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

GENERALLY AVOID: Coadministration with potent and some moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of simeprevir, which is primarily metabolized by the isoenzyme. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions including rash and photosensitivity. In 24 healthy study subjects administered simeprevir (150 mg once daily) in combination with the moderate CYP450 3A4 and P-glycoprotein substrate/inhibitor erythromycin (500 mg three times a day) for 7 days, mean simeprevir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) increased by approximately 4.5-, 7.5 and 12.7-fold, respectively. Erythromycin Cmax, AUC and Cmin also increased by about 1.6-, 1.9- and 3.1-fold, respectively, presumably due to inhibition of CYP450 3A4 and P-glycoprotein by simeprevir. In another study, simeprevir (200 mg once daily for 7 days) given with the potent CYP450 3A4 inhibitor ritonavir (100 mg twice daily for 15 days) to 12 healthy subjects resulted in approximately 4.7-, 7.2 and 14.4-fold increases in simeprevir Cmax, AUC and Cmin, respectively. Likewise, when simeprevir (50 mg and 150 mg once daily) was given with darunavir/ritonavir (800 mg/100 mg once daily) to 25 healthy subjects for 7 days, simeprevir Cmax, AUC and Cmin increased by about 1.8-, 2.6 and 4.6-fold, respectively, while ritonavir Cmax, AUC and Cmin increased by 1.2-, 1.3 and 1.4-fold, respectively. Darunavir Cmin increased by 1.3-fold.

MANAGEMENT: The use of simeprevir in combination with potent and some moderate CYP450 3A4 inhibitors such as azole antifungal agents, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. Some authorities recommend avoiding concomitant use of simeprevir during and for 2 weeks after treatment with itraconazole.

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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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