Viramune should be administered by physicians who are experienced in the treatment of HIV infection.
Posology
Paediatric population
Children three years and older and adolescents
Viramune prolonged-release tablets may be dosed based on a patient's weight or body surface area (BSA).
Lead-in dosing with Viramune 200 mg tablets or Viramune 50 mg/5 ml oral suspension (first 14 days):
All paediatric patients should initiate therapy with 150 mg/m2 (calculated using the Mosteller formula) or 4 mg/kg body weight administered 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. The lead-in period is not required if the patient is already on chronic Viramune 200 mg tablets or Viramune oral suspension twice daily treatment.
Once daily maintenance dosing with Viramune prolonged-release tablets (after the lead-in):
The recommended oral doses for paediatric patients based upon their BSA are described in the table below.
Recommended paediatric dosing by BSA after the lead-in period
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BSA (m2)
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Viramune prolonged-release tablets dose (mg)
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0.58-0.83
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200 (2 x 100 mg or 4 x 50 mg)
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0.84-1.16
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300 (3 x 100 mg or 6 x 50 mg)
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≥ 1.17
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400 (1 x 400 mg)
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The recommended oral doses for paediatric patients based upon their weight are described in the table below. The recommended weight-based paediatric dose is dependent upon the patient's age, with different recommended doses for children from 3 to < 8 years of age and children 8 years or older.
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Weight Range (kg) for patients < 8 yrs of age
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Weight Range (kg) for patients ≥ 8 years of age
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Viramune prolonged-release tablets dose (mg)
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12.5-17.8
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17.9 to 31.2
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200 (2 x 100 mg or 4 x 50 mg)
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17.9-24.9
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31.3 to 43.7
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300 (3 x 100 mg or 6 x 50 mg)
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25 and above
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43.8 and above
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400 (1 x 400 mg)
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All paediatric patients should have their weight or BSA checked frequently to assess if dose adjustments are necessary.
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.
Alternatively, 50 mg prolonged-release tablets for paediatric patients aged 3 years and older are available for a once daily administration after the lead-in period (please refer to the Summary of Product Characteristics of Viramune 50 mg prolonged-release tablets). Furthermore, an immediate-release oral suspension dosage form is available for all age groups for a twice daily administration (please refer to the respective Summary of Product Characteristics).
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 should not initiate treatment with Viramune prolonged-release tablets until the rash has resolved. The isolated rash should be closely monitored (see section 4.4). The 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.
There are toxicities that require interruption of Viramune therapy (see section 4.4).
Special populations
Older people
Nevirapine has not been specifically investigated in patients over the age of 65.
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.
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.
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.
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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 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 (>250/mm3 in adult females and >400/mm3 in adult males) at the initiation of nevirapine therapy are associated with a greater risk of hepatic adverse reactions 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 eva luation immediately. Nevirapine must not be restarted following severe hepatic, skin or hypersensitivity reactions (see section 4.3).
The dose must be strictly adhered to, especially the 14-days lead-in period (see section 4.2).
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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 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 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.
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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 should discontinue the medicinal product and immediately seek medical eva luation. In these patients nevirapine must not be restarted.
If patients present with a suspected nevirapine-associated rash, liver function tests should be performed. Patients with moderate to severe elevations (ASAT or ALAT > 5 ULN) should be permanently discontinued from nevirapine.
If a hypersensitivity reaction occurs, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, nevirapine must be permanently stopped and not be re-introduced (see section 4.3).
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Hepatic reactions
Severe and life-threatening hepatotoxicity, 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 reactions 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 reactions. 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 reactions 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 eva luation, 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 3rd 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).
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Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such as anorexia, nausea, jaundice, bilirubinuria, acholic stools, hepatomegaly or liver tenderness. Patients should be instructed to seek medical attention promptly if these occur.
If ASAT or ALAT increase to > 5 ULN during treatment, nevirapine should be immediately stopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs or symptoms of hepatitis, rash, constitutional symptoms or other findings suggestive of organ dysfunction, it may be possible to reintroduce nevirapine, on a case by case basis, at the starting dose regimen of Viramune immediate-release once daily for 14 days followed by Viramune prolonged-release tablets once daily. In these cases, more frequent liver monitoring is required. If liver function abnormalities recur, nevirapine should be permanently discontinued.
If clinical hepatitis occurs, characterised by anorexia, nausea, vomiting, icterus AND laboratory findings (such as moderate or severe liver function test abnormalities (excluding GGT)), nevirapine must be permanently stopped. Viramune must not be readministered to patients who have required permanent discontinuation for clinical hepatitis due to nevirapine.
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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 reactions. 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 eva luated 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 jirovecii pneumonia. Any inflammatory symptoms should be eva luated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) 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) (see 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.
There are no data on the interchangeability of 100 mg or 50 mg Viramune prolonged-release tablets compared to 400 mg prolonged-release tablets and therefore, neither 50 mg nor 100 mg prolonged-release tablets should be taken by adults.
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.
Some patients have reported the occurrence of remnants in faeces which may resemble intact tablets. Based on the data available so far, this has not been shown to affect the therapeutic response. If patients report such an event, reassurance should be obtained on the lack of impact on therapeutic response.
