Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and Timoptic-XE

MONITOR: Coadministration with inhibitors of CYP450 2D6 may increase the systemic effects of topically administered timolol, which is metabolized by the isoenzyme. Following ocular administration, timolol is systemically absorbed and can reach plasma levels associated with adverse beta-adrenergic blocking effects such as bronchospasm, depression, bradycardia, and hypotension. The risk may be increased if clearance of the drug is significantly diminished by concomitant CYP450 2D6 inhibitors. In one case report, a 70-year-old man experienced dizziness secondary to sinus bradycardia after 12 weeks of treatment with a 0.5% timolol eye drop while also taking quinidine sulfate 500 mg three times a day. The symptoms subsided and sinus rhythm returned to normal a day after discontinuation of both drugs. However, symptoms returned within 30 hours after restarting both drugs a month later. Quinidine was discontinued, and the patient did not experience further problems. In a study of 13 healthy volunteers, extensive metabolizers of CYP450 2D6 administered quinidine (50 mg single oral dose) 30 minutes before 0.5% timolol eye drop (2 drops in each nostril) demonstrated significantly greater reductions in exercise heart rate and had higher plasma timolol concentrations than when given timolol alone. The changes resulted in values that were similar to those observed in poor metabolizers given the timolol eye drop without quinidine. In another study, 12 healthy volunteers given cimetidine (400 mg orally twice a day for 7 doses) and 0.5% timolol eye drop (0.05 mL in each eye 30 minutes after last dose of cimetidine) demonstrated additional reductions in resting heart rate and intraocular pressure relative to administration of the timolol eye drop alone, although there were no additional reductions of exercise heart rate or systolic blood pressure (at rest or after exercise) compared to timolol alone.

MANAGEMENT: Patients should be monitored for systemic beta-adrenergic blocking effects of topical timolol during coadministration with CYP450 2D6 inhibitors such as cimetidine, quinidine, and certain selective serotonin reuptake inhibitors. Particular caution is warranted in elderly patients, since they are generally more susceptible to adverse effects of topically administered beta blockers.

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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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