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

MONITOR CLOSELY: Coadministration with other drugs that are known to increase triglyceride levels or cause pancreatic toxicity may potentiate the risk of pancreatitis associated with the use of bexarotene. In clinical studies consisting of a total of 152 patients with cutaneous T-cell lymphoma (CTCL) and 352 patients with non-CTCL cancers treated with bexarotene, acute pancreatitis was reported in 4 CTCL and 6 non-CTCL cancer patients, with one fatality. The reported cases were associated with marked elevations in fasting serum triglycerides, the lowest being 770 mg/dL in one patient. Major, dose-related lipid abnormalities occur in most patients treated with bexarotene. Approximately 70% of patients with CTCL who received an initial dose of 300 mg/m2/day had fasting triglyceride levels greater than 2.5 times the upper limit of normal. About 55% of these patients had values over 800 mg/dL, with a median of about 1200 mg/dL. The incidence of NCI Grade 3 or 4 triglyceride elevations was 28% in CTCL patients receiving an initial dose of 300 mg/m2/day, but increased to 45% in CTCL patients receiving greater than 300 mg/m2/day. Significant increases in total cholesterol and decreases in HDL cholesterol were also reported at a high rate. Hyperlipidemic effects were reversible with cessation of therapy, and could generally be mitigated by bexarotene dose reduction or concomitant antilipemic therapy.

MANAGEMENT: Caution is advised when bexarotene is given in combination with other medications that are known to increase triglyceride levels or associated with pancreatic toxicity. Other risk factors such as a history of pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, or biliary tract disease should also be considered when weighing benefits versus risks of bexarotene therapy. All patients treated with bexarotene should have fasting blood lipids measured before initiating therapy, weekly during therapy until the lipid response to bexarotene is established (usually within two to four weeks), and at 8-week intervals thereafter. Fasting triglycerides should be normal, or normalized with appropriate intervention, prior to initiating bexarotene. Attempts should be made to maintain triglyceride levels below 400 mg/dL to minimize the risk of pancreatitis and other clinical sequelae. If fasting triglycerides are elevated, antilipemic therapy should be instituted, and if necessary, bexarotene dose reductions or treatment discontinuation. Patients should be advised to seek medical attention if they experience potential symptoms of pancreatitis such as persistent nausea, vomiting, abdominal tenderness, and upper abdominal pain, especially that which is made worse after eating or radiates to the back.

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MONITOR: Coadministration of lopinavir-ritonavir with inducers of CYP450 3A4 may decrease the plasma concentrations of lopinavir, which is primarily metabolized by the isoenzyme. Clinical studies have shown that potent CYP450 3A4 inducers such as rifampin and phenytoin can significantly alter the plasma concentrations of lopinavir, possibly by overriding some of the inhibiting effects of ritonavir and enhancing the clearance of both lopinavir and ritonavir. In 22 healthy, HIV-negative subjects, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 20 days) with rifampin (600 mg once daily for 10 days) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 55%, 75% and 99%, respectively. In another study of 12 healthy volunteers, coadministration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) and phenytoin (300 mg once daily on days 11 thru 22) resulted in decreases in Cmax, AUC and Cmin of lopinavir 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. The extent to which other, less potent inducers of CYP450 3A4 may interact with lopinavir-ritonavir is unknown.

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 CYP450 3A4 inducers. Close clinical and laboratory monitoring of antiretroviral response is recommended.

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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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