Viramune 400 mg prolonged-release tablets

Each prolonged-release tablet contains 400 mg of nevirapine (as anhydrous).

Excipient: each prolonged-release tablet contains 400 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

Prolonged-release tablet

Yellow, oval, biconvex prolonged-release tablets. The prolonged-release tablets are about 9.3 x 19.1 mm, debossed with V04 on one side and the company symbol on the other side. The prolonged-release tablet should not be divided.

Viramune is indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infected adults, adolescents, and children three years and above and able to swallow tablets (see section 4.2 and 4.4.).

Prolonged-release tablets are not suitable for the 14-day lead-in phase for patients starting nevirapine. Other nevirapine formulations, such as immediate-release tablets or oral suspension should be used (see section 4.2).

Most of the experience with Viramune is in combination with nucleoside reverse transcriptase inhibitors (NRTIs). The choice of a subsequent therapy after Viramune should be based on clinical experience and resistance testing (see section 5.1).

Viramune should be administered by physicians who are experienced in the treatment of HIV infection.

Posology

Adults

The recommended dose of Viramune for patients initiating nevirapine therapy is one 200 mg immediate-release tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 400 mg prolonged-release tablet once daily, in combination with at least two additional antiretroviral agents.

Patients currently on a Viramune immediate-release twice daily regimen:

Patients already on a regimen of Viramune immediate-release twice daily in combination with other antiretroviral agents can be switched to Viramune 400 mg prolonged-release tablets once daily in combination with other antiretroviral agents without a lead-in period of Viramune immediate-release.

Viramune should be combined with at least two additional antiretroviral agents. For concomitantly administered therapy, the manufacturers recommended dose should be followed.

If a dose is recognized as missed within 12 hours of when it was due, the patient should take the missed dose as soon as possible. If a dose is missed and it is more than 12 hours later, the patient should only take the next dose at the usual time.

Paediatric population

Children three years and older and adolescents

According to paediatric dose recommendations Viramune 400 mg prolonged-release tablets can be also taken by children, following the adult dosing schedule, if they

• are 8 years of age and weigh 43.8 kg or more or

• are < 8 years of age and weigh 25 kg or more or

• have a body surface area of 1.17 m² or above according to the Mosteller formula.

For paediatric patients aged 3 years and older, 50 mg and 100 mg prolonged-release tablets are available.

Children less than three years old

The safety and efficacy of Viramune prolonged-release tablets in children aged less than 3 years has not been established. No data are available.

For patients less than 3 years and for all other age groups, an immediate-release oral suspension dosage form is available (please refer to the respective Summary of Product Characteristics).

Dose management considerations

The total daily dose at any time during treatment should not exceed 400 mg for any patient. Patients should be advised of the need to take Viramune every day as prescribed.

Patients experiencing rash during the 14-day lead-in period of 200 mg/day should not initiate treatment with Viramune prolonged-release tablets until the rash has resolved. The isolated rash should be closely monitored (please refer to section 4.4). The 200 mg once daily Viramune immediate-release lead-in dosing regimen should not be continued beyond 28 days at which point in time an alternative treatment should be sought due to the possible risk of underexposure and resistance.

Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing regimen using the two week lead-in period of Viramune immediate-release.

For toxicities that require interruption of Viramune therapy, see section 4.4.

Special populations

Renal impairment

In adult patients with renal dysfunction requiring dialysis an additional 200 mg dose of nevirapine immediate-release following each dialysis treatment is recommended. Patients with CLcr 20 ml/min do not require a dose adjustment, see section 5.2. In paediatric patients with renal dysfunction who are undergoing dialysis it is recommended that following each dialysis treatment patients receive an additional dose of Viramune oral suspension or immediate-release tablets representing 50% of the recommended daily dose of Viramune oral suspension or immediate-release tablets which would help offset the effects of dialysis on nevirapine clearance. Viramune prolonged-release tablets have not been studied in patients with renal dysfunction and Viramune immediate-release should be used.

Hepatic impairment

Nevirapine should not be used in patients with severe hepatic impairment (Child-Pugh C, see section 4.3). No dose adjustment is necessary in patients with mild to moderate hepatic impairment (see sections 4.4 and 5.2). Viramune prolonged-release tablets have not been studied in patients with hepatic impairment and Viramune immediate-release should be used.

Elderly

Nevirapine has not been specifically investigated in patients over the age of 65.

Method of administration

The prolonged-release tablets shall be taken with liquid, and should not be broken or chewed. Viramune can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients.

Readministration to patients who have required permanent discontinuation for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to nevirapine.

Patients with severe hepatic impairment (Child-Pugh C) or pre-treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN.

Readministration to patients who previously had ASAT or ALAT > 5 ULN during nevirapine therapy and had recurrence of liver function abnormalities upon readministration of nevirapine (see section 4.4).

Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used while taking Viramune due to the risk of decreased plasma concentrations and reduced clinical effects of nevirapine (see section 4.5).

Viramune should only be used with at least two other antiretroviral agents (see section 5.1).

Viramune should not be used as the sole active antiretroviral, as monotherapy with any antiretroviral has shown to result in viral resistance.

Cutaneous reactions

Severe and life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine mainly during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterised by rash, constitutional findings and visceral involvement. Patients should be intensively monitored during the first 18 weeks of treatment. Patients should be closely monitored if an isolated rash occurs. Nevirapine must be permanently discontinued in any patient experiencing severe rash or a rash accompanied by constitutional symptoms (such as fever, blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, or general malaise), including Stevens-Johnson syndrome, or toxic epidermal necrolysis. Nevirapine must be permanently discontinued in any patient experiencing hypersensitivity reaction (characterised by rash with constitutional symptoms, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction), see section 4.4.

Viramune administration above the recommended dose might increase the frequency and seriousness of skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with Viramune use.

Concomitant prednisone use (40 mg/day for the first 14 days of Viramune immediate-release administration) has been shown not to decrease the incidence of nevirapine-associated rash, and may be associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy.

Some risk factors for developing serious cutaneous reactions have been identified; they include failure to follow the initial dosing of 200 mg daily during the lead-in period and a long delay between the initial symptoms and medical consultation. Women appear to be at higher risk than men of developing rash, whether receiving nevirapine or non-nevirapine containing therapy.

Patients should be instructed that a major toxicity of nevirapine is rash. They should be advised to promptly notify their physician of any rash and avoid delay between the initial symptoms and medical consultation. The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Therefore, patients should be monitored carefully for the appearance of rash during this period.

Patients should be instructed that they should not begin Viramune prolonged-release tablets until any rash that has occurred during the 14-day lead-in period of Viramune immediate-release has resolved. The 200 mg once daily dosing regimen of Viramune immediate-release should not be continued beyond 28 days at which point in time an alternative treatment should be sought due to the possible risk of underexposure and resistance.

Hepatic reactions

Severe and life-threatening hepatoxicity, including fatal fulminant hepatitis, has occurred in patients treated with nevirapine. The first 18 weeks of treatment is a critical period which requires close monitoring. The risk of hepatic events is greatest in the first 6 weeks of therapy. However the risk continues past this period and monitoring should continue at frequent intervals throughout treatment.

Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with nevirapine use.

Increased ASAT or ALAT levels > 2.5 ULN and/or co-infection with hepatitis B and/or C at the start of antiretroviral therapy is associated with greater risk of hepatic adverse reactions during antiretroviral therapy in general, including nevirapine containing regimens.

Female gender and higher CD4 counts at the initiation of nevirapine therapy in treatment-naïve patients is associated with increased risk of hepatic adverse events. In a retrospective analysis of pooled clinical studies with Viramune immediate-release tablets, women had a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and treatment-naïve patients of either gender with detectable HIV-1 RNA in plasma with higher CD4 counts at initiation of nevirapine therapy were at higher risk for symptomatic hepatic events with nevirapine. Predominantly patients with a plasma HIV-1 viral load of 50 copies/ml or higher, women with CD4 counts >250 cells/mm³ had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts <250 cells/mm³ (11.0% versus 0.9%). An increased risk was observed in men with detectable HIV-1 RNA in plasma and CD4 counts > 400 cells/mm³ (6.3% versus 1.2% for men with CD4 counts <400 cells/mm³). This increased risk for toxicity based on CD4 count thresholds has not been detected in patients with undetectable (i.e. < 50 copies/ml) plasma viral load.

Patients should be informed that hepatic reactions are a major toxicity of nevirapine requiring close monitoring during the first 18 weeks. They should be informed that occurrence of symptoms suggestive of hepatitis should lead them to discontinue nevirapine and immediately seek medical evaluation, which should include liver function tests.

Liver monitoring

Clinical chemistry tests, which include liver function tests, should be performed prior to initiating nevirapine therapy and at appropriate intervals during therapy.

Abnormal liver function tests have been reported with nevirapine, some in the first few weeks of therapy.

Asymptomatic elevations of liver enzymes are frequently described and are not necessarily a contraindication to use nevirapine. Asymptomatic GGT elevations are not a contraindication to continue therapy.

Monitoring of hepatic tests should be done every two weeks during the first 2 months of treatment, at the 3^rd month and then regularly thereafter. Liver test monitoring should be performed if the patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity.

For patients already on a regimen of Viramune immediate-release twice daily who switch to Viramune prolonged-release once daily there is no need for a change in their monitoring schedule.

If ASAT or ALAT > 2.5 ULN before or during treatment, then liver tests should be monitored more frequently during regular clinic visits. Nevirapine must not be administered to patients with pre-treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN (see section 4.3).

Liver disease

The safety and efficacy of Viramune has not been established in patients with significant underlying liver disorders. Viramune is contraindicated in patients with severe hepatic impairment (Child-Pugh C, see section 4.3). Pharmacokinetic results suggest caution should be exercised when nevirapine is administered to patients with moderate hepatic dysfunction (Child-Pugh B). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In the case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Other warnings

Post-Exposure-Prophylaxis: Serious hepatotoxicity, including liver failure requiring transplantation, has been reported in HIV-uninfected individuals receiving multiple doses of Viramune in the setting of post-exposure-prophylaxis (PEP), an unapproved use. The use of Viramune has not been evaluated within a specific study on PEP, especially in term of treatment duration and therefore, is strongly discouraged.

Combination therapy with nevirapine is not a curative treatment of patients infected with HIV-1; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections.

Combination therapy with nevirapine has not been shown to eliminate the risk of transmission of HIV-1 to others through sexual contact or contaminated blood.

Hormonal methods of birth control other than Depo-medroxyprogesterone acetate (DMPA) should not be used as the sole method of contraception in women taking Viramune, since nevirapine might lower the plasma concentrations of these medicinal products. For this reason, and to reduce the risk of HIV transmission, barrier contraception (e.g., condoms) is recommended. Additionally, when postmenopausal hormone therapy is used during administration of nevirapine, its therapeutic effect should be monitored.

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicinal product related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

In clinical studies, Viramune has been associated with an increase in HDL- cholesterol and an overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies with nevirapine on modifying the cardiovascular risk in HIV infected patients, the clinical impact of these findings is not known. The selection of antiretroviral medicinal products must be guided primarily by their antiviral efficacy.

Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine is not recommended (please also refer to section 4.5).

Granulocytopenia is commonly associated with zidovudine. Therefore, patients who receive nevirapine and zidovudine concomitantly and especially paediatric patients and patients who receive higher zidovudine doses or patients with poor bone marrow reserve, in particular those with advanced HIV disease, have an increased risk of granulocytopenia. In such patients haematological parameters should be carefully monitored.

Lactose: Viramune prolonged-release tablets contain 400 mg of lactose per maximum recommended daily dose.

Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

The following data were generated using the Viramune immediate-release tablets but are expected to apply to all dosage forms.

Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy.

Compounds using this metabolic pathway may have decreased plasma concentrations when co-administered with nevirapine. Careful monitoring of the therapeutic effectiveness of P450 metabolised medicinal products is recommended when taken in combination with nevirapine.

The absorption of nevirapine is not affected by food, antacids or medicinal products which are formulated with an alkaline buffering agent.

The interaction data is presented as geometric mean value with 90% confidence interval (90% CI) whenever these data were available. ND = Not Determined, ↑ = Increased, = Decreased, ↔ = No Effect

Other information:

Nevirapine metabolites: Studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin, rifampicin, and trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin significantly inhibited the formation of nevirapine hydroxylated metabolites.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should not use oral contraceptives as the sole method for birth control, since nevirapine might lower the plasma concentrations of these medicinal products (see sections 4.4 & 4.5).

Pregnancy

Currently available data on pregnant women indicate no malformative or foeto/ neonatal toxicity. To date no other relevant epidemiological data are available. No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits (see section 5.3). There are no adequate and well-controlled studies in pregnant women. Caution should be exercised when prescribing nevirapine to pregnant women (see section 4.4). As hepatotoxicity is more frequent in women with CD4 cell counts above 250 cells/mm³ with detectable HIV-1 RNA in plasma (50 or more copies/ml), these conditions should be taken in consideration on therapeutic decision (see section 4.4). There is not enough evidence to substantiate that the absence of an increased risk for toxicity seen in pre-treated women initiating nevirapine with an undetectable viral load (less than 50 copies/ml of HIV-1 in plasma) and CD4 cell counts above 250 cells/mm³ also applies to pregnant women. All the randomised studies addressing this issue specifically excluded pregnant women, and pregnant women were under-represented in cohort studies as well as in meta-analyses.

Breastfeeding

Nevirapine readily crosses the placenta and is found in breast milk.

It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV and that mothers should discontinue breast-feeding if they are receiving nevirapine.

Fertility

In reproductive toxicology studies, evidence of impaired fertility was seen in rats.

There are no specific studies about the ability to drive vehicles and use machinery. However, patients should be advised that they may experience adverse reactions such as fatigue during treatment with nevirapine. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue they should avoid potentially hazardous tasks such as driving or operating machinery.

a. Summary of the safety profile

The most frequently reported adverse reactions related to Viramune prolonged-release therapy in treatment naïve patients (including lead-in phase with immediate-release) in clinical study 1100.1486 (VERxVE) were rash, nausea, liver function test abnormal, headache, fatigue, hepatitis, abdominal pain, diarrhoea and pyrexia. There are no new adverse drug reactions for Viramune prolonged-release tablets that have not been previously identified for Viramune immediate-release tablets and oral suspension.

b. Tabulated summary of adverse reactions

The following adverse reactions which may be causally related to the administration of Viramune prolonged-release tablets have been reported. The frequencies given below are based on crude incidence rates of adverse reactions observed in the Viramune immediate-release (lead-in phase, table 1) and Viramune prolonged-release (randomised-phase/maintenance phase, table 2) groups of clinical study 1100.1486 with 1,068 patients exposed to Viramune on a backbone of tenofovir/emtricitabine.

Frequency is defined using the following convention: very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000)

Table 1: Lead-in phase with Viramune immediate-release

* This adverse reaction was identified in other nevirapine studies or by post-marketing surveillance but not observed in the randomised, controlled clinical study 1100.1486. As this adverse reaction was not seen in study 1100.1486 the frequency category was estimated from a statistical calculation based on the total number of patients exposed to nevirapine immediate-release in the lead-in phase of the randomised controlled clinical study 1100.1486 (n= 1,068).

Table 2: Maintenance phase of Viramune prolonged-release

* This adverse reaction was identified in other nevirapine studies or by post-marketing surveillance but not observed in the randomised, controlled clinical study 1100.1486. As this adverse reaction was not seen in study 1100.1486 the frequency category was estimated from a statistical calculation based on the total number of patients exposed to nevirapine prolonged-release in the maintenance phase of the randomised controlled clinical study 1100.1486 (n= 505).

c. Description of selected adverse reactions

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

The following adverse reactions have also been reported when nevirapine has been used in combination with other anti-retroviral agents: pancreatitis, peripheral neuropathy and thrombocytopaenia. These adverse reactions are commonly associated with other antiretroviral agents and may be expected to occur when nevirapine is used in combination with other agents; however it is unlikely that these adverse reactions are due to nevirapine treatment. Hepatic-renal failure syndromes have been reported rarely.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Skin and subcutaneous tissues

The most common clinical toxicity of nevirapine is rash. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Hypersensitivity (incl. anaphylactic reaction, angioedema and urticaria) has been reported. Rashes occur alone or in the context of drug rash with eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lympadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction.

Severe and life-threatening skin reactions have occurred in patients treated with nevirapine, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Fatal cases of SJS, TEN and drug rash with eosinophilia and systemic symptoms have been reported. The majority of severe rashes occurred within the first 6 weeks of treatment and some required hospitalisation, with one patient requiring surgical intervention (see section 4.4).

In study 1100.1486 (VERxVE) antiretroviral-naïve patients received a lead-in dose of Viramune 200 mg immediate-release once daily for 14 days (n=1068) and then were randomised to receive either Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. All patients received tenofovir + emtricitabine as background therapy. The safety data include all patient visits up to the time of the last patient's completion of the 48-week primary endpoint in the study (mean observation period 61 weeks). Severe or life-threatening rash considered related to nevirapine treatment occurred in 1.1% of patients during the lead-in phase with Viramune immediate-release, and in 0.8% and 0.6% of the Viramune immediate-release and Viramune prolonged-release groups respectively during the randomisation phase. In addition, five cases of Stevens-Johnson Syndrome were reported in the study, all of which occurred within the first 30 days of nevirapine treatment.

In study 1100.1526 (TRANxITION) patients on Viramune 200 mg immediate-release twice daily treatment for at least 18 weeks were randomised to either receive Viramune 400 mg prolonged-release once daily (n=295) or remain on their Viramune immediate-release treatment (n=148). In this study, no Grade 3 or 4 rash was observed in either treatment group.

Hepato-biliary

The most frequently observed laboratory test abnormalities are elevations in liver function tests (LFTs), including ALAT, ASAT, GGT, total bilirubin and alkaline phosphatase. Asymptomatic elevations of GGT levels are the most frequent. Cases of jaundice have been reported. Cases of hepatitis (severe and life-threatening hepatoxicity, including fatal fulminant hepatitis) have been reported in patients treated with nevirapine. The best predictor of a serious hepatic event was elevated baseline liver function tests. The first 18 weeks of treatment is a critical period which requires close monitoring (see section 4.4).

In study 1100.1486 (VERxVE) treatment-naïve patients received a lead-in dose of Viramune 200 mg immediate-release once daily for 14 days and then were randomised to receive either Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. All patients received tenofovir + emtricitabine as background therapy. Patients were enrolled with CD4 counts <250 cells/mm³ for women and <400 cells/mm³ for men. Data on potential symptoms of hepatic events were prospectively collected in this study. The safety data include all patient visits up to the time of the last patient's completion of the 48-week primary endpoint in the study (mean observation period 61 weeks). The incidence of symptomatic hepatic events during the Viramune immediate-release lead-in phase was 0.5%. After the lead-in period the incidence of symptomatic hepatic events was 2.8% in the Viramune immediate-release group and 1.6% in the Viramune prolonged-release group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE.

In study 1100.1526 (TRANxITION) no Grade 3 or 4 clinical hepatic events were observed in either treatment group.

d. Paediatric population

Based on clinical study experience with Viramune immediate-release tablets and oral suspension of 361 paediatric patients the majority of which received combination treatment with ZDV or/and ddI, the most frequently reported adverse events related to nevirapine were similar to those observed in adults. Granulocytopenia was more frequently observed in children. In an open-label clinical study (ACTG 180) granulocytopenia assessed as medicinal product-related occurred in 5/37 (13.5%) of patients. In ACTG 245, a double-blind placebo controlled study, the frequency of serious medicinal product-related granulocytopenia was 5/305 (1.6%). Isolated cases of Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome have been reported in this population.

There is no known antidote for nevirapine overdose. Cases of overdose with Viramune immediate-release at doses ranging from 800 to 6,000 mg per day for up to 15 days have been reported. Patients have experienced oedema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, increase in transaminases and weight decrease. All of these effects subsided following discontinuation of nevirapine.

Paediatric Population

One case of massive accidental overdose in a newborn was reported. The ingested dose was 40 times the recommended dose of 2 mg/kg/day. Mild isolated neutropenia and hyperlactataemia was observed, which spontaneously disappeared within one week without any clinical complications. One year later, the child's development remained normal.

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors, ATC code J05AG01.

Mechanism of action

Nevirapine is a NNRTI of HIV-1. Nevirapine is a non-competitive inhibitor of the HIV-1 reverse transcriptase, but it does not have a biologically significant inhibitory effect on the HIV-2 reverse transcriptase or on eukaryotic DNA polymerases α, β, γ, or δ.

Antiviral activity in vitro

Nevirapine had a median EC₅₀ value (50% inhibitory concentration) of 63 nM against a panel of 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 replicating in human embryonic kidney 293 cells. In a panel of 2,923 predominantly subtype B HIV-1 clinical isolates, the mean EC₅₀ value was 90nM. Similar EC₅₀ values are obtained when the antiviral activity of nevirapine is measured in peripheral blood mononuclear cells, monocyte derived macrophages or lymphoblastoid cell line. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates or HIV-2 isolates.

Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity in vitro (see section 4.5) 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 medicinal product adefovir and by the anti-HCV medicinal product ribavirin in vitro.

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 Y181C and/or V106A 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 I/II studies 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 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.

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 prolonged-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 prolonged-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 prolonged-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.

Cross resistance to delavirdine and efavirenz is expected after virologic failure with nevirapine. Depending on resistance testing results, an etravirine-containing regimen may be used subsequently.

Cross-resistance between nevirapine and either HIV protease inhibitors, HIV integrase inhibitors or HIV entry inhibitors is unlikely because the enzyme targets involved are different. Similarly the potential for cross-resistance between nevirapine and NRTIs is low because the molecules have different binding sites on the reverse transcriptase.

Clinical results

Viramune has been evaluated in both treatment-naïve and treatment-experienced patients.

Studies in treatment-naïve patients

2NN study

The double non-nucleoside study 2 NN was a randomised, open-label, multicentre prospective study comparing the NNRTIs nevirapine, efavirenz and both medicinal products given together.

1216 antiretroviral-therapy naïve patients with plasma HIV-1 RNA > 5000 copies/ml at baseline were assigned to Viramune 400 mg once daily, Viramune 200 mg twice daily, efavirenz 600 mg once daily, or Viramune (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine for 48 weeks.

The primary endpoint, treatment failure, was defined as less than 1 log₁₀ decline in plasma HIV-1 RNA in the first 12 weeks, or two consecutive measurements of more than 50 copies/ ml from week 24 onwards, or disease progression (new Centers for Disease Control and Prevention grade C event or death), or change of allocated treatment.

Median age was 34 years and about 64% were male patients, median CD4 cell count was 170 and 190 cells per mm³ in the Viramune twice daily and efavirenz groups, respectively. There were no significant differences in demographic and baseline characteristics between the treatment groups.

The predetermined primary efficacy comparison was between the Viramune twice daily and the efavirenz treatment groups. Details of the primary efficacy comparison are given in table 1.

Table 1: Number of patients with treatment failure, components of treatment failure, and number of patients with plasma HIV-RNA concentration < 50 c/ml, at week 48 (Intention-To-Treat (ITT) Analysis).

* ART = antiretroviral therapy

Although, overall, treatment failure was numerically lower in the efavirenz group than in the nevirapine-only groups, the findings of this study show no evidence that efavirenz is superior to nevirapine twice daily in terms of treatment failure. However, equivalence within the 10% limits of these treatment groups was not shown even though the study was adequately powered for such an analysis. The nevirapine twice daily regimen and the efavirenz regimen were not significantly different (p= 0.091) in terms of efficacy as measured by incidence of treatment failure. There was also no significant difference between Viramune twice daily and efavirenz regarding any components of treatment failure including virological failure.

The simultaneous use of nevirapine (400 mg) plus efavirenz (800 mg) was associated with the highest frequency of clinical adverse events and with the highest rate of treatment failure (53.1%). As the regimen of nevirapine plus efavirenz did not have additional efficacy and caused more adverse events than each medicinal product separately, this regimen is not recommended.

Twenty per cent of patients assigned to nevirapine twice daily and 18% of patients assigned to efavirenz had at least one grade 3 or 4 clinical adverse event. Clinical hepatitis reported as clinical adverse event occurred in 10 (2.6%) and 2 (0.5%) patients in the nevirapine twice daily and efavirenz groups respectively. The proportion of patients with at least one grade 3 or 4 liver-associated laboratory toxicity was 8.3% for nevirapine twice daily and 4.5% for efavirenz. Of the patients with grade 3 or 4 liver-associated laboratory toxicity, the proportions coinfected with hepatitis B or hepatitis C virus were 6.7% and 20.0% in the nevirapine twice daily group, 5.6% and 11.1% in the efavirenz group.

2NN Three-year follow-up-study

This is a retrospective multicentre study comparing the 3-year antiviral efficacy of Viramune and efavirenz in combination with stavudine and lamivudine in 2NN patients from week 49 to week 144.

Patients who participated in the 2NN study and were still under active follow-up at week 48 when the study closed and were still being treated at the study clinic, were asked to participate in this study. Primary study endpoints (percentage of patients with treatment failures) and secondary study endpoints as well as backbone therapy were similar to the original 2NN study.

Table 2 shows the main efficacy results of this study.

Table 2: Number of patients with treatment failure, components of treatment failure, and number of patients with plasma HIV-RNA concentration < 400 copies/ml, between week 49 to 144 (ITT analysis).

A durable response to Viramune for at least three years was documented in this study. Equivalence within a 10% range was demonstrated between Viramune 200 mg twice daily and efavirenz with respect to treatment failure. Both, the primary (p = 0.92) and secondary endpoints showed no statistically significant differences between efavirenz and Viramune 200 mg twice daily.

Studies in treatment-experienced patients

NEFA study

The NEFA study is a controlled prospective randomised study which evaluated treatment options for patients who switch from protease inhibitor (PI) based regimen with undetectable load to either Viramune, efavirenz or abacavir.

The study randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one PI and whose plasma HIV-1 RNA levels had been less than 200 c/ml for at least the previous six months to switch from the PI to Viramune (155 patients), efavirenz (156), or abacavir (149).

The primary study endpoint was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per millilitre. The main results regarding the primary endpoint are given in table 3.

Table 3: Outcome of Therapy 12 months after switch from PI based therapy

At 12 months, the Kaplan–Meier estimates of the likelihood of reaching the endpoint were 10 % in the Viramune group, 6 % in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis).

The overall incidence of adverse events was significantly lower (61 patients, or 41%) in the abacavir group than in the nevirapine group (83 patients, or 54%) or the efavirenz group (89 patients, or 57%). Significantly fewer patients in the abacavir group (9 patients, or 6%) than in the nevirapine group (26 patients, or 17%) or the efavirenz group (27 patients, or 17%) discontinued the medicinal product because of adverse events (see table below).

Clinical studies with prolonged-release tablets

The clinical efficacy of Viramune prolonged-release is based on 48-week data from an ongoing, randomised, double-blind, double-dummy phase 3 study (VERxVE – study 1100.1486) in treatment-naïve patients and on 24-week data from an ongoing, randomised, open-label study in patients who transitioned from Viramune immediate-release tablets administered twice daily to Viramune prolonged-release tablets administered once daily (TRANxITION – study 1100.1526).

Treatment-naïve patients

VERxVE (study 1100.1486) is a phase 3 study in which treatment-naïve patients received Viramune 200 mg immediate-release once daily for 14 days and then were randomised to receive either Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release 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 4.

Table 4: Demographic and Baseline Disease Characteristics in study 1100.1486

* Includes 2 patients who were randomised but never received blinded medicinal products.

** Includes American Indians/Alaska natives and Hawaiian/Pacific islanders.

Table 5 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 medicinal product.

Table 5: Outcomes at week 48 in study 1100.1486*

* Includes patients who received at least one dose of blinded medicinal product after randomisation. Patients who discontinued treatment during the lead-in period are excluded.

** Includes lost to follow-up, consent withdrawn, noncompliance, lack of efficacy, pregnancy, and other.

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 prolonged-release respectively.

Table 6 shows outcomes at 48-weeks in study 1100.1486 (after randomization) by baseline viral load.

Table 6: Outcomes at 48 weeks in study 1100.1486 by baseline viral load*

* Includes patients who received at least one dose of blinded medicinal product after randomisation. Patients who discontinued treatment during the lead-in period are excluded.

** Based on Cochran's statistic with continuity correction for the variance calculation

The overall percentage of treatment responders observed in study 1100.1486 (including lead-in phase), regardless of the formulation is 793/1,068 = 74.3%. The denominator 1,068 includes 55 patients who stopped treatment during the lead in phase and two patients randomized but never treated with randomized dose. The numerator 793 is the number of patients who were treatment responders at 48 weeks (384 from immediate-release and 409 from prolonged-release treatment groups).

Lipids, Change from baseline

Changes from baseline in fasting lipids are shown in Table 7.

Table 7: Summary of lipid laboratory values at baseline (screening) and week 48 - study 1100.1486

^* Percent change is the median of within-patient changes from baseline for patients with both baseline and week 48 values and is not a simple difference of the baseline and week 48 mean values, respectively.

Patients switching from Viramune immediate-release to Viramune prolonged-release

TRANxITION (study 1100.1526) is a Phase 3 study to evaluate safety and antiviral activity in patients switching from Viramune immediate-release to Viramune prolonged-release. In this open-label study, 443 patients already on an antiviral regimen containing Viramune 200 mg immediate-release twice daily with HIV-1 RNA < 50 copies/ml were randomised in a 2:1 ratio to Viramune 400 mg prolonged-release once daily or Viramune 200 mg immediate-release 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 study 1100.1526.

At 24 weeks after randomisation in the TRANxITION study, 92.6% and 93.6% of patients receiving Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily, respectively, continued to have HIV-1 RNA < 50 copies/ml.

Paediatric population

Results of a 48-week analysis of the South African study BI 1100.1368 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.

There are no data available on interchangeability for 400 mg prolonged-release tablets and 100 mg prolonged-release tablets.

Absorption:

The pharmacokinetics of nevirapine has been studied in a single dose study (study 1100.1485) of Viramune prolonged-release in 17 healthy volunteers. The relative bioavailability of nevirapine when dosed as one 400 mg Viramune prolonged-release tablet, relative to two 200 mg Viramune immediate-release tablets, was approximately 75%. The mean peak plasma concentration of nevirapine was 2,060 ng/ml measured at a mean 24.5 hours after administration of 400 mg Viramune prolonged-release tablets.

The pharmacokinetics of Viramune prolonged-release has also been studied in a multiple dose pharmacokinetics study (study 1100.1489) in 24 HIV-1 infected patients who switched from chronic Viramune immediate-release therapy to Viramune prolonged-release. The nevirapine AUC_0-24,ss and C_min,ss measured after 19 days of fasted dosing of Viramune 400 mg prolonged-release tablets once daily were approximately 80% and 90%, respectively, of the AUC_0-24,ss and C_min,ss measured when patients were dosed with Viramune 200 mg immediate-release tablets twice daily. The geometric mean nevirapine C_min,ss was 2,770 ng/ml.

When Viramune prolonged-release was dosed with a high fat meal, the nevirapine AUC_0-24,ss and C_min,ss were approximately 94% and 98%, respectively, of the AUC_0-24,ss and C_min,ss measured when patients were dosed with Viramune immediate-release tablets. The difference in nevirapine pharmacokinetics observed when Viramune prolonged-release tablets are dosed under fasted or fed conditions is not considered clinically relevant. Viramune prolonged-release tablets can be taken with or without food.

Occasionally, the excipients of Viramune prolonged-release tablets will be eliminated in the faeces as soft, hydrated remnants.

Distribution: Nevirapine is lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the 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 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.

Biotransformation and 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 isozymes from the CYP3A family, 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 radiolabelled 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 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 has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The pharmacokinetics of autoinduction is 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 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 dysfunction: The single-dose pharmacokinetics of nevirapine immediate-release has been compared in 23 patients with either mild (50 CLcr < 80 ml/min), moderate (30 CLcr < 50 ml/min) or severe renal dysfunction (CLcr < 30 ml/min), renal impairment or end-stage renal disease (ESRD) requiring dialysis, and 8 patients with normal renal function (CLcr > 80 ml/min). Renal impairment (mild, moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine. However, patients with ESRD requiring dialysis exhibited a 43.5% reduction in nevirapine AUC over a one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in plasma. The results suggest that supplementing nevirapine therapy for adults with an additional 200 mg immediate-release tablet following each dialysis treatment would help offset the effects of dialysis on nevirapine clearance. Otherwise patients with CLcr 20 ml/min do not require an adjustment in nevirapine dosing. In paediatric patients with renal dysfunction who are undergoing dialysis it is recommended following each dialysis treatment patients receive an additional dose of Viramune oral suspension or immediate-release tablets representing 50% of the recommended daily dose of Viramune oral suspension or immediate-release tablets, which would help offset the effects of dialysis on nevirapine clearance. Viramune prolonged-release tablets have not been studied in patients with renal dysfunction and Viramune immediate-release should be used.

Hepatic dysfunction: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 immediate-release tablets 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 five oxidative metabolites were not altered.

However, approximately 15% of these patients with hepatic fibrosis had nevirapine trough concentrations above 9,000 ng/ml (2 fold the usual mean trough). Patients with hepatic impairment should be monitored carefully for evidence of medicinal product induced toxicity.

In a single dose pharmacokinetic study of 200 mg Viramune immediate-release tablets in 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 one 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 section 4.4). Viramune prolonged-release tablets have not been evaluated in patients with hepatic impairment and Viramune immediate-release should be used.

In the multinational 2NN study with Viramune immediate-release, 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.

The effects of gender on the pharmacokinetics of Viramune prolonged-release have been investigated in study 1100.1486. Female patients tend to have higher (approximately 20 - 30%) trough concentrations in both Viramune prolonged-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). Nevirapine has not been specifically investigated in patients over the age of 65. Black patients (n=80/group) in study 1100.1486 showed approximately 30% higher trough concentrations than Caucasian patients (250-325 patients/group) in both the Viramune immediate-release and Viramune prolonged-release treatment groups over 48 weeks of treatment at 400 mg/day.

Paediatric population

Data concerning the pharmacokinetics of nevirapine has been derived from two major sources: a 48 week paediatric study in South Africa (BI 1100.1368) involving 123 HIV-1 positive, antiretroviral naïve patients aged 3 months to 16 years; and a consolidated analysis of five Paediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 patients aged 14 days to 19 years.

Pharmacokinetic data on 33 patients (age range 0.77 – 13.7 years) in the intensive sampling group demonstrated that clearance of nevirapine increased with increasing age in a manner consistent with increasing body surface area. Dosing of nevirapine at 150 mg/m² BID (after a two-week lead in at 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 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 less than 3 months of age (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 second month of age.

The pharmacokinetics of Viramune prolonged-release was assessed in study 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 prolonged-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 prolonged-release to Viramune immediate-release were ~90% for C_min,ss and AUC_ss with 90% confidence intervals within 80%-125%; the ratio for C_max,ss was lower and consistent with a once-daily prolonged-release dosage form. Geometric mean steady-state plasma Viramune prolonged-release pre-dose trough concentrations were 3,880 ng/ml, 3,310 ng/ml and 5,350 ng/ml in age groups 3 to <6 years, 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 prolonged-release in study 1100.1486.

In single dose, parallel group bioavailability studies (studies 1100.1517 and 1100.1531), the Viramune 50 and 100 mg prolonged-release tablets exhibited extended release characteristics of prolonged absorption and lower maximal concentrations, similar to the findings when a 400 mg prolonged-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 medicinal product release rates. The observed pharmacokinetic difference between the 50 mg and 100 mg Viramune prolonged-release tablets is not clinically relevant, and the 50 mg prolonged-release tablet can be used as an alternative to the slightly larger 100 mg tablet.

Non-clinical data reveal no special hazard for humans other than those observed in clinical studies based on conventional studies of safety, pharmacology, repeated dose toxicity, and genotoxicity. In carcinogenicity studies, nevirapine induces hepatic tumours in rats and mice. These findings are most likely related to nevirapine being a strong inducer of liver enzymes, and not due to a genotoxic mode of action.

Lactose monohydrate

Hypromellose

Iron oxide yellow

Magnesium stearate

Not applicable.

2 years

If bottles are taken the medicinal product should be used within 2 months of opening.

This medicinal product does not require any special storage conditions.

Maintenance packs:

Polyvinyl chloride (PVC)/aluminium foil push through blister units. Cartons containing 30 prolonged-release tablets or 90 prolonged-release tablets.

or

High density polyethylene (HDPE) plastic bottle, with a plastic cap and an induction foil seal liner. Bottles contain 30 prolonged-release tablets.

Any unused product or waste material should be disposed of in accordance with local requirements.

Boehringer Ingelheim International GmbH

Binger Strasse 173

55216 Ingelheim am Rhein, Germany

EU/1/97/055/007 (30 tablets, bottle)

EU/1/97/055/008 (30 tablets, blister)

EU/1/97/055/009 (90 tablets, blister)

Date of first authorisation: 5 February 1998

Date of latest renewal: 5 February 2008

19 January 2012

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu