Drug Interactions between AccessPak for HIV PEP Expanded with Viracept and Symfi Lo

GENERALLY AVOID: Concomitant use of the cytidine analog nucleoside reverse transcriptase inhibitors (NRTI) lamivudine and emtricitabine may inhibit the intracellular phosphorylation of one another to their respective active derivative in vivo. This could result in diminished antiretroviral effects of these drugs. However, clinical experience on the coadministration of cytidine analogs is lacking. This interaction may also occur with zalcitabine. In addition, the therapeutic efficacy of these drugs in combination appears limited, since lamivudine and emtricitabine have similar resistance profiles via mutation of the same viral reverse transcriptase gene (M184V).

MANAGEMENT: The use of the cytidine analog NRTIs lamivudine, emtricitabine, or zalcitabine in any combination in an antiretroviral treatment regimen that consists of two NRTIs is not recommended. Local antiretroviral treatment experts should be consulted for current practice.

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MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

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MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

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MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

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Coadministration with efavirenz may modestly increase the plasma concentrations of nelfinavir. The proposed mechanism is efavirenz inhibition of nelfinavir metabolism via CYP450 2C19 to its active metabolite M8, which is a secondary pathway to CYP450 3A4 metabolism that yields inactive metabolites. In 10 study subjects, coadministration of nelfinavir (750 mg every 8 hours) and efavirenz (600 mg once a day) for 7 days resulted in an approximately 20% increase in nelfinavir peak plasma concentration (Cmax) and area under the concentration-time curve (AUC). Efavirenz Cmax and AUC decreased by 12%, while M8 Cmax and AUC decreased by 40% and 37%, respectively. The effect of efavirenz on the pharmacokinetics of nelfinavir boosted by ritonavir, and vice versa, have also been studied. In 24 healthy subjects, coadministration of efavirenz (600 mg) in combination with ritonavir (200 mg) and nelfinavir (1875 mg) once a day in the evening with a snack for 10 days resulted in an increase in nelfinavir Cmax, AUC and C24 (plasma concentration at 24 hours postdose) by 29%, 30% and 48%, respectively, compared to administration of nelfinavir and ritonavir alone. No changes were observed for efavirenz or M8, presumably due to inhibition of CYP450 3A4 metabolism by ritonavir. Although ritonavir Cmax, AUC and C24 were decreased by 24%, 20% and 12%, respectively, its boosting effects apparently remained. No dosage adjustment should be necessary when efavirenz is prescribed with nelfinavir, with or without ritonavir.

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