Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and Tegretol XR

ADJUST DOSING INTERVAL: Coadministration of lopinavir-ritonavir with carbamazepine may result in decreased plasma concentrations of lopinavir and increased plasma concentrations of carbamazepine. The proposed mechanism involves carbamazepine induction of lopinavir metabolism via CYP450 3A4 and conversely, lopinavir-ritonavir inhibition of carbamazepine metabolism via the same enzymatic pathway. Clinical studies have shown that potent CYP450 3A4 inducers can significantly alter the plasma concentrations of lopinavir, possibly by overriding some of the boosting effects of ritonavir and enhancing the clearance of both lopinavir and ritonavir. In 12 healthy volunteers, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) with potent CYP450 3A4 inducer phenytoin (300 mg once daily on days 11 through 22) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) by 24%, 33%, and 46%, respectively. Ritonavir Cmax, AUC, and Cmin were also reduced by 20%, 28%, and 47%, respectively, although only the change in Cmin was statistically significant. In addition, in one case report a 50-year-old HIV-positive male who had been stabilized on carbamazepine (400 mg three times a day), developed excessive drowsiness within 9 days of starting an antiretroviral regimen containing lopinavir-ritonavir (400 mg-100 mg twice daily), tenofovir, and lamivudine. The carbamazepine serum concentration was found to have increased from a pre-antiretroviral treatment level of 10.3 mg/L, up to 15 mg/L by day 9 of the concomitant antiretroviral treatment regimen. However, symptoms resolved when the carbamazepine dose was reduced to 400 mg twice daily, and carbamazepine serum concentrations measured on day 11 had fallen to 7.4 mg/L.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if lopinavir-ritonavir is prescribed with carbamazepine. Once-daily administration of lopinavir-ritonavir should be avoided when used concomitantly with carbamazepine. An increase in the dosage of lopinavir-ritonavir may be necessary, although dosage adjustment has not been evaluated in clinical studies. Close clinical and laboratory monitoring of antiretroviral response is recommended following the addition or discontinuation of carbamazepine in patients already receiving lopinavir-ritonavir as part of their HIV treatment regimen. Likewise, if lopinavir-ritonavir is added to stable carbamazepine therapy, serum drug levels and pharmacologic effects should be closely monitored and the carbamazepine dose adjusted accordingly. Patients should be advised to contact their doctor if they develop signs of carbamazepine toxicity such as ataxia, disorientation, dizziness, nausea, vomiting, and visual disturbances.

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ADJUST DOSE: Coadministration with inducers of P-glycoprotein (P-gp), such as carbamazepine, may decrease the oral bioavailability and plasma concentrations of tenofovir alafenamide (TAF), which is a substrate of the efflux transporter. In 26 healthy study subjects, administration of TAF (25 mg once daily) with the P-gp inducer carbamazepine (300 mg twice daily) decreased TAF plasma concentration (Cmax) and systemic exposure (AUC) by an average of 57% and 55%, respectively, compared to TAF administered alone. It is not known if, and to what extent, tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, may interact with P-gp inducers. The interaction has not been studied with TDF, and no information is found in the labeling of various products containing TDF, although it has been reported to be a P-gp substrate also.

MANAGEMENT: When coadministered with carbamazepine, the dose of tenofovir alafenamide should be increased to 50 mg once daily. Patients should be monitored for subtherapeutic antiviral drug levels and loss of antiviral activity. Some authorities recommend avoiding concomitant administration of tenofovir alafenamide with carbamazepine (UK). Whether this interaction also applies to tenofovir disoproxil fumarate has not been established.

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MONITOR: Coadministration with ritonavir may significantly increase the plasma concentrations and pharmacologic effects of carbamazepine. The proposed mechanism is ritonavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of carbamazepine. There have been case reports of patients stabilized on carbamazepine therapy who developed ataxia, disorientation, vertigo, vomiting, and transient liver dysfunction following the addition of ritonavir, subsequently requiring discontinuation of ritonavir or substantial reductions of carbamazepine dosage. The effect of carbamazepine on ritonavir clearance has not been reported. Theoretically, ritonavir plasma levels may decrease due to carbamazepine induction of CYP450 3A4, which also metabolizes ritonavir.

MANAGEMENT: Given its narrow therapeutic index, caution is advised if carbamazepine must be used concomitantly with ritonavir. Carbamazepine levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of ritonavir in patients who are stabilized on their anticonvulsant regimen. Patients should be advised to contact their physician if they develop signs of carbamazepine toxicity such as ataxia, dizziness, nausea, vomiting, and visual disturbances. In addition, it may be appropriate to monitor patients for potentially reduced antiretroviral response due to decreased plasma levels of ritonavir and other antiretroviral agents induced by carbamazepine.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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