twice daily) increased plasma levels of a single dose of metoprolol (100 mg) by 1.8-fold.(6) CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, bupropion, capivasertib, celecoxib, chloroquine, cinacalcet, citalopram, clomipramine, dacomitinib, diphenhydramine, dronabinol, duloxetine, eliglustat, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, levomepromazine, lorcaserin, moclobemide, osilodrostat, paroxetine, quinine, ranitidine, ranolazine, rolapitant, and sertraline.
Selected Cyp2d6 Inhibitors/Perhexiline
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the metabolism of perhexiline by CYP2D6.
CLINICAL EFFECTS: Concurrent use of perhexiline and a CYP2D6 inhibitor may result in elevated levels of perhexiline and toxicity, including risk of QT prolongation or torsade 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.(1,2) 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: Patients maintained on perhexiline should be carefully monitored if a CYP2D6 inhibitor is initiated or discontinued. The dosage of perhexiline may need to be adjusted. 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: The Adverse Drug Reactions Advisory Committee has received five reports of an interaction between perhexiline and SSRIs.(1) In one report, an 82 year-old male developed symptoms of perhexiline toxicity ten days after the addition of citalopram to his regimen. Citalopram was discontinued on Day 10. The patient's perhexiline level, previously stable between 0.29 mg/L and 0.34 mg/l, was found to be 0.82 mg/L on day 15. Perhexiline dosage was reduced.(1) In another report, a 62 year-old male developed perhexiline toxicity following the addition of paroxetine to his regimen. After paroxetine was discontinued, perhexiline levels returned to baseline.(3) In another report, an 84 year-old female developed perhexiline toxicity following the addition of fluoxetine to her regimen. Despite the discontinuation of fluoxetine, perhexiline levels were slow to return to baseline.(3) Selected CYP2D6 inhibitors linked to this monograph include: bupropion, citalopram, dacomitinib, escitalopram, fluoxetine, hydroquinidine, levomepromazine, paroxetine, quinidine, and terbinafine.(4)
Selected Cyp2d6 Inhibitors/Propranolol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of propranolol.(1)
CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from propranolol, including hypotension and bradycardia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with propranolol and CYP2D6 inhibitors. The dosage of propranolol may need to be adjusted.(1)
DISCUSSION: In a pharmacokinetic study in 16 healthy volunteers, concurrent use of quinidine 200 mg (a CYP2D6 inhibitor) increased the area-under-curve (AUC) of propranolol by 2.29-fold.(2) In a pharmacokinetic study in 6 healthy subjects, concurrent use of quinidine increased propranolol AUC 2-fold.(3) A retrospective review of concurrent use of propranolol and antidepressants evaluated the risk of hospitalization or emergency room visit within 30 days of concurrent prescription. In patients receiving antidepressants with moderate to strong CYP2D6 inhibitory effects, patient were an increased risk compared to patients receiving no antidepressants (Hazard Ratio (HR) = 1.53; 95% CI 1.03-2.81 vs. HR = 1.24; 95% CI 0.82-1.88).(4) Case reports of bradycardia and cardiac adverse effects have been reported with concurrent use of propranolol and the antidepressants fluoxetine and paroxetine (strong CYP2D6 inhibitors).(5) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, mavorixafor, and paroxetine. Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, levomepromazine, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and rolapitant. Weak CYP2D6 inhibitors include: desvenlafaxine, diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine, imatinib, osilodrostat, ranitidine, and sertraline.(6)
Selected Kinase Inhibitors/H2 Antagonists
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The solubility of dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4) is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).
CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Consider the use of short-acting antacids in patients taking dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4). If antacids are used, separate the administration times by several hours(1-7) but at least 2 hours for bosutinib,(1) and nilotinib,(4) and 6 hours for gefitinib.(3) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(1) If H2 antagonist therapy is required with erlotinib or nilotinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(2-4) If H2 antagonist therapy is required with gefitinib, gefitinib should be given at least 6 hours before or after the H2 antagonist.(3) Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment dacomitinib,(1) erlotinib,(2) gefitinib,(3) and nilotinib(4).
DISCUSSION: In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(1) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(2) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(2) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(5) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(4,7) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(4) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(4) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(4)
Selected Moderate To Strong Cyp2d6 Inhibitors/Tramadol
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Abiraterone, asunaprevir, berotralstat, bupropion, cinacalcet, dacomitinib, dronedarone, duloxetine, eliglustat, fluoxetine, hydroquinidine, levomepromazine, levomethadone, lorcaserin, mirabegron, paroxetine, quinidine, rolapitant, oral terbinafine, and tipranavir are moderate or strong inhibitors of CYP2D6 and may decrease conversion of tramadol to its more active O-demethylated metabolite (M1).(1-6) M1 is up to 6 times more potent than tramadol in producing analgesia.(1)
CLINICAL EFFECTS: Tramadol analgesic efficacy may be decreased due to lower mu-opioid receptor mediated analgesia.(1,9,10) Higher concentrations of tramadol may be associated with increased inhibition of norepinephrine and serotonin reuptake, increasing risk for seizures and serotonin syndrome.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(7)
PREDISPOSING FACTORS: Risk for seizure may be increased with tramadol doses above the recommended range, in patients with metabolic disorders, alcohol or drug withdrawal, infection of the central nervous system, or with a history of seizures or head trauma.(1) Treatment with multiple medications which increase serotonin levels, or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(1,7) Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer.(14) Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.(14)
PATIENT MANAGEMENT: If a CYP2D6 inhibitor is started in a patient stabilized on long term tramadol therapy, monitor for loss of analgesic efficacy. When initiating tramadol in a patient stabilized on a moderate or strong CYP2D6 inhibitor, anticipate lower analgesic efficacy. Hospitalized patients may need added doses of rescue analgesics to achieve adequate pain control.(9,10) To decrease risk for serotonin syndrome, consider change to an alternative analgesic for patients taking other serotonin increasing drugs in addition to concomitant tramadol and a CYP2D6 inhibitor. If a CYP2D6 inhibitor is discontinued, consider lowering the dose of tramadol until patient achieves stable drug effects. The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(12)
DISCUSSION: Tramadol and its M1 metabolite both contribute to analgesic efficacy. Tramadol inhibits the reuptake of norepinephrine and serotonin with minimal opioid receptor binding. The M1 metabolite has 200 times greater binding affinity for the mu-opioid receptor than tramadol and is 6 times more potent in producing analgesia.(1) CYP2D6 converts tramadol to M1.(1,8) A prospective study evaluated the impact of 2D6 genotype on tramadol analgesia after abdominal surgery. Rescue doses of opioids were required in 47% of poor metabolizers (PM) versus 22% of extensive metabolizers (EM) of 2D6.(9) A follow-up study included 2D6 EM patients who received concomitant treatment with 2D6 inhibitors. Levels of the M1 metabolite were decreased by 80-90% compared with EM patients not taking 2D6 inhibitors. The authors noted some EM patients were converted to the PM phenotype.(10) In both studies, higher M1 levels were associated with greater analgesic efficacy and decreased need for rescue opioid treatment.(9,10) A study in 12 healthy volunteers found that a single dose of tramadol (50 mg) given to patients on terbinafine (a strong CYP2D6 inhibitor) resulted in tramadol AUC and Cmax that were 2.1-fold and 1.5-fold higher, respectively, than tramadol given alone. The AUC and Cmax of M1 were decreased by 64 % and 78 %, respectively.(13) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(12)
Selected Strong Cyp2d6 Inhibitors/Aripiprazole Im Monthly
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)
PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)
PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM monthly injection (Abilify Maintena) recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 400 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 300 mg per month. - if the aripiprazole dose is 400 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 200 mg per month. - if the aripiprazole dose is 300 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 200 mg per month. - if the aripiprazole dose is 300 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 160 mg per month.(1)
DISCUSSION: There have been no drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(3,4)
Selected Strong Cyp2d6 Inhibitors/Dextromethorphan
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of dextromethorphan.(1-4)
CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Elevated levels of dextromethorphan or concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(5) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(5) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(5) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(5)
PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(5)
PATIENT MANAGEMENT: Monitor patients for elevated dextromethorphan levels or on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Results: overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(1) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(4) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(6,7) and paroxetine.(8) Selected strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, quinidine, and terbinafine.(8)
Selected Strong Cyp2d6 Inhibitors/Dextromethorphan-Bupropion
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of dextromethorphan.(1-5)
CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Elevated levels of dextromethorphan or concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(6) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(6) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(6) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(6)
PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(6)
PATIENT MANAGEMENT: The manufacturer of dextromethorphan-bupropion recommends a dose reduction when coadministered with strong CYP2D6 inhibitors as follows: - For major depressive disorder, the maximum dosage is 45 mg/105 mg daily. - For agitation associated with Alzheimer's dementia, start with 30 mg/105 mg daily then increase to a maximum dosage of 45 mg/105 mg daily on day 8.(1) Monitor patients for elevated dextromethorphan levels or symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: In a clinical trial, paroxetine 20 mg (a strong CYP2D6 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of dextromethorphan by 2.69- and 2.38-fold, respectively.(1) An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(2) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(7,8) and paroxetine.(9) Selected strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, quinidine, and terbinafine.(10)
Selected Strong Cyp2d6 Inhibitors/Doxepin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of doxepin.(1)
CLINICAL EFFECTS: Concurrent use of doxepin and strong CYP2D6 inhibitors may increase levels of doxepin and the risk for toxicities, including anticholinergic, sedative, alpha-blocking effects, and seizures.(1-2)
PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)
PATIENT MANAGEMENT: The US manufacturer of doxepin states if concurrent use of doxepin and strong CYP2D6 inhibitors is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on plasma concentrations.(1)
DISCUSSION: Doxepin is a CYP2D6 substrate and concomitant use with strong CYP2D6 inhibitors may increase doxepin exposures.(1) Selected strong CYP2D6 inhibitors linked include: dacomitinib.(3,4)
Selected Strong Cyp2d6 Inhibitors/Flecainide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, and paroxetine are strong CYP2D6 inhibitors and may inhibit the CYP2D6 mediated metabolism of flecainide.(1)
CLINICAL EFFECTS: Concurrent use may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(2-5)
PREDISPOSING FACTORS: Renal and hepatic impairment may increase risk for excessive QTc prolongation as flecainide is renally and hepatically eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, flecainide must be dose adjusted in renal and hepatic insufficiency. 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.(6) 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).(6)
PATIENT MANAGEMENT: Manufacturers of bupropion, fluoxetine, paroxetine recommend caution with concurrent use of flecainide due to the increased risk for ventricular arrhythmias (e.g. torsades de pointes) associated with higher flecainide concentrations.(2-5) Consider use of an alternative antidepressant or antiarrhythmic if possible. If concurrent therapy is deemed medically necessary, consider therapeutic drug monitoring of flecainide levels and obtain 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 drug interaction and pharmacogenomics study in 21 healthy subjects, paroxetine 20 mg daily for 7 days increased flecainide exposure (area-under-curve, AUC) by 28%.(7)
Selected Strong Cyp2d6 Inhibitors/Iloperidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors(1) such as dacomitinib, fluoxetine, paroxetine, and terbinafine may inhibit the metabolism of iloperidone.(2)
CLINICAL EFFECTS: Concurrent administration of iloperidone with dacomitinib, fluoxetine, paroxetine, or terbinafine may result in elevated iloperidone levels and toxicities, including the risk for QTc prolongation.(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, advanced age, and with concurrent use of inhibitors of CYP3A4, which metabolizes iloperidone.(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 iloperidone states that the dose of iloperidone should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors such as dacomitinib, fluoxetine or paroxetine are coadministered.(2) Due to its long half-life it may take 2 or more weeks to see the full effects of fluoxetine CYP2D6 inhibition on iloperidone exposure and tolerance. Maximal CYP2D6 inhibitory effects due to paroxetine coadministration are generally expected within one week after initiation or increase in the paroxetine dosage. When the inhibitor is discontinued iloperidone exposure will wane and the dose of iloperidone should be increased.(2) Concurrent administration of iloperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor does not have additive inhibitory effects compared to either inhibitor alone. The dose of iloperidone should be reduced to one-half of its normal dose, and further dose reduction is not required.(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 in 23 healthy subjects, fluoxetine (20 mg twice daily for 21 days) increased the AUC of iloperidone (3 mg single dose) and its P88 metabolite by 2-3-fold. The AUC of iloperidone's P95 metabolite decreased by 50%.(2) In a study in patients with schizophrenia, paroxetine (20 mg daily for 5-8 days) increased the maximum concentration (Cmax) of iloperidone and its P88 metabolite by about 1.6-fold. The Cmax of iloperidone's P95 metabolite decreased by 50%.(2) 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.(2) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(2)
Selected Strong Cyp2d6 Inhibitors/Metoclopramide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of metoclopramide.
CLINICAL EFFECTS: Concurrent use may result in elevated levels of metoclopramide, which may increase the risk of extrapyramidal symptoms such as tardive dyskinesia, which may be permanent. Tardive dyskinesia typically affects the facial muscles and may result in uncontrollable lip smacking, chewing, puckering of the mouth, frowning or scowling, sticking out the tongue, blinking and moving the eyes, and shaking of the arms and/or legs. Concurrent use may also result in serotonin syndrome. Symptoms of serotonin syndrome include irritability, altered consciousness, double vision, nausea, confusion, anxiety, hyperthermia, increased muscle tone, rigidity, myoclonus, rapid fluctuations in vital signs, and coma. Serotonin syndrome may result in death.
PREDISPOSING FACTORS: Patients with renal and/or hepatic impairment may have an increased risk from this combination.
PATIENT MANAGEMENT: Concurrent use of a strong 2D6 inhibitor requires a dosage adjustment of metoclopramide. For gastroesophageal reflux, reduce the dosage of metoclopramide to 5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg taken three times daily for a maximum daily dosage of 30 mg in patients taking strong CYP2D6 inhibitors.(1) For acute and recurrent diabetic gastroparesis, reduce the dosage of metoclopramide to 5 mg four times daily (30 minutes before each meal and at bedtime) for a maximum daily dosage of 20 mg in patients taking strong CYP2D6 inhibitors.(1) If concurrent therapy is warranted, patients should be monitored for extrapyramidal symptoms and signs and symptoms of serotonin syndrome. Instruct patients to report any abnormal/uncontrollable muscle movements, muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.
DISCUSSION: In a study in 20 healthy male subjects, concurrent fluoxetine (60 mg daily, another strong CYP2D6 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of metoclopramide (20 mg single dose) by 42% and 89%, respectively.(1,2) There have been case reports of serotonin syndrome in patients receiving concurrent metoclopramide and fluoxetine,(3) fluvoxamine,(3) sertraline,(5-7) and venlafaxine.(7) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)
Selected Strong Cyp2d6 Inhibitors/Risperidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The US manufacturer of risperidone (Risperdal) recommends that when CYP2D6 inhibitors are co-administered with risperidone that the dose should be reduced. The risperidone dose should not exceed 8 mg per day when co-administered with CYP2D6 inhibitors. When initiating therapy with risperidone, the dose of risperidone should be titrated slowly. It may be necessary to increase the risperidone dose, when CYP2D6 inhibitors are discontinued.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(2)
DISCUSSION: In a study in 7 patients maintained on risperidone (doses ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased risperidone levels by 25%. The mean plasma risperidone/9-hydroxyrisperidone ratio increased 1.95-fold. One patient developed mild extrapyramidal symptoms. His risperidone level at the time was 72 ng/ml.(3) In contrast, a retrospective chart review compared 7 patients receiving concurrent risperidone and duloxetine to control patients receiving only risperidone and found no significant effect on risperidone levels.(4) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(5) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(5) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(6) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(2) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(2) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(7)
Slt Strong 2D6 Inhibitors/Risperidone Im Every 2 Weeks
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The dosage of risperidone should be re-evaluated.(1) The US manufacturer of extended release risperidone microspheres for injection (Risperdal Consta) recommends that patients maintained on the 25 mg dose of this product continue to receive the 25 mg dose when either fluoxetine or paroxetine (strong CYP2D6 inhibitors) is initiated, unless clinical judgment necessitates lowering the dose or interrupting therapy. If a decision is made to lower the dose, the dose may be lowered 2 to 4 weeks before the initiation of fluoxetine or paroxetine.(1) When initiating the product in patients maintained on fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of this dose has not been confirmed in clinical trials.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(2)
DISCUSSION: A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(3) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(3) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(4) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(2) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(2) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)
Slt Strong Cyp2d6 Inhibitors/Aripiprazole Im Every 2 Months
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)
PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)
PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM every 2 months injection (Abilify Asimtufii) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 960 mg every 2 months and a strong CYP2D6 inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2 months. - if the patient is taking both a strong CYP2D6 inhibitor AND a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.
DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold.(1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)
Slt Strong Cyp2d6 Inhibitors/Aripiprazole Immediate Release
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of aripiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor with aripiprazole may result in elevated levels of and toxicity from aripiprazole.(1)
PREDISPOSING FACTORS: The interaction is expected to be more severe in patients taking both a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor.(1)
PATIENT MANAGEMENT: The US manufacturer of oral aripiprazole states that the dose of aripiprazole should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine and quinidine are coadministered, unless aripiprazole is being used as adjunctive therapy for Major Depressive Disorder. If the patient is also receiving a strong CYP3A4 inhibitor, the dose of aripiprazole should be reduced to one-fourth its normal dose. When the inhibitor(s) is(are) discontinued, the dose of aripiprazole should be increased.(1)
DISCUSSION: The administration of quinidine (166 mg daily for 13 days, a strong inhibitor of CYP2D6) with a single dose of aripiprazole (10 mg) resulted in a 112% increase in the area-under-curve (AUC) of aripiprazole and a 35% decrease in the AUC of dehydro-aripiprazole, the active metabolite of aripiprazole.(1) Strong CYP2D6 inhibitors linked to this monograph are dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(2-3)
Slt Strong Cyp2d6 Inhibitors/Risperidone Sq Every 1-2 Months
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms.(2) The manufacturer of extended release risperidone injectable suspension (Uzedy) recommends patients be placed on the lowest dose (50 mg monthly or 100 mg once every 2 months) of Uzedy before the planned start of strong CYP2D6 inhibitor therapy to adjust for the expected increase in risperidone plasma concentrations. When strong CYP2D6 inhibitors are initiated in patients receiving Uzedy 50 mg monthly or 100 mg once every 2 months, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of risperidone treatment.(1) One set of authors recommended a low initial dose of paroxetine of 10 mg/day to 20 mg/day in patients receiving risperidone.(3)
DISCUSSION: In a study in 7 patients maintained on risperidone (doses ranged from 2 mg daily to 4 mg daily), the addition of duloxetine (60 mg daily) increased risperidone levels by 25%. The mean plasma risperidone/9-hydroxyrisperidone ratio increased 1.95-fold. One patient developed mild extrapyramidal symptoms. His risperidone level at the time was 72 ng/ml.(4) In contrast, a retrospective chart review compared 7 patients receiving concurrent risperidone and duloxetine to control patients receiving only risperidone and found no significant effect on risperidone levels.(5) A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(6) Fluoxetine has been shown to have no effect on 9-hydroxyrisperidone plasma concentrations.(6) A study in 3 poor metabolizer and 8 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(7) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(3) Paroxetine has been shown to lower 9-hydroxyrisperidone plasma concentrations by 10%.(3) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(8)
Strong Cyp1a2 Or Cyp2d6 Inhibitors/Fenfluramine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP1A2 or CYP2D6 inhibitors may decrease the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of agents that are strong CYP1A2 or CYP2D6 inhibitors may result in elevated levels of and toxicity from fenfluramine.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of fenfluramine states that the maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6 inhibitor in patients not on stiripentol is 20 mg. In patients on concomitant stiripentol and clobazam, the maximum fenfluramine dosage with strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1) If the strong CYP1A2 or CYP2D6 inhibitors is discontinued, consider gradually increasing the fenfluramine dosage to the usual recommended dose without the inhibitor.(1)
DISCUSSION: In a study of healthy volunteers, fluvoxamine 50 mg daily (a strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%, respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and 44%, respectively.(1) In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6 inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg by 81% and 13%, respectively, and decreased the AUC and Cmax of norfenfluramine by 13% and 29%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include: Angelica root, ciprofloxacin, enasidenib, vemurafenib, and viloxazine. Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, and quinidine.(1-4)
Strong Cyp2d6 Inhibitors/Brexpiprazole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of brexpiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP2D6 inhibitor may result in elevated levels of and toxicity from brexpiprazole.(1)
PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are receiving concomitant treatment with a strong or moderate CYP3A4 inhibitor in addition to treatment with a CYP2D6 inhibitor. Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to increase brexpiprazole levels 5.1-fold in extensive metabolizers of CYP2D6.(1)
PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a strong CYP2D6 inhibitor: - in patients with major depressive disorder who are taking a strong CYP2D6 inhibitor WITHOUT a strong or moderate CYP3A4 inhibitor, no dosage adjustment is required. - in patients with major depressive disorder who are taking a strong CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor WITHOUT a strong or moderate CYP3A4 inhibitor, administer half the usual dosage of brexpiprazole. - in patients with schizophrenia who are taking a strong CYP2D6 inhibitor AND who are receiving a strong or moderate inhibitor of CYP3A4, decrease the dose to one-fourth the usual dose. The dose of brexpiprazole should be adjusted to its original level if the CYP2D6 inhibitor is discontinued.(1)
DISCUSSION: Coadministration of quinidine, a strong inhibitor of CYP2D6, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) Strong CYP2D6 inhibitors include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(2,3)
Strong Cyp2d6 Inhibitors/Codeine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of codeine to its active form, morphine.
CLINICAL EFFECTS: The concurrent administration of codeine and a strong inhibitor of CYP2D6 may result in decreased efficacy of codeine. If a strong CYP2D6 inhibitor is discontinued, the effects of codeine may be increased, including respiratory depression.
PREDISPOSING FACTORS: Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with codeine and a strong CYP2D6 inhibitor should be observed for decreased effectiveness of codeine. Dose increase of codeine may be required, or an alternative analgesic, such as morphine, may need to be considered. After discontinuation of a CYP2D6 inhibitor, consider reducing the dosage of codeine and monitor the patient for signs and symptoms of respiratory depression or sedation.
DISCUSSION: Strong inhibitors of CYP2D6 have been shown to decrease the metabolism of codeine to morphine at CYP2D6. Quinidine has also been shown to decrease cerebrospinal fluid levels of morphine after codeine administration. Concurrent administration resulted in decreased effects of codeine. Strong CYP2D6 inhibitors linked to this monograph are: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.
Strong Cyp2d6 Inhibitors/Deutetrabenazine;Tetrabenazine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: After ingestion, tetrabenazine is rapidly to converted the active agent, dihydrotetrabenazine (HTBZ, a mixture of alpha-HTBZ and beta-HTBZ). Both alpha and beta-HTBZ are metabolized by CYP2D6. Strong inhibitors of CYP2D6 may inhibit the metabolism of tetrabenazine active metabolites.(1) Deutetrabenazine is a deuterated form of tetrabenazine.(2)
CLINICAL EFFECTS: Concurrent use of a strong CYP2D6 inhibitor may result in increased levels of and adverse effects from deutetrabenazine(2) or tetrabenazine.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The maximum recommended dose of deutetrabenazine when administered with a strong inhibitor of CYP2D6 is 36 mg daily (tablets: given as 18 mg twice daily; or extended-release tablets: given as 36 mg daily).(2,3) The maximum recommended dose of tetrabenazine when administered with a strong inhibitor of CYP2D6 is 50 mg daily (given as 25 mg twice daily).(1) Monitor patients receiving concurrent deutetrabenazine or tetrabenazine and a strong CYP2D6 inhibitor for adverse effects, including depression, suicidal thoughts, stiff muscles, trouble swallowing, irritability or agitation, shaking, and restlessness. If the CYP2D6 inhibitor is discontinued, the dose of deutetrabenazine or tetrabenazine may need adjustment.
DISCUSSION: In a study in 24 healthy subjects, following the administration of a single oral dose of deutetrabenazine (22.5 mg) after 8 days of paroxetine (20 mg daily), the maximum concentration (Cmax) of alpha-HTBZ and beta-HTBZ increased by 1.2-fold and 2.2-fold, respectively. The area-under-curve (AUC) of alpha-HTBZ and beta-HTBZ increased by 1.9-fold and 6.5-fold, respectively.(2) In a study in 25 healthy subjects, following the administration of a single oral dose of tetrabenazine (50 mg) after 10 days of paroxetine (20 mg daily), the Cmax of alpha-HTBZ and beta-HTBZ increased by 30% and 2.4-fold, respectively. The AUC of alpha-HTBZ and beta-HTBZ increased by 3-fold and 9-fold, respectively.(1) Strong inhibitors of CYP2D6 include: bupropion, dacomitinib, fluoxetine, paroxetine and terbinafine.(1-4)
Strong Cyp2d6 Inhibitors/Mexiletine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine may inhibit the metabolism of mexiletine at CYP2D6.(1-7)
CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from mexiletine, including vertigo, insomnia, and abdominal pain.(1-5)
PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6.(1-5)
PATIENT MANAGEMENT: The UK manufacturer states coadministration of mexiletine with a strong CYP2D6 inhibitor may lead to increased levels and toxicity from mexiletine. Clinical monitoring is recommended during and after concurrent therapy for changes in mexiletine levels.(1) The US manufacturer states if concurrent use is warranted, mexiletine should be slowly titrated to response and closely monitored.(2)
DISCUSSION: Mexiletine is 90% metabolized in the liver, with CYP2D6 as the primary pathway. CYP2D6 phenotypes significantly affect drug levels of mexiletine.(3-5) In an interaction study (8 extensive and 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable.(2) In a pharmacokinetic study in CYP2D6 phenotypes, patients with CYP2D6 extensive metabolizers had a decreased extent of the formation of both metabolites by more than 50% and 85% for the microsomes from CYP2D6*1/*10 and 10/*10 livers, respectively.(3) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, paroxetine, and quinidine.(6-7)
Strong Cyp2d6 Inhibitors/Milsaperidone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of milsaperidone.(1)
CLINICAL EFFECTS: Concurrent administration of milsaperidone with strong CYP2D6 inhibitors may result in elevated milsaperidone levels and toxicities, including the risk for QTc prolongation.(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, advanced age, and with concurrent use of inhibitors of CYP3A4, which metabolizes milsaperidone.(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 milsaperidone states that the maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP2D6 inhibitor. If starting milsaperidone with a stable dose of a strong CYP2D6 inhibitor, follow the recommended titration schedule in the labeling.(1) Further dose reduction is not required for concurrent administration of milsaperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor. The maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor. If starting milsaperidone with a stable dose of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor, follow the recommended titration schedule in the labeling.(1) Due to its long half-life it may take 2 or more weeks to see the full effects of fluoxetine CYP2D6 inhibition on milsaperidone exposure and tolerance. Maximal CYP2D6 inhibitory effects due to paroxetine coadministration are generally expected within one week after initiation or increase in the paroxetine dosage. When the inhibitor is discontinued milsaperidone exposure will wane and the dose of milsaperidone should be titrated to the recommended dose in the labeling.(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 study in healthy subjects, fluoxetine (20 mg twice daily for 21 days) increased the area-under-curve (AUC) of iloperidone (3 mg single dose) and milsaperidone by 2-3-fold. The AUC of iloperidone's P95 metabolite decreased by 50%.(1) In a study in patients with schizophrenia, paroxetine (20 mg daily for 5-8 days) increased the maximum concentration (Cmax) of iloperidone and milsaperidone by about 1.6-fold. The Cmax of iloperidone's P95 metabolite decreased by 50%.(1) 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) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine did not increase the effects on iloperidone compared with either agent alone.(2) Coadministration of ketoconazole (200 mg twice daily, an inhibitor of CYP3A4) 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) Coadministration of paroxetine (20 mg daily, an inhibitor of CYP2D6) 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) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, paroxetine, and terbinafine.(3)
Strong Cyp2d6 Inhibitors/Oliceridine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Oliceridine is metabolized equally by CYP2D6 and CYP3A4. Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or CYP3A4.(1)
CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from oliceridine including profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater increase in the levels of and toxcity of oliceridine.(1)
PATIENT MANAGEMENT: Caution should be used when administering oliceridine to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4. Dosage adjustments should be made if warranted. Closely monitor these patients for respiratory depression and sedation at frequent intervals and evaluate subsequent doses based on response. If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is necessary, less frequent dosing of oliceridine may be required. If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued, increase of the oliceridine dosage may be necessary. Monitor for signs of opioid withdrawal. Patients receiving concurrent therapy with both a strong or moderate CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse effects. Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and a strong CYP3A4 inhibitor may require less frequent dosing of oliceridine.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)
DISCUSSION: In a study of four healthy subjects who are CYP2D6 poor metabolizers, itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1) In a study of subjects who were not CYP2D6 poor metabolizers, ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the pharmacokinetics of oliceridine.(1) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine.(4)
Strong Cyp2d6 Inhibitors/Oxycodone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may alter the metabolism of oxycodone.(1) Oxycodone is primarily metabolized by CYP3A4 to noroxycodone then by CYP2D6 to noroxymorphone as well as by CYP2D6 to oxymorphone. Noroxycodone, oxymorphone, and noroxymorphone are active metabolites.(1-3)
CLINICAL EFFECTS: The concurrent administration of oxycodone and a strong inhibitor of CYP2D6 may result in decreased efficacy or increased effects and toxicity of oxycodone. Parent and metabolite concentrations of oxycodone may be altered.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with oxycodone and a strong CYP2D6 inhibitor should be observed for decreased effectiveness as well as signs of increased effects and opioid toxicity. An alternative analgesic, such as morphine or nonopioid analgesics, may need to be considered.
DISCUSSION: Strong inhibitors of CYP2D6 have been shown to alter the metabolism of oxycodone.(1-3) A study in 10 healthy subjects who were CYP2D6 extensive metabolizers were given oxycodone 20 mg with either quinidine 200 mg or placebo, followed by quinidine 100 mg 6 hours later. Levels of oxymorphone were undetectable at any time point after quinidine administration. The psychomotor or subjective drug effects of oxycodone were unchanged.(4) A study in 10 healthy subjects received a single dose of quinidine 100 mg (a strong CYP2D6 inhibitor) followed by oxycodone 0.2 mg/kg oral drops. Oxymorphone (CYP2D6 dependent metabolite) concentration maximum (Cmax) and area-under-curve (AUC) were both decreased by 40% with quinidine administration compared to oxycodone alone. Oxycodone AUC and AUC at 90 minutes post administration were increased 1.5-fold and 8.5-fold, respectively. Total clearance of oxycodone was decreased by 20-30%. A compensatory 70% increase of noroxycodone (CYP3A4 dependent metabolite) AUC was also observed.(5) A study in 11 healthy subjects evaluated the effects of paroxetine 20 mg daily on single dose oxycodone 10 mg. Paroxetine decreased the mean AUC of CYP2D6 dependent metabolite oxymorphone by 44% (p<0.05) and increased the mean AUC of CYP3A4 dependent metabolite noroxycodone by 68% (p<0.001). Administration of paroxetine increased the VAS score for deterioration of performance for the first 6 hours following oxycodone.(6) A randomized crossover trial in 10 healthy subjects with differing CYP2D6 metabolizer statuses received oxycodone with either placebo, quinidine, ketoconazole, or both quinidine and ketoconazole. CYP2D6 activity correlated with oxymorphone and noroxymorphone AUCs and Cmax.(7) A retrospective cohort study in 111 patients found patients who received oxycodone with either a CYP2D6 or CYP3A4 inhibitor had an increased risk of gastrointestinal, dizziness, and drowsiness adverse reactions. Use of either a CYP2D6 or CYP3A4 inhibitor increase the risk by 20.4 and 25.4 times, respectively. Concurrent use of both a CYP2D6 and CYP3A4 inhibitor increased the risk with an adjusted OR of 48.6.(8) A cohort study evaluated the use of concurrent oxycodone and SSRIs that inhibit CYP2D6 on the risk of opioid overdose. The adjusted incidence rate of opioid overdose in patients on SSRIs that inhibit CYP2D6 when initiated on oxycodone was higher than SSRIs that do not inhibit CYP2D6 (9.47 per 1000 person years vs 7.66 per 1000 person years, respectively).(9) The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that CYP2D6 poor metabolizers have a lower peak concentration of oxymorphone (CYP2D6 dependent metabolite) after a dose of oxycodone compared to extensive metabolizers; however, clinical significance of metabolizer status on analgesia or risk of toxicity is unknown.(10) CPIC recommends selecting alternative drugs other than oxycodone for CYP2D6 poor and intermediate metabolizers, or be alert to insufficient pain relief; for CYP2D6 ultrarapid metabolizers, select an alternative to oxycodone, or be alert for adverse events.(10) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, and quinidine.(11)
Strong Cyp2d6 Inhibitors/Pitolisant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Bupropion, dacomitinib, fluoxetine, paroxetine, and terbinafine may inhibit the metabolism of pitolisant at CYP2D6.(1,2)
CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from pitolisant including potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. 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, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer states the concurrent use of pitolisant with strong CYP2D6 inhibitors requires dose adjustment. - Adult patients currently receiving a strong CYP2D6 inhibitor prior to initiation of pitolisant: start pitolisant at 8.9 mg once daily and increase after 7 days to a maximum dosage of 17.8 mg daily. - Patients 6 years and older weighing <40 kg: start pitolisant at 4.45 mg once daily and increase after 7 days to a maximum dosage of 8.9 mg once daily. - Patients 6 years and older weighing >=40 kg: start pitolisant at 4.45 mg once daily and increase after 7 days to 8.9 mg once daily. May increase after another 7 days to a maximum dosage of 17.8 mg once daily. - All patients who are stable on pitolisant: reduce the dose of pitolisant by half upon initiating a strong CYP2D6 inhibitor.(1) The UK manufacturer states concurrent use of pitolisant with CYP2D6 inhibitors should be done with caution and dose adjustment could be considered.(2) 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 clinical study, concurrent use of pitolisant with paroxetine increased the concentration maximum (Cmax) and area-under-curve (AUC) by approximately 1.75 and 2.25, respectively.(1) 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) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, paroxetine and terbinafine.(5,6)
Strong Cyp2d6 Inhibitors/Primaquine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of primaquine to its active metabolite.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in reduced antimalarial effect of primaquine due to decreased formation of the active primaquine metabolite.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: When possible, consider alternative medications that are not strong CYP2D6 inhibitors. If concurrent therapy is warranted, monitor patients closely for possible relapse.
DISCUSSION: Published clinical reports indicate that primaquine is a CYP2D6 substrate. Reduced CYP2D6 activity may decrease the formation of the active metabolite of primaquine.(1) Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)
Strong Cyp2d6 Inhibitors/Risperidone Intramuscular Monthly
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The US manufacturer of risperidone for monthly intramuscular injection (Risvan) makes the following recommendations for patients who receive a strong CYP2D6 inhibitor: - Initiation of a CYP2D6 inhibitor: the recommended dose of risperidone is 75 mg started at least 2 to 4 weeks prior to starting a strong CYP2D6 inhibitor to adjust for the expected increase in plasma concentrations of risperidone. When strong CYP2D6 inhibitors are initiated in patients receiving risperidone 75 mg, it is recommended to continue treatment with 75 mg unless clinical judgment necessitates interruption of risperidone treatment. - Discontinuation of a CYP2D6 inhibitor: the effects of discontinuation of strong CYP2D6 inhibitors on the pharmacokinetics of risperidone and 9-hydroxyrisperidone (active metabolite) have not been studied.(1)
DISCUSSION: A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(2) A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(3) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(4) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)
Strong Cyp2d6 Inhibitors/Risperidone Sq Monthly
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP2D6 inhibitors may inhibit the metabolism of risperidone by CYP2D6.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in elevated levels of risperidone and an increase in risperidone side effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP2D6 inhibitors with risperidone should be observed for increases in risperidone side effects, including extrapyramidal and Parkinsonian symptoms. The manufacturer of extended release risperidone injectable suspension (Perseris) recommends patients be placed on the lowest dose (90 mg) of Perseris two to four weeks before the planned start of a strong CYP2D6 inhibitor to adjust for the expected increase in risperidone plasma concentrations. When a strong CYP2D6 inhibitor is initiated in patients receiving Perseris 90 mg, it is recommended to continue treatment with 90 mg unless clinical judgment necessitates interruption of risperidone treatment.(1)
DISCUSSION: A study in 10 patients examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg/day). One patient dropped out following the development of severe akathisia after one week of fluoxetine. Her risperidone levels had increased 457%. In the remaining patients, fluoxetine increased risperidone levels by 308% at two weeks and by 733% at four weeks. Levels of the active moiety increased by 75% by four weeks. During the second week of fluoxetine therapy, two patients developed Parkinsonian symptoms.(2) A study in 3 CYP2D6 poor metabolizers and 8 CYP2D6 extensive metabolizers examined the effects of fluoxetine (20 mg daily) on risperidone (4-6 mg daily). Concurrent fluoxetine increased the area-under-curve (AUC) of risperidone and the active moiety by 29% and by 100%, respectively, in poor metabolizers. In extensive metabolizers, the AUC of risperidone and the active moiety increased by 70% and 41%, respectively.(3) A study in 10 patients examined the effects of paroxetine (20 mg daily) on risperidone (4-8 mg/day). After two and four weeks of concurrent therapy, risperidone concentrations increased 388% and 453%, respectively. Plasma concentrations of the active moiety increased 39.4% and 44.5% after two and four weeks of concurrent therapy, respectively. No symptoms of risperidone toxicity or change in extrapyramidal effects were noted. One patient developed Parkinsonism.(4) Strong CYP2D6 inhibitors linked to this monograph include: dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine, and terbinafine.(5)
Strong Cyp2d6 Inhibitors/Valbenazine (<=40 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Valbenazine's active metabolite (alpha-HTBZ) is metabolized by CYP2D6 and CYP3A4.(1) Bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine are strong inhibitors of CYP2D6.(2,3)
CLINICAL EFFECTS: Concurrent use of bupropion, dacomitinib, fluoxetine, paroxetine, quinidine or terbinafine may result in elevated levels and adverse effects of valbenazine such as somnolence and QT prolongation.
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 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 own metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(2) Concurrent use of strong CYP3A4 inhibitors may further increase levels of valbenazine.(1)
PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP2D6 inhibitor.(1) During concomitant therapy with a strong CYP2D6 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a drug interaction study in healthy subjects, coadministration of paroxetine (a strong CYP2D6 inhibitor) with valbenazine did not affect valbenazine maximum concentration (Cmax) or area-under-the-curve (AUC). However, Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 1.9- and 1.5-fold, respectively. Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.
Contraindications
None.
- Lactation
- Diarrhea
- Interstitial lung disease
- Pregnancy
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reportedin >20% of patients include diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus.
More Frequent
- Anemia
- Diarrhea
- Hyperglycemia
- Hypocalcemia
- Hypokalemia
- Hyponatremia
- Increased alanine transaminase
- Increased aspartate transaminase
- Lymphopenia
Less Frequent
- Dehydration
- Exfoliative dermatitis
- Hyperbilirubinemia
- Hypomagnesemia
- Palmar-plantar erythrodysesthesia
- Skin fissure
Rare or Very Rare
- Interstitial lung disease
More Frequent
- Alopecia
- Anorexia
- Cough
- Dry skin
- Paronychia
- Pruritus of skin
- Skin rash
- Stomatitis
- Weight loss
Less Frequent
- Chest pain
- Conjunctivitis
- Dysgeusia
- Dyspnea
- General weakness
- Hirsutism
- Insomnia
- Keratitis
- Musculoskeletal pain
- Nasal passage irritation
- Pain in extremities
- Skin inflammation
- Upper respiratory infection
- Vomiting
Precautions
No enhanced messaging available.
Safety and efficacy of dacomitinib have not been established in pediatric patients.
Dacomitinib may cause fetal harm if administered to pregnant women based on its mechanism of action and findings from animal studies.
In animals, disruption or blockade of signaling of the EGFR pathway has been associated with preimplantation loss, embryo-fetal loss during various stages of gestation, postnatal death, developmental anomalies, and visceral abnormalities. Embryo-fetal toxicity (e.g., decreased fetal body weight, postimplantation loss) and maternal toxicity have been demonstrated in animals receiving dacomitinib at exposure levels equivalent to approximately 1.2 times the human exposure at the recommended dosage.
It is not known whether dacomitinib or its metabolites distribute into human milk; the effects of the drug on breast-fed infants or on the production of breast milk are also unknown. Because of the potential for adverse reactions to dacomitinib in breast-fed infants, femalesshould be advised not to breast-feed while receiving the drug and for>=17 days after the last dose.
The manufacturer makes no specific dosage recommendations for geriatric patients.
Across 5 clinical studies of patients (N=394) receiving dacomitinib 45 mg once daily, 40% were >=65 years of age or older. Exploratory analyses suggest a higher incidence of grade 3 or 4 adverse reactions, more frequent dosage interruptions, and more discontinuations of dacomitinib due to adverse reactions in patients >=65 years of age compared to those <65 years of age.
ICD codes
| Code | Type | Description |
|---|---|---|
| Metastatic non-small cell lung cancer with EGFR exon 19 deletion | ||
| C34 | ICD10CM | Malignant neoplasm of bronchus and lung |
| C34.0 | ICD10CM | Malignant neoplasm of main bronchus |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.1 | ICD10CM | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | ICD10CM | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | ICD10CM | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | ICD10CM | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
| C39.9 | ICD10CM | Malignant neoplasm of lower respiratory tract, part unspecified |
| Metastatic non-small cell lung cancer with EGFR exon 21 l858R substitution mutation | ||
| C34 | ICD10CM | Malignant neoplasm of bronchus and lung |
| C34.0 | ICD10CM | Malignant neoplasm of main bronchus |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.1 | ICD10CM | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | ICD10CM | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | ICD10CM | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | ICD10CM | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
| C39.9 | ICD10CM | Malignant neoplasm of lower respiratory tract, part unspecified |
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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