Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and tipranavir

MONITOR CLOSELY: Coadministration of tipranavir with ritonavir 200 mg has been associated with cases of clinical hepatitis and hepatic decompensation including some fatalities.

MANAGEMENT: Close monitoring of hepatic function is recommended in patients treated with tipranavir and ritonavir. Particular caution is warranted in patients with chronic hepatitis B or C coinfection, as they may have an increased risk of hepatotoxicity. Patients should be advised to notify their physician if they experience signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

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GENERALLY AVOID: Coadministration with tipranavir plus low-dose ritonavir may significantly decrease the plasma concentrations of other protease inhibitors. The mechanism of interaction has not been described. Data are available for amprenavir, atazanavir, lopinavir, and saquinavir. In 16 HIV-positive subjects, administration of amprenavir (600 mg plus ritonavir 100 mg) in combination with tipranavir/ritonavir (500 mg/200 mg) twice a day for 14 days decreased the mean steady-state peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) of amprenavir by 39%, 44% and 55%, respectively, compared to administration without tipranavir/ritonavir. In 21 HIV-positive subjects, mean steady-state Cmax, AUC and Cmin of lopinavir (400 mg plus ritonavir 100 mg) decreased by 47%, 55% and 70%, respectively, while those of saquinavir (600 mg plus ritonavir 100 mg) decreased by 70%, 76% and 82%, respectively, during coadministration with tipranavir/ritonavir twice a day for 14 days. Likewise, mean steady-state Cmax, AUC and Cmin of atazanavir decreased by 57%, 68% and 81%, respectively, when atazanavir (300 mg plus ritonavir 100 mg once a day) was coadministered with tipranavir/ritonavir (500 mg/100 mg twice a day) for nine days in 13 subjects with unspecified HIV status. Atazanavir plus ritonavir increased tipranavir AUC by 20% and Cmin by 75%.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, use of other protease inhibitors in combination with tipranavir/ritonavir is not recommended.

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GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) 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: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of tenofovir alafenamide fumarate with P-gp inducers is not recommended. Whether this also applies to tenofovir disoproxil fumarate has not been established.

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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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