Viramune Information
Viramune () Indications And Usage
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 (BI 1090) that demonstrated prolonged suppression of HIV-1 RNA and two smaller supportive trials, one of which (BI 1046) is described below.
Additional important information regarding the use of Viramune () for the treatment of HIV-1 infection:
Viramune () Dosage And Administration
The recommended dose for Viramune () is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The lead-in period has been observed to decrease the incidence of rash. For concomitantly administered antiretroviral therapy, the manufacturer's recommended dosage and monitoring should be followed.
Viramune () XR extended release tablets (400 mg once daily) is also available for use after the lead-in period. Patients must never take more than one form of nevirapine at the same time.
The recommended oral dose for pediatric patients 15 days and older is 150 mg/m once daily for 14 days followed by 150 mg/m twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.
Viramune () suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of 5 mL or less. If a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient.
For patients who interrupt Viramune () dosing for more than 7 days, restart the recommended dosing, using one 200 mg tablet daily (150 mg/m/day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (150 mg/m twice daily for pediatric patients).
Patients with CrCL greater than or equal to 20 mL/min do not require an adjustment in Viramune () dosing. An additional 200 mg dose of Viramune () following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [].
Viramune () Dosage Forms And Strengths
Tablets: 200 mg, white, oval, biconvex, tablets embossed with 54 193 on one side Oral suspension: 50 mg per 5 mL, white to off-white oral suspension
Viramune () Warnings And Precautions
The most serious adverse reactions associated with Viramune () are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction.
Viramune () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most serious adverse reactions associated with Viramune () are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [].
Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of Viramune () (n=305) in which pediatric subjects received combination treatment with Viramune () . In this trial two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of Viramune () (n=37) in which subjects were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these subjects in trial BI 1100.892). The most frequently reported adverse events related to Viramune () in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and Viramune () . Cases of allergic reaction, including one case of anaphylaxis, were also reported.
The safety of Viramune () was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with Viramune () oral suspension, lamivudine and zidovudine for 48 weeks []. Rash (all causality) was reported in 21% of the subjects, 4 (3%) of whom discontinued drug due to rash. All 4 subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%), and hepatotoxicity (2%) [].
Safety information on use of Viramune () in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.
In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of Viramune () . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.
Viramune () Drug Interactions
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine.
The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in , Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction trials 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 trials 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 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.
Viramune () Use In Specific Populations
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Viramune () .
The safety, pharmacokinetic profile, and virologic and immunologic responses of Viramune () have been evaluated in HIV-1 infected pediatric subjects age 3 months to 18 years []. The safety and pharmacokinetic profile of Viramune () has been evaluated in HIV-1 infected pediatric subjects age 15 days to less than 3 months [].
The most frequently reported adverse events related to Viramune () in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and Viramune () [].
Viramune () Overdosage
There is no known antidote for Viramune () overdosage. Cases of Viramune () overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease. All events subsided following discontinuation of Viramune () .
Viramune () Description
Viramune () is the brand name for nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds.
The chemical name of nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one. Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula CHNO. Nevirapine has the following structural formula:
Viramune () Tablets are for oral administration. Each tablet contains 200 mg of nevirapine and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate.
Viramune () Oral Suspension is for oral administration. Each 5 mL of Viramune () suspension contains 50 mg of nevirapine (as nevirapine hemihydrate). The suspension also contains the following excipients: carbomer 934P, methylparaben, propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide and purified water.
Viramune () Clinical Studies
Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected subjects with less than 200 CD4 cells/mm at screening. Initiated in 1995, BI 1090 compared treatment with Viramune () + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were Viramune () , 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4 cell count of 96 cells/mm and a baseline HIV-1 RNA of 4.58 log copies/mL (38,291 copies/mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.
The change from baseline in CD4 cell count through one year of therapy was significantly greater for the Viramune () group compared to the placebo group for the overall trial population (64 cells/mm vs 22 cells/mm, respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm vs 25 cells/mm, respectively).
At two years into the trial, 16% of subjects on Viramune () had experienced class C CDC events as compared to 21% of subjects on the control arm.
Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4 cell counts of 200-600 cells/mm at baseline. BI 1046 compared treatment with Viramune () +zidovudine+didanosine to Viramune () +zidovudine and zidovudine+didanosine. Treatment doses were Viramune () at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log copies/mL (25,704 copies/mL) and mean baseline CD4 cell count of 376 cells/mm. The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies/mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with Viramune () +zidovudine+didanosine, 19% for subjects treated with zidovudine+didanosine, and 0% for subjects treated with Viramune () +zidovudine.
CD4 cell counts in the Viramune () +ZDV+ddI group increased above baseline by a mean of 139 cells/mm at one year, significantly greater than the increase of 87 cells/mm in the ZDV+ddI subjects. The Viramune () +ZDV group mean decreased by 6 cells/mm below baseline.
The pediatric safety and efficacy of Viramune () was examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received Viramune () oral suspension for 48 weeks. Subjects were divided into 4 age groups (3 months to less than 2 years, 2 to less than 7 years, 7 to less than 12 years, and 12 to less than or equal to 16 years) and randomized to receive one of two Viramune () doses, determined by 2 different dosing methods [body surface area (150 mg/m) and weight-based dosing (4 or 7 mg/kg)] in combination with zidovudine and lamivudine []. The total daily dose of Viramune () did not exceed 400 mg in either regimen. There were 66 subjects in the body surface area (BSA) dosing group and 57 subjects in the weight-based (BW) dosing group.
Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects had a median baseline HIV-1 RNA of 5.45 log copies/mL and a median baseline CD4 cell count of 527 cells/mm (range 37-2279). One hundred and five (85%) completed the 48-week period while 18 (15%) discontinued prematurely. Of the subjects who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of subjects who achieved and maintained an HIV-1 RNA less than 400 copies/mL at 48 weeks was 47% (58/123).
For dose recommendations for pediatric patients [].
Viramune () How Supplied/storage And Handling
Viramune () tablets, 200 mg, are white, oval, biconvex tablets, 9.3 mm x 19.1 mm. One side is embossed with "54 193", with a single bisect separating the "54" and "193". The opposite side has a single bisect.
Viramune () tablets are supplied in bottles of 60 (NDC 0597-0046-60).
Viramune () tablets are supplied in unit dose packages of 14 (NDC 0597-0046-46).
Dispense in tight container as defined in the USP/NF.
Viramune () oral suspension is a white to off-white preserved suspension containing 50 mg nevirapine (as nevirapine hemihydrate) in each 5 mL. Viramune () suspension is supplied in plastic bottles with child-resistant closures containing 240 mL of suspension (NDC 0597-0047-24).
Viramune () Patient Counseling Information
Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with Viramune () to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout Viramune () treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions. Advise patients with signs and symptoms of hepatitis to discontinue Viramune () and seek medical evaluation immediately. If Viramune () is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4 cell count at initiation of Viramune () therapy (greater than 250 cells/mm in women and greater than 400 cells/mm in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C and/or increased transaminases at the start of therapy with Viramune () are associated with a greater risk of later symptomatic events (6 weeks or more after starting Viramune () ) and asymptomatic increases in AST or ALT [].
The majority of rashes associated with Viramune () occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-in period, do not escalate the Viramune () dose until the rash resolves. The total duration of the once-daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue Viramune () immediately and consult a physician. Viramune () should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of Viramune () -associated rash [].
Inform patients to take Viramune () every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Advise patients to report to their doctor the use of any other medications.
Inform patients that it is not known whether Viramune () therapy reduces the risk of transmission of HIV-1 to others through sexual contact. Effective treatment combined with safer sex practices may reduce the chance of passing HIV to others through sexual contact. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should be advised never to re-use or share needles.
Viramune () is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Advise patients to remain under the care of a physician when using Viramune () .
Advise patients taking Viramune () oral suspension to ask their pharmacist for a dosing cup or syringe if they do not have one.
Inform patients that they should not take Viramune () tablets or oral suspension and Viramune () XR extended release tablets at the same time.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
Copyright 2011 Boehringer Ingelheim Pharmaceuticals, Inc. ALL RIGHTS RESERVED
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