Drug Interactions between efavirenz and Kaletra

ADJUST DOSE: Coadministration with efavirenz may decrease the plasma concentrations of lopinavir, even in the presence of low-dose ritonavir as a pharmacokinetic booster. The proposed mechanism is efavirenz induction of lopinavir metabolism via CYP450 3A4. In a parallel group study consisting of healthy, HIV-negative subjects, coadministration of lopinavir-ritonavir (400 mg-100 mg capsule twice a day) with efavirenz (600 mg once daily) for nine days resulted in a 19% relative decrease in lopinavir systemic exposure (AUC) and a 39% relative decrease in trough plasma concentration (Cmin) in 11 subjects compared to administration of lopinavir-ritonavir alone in 7 subjects. Efavirenz Cmax and AUC were also reduced by 16% each compared to administration of efavirenz alone in 12 healthy subjects. When the dosage of lopinavir-ritonavir was increased to 500 mg-125 mg (two 200 mg-50 mg tablets and one 100 mg-25 mg tablet) twice daily and coadministered with efavirenz for nine days in 19 healthy subjects, similar lopinavir concentrations were observed compared to lopinavir-ritonavir 400 mg-100 mg (two 200 mg-50 mg tablets) administered twice daily without efavirenz. By contrast, when the lopinavir-ritonavir dosage was increased to 600 mg-150 mg (three 200 mg-50 mg tablets) twice daily and coadministered with efavirenz for nine days in 23 healthy subjects, lopinavir plasma concentrations were significantly increased by approximately 35% and ritonavir concentrations by 56% to 92% compared to lopinavir-ritonavir 400 mg-100 mg (two 200 mg-50 mg tablets) administered twice daily without efavirenz. The clinical significance in terms of safety and efficacy is unknown. In healthy volunteers, lopinavir-ritonavir did not significantly affect the plasma concentrations of efavirenz. However, due to study discontinuations, there was limited power to detect changes in efavirenz pharmacokinetics in the presence of lopinavir-ritonavir.

MANAGEMENT: A dosage increase is recommended for lopinavir-ritonavir when used in combination with efavirenz. For adults, the dosage should be increased to 500 mg-125 mg (two 200 mg-50 mg tablets and one 100 mg-25 mg tablet) twice daily for the tablets and 533 mg-133 mg (6.5 mL) twice daily for the oral solution. Lopinavir-ritonavir should not be administered as a once daily regimen in combination with efavirenz. For pediatric patients 6 months to 18 years of age, the dosage should be increased to 300 mg-75 mg/m2 twice daily for the oral solution in both treatment-naive and treatment-experienced patients, not to exceed the recommended adult dosage of 533 mg-133 mg (6.5 mL) twice daily. If weight-based dosing is preferred, the recommended dosage is 13 mg-3.25 mg/kg given twice daily for patients under 15 kg and 11 mg-2.75 mg/kg given twice daily for patients 15 kg to 45 kg. Pediatric patients weighing more than 45 kg should receive the adult dosage of lopinavir-ritonavir. Please consult the manufacturer's product labeling for pediatric dosing of the tablet formulation. Lopinavir-ritonavir should not be administered in combination with efavirenz in patients under 6 months of age due to the lack of clinical data.

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MONITOR: Coadministration with efavirenz may variably affect the plasma concentrations of ritonavir. Specifically, ritonavir levels have been reported to increase when it is given therapeutically as an antiretroviral agent and decrease when it is used at low dosages as a pharmacokinetic booster. In 11 healthy subjects given ritonavir 500 mg every 12 hours, efavirenz (600 mg once a day) increased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) of ritonavir by 24% and 18%, respectively. Efavirenz Cmax and AUC also increased 14% and 21%, respectively. The combination was associated with a higher frequency of adverse effects and laboratory abnormalities. In contrast, addition of efavirenz in 14 healthy male volunteers given indinavir 800 mg and ritonavir 100 mg orally twice a day led to decreases of 34%, 36% and 39% in ritonavir Cmax, AUC, and trough plasma concentration (Cmin), respectively. Efavirenz is primarily an inducer but also can be an inhibitor of the CYP450 3A4 isoenzyme. At low ritonavir plasma levels, efavirenz induction appears to be the predominant effect and causes an overall increased clearance of ritonavir. At higher plasma levels, however, ritonavir inhibiting effects may take over, resulting in increased concentrations of the drugs. However, efavirenz reportedly had no effect on the pharmacokinetics of ritonavir administered as lopinavir-ritonavir (400 mg-100 mg twice daily).

MANAGEMENT: When ritonavir is given therapeutically, coadministration with efavirenz may be associated with a higher frequency of adverse clinical events (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended during combination use. When ritonavir is given as a pharmacokinetic booster, limited data suggest it may be possible to overcome the inducing effects of efavirenz by increasing the ritonavir dosage (e.g., 200 mg twice a day).

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