Mechanism of action
Viramune® (nevirapine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs block the reproduction of HIV earlier in its cycle than either the nucleoside/nucleotide analogues (NRTIs) or the protease inhibitors (PIs). By binding tightly to reverse transcriptase, VIRAMUNE prevents viral RNA from being converted to DNA. NRTIs work by becoming incorporated into the viral DNA and making it ineffective. PIs prevent copies of the HIV virus from being successfully assembled and released from the infected CD4+ cell. Fusion inhibitors, the newest class of anti-HIV medicines, work by preventing HIV from entering healthy CD4+ cells.
Indications and usage
Viramune (nevirapine) 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 (BI 1090) that demonstrated prolonged suppression of HIV-RNA and two smaller supportive studies, one of which (BI 1046) is described in Full Prescribing Information.
Additional important information regarding the use of VIRAMUNE for the treatment of HIV-1 infection:
- Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, 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 (see WARNINGS)
- The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash (see WARNINGS; DOSAGE AND ADMINISTRATION)
Pharmacokinetic profile
Viramune® (nevirapine) is widely distributed throughout the body and readily crosses the blood-brain barrier and placenta and is also found in breast milk. It is more than 90% bioavailable following single-dose oral administration. Peak plasma levels are attained 4 hours after administration of a single 200-mg dose; steady-state trough levels of 4.5±1.9 µg/mL (17±7 µM) are achieved at 400 mg/day.
Pharmacokinetic studies demonstrate comparable absorption of VIRAMUNE when administered during fasting or with a meal. Therefore, VIRAMUNE can be given with or without food.
Nevirapine concentrations in human cerebrospinal fluid were 45% (±5%) of the concentrations in plasma; this concentration is approximately equal to the fraction not bound to plasma protein. (See CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults section in Full Prescribing Information.) The pediatric pharmacokinetics of VIRAMUNE have also been evaluated.
Pharmacokinetics
The pharmacokinetics of nevirapine have been studied in 2 open-label studies in children with HIV-1 infection. In 1 study (BI 853; ACTG 165), 9 HIV-1-infected children ranging in age from 9 months to 14 years were administered a single dose (7.5 mg, 30 mg, or 120 mg per m2; n=3 per dose) of nevirapine suspension after an overnight fast. The mean nevirapine apparent clearance adjusted for body weight was greater in children compared with adults.
In a multiple-dose study (BI 882; ACTG 180), nevirapine suspension or tablets (240 or 400 mg/m2/day) were administered as monotherapy or in combination with ZDV or ZDV+ddI to 37 HIV-1-infected pediatric patients with the following demographics: male (54%), racial minority groups (73%), median age of 11 months (range: 2 months to 15 years). The majority of these patients received 120 mg/m2/day of nevirapine for approximately 4 weeks followed by 120 mg/m2/bid (patients >9 years of age) or 200 mg/m2/bid (patients =9 years of age). Nevirapine apparent clearance adjusted for body weight reached maximum values by age 1 to 2 years and then decreased with increasing age. Nevirapine apparent clearance adjusted for body weight was at least two-fold greater in children younger than 8 years compared with adults. The pediatric dosing regimens were selected in order to achieve steady-state plasma concentrations in pediatric patients that approximate those in adults (see DOSAGE AND ADMINISTRATION, Pediatric Patients section in Full Prescribing Information).
Pharmacokinetics in patients with renal and hepatic impairment
Renal impairment
HIV seronegative adults with mild (CrCL 50-79 mL/min; n=7), moderate (CrCL 30-49 mL/min; n=6), or severe (CrCL <30 mL/min; n=4) renal impairment received a single 200-mg dose of nevirapine in a pharmacokinetic study. These subjects did not require dialysis. The study included six additional subjects with renal failure requiring dialysis.
In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects requiring dialysis. An additional 200 mg dose following each dialysis treatment is indicated.
Hepatic impairment
HIV seronegative adults with mild (Child-Pugh Class A; n=6) or moderate (Child-Pugh Class B; n=4) hepatic impairment received a single 200 mg dose of nevirapine in a pharmacokinetic study.
In the majority of patients with mild or moderate hepatic impairment, no significant changes were seen in the pharmacokinetics of nevirapine. However, a significant increase in the AUC of nevirapine observed in one patient with Child-Pugh Class B and ascites suggests that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, a single dose study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics. Nevirapine should not be administered to patients with severe hepatic impairment.
Please consult Full Prescribing Information, including boxed WARNING, Medication Guide, and Important Safety Information for VIRAMUNE.
