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Viramune (Nevirapine) - Description and Clinical Pharmacology

 
 



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 C15H14N4O. 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.

CLINICAL PHARMACOLOGY

Mechanism of Action

Nevirapine is an antiviral drug [ see Clinical Pharmacology ].

Pharmacokinetics

Adults

Absorption and Bioavailability

Nevirapine is readily absorbed (>90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 μg/mL (7.5 μM) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady state trough nevirapine concentrations of 4.5 ± 1.9 μg/mL (17 ± 7 μM), (n = 242) were attained at 400 mg/day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When VIRAMUNE (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate study in HIV-1 infected patients (n=6), nevirapine steady-state systemic exposure (AUCτ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. VIRAMUNE may be administered with or without food, antacid or didanosine.

Distribution

Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk [ see Use In Specific Populations ]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 μg/mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

Metabolism/Elimination

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (<5%) of the radioactivity in urine (representing <3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5 to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg/day.

Special Populations

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 [ see Dosage and Administration and Use in Specific Populations ].

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 μg/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.

In a pharmacokinetic study where HIV-negative cirrhotic patients with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=4) hepatic impairment received a single 200 mg dose of nevirapine, a significant increase in the AUC of nevirapine was observed in one patient with Child-Pugh B and ascites suggesting 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, this single dose study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics.

Do not administer nevirapine to patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [ see Contraindications (4), Warnings and Precautions and Use in Specific Populations ].

Gender

In the multinational 2NN study, a population pharmacokinetic substudy of 1077 patients was performed that included 391 females. Female patients showed a 13.8% lower clearance of nevirapine than did men. Since neither body weight nor Body Mass Index (BMI) had an influence on the clearance of nevirapine, the effect of gender cannot solely be explained by body size.

Race

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 μg/mL Black, 3.8 μg/mL Hispanic, 4.3 μg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Geriatric Patients

Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18–68 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 55 years [ see Use in Specific Populations ].

Pediatric Patients

Pharmacokinetic data for nevirapine have been derived from two sources: a 48 week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral naïve patients aged 3 months to 16 years; and a consolidated analysis of five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 patients aged 14 days to 19 years.

BI Trial 1100.1368 studied the safety, efficacy, and pharmacokinetics of a weight-based and a body surface area (BSA)-based dosing regimen of nevirapine. In the weight-based regimen, pediatric patients up to 8 years of age received a dose of 4 mg/kg once daily for two weeks followed by 7 mg/kg twice daily thereafter. Patients 8 years and older were dosed 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. In the BSA regimen all pediatric patients received 150 mg/m2 once daily for two weeks followed by 150 mg/m2 twice daily thereafter [ see Use In Specific Populations and Adverse Reactions ]. Dosing of nevirapine at 150 mg/m2 BID (after a two-week lead in of 150 mg/m2 QD) produced geometric mean or mean trough nevirapine concentrations between 4-6 μg/mL (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the two dosing regimens studied (BSA and weight-based methods).

The consolidated analysis of Pediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation of pediatric patients less than 3 months of age (n=17). The plasma nevirapine concentrations observed were within the range observed in adults and the remainder of the pediatric population, but were more variable between patients, particularly in the second month of age. For dose recommendations for pediatric patients see Dosage and Administration .

Drug Interactions [ see Drug Interactions (7) ]

Nevirapine induces hepatic cytochrome P450 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.

While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated Ki for the inhibition of CYP3A was 270 μM, a concentration that is unlikely to be achieved in patients as the therapeutic range is <25 μM. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A.

Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9 or 2C19.

Table 5 (see below) contains the results of drug interaction studies performed with VIRAMUNE and other drugs likely to be co-administered. The effects of VIRAMUNE on the AUC, Cmax, and Cmin of co-administered drugs are summarized. 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.

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of VIRAMUNE (All interaction studies were conducted in HIV-1 positive patients)
Co-administered DrugDose of Co-administered DrugDose Regimen of VIRAMUNEn% Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)
§ = Cmin below detectable level of the assay
↑ = Increase, ↓ = Decrease, ⇔ = No Effect
a For information regarding clinical recommendations see Drug Interactions (7) .
b Pediatric subjects ranging in age from 6 months to 12 years
c Parallel group design; n for VIRAMUNE +lopinavir/ritonavir, n for lopinavir/ritonavir alone
Antiretrovirals AUC Cmax Cmin
Didanosine100-150 mg BID200 mg QD x 14 days; 200 mg BID x 14 days18§
Efavirenza600 mg QD200 mg QD x 14 days; 400 mg QD x 14 days17↓28
(↓34 to ↓14)
↓12
(↓23 to ↑1)
↓32
(↓35 to ↓19)
Indinavira800 mg q8H200 mg QD x 14 days; 200 mg BID x 14 days19↓31
(↓39 to ↓22)
↓15
(↓24 to ↓4)
↓44
(↓53 to ↓33)
Lopinavira, b300/75 mg/m2 (lopinavir/
ritonavir) b
7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week12, 15 c↓22
(↓44 to ↑9)
↓14
(↓36 to ↑16)
↓55
(↓75 to ↓19)
Lopinavira400/100 mg BID (lopinavir/ ritonavir)200 mg QD x 14 days; 200 mg BID > 1 year22, 19 c↓27
(↓47 to ↓2)
↓19
(↓38 to ↑5)
↓51
(↓72 to ↓26)
Nelfinavira750 mg TID200 mg QD x 14 days; 200 mg BID x 14 days23↓32
(↓50 to ↑5)
Nelfinavir-M8 metabolite   ↓62
(↓70 to ↓53)
↓59
(↓68 to ↓48)
↓66
(↓74 to ↓55)
Ritonavir600 mg BID200 mg QD x 14 days; 200 mg BID x 14 days18
Saquinavira600 mg TID200 mg QD x 14 days; 200 mg BID x 21 days23↓38
(↓47 to ↓11)
↓32
(↓44 to ↓6)
§
Stavudine30-40 mg BID200 mg QD x 14 days; 200 mg BID x 14 days22§
Zalcitabine0.125-0.25 mg TID200 mg QD x 14 days; 200 mg BID x 14 days6§
Zidovudine100-200 mg TID200 mg QD x 14 days; 200 mg BID x 14 days11↓28
(↓40 to ↓4)
↓30
(↓51 to ↑14)
§
Other Medications AUC Cmax Cmin
Clarithromycina500 mg BID200 mg QD x 14 days; 200 mg BID x 14 days15↓31
(↓38 to ↓24)
↓23
(↓31 to ↓14)
↓56
(↓70 to ↓36)
Metabolite
14-OH-clarithromycin
   ↑42
(↑16 to ↑73)
↑47
(↑21 to ↑80)
Ethinyl estradiola

and

Norethindronea
0.035 mg
(as Ortho-Novum® 1/35)
200 mg QD x 14 days; 200 mg BID x 14 days10↓20
(↓33 to ↓3)
§
1 mg
(as Ortho-Novum® 1/35)
↓19
(↓30 to ↓7)
↓16
(↓27 to ↓3)
§
Depomedroxy-progesterone acetate150 mg every 3 months200 mg QD x 14 days; 200 mg BID x 14 days32
Fluconazole200 mg QD200 mg QD x 14 days; 200 mg BID x 14 days19
Ketoconazolea400 mg QD200 mg QD x 14 days; 200 mg BID x 14 days21↓72
(↓80 to ↓60)
↓44
(↓58 to ↓27)
§
MethadoneaIndividual Patient Dosing200 mg QD x 14 days; 200 mg BID ≥ 7 days9In a controlled pharmacokinetic study with 9 patients receiving chronic methadone to whom steady state nevirapine therapy was added, the clearance of methadone was increased by 3-fold resulting in symptoms of withdrawal, requiring dose adjustments in 10 mg segments, in 7 of the 9 patients.  Methadone did not have any effect on nevirapine clearance.
Rifabutina150 or 300 mg QD200 mg QD x 14 days; 200 mg BID x 14 days19↑17
(↓2 to ↑40)
↑28
(↑9 to ↑51)
Metabolite
25-O-desacetyl-rifabutin
   ↑24
(↓16 to ↑84)
↑29
(↓2 to ↑68)
↑22
(↓14 to ↑74)
Rifampina600 mg QD200 mg QD x 14 days; 200 mg BID x 14 days14↑11
(↓4 to ↑28)
§

Because of the design of the drug interaction trials (addition of 28 days of VIRAMUNE therapy to existing HIV therapy) the effect of the concomitant drug on plasma nevirapine steady state concentrations was estimated by comparison to historical controls.

Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Cmax by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data [ see Drug Interactions (7) ]. The effect of other drugs listed in Table 5 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low dose ritonavir and nevirapine.

Microbiology

Mechanism of Action

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine 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 nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or δ) are not inhibited by nevirapine.

Antiviral Activity

The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte derived macrophages, and lymphoblastoid cell lines. In recent studies using human cord blood lymphocytes and human embryonic kidney 293 cells, EC50 values (50% inhibitory concentration) ranged from 14-302 nM against laboratory and clinical isolates of HIV-1. Nevirapine exhibited antiviral activity in cell culture against group M HIV-1 isolates from clades A, B, C, D, F, G, and H, and circulating recombinant forms (CRF) CRF01_AE, CRF02_AG and CRF12_BF (median EC50 value of 63 nM). Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates or HIV-2 isolates. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.

Resistance

HIV-1 isolates with reduced susceptibility (100-250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve patients receiving either nevirapine (n=24) or nevirapine and ZDV (n=14) were monitored in Phase 1 and 2 trials over 1 to ≥12 weeks. After 1 week of nevirapine monotherapy, isolates from 3/3 patients had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C and G190A were detected in HIV-1 isolates from some patients as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the patients tested (n=24) had HIV-1 isolates with a >100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the nevirapine-associated RT resistance mutations. Nineteen of these patients (80%) had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral naïve patients experiencing virologic failure (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (study 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained one or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.

Cross-resistance

Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine and efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTI's ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies were lower than that measured in humans at the 200 mg BID dose. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine treated mice and rats is not known. In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of VIRAMUNE.

Animal Toxicology and/or Pharmacology

Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.

CLINICAL STUDIES

Clinical Studies in Adults

Trial BI 1090, was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected patients with <200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with VIRAMUNE + lamivudine + background therapy versus lamivudine + background therapy in NNRTI naïve patients. 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 patients (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The patients (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV infection, with a median baseline CD4+ cell count of 96 cells/mm3 and a baseline HIV RNA of 4.58 log10 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 study. Prior to unblinding the trial, the primary endpoint was changed to proportion of patients with HIV RNA <50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.

Table 6 BI 1090 Outcomes through 48 weeks
1 including change to open-label nevirapine
2 includes withdrawal of consent, lost to follow-up, non-compliance with protocol, other administrative reasons
Outcome VIRAMUNE (N=1121)
%
Placebo
(N=1128)
%
Responders at 48 weeks: HIV RNA <50 copies/mL 18.01.6
Treatment Failure82.098.4
    Never suppressed viral load 44.6  66.4 
    Virologic failure after response 7.2  4.3 
    CDC category C event or death 9.6  11.2 
    Added antiretroviral therapy1 while <50 copies/mL 5.0  0.9 
    Discontinued trial therapy due to AE 7.0  5.9 
    Discontinued trial <48 weeks2 8.5  9.8 

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 study population (64 cells/mm3 vs 22 cells/mm3, respectively), as well as for patients who entered the trial as treatment naïve or having received only ZDV (85 cells/mm3 vs 25 cells/mm3, respectively).

At two years into the study, 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 patients with CD4+ cell counts of 200-600 cells/mm3 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 patients had mean baseline HIV RNA of 4.41 log10 copies/mL (25,704 copies/mL) and mean baseline CD4+ cell count of 376 cells/mm3. The primary endpoint was the proportion of patients with HIV-RNA < 400 copies/mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for patients treated with VIRAMUNE+zidovudine+didanosine, 19% for patients treated with zidovudine+didanosine, and 0% for patients treated with VIRAMUNE+zidovudine.

CD4+ cell counts in the VIRAMUNE+ZDV+ddI group increased above baseline by a mean of 139 cells/mm3 at one year, significantly greater than the increase of 87 cells/mm3 in the ZDV+ddI patients. The VIRAMUNE+ZDV group mean decreased by 6 cells/mm3 below baseline.

Clinical Studies in Pediatric Patients

The pediatric safety and efficacy of VIRAMUNE was examined in BI Trial 1100.1368, an open-label, randomized clinical study performed in South Africa in which 123 HIV-1 infected treatment-naïve patients between 3 months and 16 years of age received VIRAMUNE oral suspension for 48 weeks. Patients were divided into 4 age groups (3 months to <2 years, 2 to <7 years, 7 to <12 years, and 12 to ≤16 years) and randomized to receive one of two VIRAMUNE doses, determined by 2 different dosing methods [body surface area (150mg/m2)and weight-based dosing(4 or 7mg/kg)] in combination with zidovudine and lamivudine [ see Adverse Reactions Use in Specific Population and Clinical Pharmacology ]. The total daily dose of VIRAMUNE did not exceed 400 mg in either regimen. There were 66 patients in the body surface area (BSA) dosing group and 57 patients in the weight-based (BW) dosing group.

Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Patients had a median baseline HIV RNA of 5.45 log10 copies/mL and a median baseline CD4 cell count of 527 cells/mm3 (range 37-2279). One hundred and five (85%) completed the 48 weeks period while 18 (15%) discontinued prematurely. Of the patients who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of patients who achieved and maintained an HIV RNA <400 copies/mL at 48 weeks was 47% (58/123).

For dose recommendations for pediatric patients see Dosage and Administration .

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