Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir and vincristine liposome

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or P-glycoprotein may significantly increase the plasma concentrations of vinca alkaloids, which are substrates of both the hepatic microsomal isoenzyme and intracellular efflux transporter. Although pharmacokinetic data are not available, the interaction has been associated with severe and life-threatening toxicities in both adult and pediatric cancer patients. Paralytic ileus, intestinal obstruction and perforation, laryngeal nerve paresis requiring mechanical ventilation, neurogenic bladder, paresthesia, paralysis, hypotension, hypertension, heart failure, hyponatremia secondary to SIADH, seizures, profound myelosuppression, and septic shock have been reported. Most cases have involved vincristine or vinblastine in combination with itraconazole. However, the interaction has also been reported with other known potent inhibitors such as clarithromycin, erythromycin, cyclosporine, posaconazole, voriconazole and ritonavir, as well as less potent ones such as nifedipine and isoniazid. In adults with acute lymphoblastic leukemia receiving vincristine as part of their chemotherapeutic regimen, neurotoxicity (paresthesia, muscle weakness, and paralytic ileus) was more severe and occurred earlier and more frequently in 14 patients coadministered itraconazole 400 mg/day for antifungal prophylaxis than in 460 previous patients who did not receive itraconazole (29% vs. 6%). Similarly, in a retrospective cohort study consisting of 25 patients receiving 59 courses of vinorelbine-containing chemotherapy, the incidence of grade 3 or 4 neutropenia was 63.2% in patients who were coadministered clarithromycin, compared to 27.5% in those who did not receive clarithromycin. The incidence of grade 4 neutropenia was also higher in the clarithromycin group, 31.6% vs. 2.5%. Four patients who had received vinorelbine both with and without clarithromycin had lower neutrophil counts during clarithromycin coadministration. A retrospective study to assess vincristine dosing and toxicity in combination with azoles found that vincristine dosing modifications (i.e., dose reductions, dose delays, therapy discontinuation) occurred in 58.6% of patients who received concomitant azole therapy (n=29) compared to 23.8% of patients who did not (n=21). The mean dose reduction of vincristine when combined with an azole was 46.5%. Symptoms of decreased peristalsis were also more common in the azole group, 65.5% vs. 28.6%. The individual incidence was 50%, 75%, and 66.6% in patients receiving fluconazole, voriconazole, and posaconazole, respectively. In addition, patients in the azole group were more likely to have an incomplete course of vincristine, 48.3% vs. 9.5%. Most reported cases of toxicity have been reversible following discontinuation of the CYP450 3A4 inhibitor, and many of the patients tolerated their chemotherapy in the absence of the inhibitor or after dose adjustment. In one incident, however, a patient who had been on itraconazole for fungal pneumonia developed constipation, mucositis, and granulocytopenia within one week after the first dose of vinorelbine and cisplatin, and died 12 days later. No other details were available.

MANAGEMENT: Concomitant use of vinca alkaloids with potent CYP450 3A4 and/or P-glycoprotein inhibitors should be avoided if possible. Some authorities recommend avoiding concomitant use of vinca alkaloids during and for 2 weeks after treatment with itraconazole. Otherwise, conservative dosing of the antineoplastic should be considered, and the patient closely monitored for toxicity. Based on the known half-life of vinca alkaloids (24 to 48 hours), the time course of interaction is expected to be approximately 5 to 7 days. Patients should be advised to seek medical attention if they experience symptoms that could indicate neuro- or myelotoxicity, including constipation, abdominal pain or bloating, urinary retention, paresthesia, paralysis, muscle weakness, hearing loss, seizures, erratic blood pressure changes, unusual or excessive bleeding, easy bruising, pallor, fatigue, dizziness, lightheadedness, fever, chills, and sore throat. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the antineoplastic dosage is adjusted upward to the previous dosage.

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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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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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