Viramune

Viramune Mechanism of Action

nevirapine

Manufacturer:

Boehringer Ingelheim

Distributor:

DKSH
Full Prescribing Info
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Pharmacology: Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 reverse transcriptase and eukaryotic DNA polymerases (eg, human DNA polymerases α, β, γ or δ) are not inhibited by nevirapine.
In clinical studies, Viramune has been associated with an increase in HDL-cholesterol and an overall improvement in the total to HDL-cholesterol ratio, which in the general population would be considered to be associated with a lower cardiovascular risk. However, in the absence of specific studies with Viramune on modifying the cardiovascular risk in HIV-infected patients, the clinical impact of these findings is not known. The selection of antiretroviral drugs must be guided primarily by their antiviral efficacy.
In Vitro HIV Susceptibility: The in vitro 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 vitro 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 vitro against isolates from group O HIV-1 and HIV-2.
Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity in vitro 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 vitro.
Resistance: HIV isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in vitro. Genotypic analysis showed mutations in the HIV-1 RT gene Y181C and/or V106A depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in vitro was not altered when selection included nevirapine in combination with several other NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolates from patients treated with either Viramune (n=24) or Viramune+ZDV (n=14) were monitored in phase I/II trials over 1 to ≥12 weeks. After 1 week of Viramune monotherapy, isolates from 3/3 patients had decreased susceptibility to nevirapine in vitro; ≥1 of the RT mutations at amino acid positions 103, 106, 108, 181, 188 and 190 were detected in some patients as early as 2 weeks after therapy initiation. By week 8 of Viramune monotherapy, 100% of the patients tested (n=24) had HIV isolates with >100-fold decrease in susceptibility to nevirapine in vitro compared to baseline and had ≥1 of the nevirapine-associated RT resistance mutations; 19 of 24 patients (80%) had isolates with a position 181 mutation regardless of dose.
Genotypic analysis of isolates from antiretroviral-naive patients with virologic rebound (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 ≥1 of the following NNRTI resistance-associated mutations: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.
Viramune XR: Genotypic analysis was performed on isolates from 86 antiretroviral naïve patients who discontinued the VERxVE study (1100.1486) after experiencing virologic failure (rebound, partial response) or due to an adverse event or who had transient increase in viral load during the course of the study. The analysis of these samples of patients receiving VIRAMUNE immediate-release twice daily or VIRAMUNE XR extended-release once daily in combination with tenofovir and emtricitabine showed that isolates from 50 patients contained resistance mutations expected with a nevirapine-based regimen. Of these 50 patients, 28 developed resistance to efavirenz and 39 developed resistance to etravirine (the most frequently emergent resistance mutation being Y181C).
There were no differences based on the formulation taken (immediate-release twice daily or extended-release once daily).
The observed mutations at failure were those expected with a nevirapine-based regimen. Two new substitutions on codons previously associated with nevirapine resistance were observed: one patient with Y181I in the VIRAMUNE XR extended-release group and one patient with Y188N in the VIRAMUNE immediate-release group; resistance to nevirapine was confirmed by phenotype.
Cross-Resistance: Rapid emergence of HIV strains, which are cross-resistant to NNRTIs, has been observed in vitro. Data on cross-resistance between NNRTI nevirapine and nucleoside analogue RT inhibitors are very limited. In 4 patients, ZDV-resistant isolates tested in vitro retained susceptibility to nevirapine and in 6 patients, nevirapine-resistant isolates were susceptible to ZDV and ddI. Cross-resistance between nevirapine and HIV-protease inhibitors is unlikely because the enzyme targets involved are different.
Cross-resistance among the currently registered NNRTIs is broad. Some genotypic resistance data indicate that in most patients failing NNRTIs, viral strains express cross-resistance to other NNRTIs. Cross-resistance to delavirdine and efavirenz is expected after virologic failure with nevirapine.
Nevirapine must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other NNRTIs, resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross-resistance. When discontinuing an antiretroviral regimen containing nevirapine, the long half-life (t½) of nevirapine should be taken into account; if antiretrovirals with shorter t½ than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop.
Clinical Studies: Viramune XR: VIRAMUNE XR Extended-Release Tablets: The clinical efficacy of VIRAMUNE XR extended-release is based on 48-week data from an ongoing, randomised, double-blind, double-dummy Phase 3 trial (VERxVE-Study 1100.1486) in treatment-naïve patients and on 24-week data from an ongoing, randomised, open-label trial in patients who transitioned from VIRAMUNE immediate-release tablets administered twice daily to VIRAMUNE XR extended-release tablets administered once daily (TRANxITION - Study 1100.1526).
Treatment-Naive Patients: VERxVE (Study 1100.1486) is a Phase 3 study in which treatment-naïve patients received VIRAMUNE immediate-release 200 mg once daily for 14 days and then were randomised to receive either VIRAMUNE immediate-release 200 mg twice daily or VIRAMUNE XR extended-release 400 mg once daily. All patients received tenofovir + emtricitabine as background therapy. Randomisation was stratified by screening HIV-1 RNA level (≤100,000 copies/mL and >100,000 copies/mL). Selected demographic and baseline disease characteristics are displayed in Table 1. (See Table 1.)

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Table 2 describes week 48 outcomes in the VERxVE study (1100.1486). These outcomes include all patients who were randomised after the 14 day lead-in with VIRAMUNE immediate-release and received at least one dose of blinded study medication. (See Table 2.)

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At week 48, mean change from baseline in CD4+ cell count was 184 cells/mm3 and 197 cells/mm3 for the groups receiving VIRAMUNE immediate-release and VIRAMUNE XR extended-release respectively. (See Table 3.)

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Lipids, Change from Baseline: Changes from baseline in fasting lipids are shown in Table 4. (See Table 4.)

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Patients Switching from VIRAMUNE Immediate Release to VIRAMUNE XR Extended-Release: RANxITION (Study 1100.1526) is a Phase 3 study to evaluate safety and antiviral activity in patients switching from VIRAMUNE immediate-release to VIRAMUNE XR extended-release. In this open-label study, 443 patients already on an antiviral regimen containing VIRAMUNE immediate-release 200 mg twice daily with HIV-1 RNA <50 copies/mL were randomised in a 2:1 ratio to VIRAMUNE XR extended-release 400 mg once daily or VIRAMUNE immediate-release 200 mg twice daily.
Approximately half of the patients had tenofovir+emtricitabine as their background therapy, with the remaining patients receiving abacavir sulfate+lamivudine or zidovudine+lamivudine. Approximately half of the patients had at least 3 years of prior exposure to VIRAMUNE immediate-release prior to entering Trial 1100.1526.
At 24 weeks after randomisation in the TRANxITION study, 92.6% and 93.6% of patients receiving VIRAMUNE immediate-release 200 mg twice daily or VIRAMUNE XR extended-release 400 mg once daily, respectively, continued to have HIV-1 RNA <50 copies/mL.
Pharmacokinetics: Adult Patients: 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 mcg/mL (7.5 mcM) were attained by 4 hrs following a single 200-mg dose. Following multiple doses, nevirapine peak concentrations appear to increase in a linear fashion in the dose range of 200-400 mg/day. Steady-state trough nevirapine concentrations of 4.5±1.9 mcg/mL (17±7 mcM), (n=242) were attained at 400 mg/day.
The absorption of nevirapine is not affected by food, antacids or medicinal products that are formulated with an alkaline buffering agent (eg, didanosine).
Nevirapine is highly lipophilic and is essentially non-ionised at physiologic pH. Following IV 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 found in breast milk. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mcg/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.
In vivo studies in human and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P-450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P-450 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a mass balance/excretion study in 8 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 faeces (10.1±1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus, cytochrome P-450 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 the elimination of the parent compound.
Nevirapine has been shown to be an inducer of hepatic cytochrome P-450 metabolic enzymes. The pharmacokinetics of autoinduction are characterised by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2-4 weeks of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase t½ of nevirapine in plasma from approximately 45 hrs (single dose) to approximately 25-30 hrs following multiple dosing with 200-400 mg/day.
Viramune XR: The pharmacokinetics of nevirapine has been studied in a single dose study (Trial 1100.1485) of VIRAMUNE XR extended-release in 17 healthy volunteers. The relative bioavailability of nevirapine when dosed as one 400 mg VIRAMUNE XR extended-release tablet, relative to two 200 mg VIRAMUNE immediate-release tablets, was approximately 75%. The mean peak plasma concentration of nevirapine was 2060 ng/mL measured at a mean of 24.5 hours after administration of 400 mg VIRAMUNE XR extended-release.
The pharmacokinetics of VIRAMUNE XR extended-release has also been studied in a multiple dose pharmacokinetics study (Trial 1100.1489) in 24 HIV-1 infected patients who switched from chronic VIRAMUNE immediate-release therapy to VIRAMUNE XR extended-release. The nevirapine AUC0-24,ss and Cmin,ss measured after 19 days of fasted dosing of VIRAMUNE XR extended-release 400 mg once daily were approximately 80% and 90%, respectively, of the AUC0-24,ss and Cmin,ss measured when patients were dosed with VIRAMUNE immediate-release 200 mg twice daily. The geometric mean nevirapine Cmin,ss was 2,770 ng/mL.
When VIRAMUNE XR extended-release was dosed with a high fat meal, the nevirapine AUC0-24,ss and Cmin,ss were approximately 94% and 98%, respectively, of the AUC0-24,ss and Cmin,ss measured when patients were dosed with VIRAMUNE immediate-release tablets. The difference in nevirapine pharmacokinetics observed when VIRAMUNE XR extended-release tablets are dosed under fasted or fed conditions is not considered clinically relevant. VIRAMUNE XR extended-release tablets can be taken with or without food.
The effects of gender on the pharmacokinetics of VIRAMUNE XR extended-release have been investigated in Trial 1100.1486. Female patients tend to have higher (approximately 20-30%) trough concentrations in both VIRAMUNE XR extended-release and VIRAMUNE immediate-release treatment groups.
Nevirapine pharmacokinetics in HIV-1 infected adults does not appear to change with age (range 18-68 years). Black patients (n=80/group) in Trial 1100.1486 showed approximately 30% higher trough concentrations than Caucasian patients (250-325 patients/group) in both the VIRAMUNE immediate-release and VIRAMUNE XR extended-release treatment groups over 48 weeks of treatment at 400 mg/day.
VIRAMUNE XR extended-release has not been evaluated in subjects with hepatic impairment or renal dysfunction.
Occasionally, the inactive ingredients of VIRAMUNE XR extended-release tablets will be eliminated in the faeces as soft, hydrated remnants which may resemble intact tablets. These occurrences have not been shown to affect drug levels or response.
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 male patients. This difference is not considered clinically relevant. Since neither body weight nor body mass index (BMI) had influence on the clearance of nevirapine, the effect of gender cannot be explained by body size.
Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18-68 years) or race (Black, Hispanic or Caucasian). This information is derived from an evaluation of pooled data derived from several clinical trials.
Renal Dysfunction: The single-dose pharmacokinetics of Viramune have been compared in 23 subjects with either mild (50 ≤ creatinine clearance<80 mL/min), moderate (30 ≤ creatinine clearance <50 mL/min) or severe renal dysfunction (creatinine clearance <30 mL/min), renal impairment or end-stage renal disease (ESRD) requiring dialysis and 8 subjects with normal renal function (creatinine clearance >80 mL/min). Renal impairment (mild, moderate and severe) resulted in no significant change in the pharmacokinetics of Viramune. However, subjects with ESRD requiring dialysis exhibited a 43.5% reduction in Viramune area under the concentration-time curve (AUC) over a 1-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in plasma. The results suggest that supplementing Viramune therapy with an additional 200-mg dose of Viramune following each dialysis treatment would help offset the effects of dialysis on Viramune clearance. Otherwise, patients with creatinine clearance ≥20 mL/min do not require an adjustment in Viramune dosing.
Hepatic Impairment: A steady-state study comparing 46 patients with mild (n=17: Ishak score 1-2), moderate (n=20; Ishak score 3-4), or severe (n=9; Ishak score 5-6, Child-Pugh A in 8 pts, for 1 Child-Pugh score not applicable) liver fibrosis as a measure of hepatic impairment was conducted.
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 this study, the multiple dose pharmacokinetic disposition of nevirapine and the 5 oxidative metabolites were not altered.
However, approximately 15% of these patients with hepatic fibrosis had nevirapine trough concentrations above 9000 ng/mL (2-fold the usual mean trough). Patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity.
In a 200-mg nevirapine single-dose pharmacokinetic study of HIV-negative patients with mild and moderate hepatic impairment (Child-Pugh A, n=6; Child-Pugh B, n=4), a significant increase in the AUC of nevirapine was observed in 1 Child-Pugh B patient with 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 (see Precautions).
Paediatric Patients: Data concerning the pharmacokinetics of nevirapine has been derived from 2 major sources: A 48-week paediatric trial in South Africa involving 123 HIV-1 positive, antiretroviral-naive patients aged 3 months to 16 years; and a consolidated analysis of 5 Paediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 patients aged 14 days-19 years.
The results of the 48-week analysis of the South African study confirmed that the 4/7 mg/kg and 150 mg/m2 nevirapine dose groups were well tolerated and effective in treating antiretroviral naive paediatric patients. A marked improvement in the CD4+ cell percent was observed through week 48 for both dose groups. Also, both dosing regimens were effective in reducing the viral load. In this 48-week study, no unexpected safety findings were observed in either dosing group.
Pharmacokinetic data on 33 patients (age range 0.77-13.7 years) in the intensive sampling group demonstrated that after oral intake clearance of nevirapine increased with increasing age in a manner consistent with increasing body surface area. Dosing of nevirapine at 150 mg/m2 twice daily (after a 2-week lead in at 150 mg/m2 once daily) produced geometric mean or mean trough nevirapine concentrations between 4-6 mcg/mL (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the 2 methods.
The consolidated analysis of Paediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation of paediatric patients <3 months (n=17) enrolled in these PACTG studies. The plasma nevirapine concentrations observed were within the range observed in adults and the remainder of the paediatric population, but were more variable between patients, particularly in the 2nd month of age.
Viramune XR: The pharmacokinetics of VIRAMUNE XR extended-release was assessed in Trial 1100.1518. Eighty-five patients 3 to <18 years received weight or body surface area dose-adjusted VIRAMUNE immediate-release for a minimum of 18 weeks and then were switched to VIRAMUNE XR extended-release tablets (2 x 100 mg, 3 x 100 mg or 1 x 400 mg once daily) in combination with other antiretrovirals for 10 days.
The observed geometric mean ratios of VIRAMUNE XR extended-release to VIRAMUNE immediate-release were ~90% for Cmin,ss and AUCss with 90% confidence intervals within 80%-125%; the ratio for Cmax,ss was lower and consistent with a once daily extended-release dosage form. Geometric mean steady-state plasma VIRAMUNE XR extended-release pre-dose trough concentrations were 3,880 ng/mL, 3,310 ng/mL and 5,350 ng/mL in age groups 3 to <6years, 6 to <12 years, and 12 to <18 years of age, respectively. Overall, the exposure in children was similar to that observed in adults receiving VIRAMUNE XR extended-release in Trial 1100.1486.
In single-dose, parallel group bioavailability studies (Trials 1100.1517 and 1100.1531), the VIRAMUNE XR extended-release 50 and 100 mg tablets exhibited extended release characteristics of prolonged absorption and lower maximal concentrations, similar to the findings when a 400 mg extended-release tablet was compared to the VIRAMUNE immediate-release 200 mg tablet.
Dividing a 200 mg total dose into four 50 mg doses rather than two 100 mg doses produced a 7-11% greater overall absorption, but with comparable drug release rates. The observed pharmacokinetic difference between the 50 mg and 100 mg VIRAMUNE XR extended-release tablets is not clinically relevant, and the 50 mg extended -release tablet can be used as an alternative to the slightly larger 100 mg tablet.
Occasionally, the inactive ingredients of VIRAMUNE XR extended-release tablets will be eliminated in the faeces as soft, hydrated remnants which may resemble intact tablets. These occurrences have not been shown to affect drug levels or response.
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