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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). VIRAMUNE prevents viral RNA from being converted to DNA. VIRAMUNE binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of VIRAMUNE does not compete with template or nucleoside triphosphates, and HIV-2 and certain human DNA polymerases (see CLINICAL PHARMACOLOGY, Microbiology in Full Prescribing Information). 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 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 boxed Warning and WARNINGS AND PRECAUTIONS)
- The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash
- If rash persists beyond the 14 day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once daily dosing regimen should not be continued beyond 28 days, at which point an alternative regimen should be sought.
Pharmacokinetics in patients with 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.
Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known.
Pharmacokinetics in patients with hepatic impairment
Hepatic impairment
In a steady state study comparing 46 patients with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these patients with hepatic fibrosis had nevirapine trough concentrations above 9,000 g/mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug induced toxicity (see WARNINGS AND PRECAUTIONS). The patients studied were receiving antiretroviral therapy containing Viramune 200 mg twice-daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years.
Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, patients with either hepatic fibrosis or cirrhosis should be monitored carefully for evidence of drug induced toxicity.
Do not administer nevirapine to patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS in Full Prescribing Information.
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.
