Imbruvica Drug Interactions

Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A4 (CYP3A4).
Agents that may increase ibrutinib plasma concentrations: Concomitant use of Ibrutinib (Imbruvica) and drugs that strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure and strong CYP3A4 inhibitors should be avoided.
Strong CYP3A4 inhibitors: Co-administration of ketoconazole, a very strong CYP3A4 inhibitor, in 18 healthy subjects, increased exposure (C_max and AUC_0-last) of ibrutinib by 29- and 24-fold, respectively. In a dedicated drug-drug interaction study in patients with B-cell malignancies, co-administration of voriconazole increased C_max and AUC by 6.7-fold and 5.7-fold, respectively. In clinical studies, the maximal observed ibrutinib exposure (AUC) was ≤2-fold in 37 patients treated with mild and/or moderate CYP3A inhibitors when compared with the ibrutinib exposure in 76 patients not treated concomitantly with CYP3A inhibitors. Clinical safety data in 66 patients treated with moderate (n=47) or strong CYP3A inhibitors (n=19) did not reveal meaningful increases in toxicities. Voriconazole and posaconazole can be used concomitantly with Ibrutinib (Imbruvica) as per dose recommendations in the table as follows. All other strong inhibitors of CYP3A4 (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodone and cobicistat) should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, see recommended dose modifications in the table as follows.
Moderate and mild CYP3A inhibitors: In patients with B-cell malignancies, co-administration of the CYP3A inhibitor erythromycin increased C_max and AUC by 3.4-fold and 3.0-fold, respectively. If a moderate CYP3A inhibitor (e.g., fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, diltiazem, fosamprenavir, imatinib, verapamil, amiodarone and dronedarone) is indicated, reduce Ibrutinib (Imbruvica) dose as per recommended dose modifications in the table as follows.
No dose adjustment is required in combination with mild inhibitors. Monitor patient closely for toxicity and follow dose modification guidance as needed. Avoid grapefruit and Seville oranges during Ibrutinib (Imbruvica) treatment as these contain moderate inhibitors of CYP3A (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Recommended dose modifications are described as follows: see Table 36.

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After discontinuation of a CYP3A inhibitor, resume previous dose of Ibrutinib (Imbruvica) (see Dosage & Administration).
Agents that may decrease ibrutinib plasma concentrations: Administration of Ibrutinib (Imbruvica) with strong inducers of CYP3A decreases ibrutinib plasma concentrations by up to 90%.
Avoid concomitant use of strong CYP3A inducers (e.g. carbamazepine, rifampin, phenytoin and St. John's Wort). Consider alternative agents with less CYP3A induction.
Drugs that may have their plasma concentrations altered by ibrutinib: In vitro studies indicated that ibrutinib is a weak reversible inhibitor toward CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 and does not display time-dependent CYP450 inhibition. The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, CYP2C8, CYP2C9, and CYP2D6. Both ibrutinib and the dihydrodiol metabolite are at most weak inducers of CYP450 isoenzymes in vitro. However, in a drug interaction study in patients with B-cell malignancies, a single 560 mg dose of ibrutinib did not have a clinically meaningful effect on the exposure of the CYP3A4 substrate midazolam. In the same study, 2 weeks of treatment with ibrutinib at 560 mg daily had no clinically relevant effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel), the CYP3A4 substrate midazolam, nor the CYP2B6 substrate bupropion.
In vitro studies indicated that ibrutinib is not a substrate of P-gp nor other major transporters, except OCT2. The dihydrodiol metabolite and other metabolites are P-gp substrates. Ibrutinib is a mild inhibitor of P-gp and breast cancer resistance protein (BCRP). Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP after a therapeutic dose. There are no clinical data available. To minimize the potential for an interaction with the GI tract, narrow therapeutic range P-gp or BCRP substrates such as digoxin or methotrexate should be taken at least 6 hours before or after Ibrutinib (Imbruvica). Ibrutinib may also inhibit BCRP systemically and increase the exposure of drugs that undergo BCRP-mediated hepatic efflux, such as rosuvastatin.