Viramune 50 mg/5 ml oral suspension

Each ml of oral suspension contains 10 mg of nevirapine (as hemihydrate).

Each bottle contains 2.4 g of nevirapine.

Excipient: each ml of oral suspension contains 150 mg sucrose, 162 mg sorbitol, 1.8 mg of methyl parahydroxybenzoate and 0.24 mg of propyl parahydroxybenzoate.

For a full list of excipients, see section 6.1.

Oral suspension

White to off-white homogenous suspension.

Viramune is indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infected adults, adolescents, and children of any age (see section 4.4).

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

Patients 16 years and older

The recommended dose for Viramune is 20 ml (200 mg) oral suspension once 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 20 ml (200 mg) oral suspension twice daily, in combination with at least two additional antiretroviral agents.

Viramune is also available as a 200 mg tablet for patients 16 years and older, or for older children, particularly adolescents, weighing 50 kg or more or whose BSA is above 1.25 m².

If a dose is recognized as missed within 8 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 8 hours later, the patient should only take the next dose at the usual time.

Dose management considerations

Patients experiencing rash during the 14-day lead-in period of 200 mg/day (4 mg/kg/day or 150 mg/m²/day for paediatric patients) should not have their Viramune dose increased until the rash has resolved. The isolated rash should be closely monitored (please refer to section 4.4). The 200 mg once daily 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.

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

Special populations

Renal impairment

For patients with renal dysfunction requiring dialysis an additional 200 mg dose of nevirapine following each dialysis treatment is recommended. Patients with CLcr 20 ml/min do not require a dose adjustment, see section 5.2.

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).

Elderly:

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

Paediatric population

The total daily dose should not exceed 400 mg for any patient. Viramune may be dosed in paediatric patients either by body surface area (BSA) or by body weight as follows:

By BSA using the Mosteller formula the recommended oral dose for paediatric patients of all ages is 150 mg/m² once daily for two weeks followed by 150 mg/m² twice daily thereafter.

Calculation of the volume of Viramune® oral suspension (50 mg/5 ml) required for paediatric dosing on a body surface basis of 150 mg/m²:

By weight the recommended oral dose for paediatric patients up to 8 years of age is 4 mg/kg once daily for two weeks followed by 7 mg/kg twice daily thereafter. For patients 8 years and older the recommended dose is 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter.

Calculation of the volume of Viramune® oral suspension (50 mg/5 ml) required for paediatric dosing after the two weeks lead-in period.

All patients less than 16 years of age receiving Viramune oral suspension should have their weight or BSA checked frequently to assess if dose adjustments are necessary.

Method of administration

It is important that the entire measured dose of Viramune oral suspension is administered. This is assisted by the use of the supplied dispensing syringe. If an alternative measuring device is used (e.g. a dispensing cup or teaspoon for larger doses) it is important that the device is rinsed to ensure complete removal of residual oral suspension. Viramune may 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 nevirapinetherapy 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.

Nevirapine 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 nevirapine use.

Concomitant prednisone use (40 mg/day for the first 14 days of Viramune 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 (4 mg/kg or 150 mg/m² for paediatric patients) 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 dose escalation is not to occur if any rash occurs during the two-week lead-in dosing period, until the rash resolves. The 200 mg once daily 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. Careful monitoring of paediatric patients is especially warranted, particularly in the first 18 weeks of treatment, since these patients may be less likely than adults to notice, or report, skin reactions.

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. Women have 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 are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review of 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 a 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.

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 Viramune 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.

Sucrose: Viramune oral suspension contains 150 mg of sucrose per ml. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Sorbitol: Viramune oral suspension contains 162 mg of sorbitol per ml. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Methyl and propyl parahydroxybenzoates: Viramune oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate, which may cause allergic reaction (possibly delayed).

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 medications (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 Viramune. 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 therapy, across all clinical studies, were rash, allergic reactions, hepatitis, abnormal liver function tests, nausea, vomiting, diarrhoea, abdominal pain, fatigue, fever, headache and myalgia.

b. Tabulated summary of adverse reactions

The following adverse reactions which may be causally related to the administration of Viramune have been reported. The frequencies estimated are based on pooled clinical study data for adverse reactions considered related to Viramune treatment.

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).

* In study 1100.1090, from which the majority of related adverse events (n=28) were received, patients on placebo had a higher incidence of events of granulocytopenia (3.3%) than patients on nevirapine (2.5%).

** This adverse reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical studies. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to nevirapine in randomised controlled clinical studies (n= 2,718).

*** This adverse reaction was observed in clinical studies with co-administration of tenofovir/emtricitabine.

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, with Viramune attributable rash occurring in 12.5% of patients in combination regimens in controlled studies.

Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Hypersensitivity (anaphylactic reaction, angioedema and urticaria) have 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).

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).

d. Paediatric population

Based on clinical study experience 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 Viramune overdose 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 2mg/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.

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).

* A grade 3 event was defined as severe, and a grade 4 event as life-threatening

** Systemic adverse events included hypersensitivity reactions

*** P=0.02 by the chi-square test

**** P=0.01 by the chi-square test

Perinatal Transmission

The HIVNET 012 study conducted in Kampala (Uganda) evaluated the efficacy of Viramune to prevent vertical transmission of HIV-1 infection. Mothers received only study antiretroviral therapy during these studies. Mother-infant pairs were randomised to receive oral Viramune (mother: 200 mg at the onset of labour; infant: 2 mg/kg within 72 hours of birth), or an ultra-short oral zidovudine regimen (mother: 600 mg at the onset of labour and 300 mg every 3 hours until delivery; infant 4 mg/kg twice daily for 7 days). The cumulative HIV-1 infant infection rate at 14-16 weeks was 13.1% (n = 310) in the Viramune group, versus 25.1% (n = 308 in the ultra-short zidovudine group (p = 0.00063).

From a study in which infants of HIV infected mothers received either placebo or single dose nevirapine, 30 HIV infected infants, 15 who have received placebo and 15 who have received nevirapine, were subsequently treated with nevirapine combined with other anti-retroviral medicinal products. Virologic failure after 6 months of treatment with nevirapine combined with other anti-retroviral medicinal products occurred in significantly more infants who had previously received a single dose of nevirapine (10 of 15) than in infants who had received placebo previously (1 of 15). This indicates that in infants previously treated with single-dose nevirapine alone for prevention of mother to child transmission of HIV-1, the efficacy of Viramune as part of a combination therapy which they receive for their own health may be reduced.

In a study in which women who had received single dose nevirapine for prevention of mother-to-child transmission were treated with Viramune combined with other anti-retroviral medicinal products for their own health, 29 of 123, or 24% experienced virologic failure, and five (38%) of 13 women with HIV-1 detected baseline resistance to Viramune experienced virologic failure. This indicates that in women previously treated with single-dose nevirapine alone for prevention of mother to child transmission of HIV-1, the efficacy of Viramune as part of a combination therapy which the women receive for their own health may be reduced.

A blinded randomized clinical study in women already taking antiretroviral therapy throughout pregnancy (PACTG 316) demonstrated no further reduction of vertical HIV-1 transmission when the mother and the child received a single Viramune dose during labour and after birth respectively. HIV-1 transmission rates were similarly low in both treatment groups (1.3% in the Viramune group, 1.4% in the placebo group). The vertical transmission decreased neither in women with HIV-1 RNA below the limit of quantification nor in women with HIV-1 RNA above the limit of quantification prior to partus. Of the 95 women who received intrapartum Viramune, 15% developed nevirapine resistance mutations at 6 weeks post partus.

The clinical relevance of these data in European populations has not been established. Furthermore, in the case Viramune is used as single dose to prevent vertical transmission of HIV-1 infection, the risk of hepatotoxicity in mother and child cannot be excluded.

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.

Viramune tablets and oral suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg.

Absorption: 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. Data reported in the literature from 20 HIV infected patients suggest a steady state C_max of 5.74 µg/ml (5.00-7.44) and C_min of 3.73 µg/ml (3.20-5.08) with an AUC of 109.0 h_*µg/ml (96.0-143.5) in patients taking 200 mg of nevirapine bid. Other published data support these conclusions. Long-term efficacy appears to be most likely in patients whose nevirapine trough levels exceed 3.5 µg/ml.

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 characterized 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 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 with an additional 200 mg dose of Viramune 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.

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 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 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 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).

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 does not appear to change with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). Nevirapine has not been specifically investigated in patients over the age of 65.

Paediatric population

Data concerning the pharmacokinetics of nevirapine have 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.

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.

Carbomer

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Sorbitol

Sucrose

Polysorbate 80

Sodium hydroxide (for pH-adjustment)

Purified water

Not applicable.

3 years

The medicinal product should be used within 6 months of opening.

This medicinal product does not require any special storage conditions.

White high density polyethylene (HDPE) bottle with two piece child-resistant closure (outer shell white high density polyethylene, inner shell natural polypropylene) with a low density polyethylene (LDPE) foam liner. Each bottle contains 240 ml of oral suspension.

Clear polypropylene 5 ml dispensing syringe with silicone rubber piston seal.

Clear low density polyethylene bottle-syringe adapter.

Instructions for administration:

The required dose volumes should be measured employing the enclosed dispensing syringe and adapter, as described in steps 1-5 below. The maximum volume which can be measured with the dispensing syringe is 5 ml and therefore steps 3-5 must be repeated for dose volumes greater than 5 ml.

1. Shake the bottle gently

2. Fit (by first pressing and then screwing) the adapter onto the open bottle neck

3. Insert the syringe into the adapter

4. Invert the bottle

5. Withdraw the required dose volume

The bottle can be kept sealed with the flexible lid of the adapter. Viramune oral suspension should be used within 6 months after first opening of the bottle.

Disposal:

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/1/97/055/002

Date of first authorisation: 18 June 1999

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