Drug Interactions between Atripla and Malarone Pediatric

GENERALLY AVOID: Coadministration with efavirenz may significantly decrease the plasma concentrations of atovaquone and proguanil. The mechanism of interaction has not been established, but may involve induction of the glucuronidation of atovaquone and the CYP450 2C19-mediated metabolism of proguanil. According to an open-label study from the Netherlands, HIV patients stabilized on antiretroviral regimens containing efavirenz (600 mg once daily; n=20) had significantly lower plasma concentrations of atovaquone and proguanil compared to healthy volunteers (n=18) following a single 250 mg/100 mg dose of atovaquone/proguanil. Specifically, atovaquone systemic exposure (AUC) was 75% lower and proguanil AUC was 43% lower in the efavirenz group than in the control group. In another study, 10 HIV-infected patients taking efavirenz-containing antiretroviral regimens had atovaquone AUC that was approximately 47% lower when given atovaquone 750 mg twice daily for 14 days and 44% lower when given atovaquone 1500 mg twice daily for 14 days compared to 10 HIV-infected controls not taking antiretroviral therapy given the same dosages of atovaquone. Only half of the subjects receiving efavirenz and atovaquone 750 mg twice daily had an average atovaquone concentration greater than 15 mcg/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia, compared to all subjects in the control group. Moreover, just 2 of 10 subjects receiving efavirenz with atovaquone 750 mg twice daily achieved an average atovaquone concentration greater than 18.5 mcg/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis, compared to 9 of 10 controls.

MANAGEMENT: Given the potential for treatment failure when atovaquone or atovaquone/proguanil is administered with efavirenz, concomitant use is not recommended.

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GENERALLY AVOID: Coadministration with efavirenz may significantly decrease the plasma concentrations of atovaquone and proguanil. The mechanism of interaction has not been established, but may involve induction of the glucuronidation of atovaquone and the CYP450 2C19-mediated metabolism of proguanil. According to an open-label study from the Netherlands, HIV patients stabilized on antiretroviral regimens containing efavirenz (600 mg once daily; n=20) had significantly lower plasma concentrations of atovaquone and proguanil compared to healthy volunteers (n=18) following a single 250 mg/100 mg dose of atovaquone/proguanil. Specifically, atovaquone systemic exposure (AUC) was 75% lower and proguanil AUC was 43% lower in the efavirenz group than in the control group. In another study, 10 HIV-infected patients taking efavirenz-containing antiretroviral regimens had atovaquone AUC that was approximately 47% lower when given atovaquone 750 mg twice daily for 14 days and 44% lower when given atovaquone 1500 mg twice daily for 14 days compared to 10 HIV-infected controls not taking antiretroviral therapy given the same dosages of atovaquone. Only half of the subjects receiving efavirenz and atovaquone 750 mg twice daily had an average atovaquone concentration greater than 15 mcg/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia, compared to all subjects in the control group. Moreover, just 2 of 10 subjects receiving efavirenz with atovaquone 750 mg twice daily achieved an average atovaquone concentration greater than 18.5 mcg/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis, compared to 9 of 10 controls.

MANAGEMENT: Given the potential for treatment failure when atovaquone or atovaquone/proguanil is administered with efavirenz, concomitant use is not recommended.

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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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