Drug Interactions between nevirapine and Rifadin

GENERALLY AVOID: Coadministration with rifampin may substantially decrease the plasma concentrations of nevirapine, although a few studies have suggested that the combination may be used effectively without dosage adjustments. The mechanism is rifampin induction of nevirapine metabolism via CYP450 3A4. In a study of 14 subjects, rifampin was reported to decrease the peak plasma concentration (Cmax), area under the concentration-time curve (AUC), and trough plasma concentration (Cmin) of nevirapine by 50%, 58%, and 68%, respectively. In another study, the addition of rifampin (600 mg once a day) in 5 HIV-infected subjects treated with antiretroviral therapy containing nevirapine (200 mg twice a day) resulted in decreases in the median steady-state nevirapine Cmax and AUC of 36% and 31%, respectively, compared to baseline. Cmin was reduced 21% but the difference was not statistically significant, and the authors contend that it was still many fold above the IC50 for nevirapine. No effect on the pharmacokinetics of rifampin was observed based on comparison to 5 patients administered rifampin without nevirapine.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, nevirapine labeling and some experts recommend that alternative antimycobacterial agents be considered in patients already receiving effective nevirapine-containing antiretroviral therapy. For treatment of latent tuberculosis (TB) infection, a nine-month regimen of isoniazid may be considered if feasible. For treatment of HIV-related TB, a regimen that includes rifabutin is generally preferred, as rifabutin appears to be as effective as rifampin but is a much less potent inducer of CYP450 3A4. Nonrifamycin-containing regimens may be suboptimal (higher mortality rates; higher rates of treatment failure and relapse; increased adverse effects; longer treatment duration) and are usually not recommended for HIV-related TB except in patients who are intolerant of rifamycins or infected with a rifamycin-resistant isolate. In patients who have not begun antiretroviral therapy at the time TB treatment is initiated, clinicians may also consider using rifampin and postponing antiretroviral therapy. With early HIV disease, it may be reasonable to monitor CD4 cell count and postpone antiretroviral therapy until TB treatment is complete, since there is low risk of HIV disease progression or death during this period. However, the optimal time for starting antiretroviral therapy should be individualized based on initial response to TB treatment and occurrence of side effects. In patients with low CD4 cell counts, clinicians may consider delaying antiretroviral therapy until after the first one or two months of TB therapy, as side effects are common during this multi-drug phase of TB treatment and may overlap with those of antiretroviral medications. Moreover, delaying antiretroviral therapy may ameliorate adherence issues and decrease the frequency and severity of paradoxical reactions (i.e., immune restoration syndromes resembling exacerbation of TB that sometimes occur after initiation of antituberculosis treatment in patients receiving potent antiretroviral therapy). Rifabutin can be substituted approximately 2 weeks before the planned initiation of antiretroviral therapy to allow time for rifampin's enzyme induction effects to wane. In general, treatment of TB in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of HIV-related tuberculosis should be consulted, and TB and HIV care providers should work in close coordination throughout treatment.

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