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

MONITOR: Coadministration with ritonavir may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to competitive inhibition of CYP450 2D6 activity by ritonavir. The systemic exposure (AUC) of some coadministered drugs has been reported to increase by up to twofold.

MANAGEMENT: Caution is advised if ritonavir must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ritonavir is added to or withdrawn from therapy.

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MONITOR: Lopinavir in combination with ritonavir has been shown to prolong the PR interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta blockers, calcium channel blockers, atazanavir, digoxin, lacosamide, mefloquine) may result in additive effects and increased risk of conduction disturbances and atrioventricular block. In a study of 39 healthy adults who were administered lopinavir-ritonavir at a therapeutic dosage of 400 mg-100 mg twice daily and a supratherapeutic dosage of 800 mg-200 mg twice daily, mean changes from baseline in the PR interval ranged from 11.6 to 24.4 msec in the 12 hours postdose on treatment day 3 when exposures were approximately 1.5 and 3-fold higher, respectively, than those observed with recommended once-daily or twice-daily dosages of lopinavir-ritonavir at steady state. After baseline correction, the maximum mean difference from placebo in the PR interval was 24.9 msec for the lower dosage and 31.9 msec for the supratherapeutic dosage. Maximum PR interval observed was 286 msec, and no second- or third-degree heart block occurred. There have been postmarketing reports of asymptomatic prolongation of the PR interval in some patients receiving combination antiretroviral therapy containing lopinavir-ritonavir. Second- and third-degree atrioventricular block have occurred rarely in patients with underlying structural heart disease or preexisting conduction system abnormalities and in patients receiving lopinavir-ritonavir with other drugs known to prolong the PR interval.

MANAGEMENT: Caution is advised if lopinavir-ritonavir is used concomitantly with other agents that prolong the PR interval, particularly those that are metabolized by CYP450 3A4 (e.g., calcium channel blockers) because lopinavir-ritonavir is a potent inhibitor of the isoenzyme. The elderly as well as patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, or cardiomyopathies may be at increased risk for developing cardiac conduction disturbances and atrioventricular block associated with the use of lopinavir-ritonavir. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, fainting, or irregular heartbeat.

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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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