Drug Interactions between cabozantinib and cobicistat / elvitegravir / emtricitabine / tenofovir

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of cabozantinib, which is a substrate of the isoenzyme. In healthy subjects, administration of the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 27 days) increased single-dose plasma cabozantinib systemic exposure (AUC) by 38%. High plasma levels of cabozantinib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Concomitant use of cabozantinib with potent CYP450 3A4 inhibitors should generally be avoided. If concomitant use is required, the daily dosage of cabozantinib should be reduced by 40 mg (e.g., 140 mg to 100 mg daily; 100 mg to 60 mg daily). The original dosage may be resumed 2 to 3 days after discontinuation of the potent CYP450 3A4 inhibitor. However, some authorities recommend avoiding concomitant use of cabozantinib during and for 2 weeks after treatment with itraconazole. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Patients should also be advised regarding a potential increase in more common side effects of cabozantinib, such as diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), hypertension, vomiting, weight loss, and constipation.

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MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

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MONITOR: Coadministration of cabozantinib with multidrug resistance-associated proteins (MRP2) inhibitors may increase exposure and toxicity of cabozantinib. In vitro studies have shown MRP2 inhibitors may increase the plasma concentrations of cabozantinib, a MRP2 substrate. The clinical relevance of this finding is not known.

MANAGEMENT: Caution is advised if cabozantinib is used concomitantly with a MRP2 inhibitor. Monitor for cabozantinib toxicity, such as gastrointestinal perforations and fistulas, hemorrhage, thrombotic events, hypertension, diarrhea, and palmar-plantar erythrodysesthesia. Dose reductions, interruption or discontinuation of cabozantinib may be necessary if toxicity occurs.

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GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.

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MONITOR: Coadministration of cabozantinib with multidrug resistance-associated proteins (MRP2) inhibitors may increase exposure and toxicity of cabozantinib. In vitro studies have shown MRP2 inhibitors may increase the plasma concentrations of cabozantinib, a MRP2 substrate. The clinical relevance of this finding is not known.

MANAGEMENT: Caution is advised if cabozantinib is used concomitantly with a MRP2 inhibitor. Monitor for cabozantinib toxicity, such as gastrointestinal perforations and fistulas, hemorrhage, thrombotic events, hypertension, diarrhea, and palmar-plantar erythrodysesthesia. Dose reductions, interruption or discontinuation of cabozantinib may be necessary if toxicity occurs.

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