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Drug Interactions between atovaquone / proguanil and efavirenz

This report displays the potential drug interactions for the following 2 drugs:

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Major

atovaquone efavirenz

Applies to: atovaquone / proguanil and efavirenz

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.

References

  1. (2001) "Product Information. Sustiva (efavirenz)." DuPont Pharmaceuticals
  2. Van Luin M, Van der Ende ME, Richter C, et al. (2010) "Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir." AIDS, 24, p. 1223-6

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Major

efavirenz proguanil

Applies to: efavirenz and atovaquone / proguanil

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.

References

  1. (2001) "Product Information. Sustiva (efavirenz)." DuPont Pharmaceuticals
  2. Van Luin M, Van der Ende ME, Richter C, et al. (2010) "Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir." AIDS, 24, p. 1223-6

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Drug and food interactions

Moderate

atovaquone food

Applies to: atovaquone / proguanil

ADJUST DOSING INTERVAL: Food, particularly high-fat food, significantly enhances the oral absorption and bioavailability of atovaquone. In 16 healthy volunteers, administration of a single 750 mg dose of atovaquone suspension following a standard breakfast (23 g fat: 610 kCal) resulted in an approximately 3.4-fold increase in the mean peak plasma concentration (Cmax) and a 2.5-fold increase in the mean area under the plasma concentration-time curve (AUC) of atovaquone compared to administration following an overnight fast. In a study consisting of 19 HIV-infected volunteers receiving atovaquone suspension 500 mg/day, Cmax and AUC of atovaquone increased by 72% and 66%, respectively, in the fed state relative to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atovaquone products (suspension, tablet, or in combination with proguanil) should be administered with a meal or milky drink, or enteral nutrition at the same time(s) each day. Because plasma atovaquone concentrations have been shown to correlate with the likelihood of successful treatment and in some cases, survival, alternative therapies may be appropriate for patients who have difficulty taking atovaquone with food.

References

  1. (2001) "Product Information. Mepron (atovaquone)." Glaxo Wellcome
  2. (2001) "Product Information. Malarone (atovaquone-proguanil)." Glaxo Wellcome
  3. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT (2009) "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm, 66, p. 1438-67

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Moderate

efavirenz food

Applies to: efavirenz

ADJUST DOSING INTERVAL: Administration with food increases the plasma concentrations of efavirenz and may increase the frequency of adverse reactions. According to the product labeling, administration of efavirenz capsules (600 mg single dose) with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with mean increases of 39% and 51% in efavirenz peak plasma concentration (Cmax) and 22% and 17% in systemic exposure (AUC), respectively, compared to administration under fasted conditions. For efavirenz tablets, administration of a single 600 mg dose with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) resulted in a 79% increase in mean Cmax and a 28% increase in mean AUC of efavirenz relative to administration under fasted conditions.

MANAGEMENT: Efavirenz should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms such as dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations, although they often resolve on their own after the first 2 to 4 weeks of therapy . Patients should be advised of the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs, and to avoid driving or operating hazardous machinery until they know how the medication affects them.

References

  1. (2001) "Product Information. Sustiva (efavirenz)." DuPont Pharmaceuticals

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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