Drug Interactions between apalutamide and Tribenzor

GENERALLY AVOID: Potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of most calcium channel blockers (CCBs), as CYP450 3A4 is the primary isoenzyme responsible for their metabolism. Some drug interaction studies have reported a significant reduction in plasma levels for certain CCBs. For example, when a single dose of nimodipine (60 mg) was administered to patients with epilepsy (n=8) who were also receiving chronic treatment with a potent CYP450 3A4-inducing antiepileptic agent (phenytoin, phenobarbital and/or carbamazepine), the mean areas under the plasma nimodipine concentration curve (AUC) were lowered by about 7-fold compared to the control group. In another drug interaction study comparing nisoldipine pharmacokinetics in epileptic patients on concurrent phenytoin therapy (n=12) to healthy controls (n=12), the AUC of nisoldipine was approximately 90% lower (1.6 vs 15.2 mcg/L/h) in patients on concomitant phenytoin therapy. Clinical data for all calcium channel blockers with potent CYP450 3A4 inducers are not available.

MANAGEMENT: Concomitant use of calcium channel blockers (CCBs) primarily metabolized by CYP450 3A4 with potent CYP450 3A4 inducers should generally be avoided. Additional monitoring and dose adjustments may be required if coadministration is necessary, particularly during initiation, titration, or discontinuation of the CYP450 3A4 inducer. Individual product labeling for the CCB should be consulted for further guidance.

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MONITOR: Coadministration with apalutamide may decrease the plasma concentrations of drugs that are substrates of the metabolic enzymes CYP450 3A4, CYP450 2C19, CYP450 2C9, and uridine diphosphate glucuronosyltransferase (UGT), as well as substrates of the membrane transporters organic anion transporting polypeptide (OATP) 1B1, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). According to the prescribing information, coadministration of apalutamide with single oral doses of sensitive CYP450 substrates resulted in a 92% decrease in the systemic exposure (AUC) of midazolam, a CYP450 3A4 substrate; 85% decrease in the AUC of omeprazole, a CYP450 2C19 substrate; and 46% decrease in the AUC of S(-) warfarin, a CYP450 2C9 substrate. These results indicate strong induction of CYP450 3A4 and 2C19 by apalutamide, and weak induction of CYP450 2C9. Coadministration of apalutamide with single oral doses of transporter substrates resulted in a 30% decrease in the AUC of fexofenadine, a P-gp substrate, and 41% decrease in the AUC of rosuvastatin, a BCRP/OATP1B1 substrate. These results suggest that apalutamide is a weak inducer of membrane transporters. Apalutamide may also induce UGT according to the prescribing information; however, no pharmacokinetic data from studies with UGT substrates are available.

MANAGEMENT: Caution is advised when apalutamide is used concomitantly with drugs that are substrates of CYP450 3A4, CYP450 2C19, CYP450 2C9, UGT, OATP1B1, P-gp and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. Substitution for these medications is recommended when possible, or monitor for potential loss of therapeutic efficacy if coadministration is required. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a CYP450 inducer like apalutamide and for any dosage adjustments that may be required.

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The antihypertensive effect of amlodipine and thiazide diuretics may be additive. Management consists of monitoring blood pressure during coadministration, especially during the first 1 to 3 weeks of therapy.

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