Enzalutamide: Understanding and Managing Drug Interactions to Improve Patient Safety and Drug Efficacy (2024)

ADT (subcutaneous injection)LeuprolideAdvanced prostate cancerNoneNoneNoneNo concernsADT (subcutaneous injection)GoserelinAdvanced prostate cancerNoneNoneNoneNo concernsADT (intramuscular injection)TriptorelinAdvanced prostate cancerNoneNoneNoneNo concernsADT (subcutaneous injection)DegarelixAdvanced prostate cancerNoneNoneNoneNo concernsADT (oral)RelugolixAdvanced prostate cancerCYP3A4, CYP2C8, and P-gp substrate; CYP3A and CYP2B6 inducerDecrease/no effectNoneNo concernsAnticoagulantsApixabanDVT; PE; stroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation, DVT prophylaxis, and PE prophylaxisCYP3A4, P‑gp, and BCRP substrateUnclear because of opposing effects on CYP3A4 and P-gpNoneStrong CYP3A4 inducers such as enzalutamide may decrease the serum concentration of apixaban. Dose adjustment may not be required but therapy modification should be consideredRivaroxabanStroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation; treatment of VTE, such as DVT and PE, including after knee, hip, or cardiac surgeryCYP3A4/5 and P-gp substrateUnclear because of opposing effects on CYP3A4 and P-gpNoneStrong CYP3A4 inducers such as enzalutamide may decrease the serum concentration of rivaroxaban. Dose adjustment may not be required but therapy modification should be consideredDabigatranStroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation; VTE, including DVT, PE, cerebral thromboembolism (e.g., cerebral venous sinus thrombosis), and central line thrombosis; thrombosis prophylaxis including DVT prophylaxis and PE prophylaxisP-gp substrateIncreaseNoneMonitor therapy. Reduce dabigatran dose or avoid coadministration in renally impaired patientsEdoxabanStroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation; treatment of DVT or PE after 5–10 days of initial therapy with a parenteral anticoagulantP-gp substrateIncreaseNoneDose adjustment may not be required but therapy modification should be consideredWarfarinTreatment of DVT or PE and for DVT prophylaxis or PE prophylaxis; thrombosis prophylaxis (i.e., arterial thromboembolism prophylaxis, stroke prophylaxis, or coronary artery thrombosis prophylaxis)CYP2C9 and CYP3A4 substrateDecreaseNoneConsider modifying therapyAntiplatelet agentsClopidogrelArterial thromboembolism prophylaxis (i.e., MI prophylaxis, stroke prophylaxis, thrombosis prophylaxis), including in persons with acute MI, STEMI, NSTEMI, or unstable anginaSubstrate and inhibitor of CYP2C19 and strong CYP2C8 inhibitorIncreaseIncreaseMonitor therapyTicagrelorArterial thromboembolism prophylaxis in patients with ACS (unstable angina, acute MI), including those undergoing PCI; reduction in risk of first MI (MI prophylaxis) or stroke in patients with CAD at high risk for these events; stroke prophylaxis in patients with acute ischemic stroke or high-risk TIACYP3A4 substrateDecreaseNoneAvoid coadministrationPrasugrelArterial thromboembolism prophylaxis (including stent thrombosis) in persons with acute coronary syndrome (i.e., unstable angina, acute MI, NSTEMI, or STEMI) who are to be managed with PCI

CYP3A4, CYP2C9, and CYP2C19 substrate

PK not affected by CYP3A4 inducers

NoneNoneNo concernsAspirinSecondary stroke prophylaxis in patients who have had an ischemic stroke or TIANoneNoneNoneNo concernsStatinsAtorvastatinTreatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control; for the purpose of reducing the risk of CV events (e.g., MI prophylaxis, stroke prophylaxis)CYP3A4 and P-gp substrate, P‑gp inhibitorDecreaseNoneMonitor therapySimvastatinTreatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control; for the purpose of reducing the risk of CV events (e.g., MI prophylaxis, stroke prophylaxis)CYP3A4 substrateDecreaseNoneNo concernsLovastatinTreatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary controlCYP3A4 substrateDecreaseNoneNo concernsFluvastatinTreatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control; for the purpose of reducing the risk of CV events (e.g., MI prophylaxis, stroke prophylaxis)CYP2C9, CYP2C8, and CYP3A4 substrateDecreaseNoneMonitor therapyPitavastatinAdjunctive therapy to diet in adult patients with primary hyperlipidemia or mixed dyslipidemia to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and to increase HDL cholesterolMinor CYP2C9 substrateNoneNoneNo concernsPravastatinTreatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control; MI prophylaxis or stroke prophylaxisNoneNoneNoneNo concernsRosuvastatinTreatment of hypercholesterolemia, including hyperlipidemia, hyperlipoproteinemia, or hypertriglyceridemia, as an adjunct to dietary control; primary prevention of CV disease (including MI prophylaxis and stroke prophylaxis) and to reduce the risk of arterial revascularization procedures in patients without evidence of coronary heart disease but who have risk factors for CV diseaseBCRP substrateNo changeNoneNo concernsCa channel blockersAmlodipineTreatment of hypertensionCYP3A4 substrateDecreaseNoneMonitor therapyDiltiazemHypertension; chronic stable angina; variant angina; atrial flutter, atrial fibrillation, or paroxysmal supraventricular tachycardia; ongoing ischemia in acute MI, STEMI, NSTEMI, or unstable angina; idiopathic dilated cardiomyopathyCYP3A4 substrate and inhibitorDecreaseNoneConsider modifying therapyVerapamilVariant angina and chronic stable angina; rapid conversion of narrow-complex paroxysmal supraventricular tachycardia to sinus rhythm; paroxysmal supraventricular tachycardia prophylaxis due to re-entry; atrial flutter or atrial fibrillation; hypertensionCYP3A4 and P-gp substrate and inhibitorDecreaseNoneConsider modifying therapyACE inhibitorsBenazeprilHypertensionNoneNoneNoneNo concernsLisinoprilHypertension, heart failure, acute MI for reduction in cardiovascular mortalityNoneNoneNoneNo concernsCaptoprilHypertension, heart failure, left ventricular dysfunction post-MI, hypertensive urgency, or hypertensive emergencyP-gp inhibitorNoneNoneNo concernsBeta-blockersCarvedilolTreatment of essential hypertension, either as a single agent or in combination with other antihypertensive agentsCYP2C9, CYP3A4, CYP2C19, and P-gp substrateDecreaseNoneNo concernsMetoprolol succinateTreatment hypertension, angina, heart failure, acute MI, and heart rate control in patients with atrial fibrillation or atrial flutterCYP2D6 substrateNoneNoneNo concernsBisoprolol fumarateTreatment of hypertension, heart failure, angina, and heart rate control in patients who have atrial fibrillation or atrial flutterNoneNoneNoneNo concernsAntiarrhythmic agentsDisopyramideDocumented, life-threatening arrhythmias such as sustained ventricular tachycardiaCYP3A4 substrateDecreaseNoneMonitor therapy. Avoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedQuinidineConversion to and/or maintenance of sinus rhythm in patients with atrial fibrillation, atrial flutter, or ventricular tachycardia; treatment of supraventricular tachycardia; paroxysmal supraventricular tachycardia prophylaxis in patients with re-entrant tachycardia, including patients with Wolff–Parkinson–White syndromeCYP3A4 and P-gp substrate; P‑gp inhibitorDecreaseNoneMonitor therapy. Avoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedProcainamideVentricular tachycardia with pulses (stable monomorphic or wide-complex regular ventricular tachycardia) during CPR in patients with preserved left ventricular functionNoneNoneNoneAvoid coadministration if the patient has a prolonged QTc Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedAmiodaroneLife-threatening recurrent ventricular fibrillation or hemodynamically unstable (symptomatic) sustained ventricular tachycardia, including post-MI patientsCYP3A4 and CYP2C8 substrate; CYP3A4, 2C9, 2D6, and 1A2 inhibitorDecreaseNoneMonitor therapy. Avoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedDofetilideConversion of atrial fibrillation/atrial flutter to normal sinus rhythm; or for maintenance therapy of patients with highly symptomatic atrial fibrillation/atrial flutter of 1week or more durationCYP3A4 substrateDecreaseNoneAvoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedSotalolMaintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation or atrial flutter who are currently in sinus rhythmNoneNoneNoneAvoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedFlecainidePrevention of life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia (i.e., ventricular tachycardia prophylaxis)None (CYP2D6 substrate)NoneNoneAvoid coadministration if the patient has a prolonged QTc Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedPropafenoneLife-threatening ventricular arrhythmias, such as sustained ventricular tachycardiaCYP2D6 and CYP3A4 substrate; P-gp inhibitorUnclear because of opposing effects on CYP3A4 and P-gpNoneMonitor for decreased propafenone effects or therapeutic failure. Avoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedDigoxinHeart failure and atrial fibrillationP-gp substrateIncreaseNoneNo concernsAngiotensin II receptor blockerValsartanHypertension; heart failureCYP2C9 substrateNoneNoneNo concernsLosartanHypertension and stroke prophylaxis in hypertensive patients with left ventricular hypertrophyPrimarily metabolized by CYP2C9 and to a lesser extent CYP3A4DecreaseNoneMonitor therapyOlmesartanHypertensionNoneNoneNoneNo concernsAngiotensin receptor/neprilysin inhibitorSacubitril/valsartanHeart failure, including for reduction in CV mortality and reduction in heart failure hospitalizationsValsartan is a CYP2C9 substrateNoneNoneNo concernsMineralocorticoid receptor antagonistsSpironolactoneHypertensionCYP3A4/5 substrate, CYP3A4/5 inhibitorDecreaseNoneNo concernsEplerenoneTreatment of hypertension, either as monotherapy or in combination with other antihypertensive agentsCYP3A4 substrateDecreaseNoneMonitor therapySulfonylureasGlyburideTreatment of T2DM as an adjunct to diet and exerciseCYP2C9 and P-gp substrateUnclear because of opposing effects on CYP2C9 and P-gpNoneMonitor therapyGlimepirideTreatment of T2DM as an adjunct to diet and exerciseCYP2C9 substrateDecreaseNoneMonitor therapyDPP4 inhibitorsSaxagliptinTreatment of T2DM as an adjunct to diet and exerciseCYP3A4/5 and P-gp substrateUnclear because of opposing effects on CYP3A4/5 and P-gpNoneMonitor therapyBiguanideMetforminTreatment of T2DM as an adjunct to diet and exerciseNoneNoneNoneNo concernsSGLT2 inhibitorsCanagliflozinTreatment of T2DM as an adjunct to diet and exercise; to reduce cardiovascular mortality and MACE in patients with T2DM with established cardiac disease; to reduce the risk of end-stage kidney disease, doubling of serum creatinine, and reduction in heart failure hospitalizations and CV death in adults with T2DM and diabetic nephropathy with albuminuria more than 300 mg/dayP-gp substrateNoneNoneNo concernsDapagliflozinTreatment of T2DM as an adjunct to diet and exercise; reduction in heart failure hospitalizations in adults with T2DM and established CV disease or multiple CV risk factors; treatment of reduced ejection fraction heart failure and preserved ejection fraction heart failure for reduction in CV mortality and hospitalization for heart failure; treatment of chronic kidney disease to reduce the risk of sustained eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure in those at risk of disease progressionNoneNoneNoneNo concernsEmpagliflozinTreatment of T2DM as an adjunct to diet and exercise; reduction in cardiovascular MACE in patients with T2DM with established CV disease; reduction in CV death and reduction in heart failure hospitalizations in adults with heart failureNoneIncreaseNoneNo concernsSSRIsCitalopramMajor depressionMild CYP2C19 inhibitorNoneNoneMonitor therapy. Avoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedFluoxetineMajor depressionCYP2D6 substrate CYP2D6 and CYP2C19 inhibitor; weak inhibitor of CYP3A4 and CYP2C9NoneNoneAvoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedSertralineMajor depressionCYP2D6 inhibitorNoneNoneMonitor therapy. Avoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedSNRIsVenlafaxineMajor depressionCYP2D6 inhibitorNoneNoneAvoid coadministration if the patient has a prolonged QTc. Otherwise, potential risks of DDIs with enzalutamide and drugs known to prolong the QTc interval can be safely overcome for most patients through multidisciplinary monitoring of serial EKGs and ensuring that electrolytes are carefully managedDesvenlafaxineMajor depressionCYP2D6 inhibitorNoneNoneNo concernsDuloxetineMajor depressionCYP2D6 substrate and inhibitorNoneNoneNo concernsAntiseizure medicationsCarbamazepineManagement of generalized tonic-clonic seizures or for partial seizures, either simple or complex partial seizuresCYP3A4 substrate, potent CYP3A4 inducerDecreaseDecreaseConsider modifying therapyPhenobarbitalTreatment of status epilepticus; maintenance treatment of all types of seizures, including but not limited to partial, myoclonic, tonic-clonic, or neonatal seizures not responding to other anticonvulsantsCYP2C9 substrate; CYP3A and P‑gp inducerDecreaseDecreaseConsider modifying therapyPhenytoinStatus epilepticus; treatment of tonic-clonic seizures or partial seizuresCYP2C9 substrate; CYP3A4, CYP2C9, CYP2C19 inducerDecreaseDecreaseConsider modifying therapyPrimidoneAlternative to other anticonvulsants for the management of generalized tonic-clonic seizures, or for the management of complex partial seizures (e.g., psychom*otor seizures)CYP2C9 substrate; CYP3A4 and P-gp inducerDecreaseDecreaseConsider modifying therapyValproic acidMonotherapy or adjunct treatment of absence seizures (simple and complex) or complex partial seizures, and adjunctively for other seizure types that include absence or complex partial seizures (e.g., tonic-clonic seizures, myoclonic seizures)CYP2C9 substrate (minor)NoneNoneNo concernsLamotrigineTreatment of partial seizures with or without secondary generalization; adjunctive therapy to other anticonvulsants in the treatment of primary generalized tonic-clonic seizures; adjunctive therapy to other anticonvulsants in the treatment of generalized seizures of Lennox–Gastaut syndromeNoneNoneNoneNo concernsGabapentinAdjunctive treatment of partial seizures with or without secondary generalized tonic-clonic seizuresNoneNoneNoneNo concernsTopiramateTreatment of partial seizures (monotherapy or adjunctive therapy)CYP3A4 (weak inducer), CYP2C19 (weak inhibitor)NoneNoneNo concernsCommon urology medicinesOxybutyninTreatment of OAB or neurogenic bladder with symptoms of urge urinary incontinence, urinary urgency, and urinary frequencyCYP3A4 substrateDecreaseNoneNo concernsMirabegronTreatment of OAB or neurogenic bladder with symptoms of urge urinary incontinence, urinary urgency, and urinary frequencyP-gp substrateIncreaseNoneMonitor therapyTrospiumTreatment of OAB with symptoms of urge urinary incontinence, urinary urgency, and urinary frequency, including neurogenic bladderNoneNoneNoneNo concernsTamsulosinTreatment of the signs and symptoms of BPHCYP3A4 substrateDecreaseNoneNo concernsImmunosuppressantsCyclosporineKidney, heart, and liver transplant rejection prophylaxis; treatment of severe rheumatoid arthritis, severe plaque psoriasis, ocular inflammation associated with dry eye disease, and ulcerative colitisCYP3A4 substrate and inhibitor; CYP2C8 inhibitor; P-gp substrate and inhibitorDecreaseIncreaseMonitor therapyTacrolimusLiver, kidney, lung, heart, pancreas, and islet transplant rejection prophylaxis; treatment of psoriasis, uveitis, dermatitis, and lupus nephritisCYP3A4 substrateDecreaseNoneMonitor plasma concentrations of tacrolimus closely and adjust dosage accordinglyEverolimusKidney and liver transplant rejection prophylaxisCYP3A4 and P‑gp substrateDecreaseNone

Concomitant use of strong CYP3A4 inducers and everolimus should be avoided if possible

Monitor therapy closely

Dose increases of everolimus may be necessary

SirolimusKidney and heart transplant rejection prophylaxisCYP3A4 and P‑gp substrateDecreaseNone

Concomitant use of strong CYP3A4 inducers and sirolimus should be avoided if possible

Monitor therapy closely

Dose increases of sirolimus may be necessary

Antigout drugsColchicineAcute gout or gouty arthritis flare; gout prophylaxisCYP3A4 and P‑gp substrateDecreaseNoneMonitor therapyNaproxen sodiumAcute goutCYP2C8 and CYP2C9 substrateDecreaseNoneMonitor therapyPrednisoneAcute gout or gouty arthritis as adjunctive therapyCYP3A4 and P‑gp substrate,DecreaseNoneMonitor therapyAllopurinolPrimary or secondary gout (i.e., acute attacks, tophi, gouty arthritis or joint destruction, uric acid lithiasis, and/or uric acid nephropathy)NoneNoneNoneNo concernsOpioid analgesicsOxycodoneTreatment of severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequateCYP3A4 substrateDecreaseNone

Monitor therapy

Consider an oxycodone dose increase until stable drug effects are achieved

If enzalutamide is discontinued, monitor for respiratory depression, and consider an oxycodone dose reduction until stable drug effects are achieved

MethadoneFor the treatment of opiate agonist dependence; treatment of moderate pain or severe painCYP3A4 and P-gp substrateDecreaseNone

Monitor therapy

Monitor for withdrawal symptoms upon initiation of enzalutamide or increase in enzalutamide dose

If enzalutamide is discontinued, monitor for adverse methadone effects, including sedation and respiratory depression

TramadolTreatment of severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequateCYP3A4 substrateDecreaseNone

Monitor therapy

Monitor patients closely for decreased efficacy of tramadol when it is combined with enzalutamide and for signs of tramadol toxicity when enzalutamide is discontinued

FentanylTreatment of severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequateCYP3A4 and P-gp substrateDecreaseNone

Monitor therapy

Patients should be closely monitored for loss of analgesia and withdrawal symptoms when fentanyl is combined with enzalutamide and for potential fentanyl toxicity when enzalutamide is discontinued

MorphineTreatment of acute and chronic severe pain requiring an opioid analgesic and for which alternative treatments are inadequateP-gp substrateIncreaseNoneNo concernsHydromorphoneTreatment of severe pain where treatment with an opioid is appropriate and for which alternative treatments are inadequateNoneNoneNoneNo concernsOxymorphoneTreatment of severe painNoneNoneNoneNo concernsPPIsOmeprazoleShort-term self-treatment of frequent dyspepsia or pyrosis (heartburn) that occurs ≥2 times per week; treatment of erosive esophagitis (erosive GERD); treatment of nonerosive GERD; short-term treatment of active benign gastric ulcer; short-term treatment of active duodenal ulcer; Helicobacter pylori eradicationCYP2C19 and CYP3A4 substrate, CYP2C19 inhibitorDecreaseNoneMonitor therapyLansoprazoleShort-term treatment of frequent dyspepsia or pyrosis (heartburn) that occurs ≥2 times per week; treatment of non-erosive GERD; long-term treatment of pathological hypersecretory conditions, including Zollinger–Ellison syndrome; H. pylori eradicationCYP2C19 and CYP3A4 substrateDecreaseNoneNo concernsPantoprazoleTreatment of erosive esophagitis (erosive GERD); treatment of pathological hypersecretion associated with Zollinger–Ellison syndrome or other hypersecretory syndromes; short-term treatment of frequent dyspepsia or pyrosis (heartburn) that occurs ≥2 times per week; treatment of nonerosive GERD; healing of duodenal ulcer; healing of gastric ulcer; H. pylori eradicationCYP2C19 and CYP3A4 substrateDecreaseNoneNo concernsEsomeprazoleTreatment of symptomatic, nonerosive GERD; treatment of diagnostically confirmed erosive esophagitis due to GERD; short-term self-treatment of frequent dyspepsia or pyrosis (heartburn) that occurs ≥2 times per week; treatment of pathological hypersecretion associated with Zollinger–Ellison syndrome; H. pylori eradicationCYP2C19 and CYP3A4 substrate, CYP2C19 inhibitorDecreaseNoneNo concernsDexlansoprazoleSymptomatic treatment of nonerosive GERD, including treatment of pyrosis (heartburn) related to GERD; treatment of erosive esophagitisCYP2C19 and CYP3A4 substrateDecreaseNoneNo concernsRabeprazoleSymptomatic treatment of nonerosive GERD; treatment of erosive esophagitis (erosive GERD); healing of duodenal ulcer; treatment of pathological hypersecretory conditions including Zollinger–Ellison syndrome; H. pylori eradicationCYP2C19 substrateDecreaseNoneNo concerns