Viramune 200 mg Tablets

/ Boehringer Ingelheim

Patients 16 years and older: The recommended dose of Viramune is one 200 mg 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 200 mg tablet twice daily, in combination with at least one additional antiretroviral agent.
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 should not have their Viramune dose increased until the rash has resolved. The isolated rash should be closely monitored. 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.
There are toxicities that require interruption of Viramune therapy.
Elderly: Nevirapine has not been specifically investigated in patients over the age of 65.
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.
Hepatic impairment: Nevirapine should not be used in patients with severe hepatic impairment. No dose adjustment is necessary in patients with mild to moderate hepatic impairment.
Paediatric population: Viramune 200 mg tablets, following the dosing schedule described above, are suitable for larger children, particularly adolescents, below the age of 16 who weigh more than 50 kg or whose body surface area is above
1.25 m² according to the Mosteller formula. An oral suspension dosage form, which can be dosed according to body weight or body surface area, is available for children in this age group weighing less than 50 kg or whose body surface area is below 1.25 m² (please refer to the Summary of Product Characteristics of Viramune oral suspension).
Method of administration: The tablets shall be taken with liquid, and should not be crushed or chewed. Viramune may be taken with or without food.

Nevirapine (nevirapine) is a non-nucleoside reverse transcriptase inhibitor of HIV-1. It is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of changes in surrogate endpoints. At present, there are no results from controlled clinical trials evaluating the effect of Nevirapine in combination with other antiretroviral agents on the clinical progression of HIV-1 infection, such as the incidence of opportunistic infections or survival. Resistant virus emerges rapidly and uniformly when Nevirapine is administered as monotherapy. Therefore, Nevirapine should always be administered in combination with at least one additional antiretroviral agent.

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.
Coadministration with herbal preparations containing St. John’s wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of nevirapine.

Nevirapine should only be used with at least one other antiretroviral agent.
Nevirapine should not be used as the sole active antiretroviral, as monotherapy with any antiretroviral has shown to result in viral resistance.
The first 18 weeks of therapy with nevirapine are a critical period which requires close monitoring of patients to disclose the potential appearance of severe and life-threatening skin reactions (including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) and serious hepatitis/hepatic failure. The greatest risk of hepatic events and skin reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues past this period and monitoring should continue at frequent intervals. Female gender and higher CD4 counts (greater than 250 cells/mm³ in adult females and greater than 400 cells/ mm³ in adult males) at the initiation of nevirapine therapy are associated with a greater risk of hepatic adverse events if the patient has detectable plasma HIV-1 RNA-i.e. a concentration ≥ 50 copies/ml at the initiation of nevirapine. As serious and life threatening hepatotoxicity has been observed in controlled and uncontrolled studies predominantly in patients with a plasma HIV-1 viral load of 50 copies/ml or higher, nevirapine should not be initiated in adult females with CD4 cell counts greater than 250 cells/mm³ or in adult males with CD4 cell counts greater than 400 cells/mm³, who have a detectable plasma HIV-1 RNA unless the benefit outweighs the risk In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Nevirapine must not be restarted following severe hepatic, skin or hypersensitivity reactions. The dose must be strictly adhered to, especially the 14-days lead-in period.
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). Nevirapine administration above the recommended dose might increase the frequency and seriousness of skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.
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.
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.
Liver disease: The safety and efficacy of Nevirapine has not been established in patients with significant underlying liver disorders. Nevirapine is contraindicated in patients with severe hepatic impairment (Child-Pugh C). 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.
Post-Exposure-Prophylaxis: Serious hepatotoxicity, including liver failure requiring transplantation, has been reported in HIV-uninfected individuals receiving multiple doses of Nevirapine in the setting of post-exposure-prophylaxis (PEP), an unapproved use. The use of Nevirapine 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.
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
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.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
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, the clinical impact of these findings is not known. In addition, Viramune has not been shown to cause glucose disturbances.
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 carinii pneumonia. Any  inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine is not recommended. Furthermore, combining the following compounds with Viramune is not recommended: efavirenz, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (in combination with cobicistat), atazanavir (in combination with ritonavir), boceprevir; fosamprenavir (if not co-administered with low dose ritonavir).
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: Nevirapine tablets contain 636 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 medicine.

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.
The postmarketing experience has shown that the most serious adverse reactions are Stevens-Johnson syndrome/toxic epidermal necrolysis, serious hepatitis/hepatic failure and drug reaction with eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction. The first 18 weeks of treatment is a critical period which requires close monitoring.
See prescribing information for full details.

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.
See prescribing information for full details.

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. There are no adequate and well-controlled studies in pregnant women. Caution should be exercised when prescribing nevirapine to pregnant women.
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. 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.
Lactation: 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 nursing if they are receiving nevirapine.
See prescribing information for full details.               

There is no known antidote for nevirapine overdose. Cases of Nevirapine 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.