Vaprisol-5% Dextrose (conivaptan HCl/dextrose 5 % in water)
Antidiuretic Hormone Antagonists Intravenous Plastic Bag, Injection (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Conivaptan, a benzazepine derivative, is a nonpeptide antagonist of arginine vasopressin (antidiuretic hormone) V1A and V2 receptors.
Conivaptan, a benzazepine derivative, is a nonpeptide antagonist of arginine vasopressin (antidiuretic hormone) V1A and V2 receptors. Circulating concentrations of vasopressin, which usually are elevated in patients with euvolemic or hypervolemic hyponatremia, play an important role in the regulation of fluid and electrolyte balance. The activity of vasopressin at renal V2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the renal collecting ducts, helps maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water.
Vasopressin also causes vasoconstriction through its actions on vascular V1A receptors. Conivaptan antagonizes the effects of vasopressin at V2 receptors, resulting in excretion of free water (or increased effective water clearance), which generally is accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. Blockade of vascular V1A receptors may cause splanchnic vasodilation, possibly resulting in hypotension or variceal bleeding in patients with cirrhosis (especially those with portal hypertension).
Conivaptan is extensively metabolized by cytochrome P-450 (CYP) isoenzyme 3A and also is a potent inhibitor of CYP3A. Following IV or oral administration, conivaptan exhibits nonlinear pharmacokinetics, probably secondary to the drug inhibiting its own metabolism. Several active metabolites have been identified, but their contribution to the drug's clinical effects probably is minimal since exposure to the metabolites combined is only about 7% that of the parent drug.
Following administration of an IV dose of 10 mg or an oral dose of 20 mg, about 83% of the dose was excreted in the feces and about 12% in the urine over several days. About 1% of the dose was excreted in urine as unchanged drug over the first 24 hours after IV administration.
Generic name: conivaptan HCl/dextrose 5 % in water
Drug class: Antidiuretic Hormone Antagonists
Therapeutic class: Cardiovascular Therapy Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Vaprisol-5% Dextrose:
- Hyponatremia
Also known as: Decreased Serum Na, Decreased Serum Sodium, Low Serum Sodium.
Dosing
The recommended adult dosage of conivaptan hydrochloride for the treatment of euvolemic or hypervolemic hyponatremia is a loading dose of 20 mg infused IV over 30 minutes followed by continuous IV infusion of 20 mg over 24 hours; following the first day of treatment, conivaptan hydrochloride therapy should be continued for an additional 1-3 days at a dosage of 20 mg daily by continuous IV infusion. Vital signs, fluid status, and serum sodium concentration must be monitored carefully, and administration of the drug should be discontinued if hypotension or hypovolemia occurs or if serum sodium concentration increases at too rapid a rate (see Overly Rapid Correction of Serum Sodium Concentration and also see Hypovolemia and Hypotension under Cautions: Warnings/Precautions). If serum sodium concentration is not increasing at the desired rate, the dosage of conivaptan hydrochloride may be increased to 40 mg daily (the maximum recommended daily dosage (after the loading dose)) as a continuous IV infusion. In clinical trials of the drug, a dosage of 80 mg daily was not substantially more effective than 40 mg daily and was associated with a higher incidence of infusion site reactions and adverse effects requiring drug discontinuance. The total duration of conivaptan therapy should not exceed 4 days.
Conivaptan hydrochloride is administered by IV infusion. The manufacturer states that the drug should be administered to hospitalized patients only.
Commercially available premixed conivaptan hydrochloride injection containing 0.2 mg/mL of conivaptan hydrochloride in 5% dextrose injection may be used without further dilution; the manufacturer's labeling should be consulted for proper methods of administration and other associated precautions for this preparation. The premixed conivaptan hydrochloride injection is available in single-use flexible containers; any unused portions should be discarded. Additives should not be introduced into the premixed injection. The premixed conivaptan hydrochloride injection in flexible plastic containers should not be used in series connections, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.
Conivaptan hydrochloride solutions should be inspected visually for particulate matter and/or discoloration prior to administration, and the solution should be discarded if it is cloudy or discolored or contains particulates.
The commercially available premixed conivaptan hydrochloride injection is compatible with 5% dextrose injection. In addition, the premixed conivaptan hydrochloride injection is compatible with 0.9% sodium chloride injection for up to 22 hours when the 2 solutions are administered simultaneously through a Y-site connection at flow rates of 4.2 mL/hour for conivaptan hydrochloride injection and 2.1 or 6.3 mL/hour for 0.9% sodium chloride injection. Conivaptan hydrochloride injection should not be administered with lactated Ringer's injection and should not be administered simultaneously through the same IV line with other drugs.
The IV loading dose of conivaptan hydrochloride should be infused over 30 minutes, followed by a continuous IV infusion of the drug over 24 hours. Conivaptan hydrochloride should be administered into a large vein, and the infusion site should be changed every 24 hours to minimize the risk of venous irritation (see Infusion Site Reactions under Cautions: Warnings/Precautions).
Although conivaptan has been administered orally in clinical trials, the drug is not being developed commercially for oral use because of the risk of serious cytochrome P-450 (CYP) isoenzyme 3A-mediated drug interactions with longer-term oral use (see Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes and see Description).
| Drug label | Dosing type | Instructions |
|---|---|---|
| Vaprisol-Dextrose 20 Mg/100 Ml | Maintenance | Infuse 20 mg by continuous infusion route for 4 days. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Conivaptan 20 Mg/100 Ml-D5w | Maintenance | Infuse 20 mg by continuous infusion route for 4 days. |
Drug interactions
There is no enhanced messaging for this drug.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Conivaptan/Amlodipine; Levamlodipine
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: Conivaptan may inhibit the metabolism of amlodipine via CYP3A4.(1) Levamlodipine is the active isomer of amlodipine.(2)
CLINICAL EFFECTS: Concurrent use of amlodipine or levamlodipine and conivaptan may result in increased levels of amlodipine or levamlodipine, which may lead to increased clinical effects and toxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of conivaptan states that concurrent use of agents primarily metabolized by CYP3A4, such as amlodipine or levamlodipine, should be avoided. Amlodipine or levamlodipine may be initiated no sooner than 1 week after the infusion of conivaptan is completed.(1)
DISCUSSION: Conivaptan is a potent inhibitor of CYP3A4. In an evaluation of the combination of oral conivaptan (80 mg/day) and amlodipine, the area-under-curve (AUC) and half life of amlodipine were both increased 2-fold.(1)
Conivaptan/Lovastatin; Simvastatin
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: Conivaptan is a moderate CYP3A4 inhibitor and may inhibit the metabolism of lovastatin(1,2) and simvastatin(2,3) via CYP3A4.
CLINICAL EFFECTS: Concurrent use of conivaptan may result in increased levels of lovastatin(1,2) or simvastatin,(2,3) which may lead to increased clinical effects and toxicity, including rhabdomyolysis.
PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.
PATIENT MANAGEMENT: Concurrent use of lovastatin(1) or simvastatin(3) with inhibitors of CYP3A4 may increase the risk of myopathy. The manufacturer of conivaptan recommends avoiding concurrent use of drugs primarily metabolized by CYP3A4.(2) Therapy with lovastatin and simvastatin may be initiated no sooner than 1 week after the infusion of conivaptan is completed.(2)
DISCUSSION: Conivaptan is a moderate inhibitor of CYP3A4. In an evaluation of the combination of intravenous conivaptan (30 mg) and simvastatin, the area-under-curve (AUC) of simvastatin was increased 3-fold. Two cases of rhabdomyolysis occurred in patients who were also receiving a CYP3A4 metabolized HMG-CoA reductase inhibitor.(3)
Conivaptan/Midazolam
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: Conivaptan may inhibit the metabolism of midazolam via CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of midazolam and conivaptan may result in increased levels of midazolam, which may lead to increased clinical effects and toxicity, including respiratory depression.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of conivaptan states the concurrent use of agents primarily metabolized by CYP3A4, such as midazolam, should be avoided. Treatment with midazolam may be initiated no sooner than 1 week after the infusion of conivaptan is completed.(1)
DISCUSSION: Conivaptan is a potent inhibitor of CYP3A4. In an evaluation of the combination of intravenous conivaptan (40 mg) with either an intravenous dose of midazolam (1 mg) or an oral dose of midazolam (2 mg), mean area under the curve (AUC) values of midazolam were increased 2- and 3-fold, respectively.(1)
Conivaptan/Selected Immunosuppressants
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: Conivaptan increases plasma levels of cyclosporine, sirolimus, and temsirolimus by inhibition of CYP3A4.(1-4)
CLINICAL EFFECTS: Concurrent conivaptan may result in elevated levels of and toxicity from cyclosporine, sirolimus, and temsirolimus.(1-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of conivaptan states that concomitant use of drugs eliminated primarily by CYP3A-mediated metabolism should be avoided.(1) Cyclosporine, sirolimus, or temsirolimus levels and renal function should be monitored if conivaptan is initiated or discontinued from concurrent therapy. The dosage of cyclosporine, sirolimus, or temsirolimus may need to be adjusted. The US manufacturer of sirolimus states that concurrent therapy with moderate CYP3A4 inhibitors such as conivaptan should be used with caution. The dosage of sirolimus or conivaptan may require adjustment.(3)
DISCUSSION: Erythromycin 800 mg every 8 hours, a moderate CYP3A4 and P-gp inhibitor, given to 24 healthy volunteers increased the maximum concentration (Cmax) and area-under-curve (AUC) of sirolimus 2 mg by 4.4-fold and 4.2-fold, respectively.(3) In a study of 18 healthy volunteers, diltiazem 120 mg, a moderate CYP3A4 inhibitor and P-gp inhibitor, increased the Cmax and AUC of sirolimus 10 mg by 1.4-fold and 1.6-fold, respectively.(3) In 25 healthy volunteers, verapamil 180 mg twice daily, a moderate CYP3A4 inhibitor and P-gp inhibitor, increased the max and AUC of sirolimus 2 mg by 2.3-fold and 2.2-fold, respectively.(3) Concurrent administration of ketoconazole, another inhibitor of CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.(4)
Conivaptan/Selected Strong Cyp3a4 Inhibitors
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of conivaptan.(1) Toxicity may result from an overly rapid correction of serum sodium. Conivaptan may also increase levels of levoketoconazole.(4)
CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of conivaptan.(1) Elevated levels of these agents may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of conivaptan and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent use with conivaptan is contraindicated during and two weeks after itraconazole treatment.(2)
DISCUSSION: Conivaptan is a substrate of CYP3A4. Coadministration of conivaptan (10mg) and ketoconazole (a strong CYP3A4 inhibitor, 200 mg) resulted in a 4-fold increase in the AUC and an 11-fold increase in the Cmax of conivaptan.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(3)
Dual Moderate Cyp3a4 & P-Gp Inhibitors/Ensartinib
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: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism of ensartinib.(1)
CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity from ensartinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp and moderate CYP3A4 inhibitors should be avoided.(1)
DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual P-gp and moderate CYP3A4 inhibitors linked to this monograph include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, Schisandra, and verapamil.(2,3)
Dual Moderate Cyp3a4 And P-Gp Inhib/Daraxonrasib (>100 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: Daraxonrasib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Moderate CYP3A4 and P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 and P-gp inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: For patients taking agents that are both moderate CYP3A4 inhibitors and P-gp inhibitors, reduce the dose of daraxonrasib to 100 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 3 to 5 half-lives of the inhibitor.(1)
DISCUSSION: In a study, diltiazem 80 mg three times daily (a moderate CYP3A and P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 2.6-fold.(1) Dual moderate CYP3A4 and P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazole, schisandra, and verapamil.(2-3)
Moderate Cyp3a4 Inhibitors/Avanafil (> 50 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of avanafil.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of avanafil states that in patients receiving moderate inhibitors of CYP3A4, the dose of avanafil should be limited to 50 mg in 24 hours.(1)
DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of 2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold, respectively. The half-life of avanafil increased from 5 hours to 8 hours.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1-3)
Moderate Cyp3a4 Inhibitors/Avutometinib-Defactinib
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: Avutometinib and defactinib are both CYP3A4 substrates. Strong CYP3A4 inhibitors may inhibit the metabolism of defactinib. Avutometinib also undergoes non-enzymatic degradation is not affected by CYP3A4 inhibitors.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of defactinib and toxicity from avutometinib-defactinib, including hepatotoxicity, rhabdomyolysis, ocular toxicities, and skin toxicities.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of avutometinib-defactinib and moderate CYP3A4 inhibitors should be avoided.(1)
DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of defactinib has not been investigated in clinical studies. Defactinib maximum concentration (Cmax) increased by 2.2-fold and area-under-curve (AUC) by 3.9-fold following concomitant use with itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. The AUC of M4, a major active metabolite of defactinib, increased by 2.2-fold and Cmax decreased by 6.8%.(1) No clinically significant differences in avutometinib pharmacokinetics were observed when used concomitantly with itraconazole.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Bosutinib
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: Agents that inhibit CYP3A4 may inhibit the metabolism of bosutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from bosutinib.(1) Elevated levels of bosutinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients undergoing therapy with bosutinib.(1)
DISCUSSION: In a study in 24 healthy subjects, ketoconazole (400 mg daily for 5 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of bosutinib (100 mg) by 5.2-fold and 8.6-fold, respectively.(1) In a cross-over study in 18 healthy subjects, aprepitant (125 mg) increased the Cmax and AUC of bosutinib (single dose 500 mg) by 1.5-fold and 2.0-fold, respectively.(1) A study using PKPB modeling found concurrent use of bosutinib and schisandra would result in an increase in bosutinib exposure with an increased AUC by 3.0-fold.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, boceprevir, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(3-4)
Moderate Cyp3a4 Inhibitors/Dapoxetine (>30 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: Moderate CYP3A4 inhibitors may inhibit the metabolism of dapoxetine.(1-3)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of dapoxetine.(1-3)
PREDISPOSING FACTORS: If the patient is a CYP2D6 poor metabolizer, dapoxetine metabolism can be further inhibited.(1-3)
PATIENT MANAGEMENT: The manufacturers of dapoxetine state that the dose of dapoxetine should not exceed 30 mg daily if coadministered with moderate CYP3A4 inhibitors.(1-3)
DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of dapoxetine has not been investigated in clinical studies.(1-3) Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively. The Cmax and AUC of the active fraction are expected to increase by 25% and 2-fold, respectively, with strong inhibitors of CYP3A4.(1-3) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)
Moderate Cyp3a4 Inhibitors/Daridorexant (>25 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of daridorexant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from daridorexant including somnolence, fatigue, CNS depressant effects, daytime impairment, or headache.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The dose of daridorexant should be limited to 25 mg daily when used with a moderate CYP3A4 inhibitor.(1)
DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) and maximum concentration (Cmax) by 2.4-fold and 1.4-fold, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(2)
Moderate Cyp3a4 Inhibitors/Dordaviprone
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: Moderate CYP3A4 inhibitors may inhibit the metabolism of dordaviprone.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of dordaviprone, including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: This interaction may be more severe in patients with renal or hepatic impairment.(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 US manufacturer of dordaviprone states that concomitant use with moderate CYP3A4 inhibitors should be avoided.(1). If concomitant use with a moderate CYP3A4 inhibitor cannot be avoided in adult and pediatric patients who weigh at least 52.5 kg, reduce the dordaviprone dosage from 625 mg to 500 mg once weekly. Recommended doses for patients weighing less than 52.5 kg receiving moderate CYP3A4 inhibitors has not been established.(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, concomitant use of dordaviprone with itraconazole 200 mg daily for 8 days (a strong CYP3A4 inhibitor) increased dordaviprone maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and 4-fold, respectively.(1) Moderate CYP3A4 inhibitors (fluconazole or erythromycin) are predicted to increase dordaviprone Cmax and AUC by 1.5-fold and 2.5-fold.(1) Dordaviprone causes concentration-dependent QTc interval prolongation. In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8, 13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1) In a pooled safety analysis, out of 82 patients with a post-baseline ECG, 6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had an increase in QTc >500 msec.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Lumateperone (>21 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of lumateperone.(1)
CLINICAL EFFECTS: Concurrent use of lumateperone with moderate CYP3A4 inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1)
PREDISPOSING FACTORS: Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) may be at higher risk of increased lumateperone exposure.(1)
PATIENT MANAGEMENT: The manufacturer of lumateperone recommends decreasing the dosage of lumateperone to 21 mg once daily in patients receiving moderate CYP3A4 inhibitors.(1)
DISCUSSION: Coadministration of lumateperone with itraconazole, a strong CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Coadministration of lumateperone with diltiazem, a moderate CYP3A4 inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax, respectively.(1) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, verapamil, treosulfan, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Mitapivat (50 Mg Bid)
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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be monitored closely for increased risk of adverse reactions. Mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, tofisopam, and verapamil.(2)
Moderate Cyp3a4 Inhibitors/Naloxegol (> 12.5 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: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)
PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)
PATIENT MANAGEMENT: The daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) If concurrent use is deemed medically necessary, monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)
DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)
Moderate Cyp3a4 Inhibitors/Olverembatinib
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: Olverembatinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of olverembatinib.(1)
CLINICAL EFFECTS: Concurrent use of olverembatinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of olverembatinib, including myelosuppression, bleeding, and hepatotoxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of olverembatinib states coadministration with moderate CYP3A4 inhibitors should be avoided.(1)
DISCUSSION: In a clinical study of 16 healthy subjects, coadministration of olverembatinib 20 mg with itraconazole 200 mg daily, a strong CYP3A4 inhibitor, resulted in a 2.59-fold increase in olverembatinib's area-under-curve (AUC) and a 1.76-fold increase in olverembatinib's maximum concentration (Cmax).(2) In a PBPK model, the moderate CYP3A4 inhibitors verapamil 80 mg three times daily, fluconazole 200 mg daily, and erythromycin 500 mg every 6 hours increased the AUC of olverembatinib 40 mg by 2.25-, 1.8-, and 2.39-fold, respectively. Olverembatinib Cmax was increased by 1.55-, 1.42-, and 1.6-fold, respectively.(3) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4-5)
Moderate Cyp3a4 Inhibitors/Oveporexton (>0.5 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: Oveporexton is metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of oveporexton.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of oveporexton, including insomnia, urinary frequency and urgency, and CPK elevation.(1)
PREDISPOSING FACTORS: Adverse reactions from oveporexton may be more likely in patients with Child-Pugh class C hepatic impairment and in patients with severe renal impairment on dialysis.
PATIENT MANAGEMENT: In patients on concomitant moderate CYP3A4 inhibitors with oveporexton, reduce the dosage of oveporexton to 0.5 mg after awakening and then 0.5 mg three to five hours later (maximum recommended dosage is 1 mg per day).(1)
DISCUSSION: In a study, fluconazole (a moderate CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oveporexton by 2.9-fold and 1.5-fold, respectively. Oveporexton half-life was increased by about 2-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Pyrotinib (> 80 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: Pyrotinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of pyrotinib.(1)
CLINICAL EFFECTS: Concurrent use of pyrotinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of pyrotinib, including hepatotoxicity, decreased left ventricular ejection fraction, bone marrow suppression and gastrointestinal adverse effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of pyrotinib states coadministration with moderate CYP3A4 inhibitors requires a dose adjustment. Reduce the dose of pyrotinib to 80 mg daily with moderate CYP3A4 inhibitors.(1)
DISCUSSION: In a clinical study of healthy subjects, coadministration of pyrotinib with fluconazole, a moderate CYP3A4 inhibitor, resulted in a 3.6-fold increase in area-under-curve (AUC) and a 2.16-fold increase in maximum concentration (Cmax).(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Ranolazine (> 500 Mg Bid)
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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ranolazine. Verapamil may also increase the absorption of ranolazine by inhibiting P-glycoprotein.(1)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of and clinical effects from ranolazine. Elevated ranolazine levels may result in QTc prolongation, which may result in life-threatening cardiac arrhythmia, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of ranolazine states that the dosage of ranolazine should be limited to 500 mg twice daily in patients receiving moderate inhibitors of CYP3A4.(1) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Concurrent use of diltiazem, a moderate inhibitor of CYP3A4, at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000 mg twice daily) by 50% and 130%, respectively.(1,4) In healthy subjects, concurrent ranolazine (1000 mg twice daily) had no effects on the pharmacokinetics of diltiazem (60 mg three times daily).(1) Concurrent use of verapamil (120 mg three times daily) increased plasma levels of ranolazine (750 mg twice daily) by 100%.(1) In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg three times daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine IR steady state, diltiazem increased ranolazine IR area under the curve (AUC) by 85%, on average, and increased maximum concentration (Cmax) by 1.9-fold and minimum concentration (Cmin) by 2.1-fold.(4) In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine steady state, diltiazem increased ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%, on average, respectively.(4) In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or 240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR, 1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine half-lives did not show any consistent trend of changes with increasing doses of diltiazem.(4) In a study of patients with severe chronic angina, the addition of ranolazine 750 mg twice daily or 1,000 mg twice daily along with their standard dose of diltiazem (180 mg once daily) provided additional antianginal relief, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.(5) Ranolazine-induced QTc prolongation is dose and concentration-related.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(1,3,6,7)
Moderate Cyp3a4 Inhibitors/Remibrutinib
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: Remibrutinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of remibrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from remibrutinib, including bleeding.(1)
PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in older patients (65 years and over) and patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).
PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients taking remibrutinib.(1)
DISCUSSION: Remibrutinib maximum concentration (Cmax) is predicted to increase by approximately 1.9-fold and area-under-curve (AUC) is predicted to increase by approximately 2.3-fold following concomitant administration with erythromycin (a moderate CYP3A4 inhibitor) 500 mg four times a day for 7 days. Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Rilzabrutinib
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: Rilzabrutinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of rilzabrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from rilzabrutinib, including hepatotoxicity and immunosuppression.(1)
PREDISPOSING FACTORS: Patients with moderate to severe hepatic impairment (Child-Pugh class B-C) may be more susceptible to the effects of this drug interaction due to the potential for increased rilzabrutinib exposure.(1)
PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients taking rilzabrutinib. If concurrent use cannot be avoided and the CYP3A4 inhibitor will be used short term (i.e., less than 7 days), interrupt treatment with rilzabrutinib.(1)
DISCUSSION: Concurrent use of rilzabrutinib with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil) is predicted to increase rilzabrutinib Cmax and AUC by 3-fold at steady state.(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Taletrectinib
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: Taletrectinib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of taletrectinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels and toxicity from taletrectinib including hepatotoxicity, myalgia, and prolongation of the QT interval, which may result in life-threatening arrhythmia and death.(1))
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Taletrectinib should be taken on an empty stomach. Administration with food may increase the risk of QT prolongation or torsade de pointes.
PATIENT MANAGEMENT: The manufacturer of taletrectinib recommends avoiding concurrent administration with moderate CYP3A4 inhibitors.(1) If concurrent therapy cannot be avoided, adjust the frequency of monitoring as recommended in the prescribing information. Withhold taletrectinib if the QTc interval is >500 msec or the change from baseline is >60 msec.(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: Concomitant administration with moderate inhibitors of CYP3A4 (fluconazole, erythromycin, or verapamil) is predicted to increase taletrectinib area under the curve (AUC) up to 2.6-fold and maximum concentration (Cmax) up to 1.5-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, and voxelotor.(3)
Moderate Cyp3a4 Inhibitors/Ubrogepant (> 50 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)
DISCUSSION: Co-administration with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)
Moderate Cyp3a4 Inhibitors/Zidesamtinib
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: Moderate CYP3A4 inhibitors may inhibit the metabolism of zidesamtinib.(1)
CLINICAL EFFECTS: Concurrent use of zidesamtinib with moderate CYP3A4 inhibitors may result in elevated zidesamtinib levels and toxicities, including interstitial lung disease, pneumonitis, pancreatitis, myalgias, and QT prolongation, which may lead to potentially life-threatening cardiac arrhythmias like torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of zidesamtinib states that concurrent use of moderate CYP3A4 inhibitors should be avoided.(1) If concurrent use is warranted, monitor ECG and electrolytes when initiating zidesamtinib, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG and electrolyte monitoring. Withhold, then resume at same or reduced dose, or permanently discontinue zidesamtinib based on severity.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Zidesamtinib is a CYP3A4 substrate. In a study, itraconazole 200 mg daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of zidesamtinib by 2.6-fold and 1.8-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
P-Glycoprotein (P-Gp) Inhibitors/Topotecan
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: Inhibitors of P-glycoprotein may increase the absorption of topotecan.(1)
CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of P-glycoprotein may result in elevated levels of topotecan and signs of toxicity. These signs may include but are not limited to anemia, diarrhea, and thrombocytopenia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of topotecan states that the use of topotecan and P-glycoprotein inhibitors should be avoided. If concurrent use is warranted, carefully monitor patients for adverse effects.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)
DISCUSSION: In clinical studies, the combined use of elacridar (100 mg to 1000 mg) increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) Oral cyclosporine (15 mg/kg) increased the AUC of topotecan lactone and total topotecan to 2-fold to 3-fold of the control group, respectively.(1) P-gp inhibitors linked to this monograph include: adagrasib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, bosutinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, ginseng, hydroquinidine, imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir/glecaprevir, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)
Select P-Gp Inhibitors/Aumolertinib
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: Aumolertinib is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease elimination of aumolertinib.(1)
CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of aumolertinib which may increase the risk for cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, hematologic toxicity, and QT prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsade de pointes (TdP).(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of rhabdomyolysis.
PATIENT MANAGEMENT: The manufacturer of aumolertinib states concomitant administration of aumolertinib should be avoided with P-gp inhibitors.(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: Based on in vitro data, aumolertinib is a substrate of P-gp.(1) P-gp inhibitors linked to this interaction are: abrocitinib, asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, cobicistat, conivaptan, curcumin, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, grapefruit, imlunestrant, indinavir, isavuconazole, itraconazole, ivacaftor, josamycin, ketoconazole, mifepristone, neratinib, nirmatrelvir, pirtobrutinib, ritonavir, telaprevir, tepotinib, tezacaftor, tipranavir, tucatinib, valbenazine, velpatasvir, verapamil, vimseltinib, voclosporin, and voxilaprevir.(3)
Selected Cyp3a4 Moderate Inhibitors/Lurasidone (> 80 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: Moderate CYP3A4 inhibitors may inhibit the metabolism of lurasidone.(1)
CLINICAL EFFECTS: Concomitant use of lurasidone with inhibitors of CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism or other lurasidone toxicities.(1)
PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls or swallowing disorders, and patients with Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects.(1)
PATIENT MANAGEMENT: The US manufacturer of lurasidone states that the dose of lurasidone should not exceed 80 mg daily if coadministered with moderate CYP3A4 inhibitors.(1) If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor is added to therapy, the dose of lurasidone should be decreased by 50% of the original dose.(1) If a patient is currently on a moderate CYP3A4 inhibitor and lurasidone is added to therapy, the recommended starting dose of lurasidone is 20 mg per day.(1)
DISCUSSION: Pretreatment with diltiazem (240 mg daily for 5 days), another moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1) Agents linked to this monograph include berotralstat, clofazimine, conivaptan, crizotinib, dronedarone, duvelisib, fedratinib, fluvoxamine, imatinib, isavuconazole, letermovir, nilotinib, nirogacestat, rilzabrutinib, stiripentol, and tofisopam.(2,3)
Selected Strong And Moderate Cyp3a4 Inhibitors/Cisapride
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 and moderate CYP3A4 inhibitors impair the CYP3A4 mediated metabolism of cisapride.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from cisapride, including life-threatening cardiac arrhythmias such as torsades de pointes.(1-2)
PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Concurrent use of strong or moderate CYP3A4 inhibitors with cisapride is contraindicated. Use alternative antiemetics, or an alternative to the strong or moderate CYP3A4 inhibitor, whichever is more clinically appropriate. The US manufacturer of itraconazole states that concurrent administration with cisapride is contraindicated during and two weeks after itraconazole treatment.(4) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(5) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, atazanavir, avacopan, ciprofloxacin, clofazimine, conivaptan, darunavir, erythromycin, fosamprenavir, rilzabrutinib, and treosulfan.(5)
Slt Strong & Moderate 3A4 Inhibitors/Cilostazol (>50 Mg Bid)
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 and moderate inhibitors of CYP3A4 may inhibit the metabolism of cilostazol.(1)
CLINICAL EFFECTS: The concurrent use of cilostazol and strong and moderate inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may produce increased effects of cilostazol and adverse effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP3A4.(1)
DISCUSSION: In a study in 16 healthy males, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the maximum concentration (Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%, respectively. The Cmax and AUC of 4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(2) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%. Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%.(1) In a study, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the Cmax and AUC of cilostazol by 47% and 73%, respectively. The AUC of 4'-trans-hydroxy-cilostazol was increased by 141%.(1) In an vitro study in human liver microsomes, ketoconazole inhibited the metabolism of cilostazol.(3)
Strong And Moderate Cyp3a4 Inhibitors/Asunaprevir
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: Inhibitors of CYP3A4 may inhibit the metabolism of asunaprevir.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from asunaprevir.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use strong or moderate CYP3A4 inhibitors with asunaprevir is contraindicated.(1)
DISCUSSION: Asunaprevir is a sensitive CYP3A4 substrate. Sensitive substrates would be expected to have an area-under-curve (AUC) ratio of at least 5-fold.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, clarithromycin, ceritinib, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)
Strong And Moderate Cyp3a4 Inhibitors/Elacestrant
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: Inhibitors of CYP3A4 may inhibit the metabolism of elacestrant.(1)
CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases elacestrant plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of elacestrant states avoid concomitant use of strong or moderate CYP3A4 inhibitors with elacestrant.(1) The US manufacturer of elacestrant does not provide dose modification recommendations with strong and moderate CYP3A4 inhibitors. The Australian and UK manufacturers state concomitant use of strong or moderate CYP3A4 inhibitors should be avoided and an alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If concomitant use of a strong CYP3A4 inhibitor is unavoidable, the elacestrant dose should be reduced to 172 mg once daily with careful monitoring of tolerability. Subsequent dose reduction to 86 mg once daily may be considered with moderate CYP3A4 inhibitors based on tolerability. If the CYP3A4 inhibitor is discontinued, the elacestrant dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 5 half-lives of the CYP3A4 inhibitor).(2,3)
DISCUSSION: Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased elacestrant area-under-curve (AUC) and maximum concentration (Cmax) by 5.3-fold and 4.4-fold, respectively.(1) Coadministration of fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase elacestrant AUC and Cmax by 2.3-fold and 1.6-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)
Strong And Moderate Cyp3a4 Inhibitors/Infigratinib
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: Inhibitors of CYP3A4 may inhibit the metabolism of infigratinib.(1)
CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases infigratinib plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with infigratinib.(1)
DISCUSSION: Coadministration of multiple doses of itraconazole (a strong CYP3A4 inhibitor) increased infigratinib area-under-curve (AUC) and maximum concentration (Cmax) by 622% and 164%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)
Strong And Moderate Cyp3a4 Inhibitors/Lemborexant
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: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of strong or moderate CYP3A4 inhibitors with lemborexant should be avoided.(1)
DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)
Strong And Moderate Cyp3a4 Inhibitors/Nirogacestat
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: Inhibitors of CYP3A4 may inhibit the metabolism of nirogacestat.(1)
CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases nirogacestat plasma concentrations, which may increase the incidence and severity of adverse reactions, including hepatotoxicity, diarrhea, hypokalemia, and hypophosphatemia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with nirogacestat.(1)
DISCUSSION: In a study, itraconazole (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of nirogacestat by 8.2-fold and 2.5-fold, respectively, following a single 100 mg dose of nirogacestat. In a PKPB model, nirogacestat AUC was predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with itraconazole, ketoconazole and clarithromycin (strong CYP3A inhibitors), respectively.(1) In a PKPB model, nirogacestat AUC was predicted to increase 2.73-and 3.18-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole (moderate CYP3A inhibitor), respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2)
Strong And Moderate Cyp3a4 Inhibitors/Repotrectinib
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: Inhibitors of CYP3A4 may inhibit the metabolism of repotrectinib.(1)
CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases repotrectinib plasma concentrations, which may increase the incidence and severity of adverse reactions, including CNS effects (dizziness, ataxia, cognitive disorders), interstitial lung disease/pneumonitis, hepatotoxicity, and myalgia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with repotrectinib. Discontinue CYP3A4 inhibitors for 3 to 5 half lives of the inhibitor prior to initiating repotrectinib.(1)
DISCUSSION: In a study, itraconazole (a strong CYP3A4 and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of repotrectinib by 5.9-fold and 1.7-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)
Strong Or Moderate Cyp3a4 Inhibitors/Flibanserin
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: Flibanserin is primarily metabolized by CYP3A4, though CYP2C19 also plays a role in metabolism.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from flibanserin, including severe hypotension or syncope.(1)
PREDISPOSING FACTORS: Patients with any degree of hepatic impairment, who are poor CYP2C19 metabolizers, or who also receive concomitant therapy with strong CYP2C19 inhibitors are expected to have increased systemic concentrations of flibanserin, adding to the risk for hypotension or syncopal episodes.(1) Hypotensive or syncopal episodes are more common when flibanserin is taken during waking hours.(1)
PATIENT MANAGEMENT: The concomitant use of flibanserin with moderate or strong CYP3A4 inhibitors significantly increases flibanserin concentrations which may lead to hypotension and syncope. The manufacturer of flibanserin states moderate or strong CYP3A4 inhibitors are contraindicated.(1) If the benefit of initiating a CYP3A4 inhibitor within 2 days of stopping flibanserin clearly outweighs the risk flibanserin-associated hypotension or syncope, monitor and counsel the patient regarding symptoms of hypotension or syncope. Discontinue moderate or strong CYP3A4 inhibitors for 2 weeks before initiating or restarting flibanserin therapy.(1)
DISCUSSION: In a drug interaction study with 15 healthy subjects, the combination of flibanserin (100 mg on day 6) and fluconazole (a moderate CYP3A4 and strong CYP2C19 inhibitor, 400 mg once then 200 mg daily for 5 days) resulted in an increased flibanserin exposure of 7-fold. Hypotension or syncope requiring supine placement with leg elevation occurred in 3 subjects (20%). One patient became unresponsive with a blood pressure of 64/41 mm Hg and required emergency room treatment where she required intravenous saline.(1) Though the combination has not been studied, a similar result is plausible with voriconazole, a strong CYP3A4 inhibitor and moderate CYP2C19 inhibitor.(1) In a drug interaction study with flibanserin 50 mg (one-half of the recommended dose) and ketoconazole 400 mg, flibanserin exposure increased 4.5-fold. One of 24 patients(4%) developed syncope.(1) A study of 12 healthy men and women on itraconazole (400 mg once then 200 mg daily for 4 days) with flibanserin 50 mg given 2 hours after itraconazole found that flibanserin exposure was increased 2.6-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)
Strong Or Moderate Cyp3a4 Inhibitors/Lomitapide
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: Lomitapide is primarily metabolized via CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from lomitapide.(1)
PREDISPOSING FACTORS: The interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)
PATIENT MANAGEMENT: Given the magnitude of this interaction and the potential toxicity of lomitapide, moderate and strong CYP3A4 inhibitors are contraindicated.(1) When possible use an alternative to the CYP3A4 inhibitor. If a moderate or strong CYP3A4 inhibitor is required, discontinue lomitapide. Due to its long half-life, it will take 1 to 2 weeks for remaining lomitapide to be eliminated; thus lomitapide adverse effects could occur after discontinuation. The US manufacturer of itraconazole states that concurrent use with lomitapide is contraindicated during and two weeks after itraconazole treatment.(4)
DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased lomitapide area-under-curve (AUC) by 27-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1-3,5) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, lefamulin, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Moderate Cyp3a4 Inhibitors/Brigatinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Brigatinib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of brigatinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels and toxicity from brigatinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of brigatinib states to avoid concurrent administration with moderate CYP3A4 inhibitors. If concurrent therapy cannot be avoided, reduce the once daily dose of brigatinib by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg). Upon discontinuation of a moderate CYP3A4 inhibitor, resume the brigatinib dose that was tolerated prior to initiating the moderate CYP3A4 inhibitor.(1) Monitor patient for signs of brigatinib toxicity with concurrent use.
DISCUSSION: Brigatinib is a substrate of CYP3A4.(1) Concurrent administration of itraconazole (200 mg twice daily, a strong CYP3A4 inhibitor) with a single 90 mg dose of brigatinib increased the brigatinib maximum concentration (Cmax) by 21% and area-under-curve (AUC) by 101% compared to brigatinib alone. Moderate CYP3A4 inhibitors are expected to increase the AUC of brigatinib by approximately 40%.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)
Moderate Cyp3a4 Inhibitors/Cariprazine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cariprazine and its major active metabolite DDCAR are metabolized by CYP3A4.(1-4)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from cariprazine.(1-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors with cariprazine. The US manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors requires a dose adjustment. If a moderate CYP3A4 inhibitor is initiated in a patient on a stable dose of cariprazine, the following dose adjustments are recommended: -If current cariprazine dose is 1.5 or 3 mg daily: Decrease cariprazine dose to 0.75 mg daily. -If current cariprazine dose is 4.5 or 6 mg daily: Decrease cariprazine dose to 1.5 mg daily. In adult patients taking a moderate CYP3A4 inhibitor when cariprazine is started, the following dose adjustments are recommended: -For schizophrenia or bipolar mania: Start cariprazine dose at 0.75 mg daily; increase to 1.5 mg daily, if needed. -For bipolar depression or adjunctive therapy for treatment of Major Depressive Disorder (MDD): Start cariprazine dose at 0.75 mg daily.(1) -Initiating cariprazine is not recommended in pediatric patients while taking a moderate CYP3A4 inhibitor.(1) Cariprazine has two active metabolites, DCAR and DDCAR which have similar in vitro activity and potency. However, DDCAR has a longer half-life (1-3 weeks) than cariprazine (2-4 days), resulting in systemic DDCAR concentrations that are about 4-fold higher than cariprazine. Thus although interaction onset may begin within a few days, the full effect of inhibition may not be seen for 4 or more weeks. When the inhibitor is discontinued, cariprazine, DCAR and DDCAR will begin to fall and the dosage may need be increased. Monitor for decreased effectiveness for 4 or more weeks. The Australian, and Canadian manufacturers of cariprazine state that concurrent use of moderate CYP3A4 inhibitors is contraindicated.(2,3) The UK manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors may require a dose adjustment.(4) The Canadian manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors is also contraindicated for at least 2 weeks after cariprazine discontinuation.(3)
DISCUSSION: In an interaction study, coadministration of ketoconazole 400 mg/day with cariprazine 0.5 mg/day increased cariprazine exposure (AUC, area-under-curve) 4-fold and increased DDCAR AUC about 1.5-fold.(1) In a PKPB model, coadministration of ketoconazole 400 mg/day with cariprazine 0.5 mg/day is predicted to increase cariprazine concentration maximum (Cmax) and AUC by 5.5-fold and 6-fold, respectively. Coadministration of fluconazole 200 mg/day with cariprazine 0.5 mg/day is predicted to increased cariprazine Cmax and AUC by up to 3-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(5,6)
Moderate Cyp3a4 Inhibitors/Cobimetinib; Olaparib; Sonidegib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of cobimetinib, olaparib, and sonidegib.(1-4)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for adverse effects from cobimetinib, olaparib, or sonidegib.(1-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors in patients receiving cobimetinib, olaparib, or sonidegib.(1-4) For patients taking cobimetinib 60 mg daily, if concurrent short term use (14 days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce cobimetinib dose to 20 mg daily. After discontinuation of the moderate CYP3A4 inhibitor resume the previous 60 mg dose. Patients who are taking cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong CYP3A4 inhibitor.(1) If concomitant use with olaparib cannot be avoided, reduce the olaparib dose. Dosage adjustments are specific to the formulation of olaparib.(2,3) Reduce the dosage of the CAPsule formulation to 200 mg (four 50 mg CAPsules) taken twice daily.(2) Reduce the dosage of the TABlet formulation to 150 mg (one 150 mg TABlet) twice daily). If the CYP3A4 inhibitor is discontinued, resume the dose of olaparib taken prior to initiation of the CYP3A4 inhibitor after 3 to 5 half-lives.(3) If sonidegib and a moderate CYP3A4 inhibitor must be used, administer the moderate CYP3A4 inhibitor for less than 14 days and monitor closely for adverse effects, particularly musculoskeletal adverse reactions.(4)
DISCUSSION: In an interaction study, itraconazole (a strong CYP3A4 inhibitor) given 200 mg once daily for 14 days followed by a single dose of cobimetinib 10 mg increased mean cobimetinib AUC 6.7-fold (90% CI 5.6, 8.0). Subsequent simulations showed that predicted steady-state concentrations of cobimetinib at a reduced daily dose of 20 mg given with short term use of a moderate CYP3A4 inhibitor were similar to observed steady-state concentrations at the 60 mg dose without an inhibitor.(1) In simulations using physiologically-based pharmacokinetic (PBPK) models, concurrent use of fluconazole, a moderate CYP3A4 inhibitor, may increase the area-under-curve (AUC) of olaparib by 2.2-fold.(2,3) Based upon PBPK simulations, sonidegib mean steady-state AUC would increase 1.8-fold if administered with a moderate CYP3A4 inhibitor for 14 days and would further increase to 2.8-fold if the moderate CYP3A4 inhibitor is coadministered with sonidegib for 4 months.(4) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, schisandra, rilzabrutinib, stiripentol, tofisopam, treosulfan, and verapamil.(5)
Moderate Cyp3a4 Inhibitors/Colchicine (For Cardioprotection)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1,2)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2)
PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1,2)
PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for signs of colchicine toxicity. Avoid concurrent use in patients with existing renal or hepatic impairment.(1) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting.
DISCUSSION: There is one case report of colchicine toxicity with concurrent erythromycin.(4) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 18 subjects, pretreatment with ritonavir (100 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, and treosulfan.(1,5,6)
Moderate Cyp3a4 Inhibitors/Colchicine (For Gout & Fmf)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of colchicine(1-3)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1-3)
PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1-3)
PATIENT MANAGEMENT: Avoid use of colchicine concurrently with or within 14 days of taking moderate CYP3A4 inhibitors (without ritonavir). If concurrent use is unavoidable, the dosage of colchicine should be reduced.(1-3) For gout flares, the recommended dosage is 1.2 mg (2 tablets) for one dose. This dose should be repeated no earlier than in 3 days.(1-4) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg twice daily or 0.6 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg daily.(1-4) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a day).(1-4) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting.
DISCUSSION: Fluconazole (400 mg loading dose followed by 200 mg daily for 4 days) increased the area-under-curve (AUC) of colchicine by 40%.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, and treosulfan.(1,5,6)
Moderate Cyp3a4 Inhibitors/Elexacaftor-Tezacaftor-Ivacaftor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the CYP3A4-mediated metabolism of elexacaftor, tezacaftor, and ivacaftor.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from elexacaftor, tezacaftor, and ivacaftor.(1)
PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)
PATIENT MANAGEMENT: The dosage of elexacaftor-tezacaftor-ivacaftor should be reduced when co-administered with moderate CYP3A4 inhibitors as follows: - In patients 12 years and older and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - two tablets of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg (total dose of elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg); Day 2 - one tablet of ivacaftor 150 mg. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - two tablets of elexacaftor 50 mg-tezacaftor 25 mg-ivacaftor 37.5 mg (total daily dose of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg); Day 2 - one tablet of ivacaftor 75 mg. - In patients 2 to less than 6 years old weighing at least 14 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - one packet of oral granules containing elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg; Day 2 - one packet of oral granules containing ivacaftor 75 mg.(1) - In patients 2 to less than 6 years old weighing less than 14 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - one packet of oral granules containing elexacaftor 80 mg-tezacaftor 40 mg-ivacaftor 60 mg; Day 2 - one packet of oral granules containing ivacaftor 59.5 mg.(1)
DISCUSSION: In a study, fluconazole (400 mg on day 1 then 200 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of ivacaftor (150 mg every 12 hours) by 2.95-fold and 2.45-fold, respectively.(1) Simulations suggest that moderate CYP3A inhibitors may increase the AUC of elexacaftor and tezacaftor by approximately 1.9 to 2.3-fold and 2.1-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)
Moderate Cyp3a4 Inhibitors/Entrectinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of entrectinib.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of entrectinib, such as QT prolongation, hepatotoxicity, CNS effects, hyperuricemia, anemia, or neutropenia.(1,2) Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: The US manufacturer of entrectinib states that entrectinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If concurrent therapy cannot be avoided, reduce the entrectinib dose as follows for adult and pediatric patients 2 years and older: -If the starting dose is 600 mg, reduce the entrectinib dose to 200 mg daily. -If the starting dose is 400 mg, reduce the entrectinib dose to 200 mg daily. -If the starting dose is 300 mg, reduce the entrectinib dose to 100 mg daily. -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg daily.(1) For pediatric patients less than 2 years old, avoid coadministration with moderate CYP3A4 inhibitors.(1) If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the entrectinib dose to the dose that was used before starting the inhibitor after three to five plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST and ALT. Advise patients to immediately report any symptoms of hepatotoxicity. During concomitant therapy with a moderate CYP3A4 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. The Australian manufacturer of entrectinib states that entrectinib coadministration with moderate inhibitors of CYP3A4 should be avoided. If concurrent therapy with a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of entrectinib to 200 mg once daily.(4) If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the entrectinib dose to the dose that was used before starting the inhibitor after three to five plasma half-lives of the moderate CYP3A4 inhibitor.(4)
DISCUSSION: Coadministration of itraconazole (strong CYP3A4 inhibitor) with a single 100 mg entrectinib dose increased entrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1) Coadministration of a moderate CYP3A4 inhibitor with entrectinib is predicted to increase entrectinib Cmax and AUC by 2.9-fold and 3-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, ciprofloxacin, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,5)
Moderate Cyp3a4 Inhibitors/Ergot Alkaloids
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of ergot alkaloids.
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of the ergot alkaloid, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.
PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of ergot alkaloids may be at a higher risk of adverse effects from this combination.
PATIENT MANAGEMENT: When possible, avoid the concurrent use of moderate CYP3A4 inhibitors in patients taking ergot alkaloids. If concurrent use is warranted, consider reducing the dose of the ergot alkaloid during concurrent therapy. Patients receiving concurrent therapy should be monitored for and instructed to report any signs of ergotism.
DISCUSSION: Coadministration of dihydroergotamine and ergotamine with potent inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir, nelfinavir, ritonavir, and troleandomycin has resulted in ergotism, characterized by vasospasm and ischemia of the extremities. Inhibition of ergot alkaloid metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, tofisopam, treosulfan and verapamil.
Moderate Cyp3a4 Inhibitors/Gepotidacin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Gepotidacin is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of gepotidacin.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels and toxicity from gepotidacin,(1) including diarrhea, nausea, abdominal pain and prolongation of the QT interval, which may result in life-threatening arrhythmia and death.
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of gepotidacin states that concomitant use of moderate CYP3A4 inhibitors in patients being treated for uncomplicated urogenital gonorrhea should be avoided.(1) For patients being treated for uncomplicated UTI, no dosage adjustment is needed when taken with moderate CYP3A4 inhibitors.(1)
DISCUSSION: Gepotidacin is primarily metabolized by CYP3A4.(1) Concomitant administration of fluconazole (moderate CYP3A4 inhibitor) and single 1,500 mg dose of gepotidacin is predicted to increase gepotidacin maximum concentration (Cmax) by 1.3-fold and area-under-curve (AUC) by 1.5-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Iberdomide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Iberdomide is primarily metabolized by CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of iberdomide.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of iberdomide, including thromboembolic events and hematologic abnormalities (neutropenia, thrombocytopenia).(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of iberdomide states that concomitant use of moderate CYP3A4 inhibitors should be avoided. If concomitant use with moderate CYP3A4 inhibitors cannot be avoided, reduce iberdomide dose to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle.(1)
DISCUSSION: In a PBPK model in patients with cancer, iberdomide area-under-curve (AUC) was predicted to be increased by 1.7-fold and maximum concentration (Cmax) by 1.5-fold following concomitant use with fluconazole or diltiazem (moderate CYP3A4 inhibitors).(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Ivabradine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ivabradine. Increased levels of ivabradine may cause ivabradine-induced reduction in heart rate which can contribute to increased QT prolongation risk.(1-3)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors may result in elevated levels of and toxicity from ivabradine including a reduction in heart rate which can contribute to QT prolongation or torsades de pointes.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: The US manufacturer of ivabradine states that concurrent use of moderate inhibitors of CYP3A4, including diltiazem and verapamil, should be avoided.(1) The Australian and UK manufacturers of ivabradine state that concurrent use of diltiazem or verapamil is contraindicated but that other moderate inhibitors of CYP3A4 may be considered with monitoring of heart rate and with a starting dose of 2.5 mg ivabradine twice daily if resting heart rate is above 70 bpm.(2-3) Monitor patients receiving concurrent therapy for bradycardia (heart rate less than 50 bpm), dizziness, fatigue, hypotension, and/or symptoms of atrial fibrillation (heart palpitations, chest pressure, shortness of breath).
DISCUSSION: Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma exposure by 7- to 8-fold. Concurrent use of moderate CYP3A4 inhibitors diltiazem and verapamil increased ivabradine area-under-curve (AUC) by 2- to 3-fold and reduced heart rate by an additional 5 bpm.(2) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(5)
Moderate Cyp3a4 Inhibitors/Lirafugratinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Lirafugratinib is primarily metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of lirafugratinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of lirafugratinib, including ocular toxicities (retinal pigment epithelial detachment, blurred vision, corneal keratitis) and hyperphosphatemia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use of moderate CYP3A4 inhibitors with lirafugratinib. If concomitant use cannot be avoided, reduce the dosage of lirafugratinib to 50 mg once daily. If the CYP3A4 inhibitor is discontinued, resume the prior dosage of lirafugratinib after 3 elimination half-lives of the inhibitor.(1)
DISCUSSION: In a pharmacokinetic model, erythromycin 500 mg four times daily for 15 days was predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of lirafugratinib by 1.7-fold and 1.1-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Lurbinectedin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of lurbinectedin.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors with lurbinectedin may increase systemic exposure and the risk for toxicities such as myelosuppression, hepatotoxicity, neuropathy, fatigue, nausea, and musculoskeletal pain.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of lurbinectedin states that the concurrent use of lurbinectedin with moderate CYP3A4 inhibitors should be avoided. If the use of a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of lurbinectedin by 50%. After discontinuation of the moderate CYP3A4 inhibitor for 5 half-lives of the inhibitor, resume the lurbinectedin dose used before starting the inhibitor.(1)
DISCUSSION: Itraconazole (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4-fold.(1) In a study including data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents, lurbinectedin clearance decreased by 30%, area-under-curve (AUC) increased by 42%, and concentration maximum (Cmax) increased by 7% when coadministered with a CYP3A inhibitor.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Mavacamten
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may decrease the metabolism of mavacamten.(1-3)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the plasma levels and the incidence and severity of adverse reactions of mavacamten.(1-3)
PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1-3)
PATIENT MANAGEMENT: The US manufacturer of mavacamten recommend initiating mavacamten at the recommended starting dosage in patients who are on stable therapy with a moderate CYP3A4 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(1) Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients who are on stable treatment with the lowest recommended dose of mavacamten because a lower dose is not available.(1) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the strong CYP3A4 inhibitor. After therapy with the strong CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(1) The Canadian manufacturer of mavacamten recommends additional monitoring when concurrent use of moderate CYP3A4 inhibitors is warranted. Adjust the dose of mavacamten based on clinical assessment.(2) The UK manufacturer of mavacamten states no dose adjustment is necessary when starting mavacamten in patients on moderate CYP3A4 inhibitors or in intermediate, normal, rapid, or ultra-rapid CYP2C19 metabolizers already on mavacamten and starting a moderate CYP3A4 inhibitor. If starting a moderate CYP3A4 inhibitor in a patient who is a poor CYP2C19 metabolizer, reduce mavacamten 5 mg to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule.(3)
DISCUSSION: Concomitant use of mavacamten (25 mg) with verapamil sustained release (240 mg), a moderate CYP3A4 inhibitor, increased mavacamten area-under-curve (AUC) by 15% and maximum concentration (Cmax) by 52% in intermediate metabolizers and normal metabolizers of CYP2C19.(1) Concomitant use of mavacamten with diltiazem, a moderate CYP3A4 inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten AUC and Cmax up to 55% and 42%, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, ciprofloxacin, clofazimine, conivaptan, darunavir, dronedarone, erythromycin, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, schisandra, tofisopam, and treosulfan.(1-5)
Moderate Cyp3a4 Inhibitors/Mitapivat (100 Mg)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1-2)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1-2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of mitapivat 100 mg tablets states that concurrent use with moderate CYP3A4 inhibitors should be avoided.(1) The Middle Eastern prescribing information for mitapivat states that alternative therapies that are not moderate CYP3A4 inhibitors should be considered during treatment with mitapivat. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily. Patients should be monitored for adverse reactions.(2)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 100 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.7-fold and 1.7-fold, respectively.(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3-4)
Moderate Cyp3a4 Inhibitors/Mobocertinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mobocertinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from mobocertinib.(1) Elevated levels of mobocertinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients undergoing therapy with mobocertinib.(1) If concurrent therapy with a moderate CYP3A4 inhibitor is warranted, reduce the dose of mobocertinib by approximately 50% (ie, 160 to 80 mg, 120 to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently. After the moderate CYP3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives, resume mobocertinib at the dose taken prior to initiating the moderate CYP3A4 inhibitor. Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Increase the frequency of ECG monitoring in patients with risk factors for QTc prolongation, including congenital long QT syndrome, heart disease, or electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation during mobocertinib therapy, dose modifications are recommended: - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the same dose. - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60 msec from baseline) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 and recurrence: permanently discontinue mobocertinib. - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.
DISCUSSION: Coadministration of mobocertinib with multiple doses of a moderate CYP3A inhibitor is predicted to increase the steady-state combined molar area-under curve (AUC) of mobocertinib and its active metabolites by approximately 100 to 200%.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Naloxegol (<= 12.5 Mg)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)
PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)
PATIENT MANAGEMENT: Avoid the use of moderate inhibitors of CYP3A4 in patients who require therapy with naloxegol. If concurrent use cannot be avoided, the daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) Monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)
DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)
Moderate Cyp3a4 Inhibitors/Omaveloxolone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of omaveloxolone.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from omaveloxolone including hepatotoxicity and hyperlipidemia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with omaveloxolone should be avoided. If concurrent use cannot be avoided, reduce the omaveloxolone dosage to 100 mg daily and monitor closely. If adverse reactions emerge, reduce the dose to 50 mg once daily.(1)
DISCUSSION: Coadministration of omaveloxolone with verapamil (a moderate CYP3A4 inhibitor) increased both the concentration maximum (Cmax) and area-under-curve (AUC) of omaveloxolone by 1.25-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Pexidartinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of pexidartinib.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If coadministration with a moderate CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.
DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3)
Moderate Cyp3a4 Inhibitors/Pexidartinib (200 Mg)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of pexidartinib.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If coadministration with a moderate CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 800 mg, modify the total daily dose to 400 mg by administering 200 mg twice daily. If the planned total daily dose is currently 600 mg, modify the total daily dose to 400 mg by administering 200 mg twice daily. If the planned total daily dose is currently 400 mg, modify the total daily dose to 200 mg by administering 200 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.
DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3)
Moderate Cyp3a4 Inhibitors/Selpercatinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of selpercatinib.(1) Cimetidine increases gastric pH and may decrease pH-dependent solubility and absorption of selpercatinib.(1)
CLINICAL EFFECTS: Concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from selpercatinib.(1) Elevated levels of selpercatinib may increase the risk of QTc prolongation and potentially life-threatening arrhythmias, including torsades de pointes, hepatotoxicity, hypertension, and severe or life-threatening hemorrhagic events.(1) Conversely, concurrent use of cimetidine may result in decreased levels and effectiveness of selpercatinib. The overall effect of cimetidine on selpercatinib pharmacokinetics is unknown.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of selpercatinib recommends avoiding concomitant use of moderate CYP3A4 inhibitors with selpercatinib. If concomitant use cannot be avoided, reduce the dose of selpercatinib as follows: - If the current dose of selpercatinib is 160 mg twice daily, decrease the dose to 120 mg twice daily. - If the current dose of selpercatinib is 120 mg twice daily, decrease the dose to 80 mg twice daily. - If the current dose of selpercatinib is 80 mg twice daily, decrease the dose to 40 mg twice daily. - If the current dose of selpercatinib is 40 mg three times daily, decrease the dose to 40 mg once daily. If concomitant use of cimetidine is unavoidable, take selpercatinib at least 2 hours before or 10 hours after cimetidine. When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If grade 3 QT interval prolongation occurs, withhold selpercatinib until recovery to baseline or Grades 0 or 1, then resume selpercatinib at a reduced dose. If grade 4 QT interval prolongation occurs, discontinue selpercatinib.(1) After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume selpercatinib at the dose taken prior to initiating the CYP3A inhibitor.(1)
DISCUSSION: Coadministration of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib by 60-99% and 46-76%, respectively.(1) In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec). An increase in QTcF interval to greater than 500 msec was measured in 6% of patients and an increase in the QTcF interval of at least 60 msec over baseline was measured in 15% of patients.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3)
Moderate Cyp3a4 Inhibitors/Sonrotoclax
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors inhibit the metabolism of sonrotoclax.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of sonrotoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)
PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include higher tumor burden such as bulky lymphadenopathy or lymphocytosis and reduced renal function.(1)
PATIENT MANAGEMENT: Recommendations vary depending the stage of therapy. During sonrotoclax initiation and at the 1 mg and 2 mg dose of sonrotoclax ramp-up therapy, avoid moderate CYP3A4 inhibitors. Reduce all other ramp-up doses of sonrotoclax by at least 4-fold as follows: - If original sonrotoclax dose is 5 mg, reduce sonrotoclax dose to 1 mg. - If original sonrotoclax dose is 10 mg, reduce sonrotoclax dose to 2 mg. - If original sonrotoclax dose is 20 mg, reduce sonrotoclax dose to 5 mg. - If original sonrotoclax dose is 40 mg, reduce sonrotoclax dose to 10 mg. - If original sonrotoclax dose is 80 mg, reduce sonrotoclax dose to 20 mg. - If original sonrotoclax dose is 160 mg, reduce sonrotoclax dose to 40 mg. - If original sonrotoclax dose is 320 mg, reduce sonrotoclax dose to 80 mg. In patients taking the target daily dose of sonrotoclax after the ramp-up phase who start a moderate CYP3A4 inhibitor, decrease sonrotoclax daily dose to 80 mg. Monitor for tumor lysis syndrome, hematologic and non-hematologic toxicity and adjust dosage as directed in prescribing information. If the moderate CYP3A4 inhibitor is discontinued, resume the prior (i.e., pre-inhibitor) sonrotoclax dose at least 5 days after discontinuation of the inhibitor.(1)
DISCUSSION: In a study, itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of sonrotoclax by 11-fold and 4-fold, respectively. Posaconazole (a strong CYP3A inhibitor) increased sonrotoclax AUC and Cmax by 13-fold and 7-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3-4)
Moderate Cyp3a4 Inhibitors/Suvorexant (> 10 Mg)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate and strong inhibitors of CYP3A4 may inhibit the metabolism of suvorexant.(1)
CLINICAL EFFECTS: Concurrent use of an agent that is a moderate or strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of suvorexant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of suvorexant recommends a starting dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving concomitant therapy with a moderate inhibitor of CYP3A4.(1) Concurrent use with strong inhibitors of CYP3A4 is not recommended.(1)
DISCUSSION: Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1) Ketoconazole, a strong inhibitor of CYP3A4, increased suvorexant area-under-curve (AUC) and maximum concentration (Cmax) by approximately 2.75-fold and 1.25-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)
Moderate Cyp3a4 Inhibitors/Tavapadon
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Tavapadon is primarily metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of tavapadon.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of tavapadon, including hypotension, altered impulse control, hallucinations, and dyskinesias.(1)
PREDISPOSING FACTORS: The risk of hallucinations appears to be increased in patients 65 years of age and older.
PATIENT MANAGEMENT: During tavapadon titration, concomitant use with moderate CYP3A4 inhibitors should be avoided. During tavapadon maintenance, if moderate CYP3A4 inhibitors are initiated, decrease the dosing frequency from once daily to every 3 days: - If the current dose of tavapadon is 5 mg daily, lower dosage to 5 mg every 3 days. - If the current dose of tavapadon is 10 mg daily, lower dosage to 10 mg every 3 days. - If the current dose of tavapadon is 15 mg daily, lower dosage to 15 mg every 3 days. If the CYP3A4 inhibitor is discontinued, resume the prior maintenance dosage of tavapadon and monitor patients for clinical response and tolerability.(1)
DISCUSSION: In a clinical study, fluconazole 200 mg daily was predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of tavapadon 15 mg by approximately 2.6-fold and 2.3-fold, respectively. When fluconazole is given with tavapadon once every 3 days, steady-state AUC and Cmax are predicted to fluctuate between +14% to -40% and +1 to -43%, respectively from Day 1 to Day 3 of the dosing interval, compared to tavapadon once daily alone.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Tazemetostat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of tazemetostat.(1)
CLINICAL EFFECTS: Coadministration of tazemetostat with a moderate CYP3A4 inhibitor may increase tazemetostat plasma concentrations and increase the frequency or severity of adverse reactions.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of tazemetostat states to avoid coadministration of moderate CYP3A4 inhibitors with tazemetostat.(1) If coadministration of moderate CYP3A4 inhibitors cannot be avoided, reduce the tazemetostat dose as follows: If the current tazemetostat dose is 800 mg twice daily, reduce the dose to 400 mg twice daily. If the current tazemetostat dose is 600 mg twice daily, reduce the dose to 400 mg for the first dose and 200 mg for the second dose. If the current tazemetostat dose is 400 mg twice daily, reduce the dose to 200 mg twice daily.(1) After discontinuation of the moderate CYP3A4 inhibitor for 3 elimination half-lives, resume the prior tazemetostat dose.(1)
DISCUSSION: Coadministration of fluconazole, a moderate CYP3A4 inhibitor, with tazemetostat 400 mg twice daily in patients increased tazemetostat area-under-curve (AUC) by 3.1-fold and maximum concentration (Cmax) by 2.3-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)
Moderate Cyp3a4 Inhibitors/Venetoclax
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors inhibit the metabolism of venetoclax.(1)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of venetoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)
PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include (1): - the ramp-up phase of venetoclax therapy when tumor burden is highest - initial magnitude of tumor burden - renal impairment The risk of venetoclax toxicities may be increased in patients with severe hepatic impairment.(1)
PATIENT MANAGEMENT: Avoid moderate CYP3A4 inhibitors and consider alternative treatments when possible. If a moderate CYP3A4 inhibitor must be used, reduce venetoclax dose by at least 50%. Monitor more closely for signs of toxicity such as tumor lysis syndrome, hematologic and non-hematologic toxicities.(1) Canadian labeling for atazanavir contraindicates concurrent use of atazanavir/ritonavir with venetoclax at venetoclax dose initiation and during the ramp-up phase.(2) If the moderate CYP3A4 inhibitor is discontinued, the manufacturer of venetoclax recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3 days after discontinuation of the moderate CYP3A4 inhibitor.
DISCUSSION: In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of venetoclax 2.3-fold and 6.4-fold respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3-4)
Moderate Cyp3a4 Inhibitors/Voclosporin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of voclosporin.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from voclosporin, including infection, neurotoxicity, nephrotoxicity, hypertension, or hyperkalemia.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The prescribing information for voclosporin states the use of moderate CYP3A4 inhibitors in patients undergoing therapy with voclosporin requires a dose adjustment. Voclosporin dose should be reduced to 15.8 mg in the morning and 7.9 mg in the evening.(1) Consider alternatives with no or minimal enzyme inhibition.
DISCUSSION: Concurrent use of voclosporin and ketoconazole 400 mg daily (strong CYP3A4 inhibitor) for 9 days increased the concentration maximum (Cmax) and area-under-curve (AUC) by 6.45-fold and 18.55-fold, respectively.(1) Concurrent use of voclosporin and verapamil 80 mg three times a day for 10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and AUC by 2.08-fold and 2.71-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
P-Glycoprotein (P-Gp) Inhibitors/Relugolix
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter. Inhibitors of P-gp may increase the absorption of relugolix.(1)
CLINICAL EFFECTS: The concurrent administration of relugolix with an inhibitor of P-glycoprotein may result in elevated levels of relugolix and adverse effects, including hot flashes, skin flushing, musculoskeletal pain, hyperglycemia, acute renal injury, transaminitis, arrhythmias, and hemorrhage.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of relugolix states that the coadministration of relugolix with P-gp inhibitors should be avoided. If the P-gp inhibitor is to be used short-term, relugolix may be held for up to 2 weeks. If treatment with relugolix is interrupted for longer than 7 days, resume relugolix with a loading dose of 360 mg on the first day, followed by 120 mg once daily.(1) If coadministration with a P-gp inhibitor cannot be avoided, relugolix should be taken at least 6 hours before the P-gp inhibitor. Monitor the patient more frequently for adverse events.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)
DISCUSSION: Coadministration of relugolix with erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 6.2-fold. Voriconazole (a strong CYP3A4 inhibitor) did not have a clinically significant effect on the pharmacokinetics of relugolix.(1) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil, mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline, schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)
Selected Cyp3a4 Inhibitors/Carbamazepine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the hepatic metabolism of carbamazepine.(1,2)
CLINICAL EFFECTS: Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine.
PREDISPOSING FACTORS: Simultaneous use of other drugs (i.e., other anticonvulsants) or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.
PATIENT MANAGEMENT: The manufacturer of carbamazepine states that CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(1) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient should be observed for signs of toxicity (dizziness, ataxia, blurred vision, or SIADH). The dosage of carbamazepine may need to be adjusted or carbamazepine may need to be discontinued.(1)
DISCUSSION: Carbamazepine is almost completely metabolized to carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged. Pharmacokinetic studies have indicated the major pathway for carbamazepine metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and CYP3A5.(1,2) In a randomized, cross-over study of ten seizure patients, the effects of grapefruit juice on the pharmacokinetics of carbamazepine were determined. Results indicate a statistically significant increase in serum concentrations and area under the concentration-time curve (AUC) in the grapefruit juice arm.(3) Selected CYP3A4 inhibitors linked to this monograph include: conivaptan, grapefruit, mibefradil, relacorilant, schisandra, and tofisopam.(4)
Selected Moderate Cyp3a4 Inhibitors/Alprazolam
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of alprazolam.(1)
CLINICAL EFFECTS: Concurrent use may result in increased pharmacologic or toxic effects of alprazolam. Toxic effects include profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use with moderate CYP3A4 inhibitors. Consider reducing the dose of alprazolam when coadministered with a moderate CYP3A4 inhibitor. If fluvoxamine is concurrently administered with alprazolam, the manufacturer of fluvoxamine recommends that the initial dose of alprazolam be reduced by 50%, followed by titration to the lowest effective dose.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.
DISCUSSION: Coadministration of cimetidine, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) of alprazolam by 82%.(1) Coadministration with erythromycin, a moderate CYP3A4 inhibitor, increased the area-under-curve (AUC) of alprazolam by 1.61-fold.(1) Coadministration of fluvoxamine 100 mg daily and alprazolam 1 mg given 4 times per day resulted in a 2-fold increase of AUC, Cmax, and half-life of alprazolam.(2) Selected moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3,4)
Selected Moderate Cyp3a4 Inhibitors/Domperidone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors impair the CYP3A4 mediated metabolism of domperidone.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from domperidone, including life-threatening cardiac arrhythmias such as torsades de pointes.(1)
PREDISPOSING FACTORS: In epidemiologic studies and post-market safety data, domperidone was associated with an increased risk for serious ventricular arrhythmias in patients > 60 years of age, using more than 30 mg of domperidone daily, and having other risk factors for QT prolongation.(1) In general, 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: Concurrent use of moderate CYP3A4 inhibitors with domperidone is not recommended. Use alternative antiemetics, or an alternative to the moderate CYP3A4 inhibitor, whichever is more clinically appropriate. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a study in 24 healthy subjects, ketoconazole (200 mg twice daily) tripled plasma levels of domperidone (10 mg four times daily). In male subjects, the combination significantly increased QTc interval greater than either agent alone. In females, there were no significant changes in QTc intervals, but QTc intervals were correlated with domperidone levels.(3) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, conivaptan, crizotinib, diltiazem, duvelisib, fedratinib, fluvoxamine, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4-5)
Selected Moderate Cyp3a4 Inhibitors/Eplerenone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of eplerenone.(1)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in a 2-fold increase in eplerenone concentration and toxicity (e.g. hyperkalemia, hypotension).(1)
PREDISPOSING FACTORS: Severe renal disease increases the risk for hyperkalemia.
PATIENT MANAGEMENT: The starting dose of eplerenone for hypertension should be reduced to 25 mg in patients receiving moderate CYP3A4 inhibitors. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily. Do not exceed 25 mg once daily in post-MI CHF patients receiving a moderate CYP3A4 inhibitor.(1) In all patients taking eplerenone who start taking a moderate CYP3A4 inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.(1)
DISCUSSION: Ketoconazole (200 mg BID) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of eplerenone (100 mg) by 1.7-fold and 5.4-fold, respectively.(1) The concurrent use of eplerenone with less potent CYP3A4 inhibitors (erythromycin 500 mg BID, fluconazole 200 mg daily, saquinavir 1200 mg TID, and verapamil 240 mg daily) increased the Cmax of eplerenone by 1.4-fold to 1.6-fold and the AUC of eplerenone by 2.0-fold and 2.9-fold.(1) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)
Selected Moderate Cyp3a4 Inhibitors/Pimozide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of pimozide.(1)
CLINICAL EFFECTS: Concurrent administration of a moderate inhibitor of CYP3A4 may result in elevated levels of pimozide, which may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) 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.(3)
PATIENT MANAGEMENT: Avoid concurrent use, especially when other risk factors for QT prolongation are present. The manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, e.g. correct electrolyte disturbances, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. Consider ECG to evaluate baseline and/or concurrent QT prolongation risk. Monitor patients on the combination and counsel patients accordingly.
DISCUSSION: Pimozide is metabolized at CYP3A.(1,4) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Moderate inhibitors of CYP3A4 include: avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, rilzabrutinib, schisandra, tofisopam, treosulfan and verapamil.(5,6)
Selected P-Glycoprotein (P-Gp) Inhibitors/Dabigatran
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Dabigatran etexilate is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of dabigatran.(1-3)
CLINICAL EFFECTS: The concurrent use dabigatran with P-gp inhibitors may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.
PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1-4)
PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients with moderate renal impairment (CrCl less than 50 ml/min) being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(1) The concomitant use of dabigatran with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.(1) While the US manufacturer of dabigatran states that no dosage adjustment is necessary in other patients,(1) the Canadian manufacturer of dabigatran states that concomitant use of strong P-gp inhibitors (e.g., glecaprevir-pibrentasvir) is contraindicated. When dabigatran is used for the prevention of venous thromboembolism (VTE) after total hip or knee replacement concurrently with amiodarone, quinidine, or verapamil, the dose of dabigatran should be reduced from 110 mg twice daily to 150 mg once daily. For patients with CrCl less than 50 ml/min on verapamil, a further dabigatran dose reduction to 75 mg once daily should be considered. Verapamil should be given at least 2 hours after dabigatran to minimize the interaction.(2) The UK manufacturer of dabigatran also states the use of dabigatran with strong P-gp inhibitors (e.g., cyclosporine, glecaprevir-pibrentasvir or itraconazole) is contraindicated. Concurrent use of ritonavir is not recommended. When dabigatran is used in atrial fibrillation patients and for treatment of DVT and PE concurrently with verapamil, the UK manufacturer recommends reducing the dose of dabigatran from 150 mg twice daily to 110 mg twice daily, taken simultaneously with verapamil. When used for VTE prophylaxis after orthopedic surgery concurrently with amiodarone, quinidine, or verapamil, the dabigatran loading dose should be reduced from 110 mg to 75 mg, and the maintenance dose should be reduced from 220 mg daily to 150 mg daily, taken simultaneously with the P-gp inhibitor. For patients with CLcr 30-50 mL/min on concurrent verapamil, consider further lowering the dabigatran dose to 75 mg daily.(3) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(10)
DISCUSSION: When dabigatran was co-administered with amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2) however, dabigatran clearance was increased by 65%.(1) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg) increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(1,2) Chronic administration of immediate release verapamil one hour prior to dabigatran dose increased dabigatran AUC by 154%.(4) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(1) Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by 2.87-fold and 2.61-fold, respectively.(5) Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC by 2.05-fold and 2.38-fold, respectively.(6) A retrospective comparative effectiveness cohort study including data from 9,886 individuals evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with nonvalvular atrial fibrillation and normal kidney function. The study compared rates of bleeding following co-administration of either dabigatran, rivaroxaban, or apixaban with verapamil or diltiazem, compared to co-administration with amlodipine or metoprolol. Results of the study found that concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR 2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine. When compared to metoprolol, concomitant dabigatran use with verapamil or diltiazem was also associated with increased overall bleeding (HR, 1.43; 95% CI, 1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI, 1.42-3.79, p<0.05). No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(7) A summary of pharmacokinetic interactions with dabigatran and amiodarone or verapamil concluded that concurrent use is considered safe if CrCl is greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min in VTE and less than 30 ml/min for NVAF. Concurrent use with diltiazem was considered safe.(9) P-gp inhibitors include amiodarone, asunaprevir, aumolertinib, belumosudil, capmatinib, carvedilol, cimetidine, conivaptan, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, diosmin, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir, posaconazole, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, voclosporin, and voxilaprevir.(1-9)
Selected P-Gp And Moderate Cyp3a4 Inhibitors/Rivaroxaban
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Diltiazem, dronedarone, and isavuconazonium may inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1-5)
CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects of rivaroxaban, including an increased risk of bleeding, in patients with decreased renal function.(1,2)
PREDISPOSING FACTORS: It is expected that this interaction will only be clinically significant in patients with decreased renal function.(1) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit CYP3A4,(6) inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (NSAIDs).
PATIENT MANAGEMENT: The US manufacturer states no precautions are necessary with the concurrent use of agents that are combined moderate inhibitors of CYP3A4 and P-gp inhibitors with rivaroxaban in patients with normal renal function; however, in patients with decreased renal function (CrCL of 15 ml/min to 80 ml/min) these agents should only be used if the benefits of concurrent therapy outweigh the increased risk of bleeding.(1) The Canadian manufacturer states that if such use must be undertaken, caution is required.(3) The UK manufacturer states that concomitant use is not recommended.(7) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.
DISCUSSION: Clarithromycin (500 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rivaroxaban by 54% and 40%, respectively.(1,2) In a study in 60 healthy males, clarithromycin (500 mg twice daily) increased the AUC and Cmax of a single dose of rivaroxaban (40 mg) by 94% and 92%, respectively.(8) In a case report, a 65 year-old male developed hemoptysis, epistaxis, and intracranial hemorrhage 3 days after the addition of clarithromycin (500 mg twice daily) to rivaroxaban (20 mg daily).(9) A study of 12 healthy volunteers found that cyclosporine increased rivaroxaban AUC and Cmax by 47% and 104%, respectively, compared to rivaroxaban alone. The combination of fluconazole and cyclosporine administered with rivaroxaban increased rivaroxaban AUC and Cmax by 86% and 115%, respectively, compared to rivaroxaban alone.(6) In a review of 9 liver transplant patients, mean rivaroxaban levels were significantly higher in patients treated with cyclosporine than with tacrolimus (131.7 ng/ml versus 20.3 ng/ml).(10) In a review of 23 patients who received concurrent rivaroxaban and dronedarone for an average of 9.1+/-6.7 months, there were no thromboembolic or major bleeding events. One fourth of the patients received a reduced dose of rivaroxaban (15 mg daily), despite having normal renal function.(11) Erythromycin (500 mg three times daily) increased the AUC and Cmax of a single dose of rivaroxaban by 30% and 30%, respectively.(1-3) In patients with mild renal impairment (CrCl of 50 ml/min to 79 ml/min) who were receiving erythromycin, rivaroxaban AUC and Cmax were increased 76% and 56% when compared to administration of rivaroxaban in patients with normal renal function receiving rivaroxaban alone. In patients with moderate renal impairment (CrCl of 30 ml/min to 49 ml/min) who were receiving erythromycin, rivaroxaban AUC and Cmax were increased 99% and 64% when compared to administration of rivaroxaban in patients with normal renal function receiving rivaroxaban alone.(1,12) In a post hoc analysis of the ROCKET-AF trial, concomitant use of non-dihydropyridine calcium channel blockers and rivaroxaban was associated with an increased risk of major bleeding and intracranial hemorrhage. There was no difference in efficacy or safety of rivaroxaban versus warfarin and concomitant use of CCB across renal function subgroups.(13) In a study in subjects who were taking verapamil, the combination of verapamil and mild renal insufficiency produced additive effects on the AUC of a single dose of rivaroxaban (20 mg).(14) A propensity matched cohort evaluated the concurrent use of combined P-gp and moderate CYP3A4 inhibitors with apixaban or rivaroxaban. Combined inhibitors included amiodarone, diltiazem, erythromycin, dronedarone, and verapamil. Bleeding occurred in 26.4% of patients in the inhibitor group compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73; p=0.006). Although not statistically significant, patients in the inhibitor group also had a higher rate of major bleeding (15% vs 10.3%) and minor bleeding (8.9% vs 5.2%), respectively.(15) A summary of pharmacokinetic interactions with rivaroxaban and dronedarone concluded that concurrent use should be avoided if CrCl < 80 ml/min.(16) These changes are not expected to be clinically significant in patients with normal renal function.(1-3)
Selected Sensitive Cyp3a4 Substrates/Voxelotor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Voxelotor is an inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.
CLINICAL EFFECTS: Concurrent use of voxelotor may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)
PREDISPOSING FACTORS: A greater risk for serious adverse events would be expected from drugs having a narrow therapeutic window.
PATIENT MANAGEMENT: The manufacturer of voxelotor states that co-administration of sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. If concomitant use is unavoidable, consider dose reduction of the sensitive substrate.(1)
DISCUSSION: In a study, voxelotor increased the AUC of a single dose of midazolam by 1.6-fold. After multiple doses of midazolam, a 2.5-fold increase in AUC is predicted.(1) Sensitive CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: avanafil, conivaptan, cyclosporine, dihydroergotamine, eplerenone, ergotamine, everolimus, felodipine, fentanyl, lomitapide, lovastatin, methylergonovine, midazolam, nisoldipine, sildenafil, simvastatin, ticagrelor, tolvaptan, triazolam, and vardenafil.(2,3)
Strong & Moderate Cyp3a4 Inhibitors/Eliglustat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1)
CLINICAL EFFECTS: Concurrent use of an agent that is a strong or moderate inhibitor of CYP3A4 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 liver disease, is also taking an inhibitor of CYP2D6 and/or is an intermediate or poor 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 concurrent use of eliglustat with strong or moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate metabolizers of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 in intermediate and poor metabolizers of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 in intermediate and poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 should be limited to 84 mg 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.
DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-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 fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-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) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3,4) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, casopitant, clofazimine, conivaptan, crizotinib, darunavir, duvelisib, erythromycin, fluconazole, fosamprenavir, fosnetupitant, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(1,3,4)
Strong & Moderate Cyp3a4 Inhibitors/Guanfacine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate inhibitors of CYP3A4 may inhibit the metabolism of guanfacine.(1)
CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP3A4 inhibitor may result in elevated levels of guanfacine, which may result in increased adverse effects such as hypotension, bradycardia, loss of consciousness, and drowsiness.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients maintained on guanfacine may need dosage adjustments if strong or moderate inhibitors of CYP3A4 are initiated or discontinued. The manufacturer of extended-release guanfacine recommends a starting dose of extended-release guanfacine initiated at half the recommended level of the weight based dosing in patients receiving strong or moderate inhibitors of CYP3A4. If a patient has been maintained on extended-release guanfacine and is started on a strong or moderate CYP3A4 inhibitor, the dose of extended-release guanfacine should be decreased to half the recommended weight based dose. If a patient has been maintained on extended-release guanfacine and a strong or moderate CYP3A4 inhibitor and the strong or moderate CYP3A4 inhibitor is discontinued, the dose of extended-release guanfacine may need to be increased to the recommended weight based dose based upon patient response. Extended-release guanfacine target dose range for attention deficit hyperactivity disorder is 0.05-0.12 mg/kg/day. Doses above 4 mg/day have not been evaluated in children ages 6-12 years and doses above 7 mg/day have not been evaluated in adolescents ages 13-17 years.(1)
DISCUSSION: Ketoconazole (dosage not stated), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of guanfacine (dosage not stated) by approximately 1.75-fold and 3-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)
Strong And Moderate Cyp3a4 Inhibitors/Bosentan
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Strong and moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2)
CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 may result in elevated levels of and toxicity from bosentan.(1)
PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)
PATIENT MANAGEMENT: Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. In patients who have been receiving a strong CYP3A4 inhibitor for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of a strong CYP3A4 inhibitor. After at least 10 days following the initiation of a strong CYP3A4 inhibitor, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
DISCUSSION: In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(2) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, itraconazole, josamycin, ketoconazole, levoketoconazole, mibefradil, mifepristone, nefazodone, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, berotralstat, clofazimine, conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, and verapamil.(3)
Strong And Moderate Cyp3a4 Inhibitors/Deflazacort
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Deflazacort is a prodrug and is rapidly metabolized to the active metabolite, 21-desDFZ, by esterases. The metabolite 21-desDFZ is metabolized by CYP3A4 to inactive metabolites.(1) Inhibitors of CYP3A4 may inhibit the metabolism of the active metabolite of deflazacort metabolized by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in increased systemic exposure to and effects from deflazacort.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer recommends decreasing the dose to one-third of the recommended dose of deflazacort when used concurrently with strong or moderate CYP3A4 inhibitors. For example, if the recommended dose of deflazacort is 36 mg per day, the reduced dose would be 12 mg per day when administered with strong or moderate CYP3A4 inhibitors.(1)
DISCUSSION: Deflazacort is a prodrug and is rapidly metabolized to the active metabolite, 21-desDFZ. The metabolite 21-desDFZ is metabolized by CYP3A4.(1) Coadministration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total geometric mean exposure (maximum concentration (Cmax) and area-under-curve (AUC)) to the active metabolite 21-desDFZ by 2.3- to 3.4-fold.(1)
Strong And Moderate Cyp3a4 Inhibitors/Encorafenib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of encorafenib.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from encorafenib, including QT 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, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib should be avoided. If concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib is unavoidable, reduce the encorafenib dose as follows: - If the current daily dose of encorafenib is 450 mg, reduce encorafenib to 150 mg with strong CYP3A4 inhibitors, and 225 mg with moderate CYP3A4 inhibitors. - If the current daily dose of encorafenib is 300 mg, reduce encorafenib to 75 mg with strong CYP3A4 inhibitors, and 150 mg with moderate CYP3A4 inhibitors. - If the current daily dose of encorafenib is 225 mg or 150 mg, reduce encorafenib to 75 mg with both strong and moderate CYP3A4 inhibitors. - After the inhibitor has been discontinued for 3 to 5 half-lives, resume encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.(1) When concurrent therapy cannot be avoided, monitor patients closely for prolongation of the QT interval. Obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Recommended dosage modifications for encorafenib and QTc prolongation adverse reactions include: - QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline: Withhold encorafenib until QTcF less than or equal to 500 ms. Resume at reduced dose. If more than one recurrence, permanently discontinue encorafenib. - QTcF greater than 500 ms and greater than 60 ms increase from baseline: Permanently discontinue encorafenib.(1) See prescribing information for additional information regarding dose reductions.(1)
DISCUSSION: Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem (moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) of encorafenib by 3-fold and 2-fold, respectively, and increased the maximum concentration (Cmax) by 68% and 45%, respectively, after a single dose of encorafenib 50 mg (0.1 times the recommended dose).(1) Encorafenib has been associated with a dose-dependent QTc interval prolongation. Following administration of encorafenib in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms (14-22 ms), based on central tendency analysis. Following administration of encorafenib in combination with cetuximab and mFOLFOX6, an increase of QTcF >500 ms was measured in 4% (9/226) of patients. Following administration of encorafenib with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) of patients.(1) Strong inhibitors of CYP3A4 include: indinavir, josamycin, ketoconazole, mibefradil, nefazodone, nelfinavir, relacorilant, tipranavir, and troleandomycin.(4-6) Moderate inhibitors of CYP3A4 include: amprenavir, berotralstat, conivaptan, fluvoxamine, fosamprenavir, letermovir, schisandra, stiripentol, and treosulfan.(4-6)
Strong And Moderate Cyp3a4 Inhibitors/Fexinidazole
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of fexinidazole to its active metabolites.(1)
CLINICAL EFFECTS: The concurrent use of fexinidazole with inhibitors of CYP3A4 may result in decreased levels of its active metabolites, resulting in decreased efficacy.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of fexinidazole with strong and moderate CYP3A4 inhibitors. If coadministration cannot be avoided, monitor for lack of efficacy of fexinidazole.(1)
DISCUSSION: Although no clinical drug interaction studies were performed with CYP3A4 inhibitors, the formation of the M1 and M2 metabolites may be decreased.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, relacorilant, telaprevir, tipranavir, troleandomycin, and tucatinib.(2,3) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, berotralstat, conivaptan, diltiazem, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)
Strong And Moderate Cyp3a4 Inhibitors/Ivacaftor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of ivacaftor.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from ivacaftor.(1)
PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)
PATIENT MANAGEMENT: In patients receiving concurrent strong CYP3A4 inhibitors such as boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, or voriconazole, the dose of ivacaftor should be reduced to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50 mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) two times a week.(1) In patients receiving concurrent moderate CYP3A4 inhibitors such as amprenavir, aprepitant, atazanavir, berotralstat, crizotinib, cyclosporine, darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, fosaprepitant, imatinib, isavuconazonium, ledipasvir, netupitant, schisandra or verapamil, the dose of ivacaftor should be reduced to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50 mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) daily.(1) In patients who are less than 6 months of age, concurrent use of ivacaftor with strong or moderate CYP3A4 inhibitors is not recommended.(1)
DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 3-fold.(1) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3-5) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(3-5)
Strong And Moderate Cyp3a4 Inhibitors/Pemigatinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of pemigatinib.(1)
CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases pemigatinib plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of pemigatinib states that coadministration with strong or moderate CYP3A4 inhibitors should be avoided. If coadministration cannot be avoided, the dosage of pemigatinib should be reduced as follows: -Reduce dose from 13.5 mg to 9 mg. -Reduce dose from 9 mg to 4.5 mg. If the strong or moderate CYP3A4 inhibitor is discontinued, resume the pemigatinib dose that was taken prior to the initiation of the inhibitor after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)
DISCUSSION: Itraconazole, a strong CYP3A4 inhibitor, increased the maximum concentration (Cmax) by 17% and area-under-curve (AUC) by 88% following a single oral pemigatinib dose of 4.5 mg. Concomitant use of moderate CYP3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50-80%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)
Strong And Moderate Cyp3a4 Inhibitors/Pralsetinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong and moderate CYP3A4 inhibitors (including combined moderate CYP3A4 and P-glycoprotein (P-gp) inhibitors) may inhibit the metabolism of pralsetinib.(1)
CLINICAL EFFECTS: Concurrent administration of a strong or moderate CYP3A4 inhibitor (including combined moderate CYP3A4 and P-gp inhibitors) may result in elevated levels of and toxicity from pralsetinib, including QTc prolongation which may lead to potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP). Other toxicities include hemorrhagic events, pneumonitis, hepatotoxicity, and hypertension.(1-3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: Coadministration of pralsetinib with strong or moderate CYP3A4 inhibitors (including combined moderate CYP3A4 and P-gp inhibitors) should be avoided.(1) If coadministration with a strong or moderate CYP3A4 inhibitor cannot be avoided, use with caution and reduce the dose of pralsetinib as follows: -If the current dose is 400 mg once daily, decrease the dose to 300 mg daily. -If the current dose is 300 mg once daily, decrease the dose to 200 mg daily. -If the current dose is 200 mg once daily, decrease the dose to 100 mg daily. After the inhibitor is discontinued for three to five half-lives, resume the dose of pralsetinib at the dose taken prior to initiation of the inhibitor.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until QTc is <470 ms. Resume pralsetinib at the same dose if risk factors that cause QT prolongation an are identified and corrected. If risk factors that cause QT prolongation are not identified, resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib if the patient develops life-threatening arrhythmia.(3)
DISCUSSION: Coadministration of voriconazole 400 mg twice daily for 1 day then 200 mg twice daily (a strong CYP3A inhibitor) resulted in 122% and 20% increase in pralsetinib area-under-curve (AUC) and maximum concentration (Cmax), respectively.(1) Fluconazole 400 mg daily (a moderate CYP3A4 inhibitor) increased pralsetinib AUC and Cmax by 71% and 15%, respectively.(1) Verapamil 80 mg three times daily (a moderate CYP3A4 and P-glycoprotein inhibitor) increased pralsetinib AUC and Cmax by 108% and 60%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ensitrelvir, idelalisib, nelfinavir, relacorilant, and troleandomycin.(5,6) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, darunavir, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(5,6) Dual moderate CYP3A4 and P-gp inhibitors include: berotralstat, diltiazem, fluvoxamine, isavuconazonium, lenacapavir, schisandra, and verapamil.(5,6)
Strong And Moderate Cyp3a4 Inhibitors/Selumetinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of selumetinib.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from selumetinib, including vomiting, diarrhea, skin rashes, ocular toxicity (e.g., blurred vision, visual loss), cardiomyopathy, and rhabdomyolysis.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of selumetinib states that the coadministration of selumetinib with strong or moderate CYP3A4 inhibitors should be avoided. If coadministration cannot be avoided, the dosage of selumetinib should be reduced as follows: -If the current dose is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily. -If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily. If the strong or moderate CYP3A4 inhibitor is discontinued, resume the selumetinib dose that was taken prior to the initiation of the inhibitor after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)
DISCUSSION: In a study of 26 healthy subjects, itraconazole 200 mg twice daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of selumetinib 25 mg by 49% and 19%, respectively. Fluconazole 400 mg loading dose then 200 mg daily (a moderate CYP3A4 inhibitor and strong CYP2C19 inhibitor) increased AUC and Cmax of selumetinib (25 mg) by 53% and 26%.(1,2) In a pharmacokinetic model, erythromycin (a moderate CYP3A4 inhibitor) was predicted to increase selumetinib AUC and Cmax by 41% and 23%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib and voriconazole.(3) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3)
Strong And Moderate Cyp3a4 Inhibitors/Tezacaftor-Ivacaftor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of tezacaftor-ivacaftor.(1,2)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from tezacaftor-ivacaftor.(1,2)
PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1,2)
PATIENT MANAGEMENT: Refer to current prescribing information for tezacaftor-ivacaftor for dose adjustment recommendations with strong and moderate CYP3A4 inhibitors.(2) Dose modifications for concurrent use of strong CYP3A4 inhibitors: - In adults, patients 12 years and older, and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent strong CYP3A4 inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be given twice a week, approximately 3 to 4 days apart. The evening dose of ivacaftor 150 mg should not be taken. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent strong CYP3A4 inhibitors, the morning dose of tezacaftor 50 mg/ivacaftor 75 mg should be given twice a week, approximately 3 to 4 days apart. The evening dose of ivacaftor 75 mg should not be taken.(2) Dose modifications for concurrent use of moderate CYP3A4 inhibitors: - In adults, patients 12 years and older, and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be given every other day alternating with ivacaftor 150 mg. The evening dose of ivacaftor 150 mg should not be taken. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the morning dose of tezacaftor 50 mg/ivacaftor 75 mg should be given every other day alternating with ivacaftor 75 mg. The evening dose of ivacaftor 75 mg should not be taken.(2)
DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased ivacaftor AUC by 3-fold.(1) Concurrent administration with itraconazole (a strong inhibitor of CYP3A4) increased tezacaftor AUC by 4-fold and ivacaftor by 15.6-fold.(2) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased tezacaftor AUC by 2-fold.(2) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(4-6) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(4-6)
Strong Cyp3a4 Inhib;Moderate 3A4 & P-Gp Dual Inhib/Neratinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of neratinib.(1)
CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors or moderate CYP3A4 and P-glycoprotein (P-gp) dual inhibitors may result in increased systemic exposure to and effects from neratinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of neratinib with strong CYP3A4 inhibitors or moderate CYP3A4 and P-gp dual inhibitors.(1) The Australian and Canadian manufacturer of nirmatrelvir/ritonavir state that concurrent use with neratinib is contraindicated due to the potential for hepatotoxicity and other serious reactions.(2,3) Canadian labeling contraindicates concurrent use of atazanavir/ritonavir and lopinavir/ritonavir with neratinib.(4,5) If concurrent use is warranted, monitor patients closely for increased incidence and severity of diarrhea, abdominal pain, nausea, vomiting, and dehydration.
DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong CYP3A4 inhibitor, increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of neratinib by 221% and 381%, respectively.(1) Pharmacokinetic models predicted that verapamil, a moderate CYP3A4 and P-gp dual inhibitor, would increase the Cmax and AUC of neratinib by 203% and 299%, respectively. Fluconazole, a moderate CYP3A4 inhibitor, is not expected to have a significant interaction with neratinib.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, clarithromycin, cobicistat, diltiazem, ensitrelvir, grapefruit juice, idelalisib, indinavir, itraconazole, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(1,6) Moderate CYP3A4 and P-gp dual inhibitors include: atazanavir, conivaptan, diltiazem, dronedarone, erythromycin, isavuconazole, istradefylline, josamycin, nilotinib, and verapamil.(1,6)
Strong Or Moderate Cyp3a4 Inhibitors/Simeprevir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate inhibitors of CYP3A4 may slow down the metabolism of simeprevir.(1) Simeprevir may inhibit the metabolism of darunavir, diltiazem, erythromycin, and verapamil.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from simeprevir.(1) Simeprevir may increase levels and toxicity of darunavir, diltiazem, erythromycin, and verapamil.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of simeprevir states that concurrent administration of strong or moderate inhibitors of CYP3A4 is not recommended due to risk of toxicity.(1) The American Society of Transplantation guidelines state that the combination of cyclosporine and simeprevir is contraindicated.(7) The US manufacturer of itraconazole states that concurrent administration with simeprevir is not recommended during and two weeks after itraconazole treatment (6).
DISCUSSION: In a study in 24 subjects, erythromycin (500 mg TID for 7 days) increased the maximum concentration (Cmax), area-under-curve (AUC) and Cmin of simeprevir (150 mg daily for 7 days) by 4.53-fold, 7.47-fold, and 12.74-fold, respectively. The Cmax and AUC of erythromycin increased by 1.59-fold and 1.39-fold, respectively.(1) In a study in 9 subjects, an individualized dose of cyclosporine increased the Cmax and AUC of simeprevir (150 mg daily for 14 days) by 4.74 fold and 5.81-fold.(1) In a study in 25 subjects, simeprevir (50 mg once daily) increased the Cmax, AUC, and Cmin of darunavir (800 mg once daily) by 4%, 18%, and 31%.(4) In a study in 25 subjects, darunavir-ritonavir (800 mg-100 mg once daily) increased the Cmax, AUC, and Cmin of simeprevir (50 mg once daily) by 1.79-fold, 2.59-fold, and 4.58-fold.(4) In a study in 12 subjects, ritonavir (100 mg twice daily, 15 days) increased the AUC, Cmax, and Cmin of simeprevir (200 mg daily, 7 days) by 618% (463-815%), 370% (284-476%), and 1335% (929-1901%).(5) Strong and moderate inhibitors of CYP3A4 linked to this monograph include adagrasib, amprenavir, aprepitant, atazanavir, avacopan, berotralstat, boceprevir, ceritinib, clarithromycin, clofazimine, cobicistat, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, ensitrelvir, erythromycin, fedratinib, fosamprenavir, fluconazole, fluvoxamine, fosnetupitant, idelalisib, imatinib, indinavir, isavuconazonium, itraconazole, josamycin, ketoconazole, lefamulin, lenacapavir, lonafarnib, lopinavir, mibefradil, mifepristone, milk thistle, nefazodone, nelfinavir, netupitant, nilotinib, nirmatrelvir/ritonavir, nirogacestat, posaconazole, relacorilant, ribociclib, rilzabrutinib, ritonavir, saquinavir, schisandra, silibinin, stiripentol, telaprevir, telithromycin, tipranavir, treosulfan, troleandomycin, tucatinib, verapamil, and voriconazole.(1-3)
Vasopressin Antagonists/Hypertonic Saline
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent administration of vasopressin antagonists and hypertonic saline may result in overly rapid correction of serum sodium levels.(1,2)
CLINICAL EFFECTS: Overly rapid correction of serum sodium levels may result in osmotic demyelination. Symptoms of osmotic demyelination include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and/or death.(1,2)
PREDISPOSING FACTORS: Patients who are malnourished, have a history of alcoholism, and/or advanced liver disease may be more susceptible to adverse effects of overly rapid hyponatremia correction.(1,2)
PATIENT MANAGEMENT: Avoid the concurrent use of vasopressin antagonists and hypertonic saline. In patients who are malnourished, have a history of alcoholism, and/or advanced liver disease, use slower rates of sodium correction.(1,2)
DISCUSSION: Overly rapid correction of serum sodium levels may result in osmotic demyelination. Symptoms of osmotic demyelination include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and/or death. Patients who are malnourished, have a history of alcoholism, and/or advanced liver disease may be more susceptible to adverse effects of overly rapid hyponatremia correction. Avoid the concurrent use of vasopressin antagonists and hypertonic saline. In patients who are malnourished, have a history of alcoholism, and/or advanced liver disease, use slower rates of sodium correction.(1,2)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Conivaptan/Digoxin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Conivaptan may inhibit the metabolism of digoxin via P-glycoprotein (P-gp).(1)
CLINICAL EFFECTS: Concurrent use of conivaptan and digoxin may result in an increased concentration of digoxin, which may lead to increased clinical effects and toxicity. Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.(1)
PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.
PATIENT MANAGEMENT: Dosage of digoxin may need to be altered based on the individual patient response. Monitor for signs and symptoms of digoxin toxicity and adjust dose accordingly.(1) The manufacturer of digoxin recommends reducing digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency of digoxin.(2)
DISCUSSION: Conivaptan is a P-gp inhibitor. Digoxin is a P-glycoprotein substrate. Coadministration of conivaptan (80 mg/day) and digoxin (0.5 mg) resulted in a 30% decrease in the clearance, 79% increase in the maximum concentration (Cmax), and a 43% increase in the area under the curve (AUC) of digoxin.(1)
Cyp3a4; Cyp2c8; P-Glycoprotein (P-Gp) Inhibitors/Loperamide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase loperamide systemic absorption and facilitate entry into central nervous system (CNS).(1)
CLINICAL EFFECTS: Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase levels of loperamide, resulting in respiratory depression.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Use loperamide with caution in patients receiving inhibitors of CYP3A4, CYP2C8, and/or P-gp. Consider lower doses of loperamide in these patients and monitor for adverse effects. The manufacturer of lonafarnib recommends starting loperamide at a dose of 1 mg and slowly increasing the dose as needed.(2)
DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, itraconazole (100 mg twice daily for 5 days - first dose 200 mg), gemfibrozil (600 mg twice daily), and the combination of itraconazole and gemfibrozil (same dosages) increased the area-under-curve (AUC) of single doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold, respectively.(3) In a study of healthy subjects, lonafarnib (100 mg twice daily for 5 days) increased the AUC and maximum concentration (Cmax) of single dose loperamide (2 mg) by 299% and 214%, respectively.(3) In a study in 18 healthy males, quinidine increased the AUC of a single dose of loperamide by 2.2-fold and markedly decreased pupil size.(4) In a study in 8 healthy subjects, subjects experienced respiratory depression when a single dose of loperamide (16 mg) was administered with a single dose of quinidine (600 mg) but not when loperamide was administered alone.(6) Loperamide plasma levels increased 2-fold to 3-fold.(5) Coadministration of trofinetide 12,000 mg twice daily with 4 mg of loperamide increased the AUC of loperamide by 1.73-fold and the Cmax by 1.95-fold. Administration of trofinetide 2 hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the Cmax by 1.44-fold.(7)
Dual Cyp3a4 & P-Gp Inhibitors/Nintedanib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Nintedanib is a substrate for the P-glycoprotein (P-gp) transporter and is metabolized to a minor extent by CYP3A4.
CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and CYP3A4 may result in elevated levels of and clinical effects of nintedanib.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of nintedanib recommends close monitoring for nintedanib patients receiving drugs which are both P-gp and CYP3A4 inhibitors. In an interaction study ketoconazole increased exposure to nintedanib by 60%. Nintedanib therapy may need to be interrupted or the dose may need to be reduced.(1)
DISCUSSION: In an interaction study coadministration with ketoconazole, a P-gp and CYP3A4 inhibitor, increased nintedanib exposure (area-under-curve, AUC) and maximum concentration (Cmax) by 1.61-fold and 1.83 fold respectively.(1) Strong CYP3A4 & P-gp inhibitors include: adagrasib, boceprevir, clarithromycin, cobicistat, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and tucatinib. Moderate CYP3A4 & P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, schisandra, and verapamil. Weak CYP3A4 & P-gp inhibitors include: amiodarone, azithromycin, cimetidine, cyclosporine, daclatasvir, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, ivacaftor, lapatinib, mavorixafor, ranolazine, and vepdegestrant.(2)
Dual Moderate Cyp3a4 And P-Gp Inhib/Daraxonrasib (<=100 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Daraxonrasib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Moderate CYP3A4 and P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 and P-gp inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: For patients taking agents that are both moderate CYP3A4 inhibitors and P-gp inhibitors, reduce the dose of daraxonrasib to 100 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 3 to 5 half-lives of the inhibitor.(1)
DISCUSSION: In a study, diltiazem 80 mg three times daily (a moderate CYP3A and P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 2.6-fold.(1) Dual moderate CYP3A4 and P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazole, schisandra, and verapamil.(2-3)
Dual P-Gp And Moderate Cyp3a4 Inhibitors/Everolimus
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Dual P-glycoprotein (P-gp) and moderate CYP3A4 inhibitors may increase absorption and decrease elimination of everolimus.(1-2)
CLINICAL EFFECTS: Concurrent use of dual P-gp and moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from everolimus.(1-2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If concurrent therapy with everolimus and dual P-gp and moderate CYP3A4 inhibitors is warranted, reduce the dosage of everolimus.(1) In patients with advanced hormone receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); advanced renal cell carcinoma; or renal angiomyolipoma with TSC, decrease the dose of everolimus to 2.5 mg daily. An increase to 5 mg daily may be considered based on patient tolerance. If the inhibitor is discontinued, allow an elimination period of 3 days before increasing the dose to that used prior to the inhibitor.(1) In patients with subependymal giant cell astrocytoma with TSC and TSC-associated partial-onset seizures, reduce the dosage of everolimus by 50% to maintain trough concentrations of 5 ng/ml to 15 ng/ml. If the patient is already receiving 2.5 mg daily, consider a dose of 2.5 mg every other day. Assess everolimus levels 2 weeks after the addition of the inhibitor. Resume the everolimus dose used prior to initiation of the inhibitor after the inhibitor has been discontinued for 3 days, and assess everolimus trough levels 2 weeks later.(1) In patients taking everolimus for prophylaxis of organ rejection, monitor everolimus blood concentration and adjust dose as needed.(2) Guidelines from the American Society of Transplantation state that protease inhibitors are contraindicated, and recommend avoiding the use of erythromycin with everolimus. If the combination must be used, lower the dose of everolimus by up to 50% upon initiation of the antibiotic and monitor levels daily.(3)
DISCUSSION: In a study in healthy subjects, concurrent use of erythromycin, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.0-fold and 4.4-fold, respectively.(1) In a study in healthy subjects, concurrent use of ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and 15.0-fold, respectively.(1) In a study in healthy subjects, concurrent use of verapamil, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.3-fold and 3.5-fold, respectively.(1) In a study in 16 healthy subjects, concurrent use of verapamil increased everolimus Cmax and AUC by 130% and 250%, respectively.(4) Moderate CYP3A4 and/or P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, lenacapavir, rilzabrutinib, and verapamil.(5-7)
Moderat Cyp3a4 Inhibitor/Vanzacaftor-Tezacaftor-Deutivacafto
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of vanzacaftor-tezacaftor-deutivacaftor. Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from vanzacaftor-tezacaftor-deutivacaftor, such as hepatotoxicity.(1)
PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)
PATIENT MANAGEMENT: The US manufacturer of vanzacaftor-tezacaftor-deutivacaftor states that concurrent use with moderate CYP3A4 inhibitors requires a dose adjustment. If concurrent use is warranted, the following dose adjustments are recommended: -For age 6 to less than 12 years old AND less than 40 kg - Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day; -For age 6 to less than 12 years old AND greater than or equal to 40 kg - One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day; -For age 12 years and older AND any weight - One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.(1)
DISCUSSION: Concurrent administration with itraconazole (200 mg every 12 hours on Day 1, followed by 200 mg daily, a strong inhibitor of CYP3A4) with tezacaftor (25 mg daily)-ivacaftor (50 mg daily) increased tezacaftor area-under-curve (AUC) and concentration maximum (Cmax) by 4-fold and 2.83-fold, respectively.(1) Concurrent administration with itraconazole (200 mg daily, a strong inhibitor of CYP3A4) with single-dose elexacaftor 20 mg-tezacaftor 50 mg-deutivacaftor 50 mg increased tezacaftor AUC and Cmax by 4.51-fold and 1.48-fold and deutivacaftor AUC and Cmax by 11.1-fold and 1.96-fold.(1) Concurrent administration with itraconazole (200 mg daily, a strong inhibitor of CYP3A4) with vanzacaftor (5 mg single dose) increased vanzacaftor AUC and Cmax by 6.37-fold and 1.55-fold, respectively.(1) Concurrent administration with fluconazole (200 mg daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 2.55-fold and 2.48-fold and deutivacaftor by 3.13-fold and 2.27-fold, respectively.(1) Concurrent administration with erythromycin (500 mg four times daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 3.29-fold and 3.19-fold and deutivacaftor by 4.13-fold and 2.89-fold, respectively.(1) Concurrent administration with verapamil (80 mg three times daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 3.93-fold and 3.8-fold and deutivacaftor by 5.11-fold and 3.43-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-4)
Moderate And Weak Cyp3a4 Inhibitors/Tacrolimus
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ratio 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) A case report describes a 6-year-old kidney transplant recipient who was on a regimen of tacrolimus and mycophenolate mofetil. The patient was started letermovir 240 mg via G-tube 2 months post kidney transplant. One week after starting letermovir, the routine tacrolimus level showed a supratherapeutic concentration of 22.9 ng/L. A 36% dose reduction of tacrolimus was required. Upon discontinuation of letermovir, the tacrolimus level decreased by 42%.(13) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, sevabertinib, stiripentol, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6)
Moderate Cyp3a4 Inhibitors/Abemaciclib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels and toxicity from abemaciclib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of abemaciclib recommends monitoring for adverse reactions and consider a dose reduction of abemaciclib dose in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(1) Monitor patient for signs and symptoms of abemaciclib toxicity with concurrent use.
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of verapamil and diltiazem (moderate CYP3A4 inhibitors) are predicted to increase the relative adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.(1) Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the AUC of abemaciclib up to 16-fold.(1) Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1) Concurrent administration of clarithromycin (500 mg twice daily, a strong CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.5-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)
Moderate Cyp3a4 Inhibitors/Avanafil (<= 50 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of avanafil.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of avanafil states that in patients receiving moderate inhibitors of CYP3A4, the dose of avanafil should be limited to 50 mg in 24 hours.(1)
DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of 2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold, respectively. The half-life of avanafil increased from 5 hours to 8 hours.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)
Moderate Cyp3a4 Inhibitors/Avapritinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of avapritinib.(1)
CLINICAL EFFECTS: Concurrent use of avapritinib with a moderate CYP3A4 inhibitor increases avapritinib plasma concentrations, which may increase the incidence and severity of adverse reactions of avapritinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use of avapritinib with strong or moderate CYP3A4 inhibitors. If coadministration of avapritinib with a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of avapritinib to 100 mg once daily for treatment of gastrointestinal stromal tumors or 50 mg once daily for treatment of advanced systemic mastocytosis.(1)
DISCUSSION: Coadministration of avapritinib 300 mg once daily with fluconazole 200 mg once daily, a moderate CYP3A4 inhibitor, is predicted to increase avapritinib AUC by 210% at steady state.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)
Moderate Cyp3a4 Inhibitors/Brexpiprazole
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of brexpiprazole.(1)
CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 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 CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong or moderate CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a moderate CYP3A4 inhibitor.
PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a moderate CYP3A4 inhibitor: - in patients taking a moderate CYP3A4 inhibitor who are poor CYP2D6 metabolizers or are receiving a strong or moderate inhibitor of CYP2D6, decrease the dose to one-fourth the usual dose. The dose of brexpiprazole should be adjusted to its original level if the CYP3A4 inhibitor is discontinued.(1) No empiric dosage adjustment is recommended in other patients.
DISCUSSION: Coadministration of ketoconazole, a strong inhibitor of CYP3A4, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include aprepitant, avacopan, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.
Moderate Cyp3a4 Inhibitors/Bromocriptine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of bromocriptine.
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of bromocriptine, which may result in increased side effects of these agents.
PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of ergotamine derivatives may be at a higher risk of adverse effects from this combination.
PATIENT MANAGEMENT: Use caution with concurrent therapy with bromocriptine with azole antifungals. The US manufacturer of bromocriptine states use caution when co-administering drugs that are inhibitors of CYP3A4. Bromocriptine dose should not exceed 1.6 mg per day when used with a moderate CYP3A4 inhibitor. Concomitant use of strong CYP3A4 inhibitors should be avoided. Ensure adequate washout of strong CYP3A4 inhibitor drug before initiating bromocriptine.(1)
DISCUSSION: A study in five healthy subjects found that concurrent administration of erythromycin and bromocriptine resulted in a 268% increase in area-under-curve (AUC) for bromocriptine and a 4.6-fold increase in bromocriptine maximum concentration (Cmax).(2) Inhibition of ergotamine derivative metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(3,4)
Moderate Cyp3a4 Inhibitors/Cabergoline
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of cabergoline.
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of cabergoline, which may result in increased side effects of cabergoline.
PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of cabergoline may be at a higher risk of adverse effects from this combination.
PATIENT MANAGEMENT: Use caution with concurrent therapy with cabergoline and moderate CYP3A4 inhibitors.
DISCUSSION: Cabergoline metabolism has been shown to be inhibited by strong CYP3A4 inhibitors, including macrolides and itraconazole.(1,2) Inhibition of cabergoline metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(3,4)
Moderate Cyp3a4 Inhibitors/Capivasertib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the CYP3A4 metabolism of capivasertib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased systemic exposure to and effects from capivasertib, hyperglycemia, severe diarrhea, and cutaneous adverse reactions.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concomitant use of capivasertib with moderate CYP3A4 inhibitors requires a dose reduction of capivasertib. Reduce the capivasertib dose to 320 mg twice daily for 4 days followed by 3 days off.(1) After discontinuation of the strong CYP3A4 inhibitor for 3 to 5 half-lives of the inhibitor, resume the capivasertib dosage that was taken prior to initiating the strong CYP3A4 inhibitor.(1)
DISCUSSION: Itraconazole (strong CYP3A4 inhibitor) is predicted to increase capivasertib area-under-curve (AUC) by up to 1.7-fold and maximum concentration (Cmax) by up to 1.4-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Dapoxetine (<= 30 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of dapoxetine.(1-3)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of dapoxetine.(1-3)
PREDISPOSING FACTORS: If the patient is a CYP2D6 poor metabolizer, dapoxetine metabolism can be further inhibited.(1-3)
PATIENT MANAGEMENT: The manufacturers of dapoxetine state that the dose of dapoxetine should not exceed 30 mg daily if coadministered with moderate CYP3A4 inhibitors.(1-3)
DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of dapoxetine has not been investigated in clinical studies.(1-3) Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively. The Cmax and AUC of the active fraction are expected to increase by 25% and 2-fold, respectively, with strong inhibitors of CYP3A4.(1-3) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)
Moderate Cyp3a4 Inhibitors/Daridorexant (<=25 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of daridorexant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from daridorexant including somnolence, fatigue, CNS depressant effects, daytime impairment, or headache.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The dose of daridorexant should be limited to 25 mg daily when used with a moderate CYP3A4 inhibitor.(1)
DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) and maximum concentration (Cmax) by 2.4-fold and 1.4-fold, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)
Moderate Cyp3a4 Inhibitors/Elinzanetant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Elinzanetant is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of elinzanetant.(1,2)
CLINICAL EFFECTS: Concurrent use of elinzanetant with moderate CYP3A4 inhibitors may result in an increase in exposure of elinzanetant.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Canadian(1) and US(2) manufacturers of elinzanetant recommends reducing the dose of elinzanetant to 60 mg once daily at bedtime when coadministered with moderate CYP3A4 inhibitors. After discontinuation of the moderate inhibitor (after 3 to 5 half lives of the inhibitor), elinzanetant should be used at the usual dose of 120 mg once daily.(1,2)
DISCUSSION: Concomitant use of erythromycin (moderate CYP3A4 inhibitor) increased elinzanetant 120 mg area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold and 2-fold, respectively. Concomitant use of erythromycin with elinzanetant 60 mg increased elinzanetant AUC by 1.4-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Finerenone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of finerenone.(1)
CLINICAL EFFECTS: Concurrent use of finerenone with a moderate inhibitor of CYP3A4 increases finerenone concentrations and may increase the risk of toxicity (e.g., hyperkalemia, hypotension).(1)
PREDISPOSING FACTORS: Severe renal disease and concurrent use of potassium supplements increase the risk for hyperkalemia.
PATIENT MANAGEMENT: The manufacturer of finerenone states that use with moderate CYP3A4 inhibitors should be closely monitored. Check serum potassium during drug initiation or dosage adjustment of either finerenone or the moderate CYP3A4 inhibitor. Dose adjustment of finerenone may be necessary.(1)
DISCUSSION: Concurrent use of finerenone with erythromycin, a moderate CYP3A4 inhibitor, increased finerenone area-under-curve (AUC) by 248% and maximum concentration (Cmax) by 88%.(1) Concurrent use of finerenone with verapamil, a moderate CYP3A4 inhibitor, increased finerenone AUC by 170% and Cmax by 122%.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Gepirone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of gepirone.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels of and effects from gepirone, including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Serotonin syndrome may also result. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: If gepirone is used concurrently with a moderate CYP3A4 inhibitor, reduce the dose of gepirone by 50%.(1) Monitor for prolongation of the QTc interval.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTcF is > 450 msec at baseline, do not initiate gepirone. If QTc increases to > 450 msec during treatment, monitor ECGs more frequently and do not increase the dose of gepirone.(1)
DISCUSSION: In a study, verapamil (80 mg 3 times daily), a moderate CYP3A4 inhibitor, increased both the maximum concentration (Cmax) and area-under-curve (AUC) of gepirone 18.2 mg by about 2.75-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Ibrutinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ibrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from ibrutinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inhibitors in patients undergoing therapy with ibrutinib requires a dose adjustment.(1) If a moderate CYP3A4 inhibitor is required for B-cell malignancies treatment, reduce the dose of ibrutinib to 280 mg daily.(1) If a moderate CYP3A4 inhibitor is required for chronic graft versus host disease treatment, reduce the dose of ibrutinib in patients 12 years and older to 420 mg once daily, and in patients 1 year to 12 years old to 240 mg/m2 once daily.(1) After discontinuation of a CYP3A4 inhibitor, resume previous dose of ibrutinib.(1)
DISCUSSION: The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased ibrutinib's concentration maximum (Cmax) and area-under-curve (AUC) by 3.4-fold and 3-fold.(1) In a case report, concomitant administration of ibrutinib and verapamil/trandolapril resulted in ibrutinib toxicity consisting of nausea, dizziness, malaise, and severe diarrhea.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, casopitant, clofazimine, clotrimazole, conivaptan, crizotinib, darunavir, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, ledipasvir, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3,4)
Moderate Cyp3a4 Inhibitors/Larotrectinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of larotrectinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for larotrectinib toxicities such as neurotoxicity or hepatotoxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving a moderate CYP3A4 inhibitor concurrently with larotrectinib should be monitored for adverse effects more frequently. A dose reduction may be needed based on the severity of adverse effects. Refer to prescribing information for dosage modifications.
DISCUSSION: In a drug interaction study in healthy subjects, coadministration of itraconazole (a strong CYP3A4 inhibitor) with a single dose of larotrectinib (100 mg) increased larotrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 2.8 and 4.3-fold, respectively.(1) Fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase the AUC and Cmax of larotrectinib by 2.7-fold and 1.9-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Lumateperone (<=21 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of lumateperone.(1)
CLINICAL EFFECTS: Concurrent use of lumateperone with moderate CYP3A4 inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1)
PREDISPOSING FACTORS: Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) may be at higher risk of increased lumateperone exposure.(1)
PATIENT MANAGEMENT: The manufacturer of lumateperone recommends decreasing the dosage of lumateperone to 21 mg once daily in patients receiving moderate CYP3A4 inhibitors.(1)
DISCUSSION: Coadministration of lumateperone with itraconazole, a strong CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Coadministration of lumateperone with diltiazem, a moderate CYP3A4 inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax, respectively.(1) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Macitentan
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Macitentan is primarily metabolized by CYP3A4, with minor contributions from CYP2C8, CYP2C9, and CYP2C19. Moderate inhibitors of CYP3A4 may inhibit the metabolism of macitentan.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of macitentan, including hepatotoxicity and fluid retention.(1)
PREDISPOSING FACTORS: Concomitant use of a moderate CYP2C9 inhibitor increases the magnitude of this interaction and the risk of adverse events.
PATIENT MANAGEMENT: The US manufacturer of macitentan states that concurrent use of both a moderate CYP2C9 inhibitor and a moderate CYP3A4 inhibitor should be avoided.(1) The Australian and Canadian manufacturers of macitentan state caution should be exercised when macitentan is administered concomitantly with a moderate CYP3A4 inhibitor.(2,3) While the manufacturer does not provide recommendations for concurrent use of a moderate CYP3A4 inhibitor alone, it would be prudent to use caution and monitor for adverse effects.
DISCUSSION: Based on pharmacokinetic (PBPK) modeling, dual moderate inhibitors of CYP2C9 and CYP3A4 such as fluconazole are predicted to increase macitentan exposure by 4-fold.(1) Pretreatment with ketoconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of macitentan by approximately 2.3 and 1.3-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4)
Moderate Cyp3a4 Inhibitors/Mavorixafor
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of mavorixafor.(1) Mavorixafor is also a substrate of P-glycoprotein (P-gp). P-gp inhibitors may increase mavorixafor exposure.(1) Many CYP3A4 inhibitors also inhibit P-glycoprotein (P-gp), including cimetidine, diltiazem, fluvoxamine, isavuconazonium, schisandra, and verapamil.(2)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of mavorixafor, including thrombocytopenia and QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: When used concomitantly with moderate CYP3A4 inhibitors, monitor more frequently for mavorixafor adverse effects and reduce the dose in 100 mg increments, if necessary, but not to a dose less than 200 mg.(1) When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: There are no clinical studies for the combination of mavorixafor and moderate CYP3A4 inhibitors. In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(4) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, cimetidine, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil and voxelotor.(2,5)
Moderate Cyp3a4 Inhibitors/Mitapivat (<= 20 Mg Bid)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be monitored closely for increased risk of adverse reactions. Mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)(2)
Moderate Cyp3a4 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: Patients with CYP2D6 poor metabolizer phenotype may be affected to a greater extent by CYP3A4 inhibitors. 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) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4)
Moderate Cyp3a4 Inhibitors/Oral Lefamulin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of oral lefamulin.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of lefamulin, such as 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.(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).(4)
PATIENT MANAGEMENT: The US manufacturer of lefamulin states that oral lefamulin coadministration with moderate inhibitors of CYP3A4 should be monitored for adverse effects.(1) During concomitant therapy with a moderate CYP3A4 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: Coadministration of ketoconazole (strong CYP3A4 inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and 58%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, avacopan, conivaptan, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, schisandra, stiripentol, tofisopam, and treosulfan.(1,3)
Moderate Cyp3a4 Inhibitors/Oveporexton (<=0.5 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Oveporexton is metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of oveporexton.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of oveporexton, including insomnia, urinary frequency and urgency, and CPK elevation.(1)
PREDISPOSING FACTORS: Adverse reactions from oveporexton may be more likely in patients with Child-Pugh class C hepatic impairment and in patients with severe renal impairment on dialysis.
PATIENT MANAGEMENT: In patients on concomitant moderate CYP3A4 inhibitors with oveporexton, reduce the dosage of oveporexton to 0.5 mg after awakening and then 0.5 mg three to five hours later (maximum recommended dosage is 1 mg per day).(1)
DISCUSSION: In a study, fluconazole (a moderate CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oveporexton by 2.9-fold and 1.5-fold, respectively. Oveporexton half-life was increased by about 2-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Pacritinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of pacritinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from pacritinib.(1) Elevated levels of pacritinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include bleeding, diarrhea, thrombocytopenia, major adverse cardiovascular events, thrombosis, and infection.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The manufacturer of pacritinib recommends monitoring patients concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for increased adverse reactions and considering pacritinib dose modifications based on safety.(1) When concurrent therapy is warranted monitor for prolongation of the QTc interval.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline within 1 week, resume pacritinib at the same dose. If time to resolution of the QTc interval takes greater than 1 week to resolve, reduce the pacritinib dose according to labeling.(1)
DISCUSSION: Fluconazole (200 mg once daily for 7 days, a moderate CYP3A4 inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC) of pacritinib (200 mg twice daily at steady state) by 41% and 45%, respectively.(1) Concomitant use of pacritinib with doses of fluconazole greater than 200 mg once daily have not been studied.(1) Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of pacritinib (400 mg) by 80% and 30%, respectively.(1) In a 24 week clinical study, patients treated with pacritinib 200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1) Pacritinib has been associated with QTc interval prolongation. In clinical trials, patients with QTc prolongation >500 msec occurred in 1.4% of patients in the treatment arm compared to 1% in the control arm. The treatment arm had a greater incidence of an increase in QTc > 60 msec from baseline than the control arm (1.9% vs 1%, respectively). QTc prolongation adverse reactions were higher in the treatment arm than the control group (3.8% vs 2%, respectively).(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, conivaptan, darunavir, diltiazem, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3,4)
Moderate Cyp3a4 Inhibitors/Palovarotene
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of palovarotene.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from palovarotene, including rash, alopecia, skin exfoliation, photosensitivity, reduction in bone mass, hyperostosis, and night blindness.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with palovarotene should be avoided. If concurrent use cannot be avoided, reduce the dose of palovarotene by half, according to the US prescribing information.(1)
DISCUSSION: In a clinical trial, erythromycin, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 1.6- and 2.5-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Pyrotinib (<= 80 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Pyrotinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of pyrotinib.(1)
CLINICAL EFFECTS: Concurrent use of pyrotinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of pyrotinib, including hepatotoxicity, decreased left ventricular ejection fraction, bone marrow suppression and gastrointestinal adverse effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of pyrotinib states coadministration with moderate CYP3A4 inhibitors requires a dose adjustment. Reduce the dose of pyrotinib to 80 mg daily with moderate CYP3A4 inhibitors.(1)
DISCUSSION: In a clinical study of healthy subjects, coadministration of pyrotinib with fluconazole, a moderate CYP3A4 inhibitor, resulted in a 3.6-fold increase in area-under-curve (AUC) and a 2.16-fold increase in maximum concentration (Cmax).(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Quetiapine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of quetiapine. Quetiapine is a sensitive substrate for CYP3A4 and so an approximately 2-fold or higher increase in exposure (AUC, area-under-curve) is possible when quetiapine is given with a moderate CYP3A4 inhibitor.(1-4)
CLINICAL EFFECTS: Concurrent use of a strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from quetiapine, including potentially life-threatening cardiac arrhythmias such as torsades de pointes.(2,3)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: Monitor patients when moderate inhibitors of CYP3A4 are co-prescribed with quetiapine as the magnitude of the interaction is highly variable between patients.(6) Use of higher doses of either the CYP3A4 inhibitor or quetiapine are other factors which may affect the magnitude of this interaction. Decrease the quetiapine dose if needed. 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, fainting, excessive drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle stiffness/tremors (EPS).
DISCUSSION: In a study in 19 Chinese patients with schizophrenia, patients received quetiapine (200 mg twice daily) alone and with erythromycin (500 mg 3 times daily, a moderate inhibitor of CYP3A4). Erythromycin increased the quetiapine maximum concentration (Cmax)by 68%(range approximately 20-130%), area-under-curve (AUC) 129% (range approximately 20-300%), and half-life by 92% (range approximately 0-250%). Quetiapine clearance decreased 52% (range approximately -15 to -80%).(6) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(4)
Moderate Cyp3a4 Inhibitors/Ranolazine (<=500 Mg Bid)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ranolazine. Verapamil may also increase the absorption of ranolazine by inhibiting P-glycoprotein.(1)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of and clinical effects from ranolazine. Elevated ranolazine levels may result in QTc prolongation, which may result in life-threatening cardiac arrhythmia, including torsades de pointes.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of ranolazine states that the dosage of ranolazine should be limited to 500 mg twice daily in patients receiving moderate inhibitors of CYP3A4.(1) 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: Concurrent use of diltiazem, a moderate inhibitor of CYP3A4, at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000 mg twice daily) by 50% and 130%, respectively.(1,3) In healthy subjects, concurrent ranolazine (1000 mg twice daily) had no effects on the pharmacokinetics of diltiazem (60 mg three times daily).(1) Concurrent use of verapamil (120 mg three times daily) increased plasma levels of ranolazine (750 mg twice daily) by 100%.(1) In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg three times daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine IR steady state, diltiazem increased ranolazine IR area under the curve (AUC) by 85%, on average, and increased maximum concentration (Cmax) by 1.9-fold and minimum concentration (Cmin) by 2.1-fold.(4) In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine steady state, diltiazem increased ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%, on average, respectively.(4) In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or 240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR, 1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine half-lives did not show any consistent trend of changes with increasing doses of diltiazem.(4) In a study of patients with severe chronic angina, the addition of ranolazine 750 mg twice daily or 1,000 mg twice daily along with their standard dose of diltiazem (180 mg once daily) provided additional antianginal relief, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.(5) Ranolazine-induced QTc prolongation is dose and concentration-related.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, erythromycin, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(1,3,6,7)
Moderate Cyp3a4 Inhibitors/Rimegepant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Rimegepant is primarily metabolized by CYP3A4. Moderate inhibitors of CYP3A4 may decrease the metabolism of rimegepant.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels of and toxicity from rimegepant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of rimegepant recommends avoiding a second dose of rimegepant within 48 hours of a first dose when used concomitantly with moderate CYP3A4 inhibitors.(1)
DISCUSSION: In a drug interaction study (n=23), fluconazole, a moderate CYP3A4 inhibitor, increased rimegepant mean area-under-curve from time 0 to infinity (AUC 0-inf) by 1.8-fold (90% confidence interval 1.68-1.93), with no impact on the maximum concentration (Cmax) (1.04-fold; 90% CI 0.94-1.15). (2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(3-4)
Moderate Cyp3a4 Inhibitors/Sebetralstat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of sebetralstat.(1)
CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may increase the levels and effects of sebetralstat including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: Child-Pugh class B or C hepatic impairment may increase the risk for increased exposure to sebetralstat. Sebetralstat should be avoided in patients with severe hepatic impairment (Child-Pugh class C).(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 manufacturer of sebetralstat states when used concomitantly with moderate CYP3A4 inhibitors, reduce the dose of sebetralstat to one dose of 300 mg (one tablet) orally at the earliest recognition of a hereditary angioedema attack. A second dose of 300 mg (one tablet) may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.(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: Concomitant use of sebetralstat with verapamil (240 mg once daily for 6 days), a moderate CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 1.8-fold and 2-fold, respectively.(1) In a study in healthy subjects, the largest mean increase in QTc interval was 10.4 msec (upper confidence interval = 15.3 msec) after administration of sebetralstat (2.5 times the maximum recommended dose). The increase in the QTc interval was concentration dependent.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, voxelotor.(3-4)
Moderate Cyp3a4 Inhibitors/Suvorexant (<= 10 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of suvorexant.(1)
CLINICAL EFFECTS: Concurrent use of an agent that is a moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects of suvorexant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of suvorexant recommends a starting dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving concurrent therapy with a moderate CYP3A4 inhibitor.(1)
DISCUSSION: Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, erythromycin, duvelisib, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)
Moderate Cyp3a4 Inhibitors/Suzetrigine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Suzetrigine and M6-SUZ (active metabolite of suzetrigine) are CYP3A4 substrates. Moderate CYP3A4 inhibitors increase suzetrigine and M6-SUZ exposures, which may cause suzetrigine adverse reactions.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from suzetrigine including pruritis, muscle spasms, increased blood creatine phosphokinase, and rash.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors with suzetrigine. The US manufacturer of suzetrigine states when suzetrigine is administered to patients taking moderate CYP3A4 inhibitors reduce the suzetrigine dose as follows: -Dose 1: The recommended starting dose of suzetrigine is 100 mg orally. -Dose 2, 3, and 4: Starting 12 hours after the initial dose, take 50 mg of suzetrigine orally every 12 hours. -Dose 5 and Subsequent Doses: Starting 12 hours after Dose 4, take 50 mg of suzetrigine orally every 24 hours.(1)
DISCUSSION: In a PKPB model, concomitant administration of fluconazole (a moderate CYP3A4 inhibitor) with suzetrigine with the recommended dosage modification is predicted to increase the area-under-curve (AUC) of suzetrigine and active metabolite M6-SUZ by 1.5-fold and 1.2-fold, respectively, while the maximum concentration (Cmax) of suzetrigine and M6-SUZ by 1.4-fold and 1.1-fold, respectively, when compared to the regular recommended dosage in the absence of fluconazole.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Tofacitinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of tofacitinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from tofacitinib, including serious infections, thrombosis, gastrointestinal perforation, neutropenia, anemia, elevated liver enzymes, or lipid elevations.(1)
PREDISPOSING FACTORS: Patients who are also on a drug that is a strong inhibitor of CYP2C19 are at higher risk of increased tofacitinib levels and effects.
PATIENT MANAGEMENT: In patients taking a moderate CYP3A4 inhibitor but not also a strong CYP2C19 inhibitor, no dosage modification of tofacitinib is recommended. Concurrent therapy with tofacitinib should be approached with caution as an interaction is likely.(1) In patients taking a strong CYP2C19 inhibitor in addition to a moderate CYP3A4 inhibitor, the dose of tofacitinib should be reduced as follows: - Xeljanz for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: reduce to 5 mg once daily. - Xeljanz XR for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: switch to Xeljanz 5 mg once daily. - Xeljanz for ulcerative colitis: - Induction: 5 mg twice daily for 8 weeks. If needed continue for maximum of 16 weeks. - Maintenance: 5 mg once daily. May consider 5 mg twice daily if loss of response. Use the lowest effective dosage for the shortest possible duration needed to maintain response. - Xeljanz XR for ulcerative colitis: - Induction: 11 mg once daily for 8 weeks. If needed continue for maximum of 16 weeks. - Maintenance: Not recommended. Switch to Xeljanz and follow recommendations with Xeljanz. - Xeljanz oral solution for polyarticular course juvenile idiopathic arthritis (pcJIA) or psoriatic arthritis (patients 2 years or older): - >= 10 kg to <20 kg: 3.2 mg once daily - >= 20 kg to <40 kg: 4 mg once daily - >= 40 kg: 5 mg once daily.(1)
DISCUSSION: In a study, administration of ketoconazole (a strong CYP3A4 inhibitor), increased the area-under-curve (AUC) of tofacitinib by more than 2-fold. Fluconazole (a moderate CYP3A4 and strong CYP2C19 inhibitor) increased tofacitinib AUC by about 1.75-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluvoxamine, fosamprenavir, fosnetupitant, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nirogacestat, schisandra, stiripentol, tofisopam, verapamil, and voxelotor.(3-4)
Moderate Cyp3a4 Inhibitors/Tretinoin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of tretinoin.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of and effects from tretinoin including hepatotoxicity and hyperlipidemia.(1) Retinoids, including tretinoin, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of tretinoin recommends monitoring patients taking a moderate CYP3A4 inhibitor in combination with tretinoin more frequently for adverse reactions.(1) Evaluate patients with symptoms for intracranial hypertension (such as papilledema, headache, nausea, vomiting, and visual disturbances), and, if present, institute care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin as appropriate.(1)
DISCUSSION: In 13 patients on tretinoin for 4 weeks, single-dose ketoconazole (400 to 1200 mg) (strong CYP3A4 inhibitor) increased tretinoin area-under-curve (AUC) by 72%.(1) There are no clinical pharmacokinetic studies on the combination of tretinoin with a moderate CYP3A4 inhibitor. The US manufacturer of tretinoin states increased tretinoin toxicity following concomitant use of tretinoin with certain antimycotics that are moderate CYP3A4 inhibitors has been reported post-marketing.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(2-3)
Moderate Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)
DISCUSSION: Co-administration with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)
Moderate Cyp3a4 Inhibitors/Zanubrutinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of zanubrutinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from zanubrutinib.(1)
PREDISPOSING FACTORS: Patients with severe hepatic impairment (Child-Pugh class C) have elevated zanubrutinib plasma concentrations and may be more susceptible to the effects of this interaction.(1)
PATIENT MANAGEMENT: The dosage of zanubrutinib should be reduced to 80 mg twice daily when co-administered with moderate CYP3A4 inhibitors. Modify the dose as recommended by prescribing information for adverse reactions.(1)
DISCUSSION: Co-administration with itraconazole 200 mg once daily, a strong CYP3A4 inhibitor, increased zanubrutinib concentration maximum (Cmax) and area-under-curve (AUC) by 157% and 278%, respectively. It is predicted co-administration with fluconazole 200 mg daily, a moderate CYP3A4 inhibitor, would increase zanubrutinib Cmax and AUC by 179% and 177%, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)
Moderate Cyp3a4 Inhibitors/Ziftomenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of ziftomenib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of ziftomenib, including differentiation syndrome, neutropenia, and QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of ziftomenib states that concomitant use with moderate CYP3A4 inhibitors should be monitored more closely for adverse reactions.(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: Concomitant use of ziftomenib with itraconazole, voriconazole, and posaconazole (strong CYP3A4 inhibitors) is predicted to increase ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold and 2-fold, respectively.(1) Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole) are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold, respectively.(1) Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, Schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
P-Gp And Moderate Cyp3a4 Inhibitors/Apixaban
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Cimetidine, diltiazem, dronedarone, erythromycin, isavuconazonium and verapamil may inhibit the metabolism of apixaban by CYP3A4 and by P-glycoprotein.(1,2)
CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding.(1,2)
PREDISPOSING FACTORS: This interaction may be more clinically significant in patients with decreased renal function.(1) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).
PATIENT MANAGEMENT: The Australian(1), Canadian(2), UK(3), and US(4) manufacturers state concurrent use of agents that are P-gp and moderate CYP3A4 inhibitors are expected to increase apixaban levels to a lesser extent than agents that are P-gp and strong CYP3A4 inhibitors. No dose adjustment of apixaban is necessary. Use caution when administering apixaban with moderate inhibitors of CYP3A4. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.
DISCUSSION: Concurrent ketoconazole (400 mg daily, a strong inhibitor of CYP3A4) increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1) A propensity matched cohort evaluated the concurrent use of combined P-gp and moderate CYP3A4 inhibitors with apixaban or rivaroxaban. Combined inhibitors included amiodarone (weak CYP3A4 inhibitor), diltiazem, erythromycin, dronedarone, and verapamil. Bleeding occurred in 26.4% of patients in the inhibitor group compared to 18.4% in the control group (hazard ratio 1.8; 95% CI 1.19-2.73; p=0.006). Although not statistically significant, patients in the inhibitor group also had a higher rate of major bleeding (15% vs 10.3%) and minor bleeding (8.9% vs 5.2%), respectively. This study's sample size was not large enough to evaluate individual drug pairs.(6) A summary of pharmacokinetic interactions with apixaban and calcium-channel blockers, including diltiazem and verapamil, concluded that concurrent use is considered safe based on a lesser increase in apixaban exposure with moderate CYP3A4 inhibitors.(7) A population cohort study of 48,422 patients evaluated overall and gastrointestinal major, moderate or minor bleeding in patients on concurrent therapy with apixaban and diltiazem or verapamil. Concurrent therapy was not associated with increased bleeding rates compared to patients receiving amlodipine or metoprolol.(8) A retrospective study of two propensity matched cohorts of 1681 patients each found a bleeding rate of 1.31 and 2.14 per 100 years at risk with apixaban and warfarin, respectively, when used concurrently with dronedarone in patients with atrial fibrillation. The hazard ratio with apixaban and dronedarone was 0.66 compared to warfarin and dronedarone.(9) An observational study of 29 patients evaluated concurrent administration of apixaban (5 mg) with diltiazem or diltiazem with atorvastatin or rosuvastatin. Administration of apixaban with diltiazem and rosuvastatin resulted in a greater than 1.5-fold increate in apixaban concentrations. Concurrent administration of apixaban with diltiazem alone or diltiazem with atorvastatin did not result in a statistically significant increase in apixaban concentration.(11) P-gp and moderate CYP3A4 inhibitors linked to this monograph are: conivaptan, diltiazem, dronedarone, erythromycin, isavuconazonium and verapamil.(10)
Select P-Gp Inhibitors/Edoxaban (<= 30 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2)
CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2)
PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).
PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. anti Factor Xa inhibition) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(9)
DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(8)
Select P-Gp Inhibitors/Edoxaban (> 30 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2)
CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2)
PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).
PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. anti Factor Xa inhibition) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(9)
DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, neratinib, osimertinib, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(8)
Selected Cyp3a4 Inhibitors/Felodipine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of felodipine by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent administration of strong CYP3A4 inhibitors may result in elevated levels of felodipine leading to adverse effects, including severe hypotension and peripheral edema.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of felodipine with strong CYP3A4 inhibitors should be approached with caution.(1) When these agents are used concurrently, the dose of felodipine may need to be decreased and patients should be observed for increased effects.(1) If the strong CYP3A4 inhibitor is discontinued, the dose of felodipine may need to be increased and patients should be observed for decreased effects.(1)
DISCUSSION: Concurrent use of an extended release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of felodipine.(1) A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole, a strong CYP3A4 inhibitor, on felodipine. The half-life of felodipine increased by 71% during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(1,2) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy.(5) In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(3) Voriconazole has been shown to inhibit the metabolism of felodipine in vitro.(4) Selected strong CYP3A4 inhibitors linked to this monograph are: adagrasib, cobicistat, conivaptan, ensitrelvir, grapefruit, idelalisib, indinavir, lopinavir, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, relacorilant, ribociclib, ritonavir, saquinavir, troleandomycin, and tucatinib.(5)
Selected Cyp3a4 Moderate Inhibitors/Lurasidone (<= 80 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of lurasidone.(1)
CLINICAL EFFECTS: Concomitant use of lurasidone with inhibitors of CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism or other lurasidone toxicities.(1)
PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls or swallowing disorders, and patients with Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects.(1)
PATIENT MANAGEMENT: The US manufacturer of lurasidone states that the dose of lurasidone should not exceed 80 mg daily if coadministered with moderate CYP3A4 inhibitors.(1) If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor is added to therapy, the dose of lurasidone should be decreased by 50% of the original dose.(1) If a patient is currently on a moderate CYP3A4 inhibitor and lurasidone is added to therapy, the recommended starting dose of lurasidone is 20 mg per day.(1)
DISCUSSION: Pretreatment with diltiazem (240 mg daily for 5 days), another moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1) Agents linked to this monograph include berotralstat, clofazimine, conivaptan, crizotinib, dronedarone, duvelisib, fedratinib, fluvoxamine, imatinib, isavuconazonium, letermovir, nilotinib, nirogacestat, rilzabrutinib, stiripentol, and tofisopam.(2,3)
Selected Moderate Cyp3a4 Inhibitors/Acalabrutinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of acalabrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from acalabrutinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Recommendations for management of this interaction vary in different regions. The US and Australian manufacturers of acalabrutinib state that the concurrent chronic use of moderate CYP3A4 inhibitors should be approached with caution. If a moderate CYP3A4 inhibitor is required, reduce the dose of acalabrutinib to 100 mg once daily.(1,2) The UK manufacturer of acalabrutinib states no dose adjustment is needed for concurrent use of acalabrutinib with moderate CYP3A4 inhibitors. Patients should be monitored closely for adverse effects.(3)
DISCUSSION: In a study with healthy volunteers, single-dose fluconazole 400 mg and isavuconazole 200 mg daily for 5 days (both moderate CYP3A4 inhibitors) increased the maximum concentration (Cmax) and area-under-curve (AUC) of acalabrutinib by 1.4- to 2-fold. The Cmax and AUC of the active metabolite ACP-5862 was decreased by 0.65- to 0.88-fold.(2) A physiologically based pharmacokinetic simulation with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) predicted that coadministration increases acalabrutinib Cmax and AUC by 2- to almost 3-fold.(1) In a study in healthy subjects, itraconazole (200mg once daily for 5 days, a strong inhibitor) increased the Cmax and AUC of acalabrutinib by 3.9-fold and 5.1-fold, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(4,5)
Selected Moderate Cyp3a4 Inhibitors/Atorvastatin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of atorvastatin by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis.(1)
PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.
PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inhibitors with atorvastatin may require a dose reduction. Use the lowest dose possible of atorvastatin and monitor for adverse reactions, especially with higher atorvastatin doses. Patients should be instructed to report any signs of myopathy.(1) Fluvastatin, pitavastatin and pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin in patients receiving strong CYP3A4 inhibitors.
DISCUSSION: Atorvastatin is a CYP3A4 substrate.(1) In a study, itraconazole (200 mg daily for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin (40 mg single dose) by 3.3-fold and 20%, respectively.(4) Concurrent administration of atorvastatin (40 mg for 4 days) with ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and Cmax by 3.9-fold and 4.3-fold, respectively.(1) Concurrent administration of atorvastatin (20 mg) with lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by 5.9-fold.(1) In a study, concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8 days) by 4.4-fold and 5.4-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, grapefruit, imatinib, isavuconazole, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, ritlecitinib, tofisopam, treosulfan, and voxelotor.(2,3)
Selected Moderate Cyp3a4 Inhibitors/Ivosidenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of ivosidenib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for ivosidenib toxicities such as QT prolongation.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: The US manufacturer of ivosidenib recommends considering an alternative concomitant medication with less potential for CYP3A4 inhibition.(1) During concomitant therapy with a moderate CYP3A4 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 itraconazole (200 mg once daily for 18 days) with a single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve (AUC) by 269%. No change was seen in ivosidenib's maximum concentration (Cmax).(1) Data from a pharmacokinetic simulation suggests that fluconazole, a moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC by 173%. In regards to multiple-dosing, coadministration of ivosidenib with fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and 190%, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include amprenavir, berotralstat, conivaptan, fluvoxamine, fosamprenavir, letermovir, schisandra, tofisopam, and treosulfan.(3)
Selected Moderate Cyp3a4 Inhibitors/Selected Opioids
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of alfentanil, benzhydrocodone, fentanyl,(1) hydrocodone, meperidine,(2) oxycodone,(3) and sufentanil.(4)
CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil, benzhydrocodone, fentanyl,(1,5) hydrocodone, meperidine,(2) oxycodone(3) and sufentanil(4), including somnolence and potentially fatal respiratory depression.
PREDISPOSING FACTORS: Heat.
PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(4) 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.(6) 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).(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat.(1)
DISCUSSION: Fentanyl(1) and oxycodone(3) are metabolized by the CYP3A4 isoenzyme. Moderate and strong inhibitors of this isoenzyme are expected to increase fentanyl(1) and oxycodone(3) levels. In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(4) In a randomized study in 30 patients, continuous diltiazem (1 mcg/kg/min) infusion had no effect on epidural fentanyl consumption when compared to placebo. There were no significant differences in Visual Analogue Scores (VAS), Verbal Rating Scores (VRS), or incidence of side effects, although there was a trend towards increased nausea with concurrent diltiazem.(5) In a randomized study of coronary artery bypass patients, concurrent diltiazem (60 mg orally 2 hours before induction of anesthesia then 0.1 mg/kg/hr infusion) increased the area-under-curve (AUC) and half-life of alfentanil by 40% and 50%, respectively, when compared to placebo. Patients who received diltiazem were extubated an average of 2.5 hours later than in patients who received placebo.(8) In a study in 13 patients, administration of a single dose of verapamil (75mcg/kg to 150mcg/kg) had no significant effects on the pharmacodynamic effects of a single dose of fentanyl; however, individual patients had modest decreases in blood pressure.(9) In a case report, concurrent diltiazem and fentanyl produced delirium.(10) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(11,12)
Selected P-Glycoprotein (P-Gp) Inhibitors/Betrixaban
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Betrixaban is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of betrixaban.(1)
CLINICAL EFFECTS: The concurrent use betrixaban with P-gp inhibitors may lead to elevated plasma levels of betrixaban, increasing the risk for bleeding.
PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1)
PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban and P-gp inhibitors should be avoided in patients with severe renal impairment (CrCl less than 30 ml/min).(1) The recommended dose for patients receiving or starting concomitant P-gp inhibitors is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days.(1) Note that if betrixaban is used with the combination of darunavir and cobicistat, dose adjustment of betrixaban is not necessary.(2) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to betrixaban.(3) Careful monitoring for signs and symptoms of bleeding is warranted during concurrent therapy. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). Instruct patients to report any signs and symptoms of bleeding, such as bleeding from the eyes, gums or nose; unusual bruising; dark stools; red or dark brown urine; and/or abdominal pain or swelling.(1) The anticoagulant effect of betrixaban is expected to persist for at least 72 hours after the last dose. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(8)
DISCUSSION: In the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(4) In a study in 12 subjects, concomitant administration of a single dose of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(5) An open-label study looking at concomitant administration of a single dose of betrixaban with verapamil in 18 subjects found an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(5) In a study, concomitant administration of betrixaban (80 mg) with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(5) A summary of pharmacokinetic interactions with betrixaban and amiodarone, diltiazem, or verapamil concluded that if concurrent use is warranted, the betrixaban dose should be reduced to 80 mg once then 40 mg daily. Use should be avoided if CrCl is less than 30 ml/min.(6) P-gp inhibitors include asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, hydroquinidine, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, lopinavir, mavorixafor, neratinib, osimertinib, pibrentasvir, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, vimseltinib, voclosporin and voxilaprevir.(1,4-7)
Selected Sensitive Cyp3a4 Substrates/Schisandra
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)
CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)
PREDISPOSING FACTORS: With darifenacin, 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: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)
DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)
Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1)
DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, crizotinib, daclatasvir, daridorexant, delavirdine, diltiazem, diosmin, elinzanetant, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, gepotidacin, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, oral lefamulin, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, nicardipine, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, ticagrelor, tofisopam, tolvaptan, trofinetide, vonoprazan, and voxelotor.(3,4)
Slt Strong & Moderate 3A4 Inhibitors/Cilostazol (<=50Mg Bid)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of cilostazol.(1)
CLINICAL EFFECTS: The concurrent use of cilostazol and strong and moderate inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may produce increased effects of cilostazol and adverse effects.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP3A4.(1)
DISCUSSION: In a study in 16 healthy males, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the maximum concentration (Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%, respectively. The Cmax and AUC of 4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(2) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%. Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%.(1) In a study, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the Cmax and AUC of cilostazol by 47% and 73%, respectively. The AUC of 4'-trans-hydroxy-cilostazol was increased by 141%.(1) In an vitro study in human liver microsomes, ketoconazole inhibited the metabolism of cilostazol.(3)
Strong And Moderate Cyp3a4 Inhibitors/Etrasimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may impair the CYP3A4-mediated metabolism of etrasimod.(1) Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)
CLINICAL EFFECTS: In patients who are poor metabolizers of CYP2C9 or are also taking a strong or moderate CYP2C9 inhibitor, concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects from etrasimod including immunosuppression, decreased lung function, bradycardia, and AV conduction delays.
PREDISPOSING FACTORS: CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when etrasimod is used concomitantly with strong or moderate inhibitors of CYP3A4. Patients who are also taking a strong or moderate CYP2C9 inhibitor may also have decreased etrasimod clearance.(1)
PATIENT MANAGEMENT: Concomitant use of etrasimod with strong or moderate CYP3A4 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1) Concomitant use with strong or moderate CYP3A4 inhibitors in patients who are also taking a strong or moderate CYP2C9 inhibitor is not recommended. (1)
DISCUSSION: CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of moderate to strong inhibitors of CYP3A4.(1) Concomitant use of etrasimod with steady-state fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, ensitrelvir, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, relacorilant, telaprevir, tipranavir, troleandomycin, and tucatinib.(2,3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, fluvoxamine, fosamprenavir, fosnetupitant, isavuconazonium, letermovir, lenacapavir, netupitant, schisandra, stiripentol, tofisopam, and voxelotor.(2,3)
Strong Or Mod 3A4 Inh; Dual 3A4 And 1A2 Inhibit/Roflumilast
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that are either strong or moderate CYP3A4 inhibitors or dual inhibitors of CYP1A2 and CYP3A4 may inhibit the metabolism of roflumilast.(1)
CLINICAL EFFECTS: The coadministration of roflumilast with strong or moderate CYP3A4 inhibitors or dual inhibitors of CY3A4 and CYP1A2 may increase roflumilast systemic exposure and may result in increased adverse reactions.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of roflumilast states concurrent use with CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP1A2 should be approached with caution and the risk should be weighed carefully against the benefit. Consider alternatives with no or minimal enzyme inhibition.(1)
DISCUSSION: In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with erythromycin, a moderate CYP3A4 inhibitor, (500 mg three times daily for 15 days) increased the area-under-curve (AUC) and concentration maximum (Cmax) of roflumilast by 70% and 40%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 4% and 34%, respectively.(1,2) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with ketoconazole, a strong CYP3A4 inhibitor, (200 mg twice daily for 13 days) increased the AUC and Cmax of roflumilast by 99% and 23%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 3% and 38%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with fluvoxamine, a dual CYP3A4 and CYP1A2 inhibitor, (50 mg daily for 14 days) increased the AUC and Cmax of roflumilast by 156% and 12%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 52% and 210%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with cimetidine, a dual CYP3A4 and CYP1A2 inhibitor, (400 mg twice daily for 14 days) increased the AUC and Cmax of roflumilast by 85% and 46%, respectively, and increased the AUC and decreased Cmax of roflumilast N-oxide by 27% and 4%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, saquinavir, telaprevir, tipranavir, tucatinib, and voriconazole.(3,4) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lefamulin (oral), lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(3,4) Dual CYP3A4 and CYP1A2 inhibitors linked to this monograph include: belumosudil, cannabidiol, cimetidine, ciprofloxacin, fluvoxamine, glecaprevir/pibrentasvir, grapefruit, osilodrostat, piperine, ribociclib, rucaparib, simeprevir, telithromycin, troleandomycin, verapamil, and viloxazine.(3,4)
Contraindications
Hypovolemic hyponatremia.
Concomitant use of potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, ritonavir). (See Inhibitors of Cytochrome P-450 3A Isoenzyme under Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)
Anuria. Anuric patients are not expected to obtain clinical benefit from conivaptan therapy.
The manufacturer states that solutions containing dextrose, including commercially available premixed conivaptan hydrochloride in 5% dextrose injection, are contraindicated in patients with known allergy to corn or corn products.
- Anuria
- Hypernatremia
- Hypovolemia
- Severe renal impairment
- Chronic heart failure
- Osmotic central pontine myelinolysis
- Severe hepatic disease
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in about 5% or more of individuals receiving conivaptan and more frequently than in those receiving placebo include infusion site reactions (including erythema, pain, phlebitis), hypokalemia, headache, peripheral edema, vomiting, diarrhea, constipation, hypertension, orthostatic hypotension, hyponatremia, thirst, anemia, hypotension, pyrexia, nausea, and confusion.
More Frequent
- Anemia
- Fever
- Hypertension
- Hypokalemia
- Hypotension
- Orthostatic hypotension
- Phlebitis after infusion
Less Frequent
- Acute cognitive impairment
- Atrial fibrillation
- Erythema
- Hypomagnesemia
- Peripheral edema
- Pneumonia
- Urinary tract infection
Rare or Very Rare
- Hypovolemia
- Osmotic central pontine myelinolysis
- ST segment changes
More Frequent
- Constipation
- Diarrhea
- Headache disorder
- Injection site sequelae
- Polydipsia
- Vomiting
Less Frequent
- Insomnia
- Nausea
Precautions
No enhanced messaging available.
Safety and efficacy have not been established in children younger than 18 years of age.
Category C. (See Users Guide.)
Conivaptan is distributed into milk in rats; it is not known whether conivaptan is distributed into human milk. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Adverse effect profile in geriatric patients is similar to that observed in younger adults.
ICD codes
| Code | Type | Description |
|---|---|---|
| Hyponatremia | ||
| E87.1 | ICD10CM | Hypo-osmolality and hyponatremia |
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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