Drug Interactions
VIRAMUNE induces hepatic cytochrome P450 (CYP) metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects (see CLINICAL PHARMACOLOGY section in full Prescribing Information). While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, VIRAMUNE may also inhibit this system.
The effects of VIRAMUNE on the AUC, Cmax, and Cmin of co-administered drugs are summarized in Table 5 in full Prescribing Information. To measure the full potential pharmacokinetic interaction effect following induction, patients on the concomitant drug at steady state were administered 28 days of VIRAMUNE (200 mg qd for 14 days followed by 200 mg bid for 14 days) followed by a steady-state reassessment of the concomitant drug.
In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. Additional clinical monitoring may be warranted when co-administering with these drugs. For a list of drugs which may require dosage adjustment, see Table 4 and Table 5 in full Prescribing Information. For a list of established drug interactions, see Table 5 in full Prescribing Information.
The data in Tables 4 and 5 are based on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 4. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when co-administering these drugs.
The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently.
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking VIRAMUNE, since nevirapine may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored. Nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with VIRAMUNE and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Concomitant use of St. John's wort and VIRAMUNE is not recommended.
INDICATION AND IMPORTANT SAFETY INFORMATION
VIRAMUNE is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on one principal clinical trial that demonstrated prolonged suppression of HIV-RNA and two smaller supportive studies.
Life-threatening and fatal hepatotoxicity has occurred in patients receiving VIRAMUNE. Any patient can experience hepatic events; however, female gender and higher CD4 counts at initiation of therapy place patients at greater risk. Women, including pregnant women, with CD4+ cell counts >250 cells/mm3 are at the greatest risk. VIRAMUNE should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 unless the benefit outweighs the risk. Hepatic events are often associated with rash. Hepatic failure has also been reported in patients without HIV taking VIRAMUNE for post-exposure prophylaxis (PEP). Use of VIRAMUNE for occupational and non-occupational PEP is contraindicated.
Life-threatening and fatal skin reactions have also occurred, including Stevens-Johnson Syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction.
Patients should be intensively monitored for hepatic and skin reactions for the first 18 weeks of therapy with extra vigilance during the first 6 weeks, which is the period of greatest risk. Frequent monitoring should be performed throughout therapy with VIRAMUNE.
VIRAMUNE should be discontinued and not restarted in patients who develop signs or symptoms of hepatitis, hypersensitivity, severe skin reactions or any rash accompanied by constitutional findings. In some cases, hepatic injury has progressed despite discontinuation of treatment.
Patients with either hepatic fibrosis or cirrhosis should be monitored carefully for evidence of drug induced toxicity. VIRAMUNE should not be administered to patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment.
Other common side effects include nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain, and myalgia. Immune reconstitution syndrome has been reported in patients treated with combination ARV therapy.
The dose of VIRAMUNE for adults is one 200-mg tablet daily for the first 14 days (this has been shown to reduce the frequency of rash), followed by one 200-mg tablet twice daily. Any patient experiencing rash during the 14-day lead-in period should not increase dose until the rash has resolved. The lead-in dosing regimen should not be continued beyond 28 days.
Please see full Prescribing Information, including boxed WARNING, for VIRAMUNE.
