Viramune

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Viramune 200 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200 mg of nevirapine (as anhydrous). 

Excipients with known effect
Each tablet contains 318 mg of lactose (as monohydrate).
Each tablet contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

White, oval, biconvex tablets. One side is embossed with the code “54 193”, with a single bisect 
separating the “54” and “193”. The opposite side is marked with the company symbol. The score line 
is not intended for breaking the tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 4.2).

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

4.2 Posology and method of administration

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

Posology

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 two additional antiretroviral agents.

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 
(see section 4.4). The 200 mg once daily dosing regimen should not be continued beyond 28 days at 



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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 (see section 4.4).

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, 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). 

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).

Children less than three years old.

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).

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

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

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

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

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 (see section 4.5).



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4.4 Special warnings and precautions for use

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.

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 evaluation 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).

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 administration) has been 
shown not to decrease the incidence of nevirapine-associated rash, and may be associated with an 
increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. 

Some risk factors for developing serious cutaneous reactions have been identified; they include failure 
to follow the initial dosing of 200 mg daily during the lead-in period and a long delay between the 



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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.

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 evaluation. 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).

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. 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 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 



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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 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. 

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).

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 200 mg/day for 14 days followed by 400 mg/day. 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.

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.



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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.

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 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 



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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.

Lactose: Viramune tablets contain 636 mg of lactose per maximum recommended daily dose.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-
galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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

Medicinal products 
by therapeutic areas

Interaction Recommendations concerning co-
administration

ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine 
100-150 mg BID

Didanosine AUC  1.08 (0.92-1.27)
Didanosine Cmin ND
Didanosine Cmax  0.98 (0.79-1.21)

Didanosine and Viramune can be co-
administered without dose 
adjustments.

Emtricitabine Emtricitabine is not an inhibitor of 
human CYP 450 enzymes.

Viramune and emtricitabine may be 
coadministered without dose 
adjustments.

Abacavir In human liver microsomes, abacavir 
did not inhibit cytochrome P450 
isoforms.

Viramune and abacavir may be 
coadministered without dose 
adjustments.

Lamivudine 
150 mg BID

No changes to lamivudine apparent 
clearance and volume of distribution, 
suggesting no induction effect of 
nevirapine on lamivudine clearance.

Lamivudine and Viramune can be co-
administered without dose 
adjustments.

Stavudine: 
30/40 mg BID 

Stavudine AUC  0.96 (0.89-1.03)
Stavudine Cmin ND
Stavudine Cmax  0.94 (0.86-1.03)

Stavudine and Viramune can be co-
administered without dose 
adjustments.



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Nevirapine: compared to historical 
controls, levels appeared to be 
unchanged.

Tenofovir 
300 mg QD

Tenofovir plasma levels remain 
unchanged when co-administered 
with nevirapine. 

Nevirapine plasma levels were not 
altered by co-administration of 
tenofovir.

Tenofovir and Viramune can be co-
administered without dose 
adjustments.

Zidovudine 
100-200 mg TID

Zidovudine AUC  0.72 (0.60-0.96) 
Zidovudine Cmin ND
Zidovudine Cmax  0.70 (0.49-1.04)

Nevirapine: Zidovudine had no 
effect on its pharmacokinetics.

Zidovudine and Viramune can be co-
administered without dose 
adjustments

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.

NNRTIs
Efavirenz 
600 mg QD

Efavirenz AUC  0.72 (0.66-0.86)
Efavirenz Cmin  0.68 (0.65-0.81)
Efavirenz Cmax  0.88 (0.77-1.01)

It is not recommended to co-
administer efavirenz and Viramune
(see section 4.4), because of additive 
toxicity and no benefit in terms of 
efficacy over either NNRTI alone (for 
results of 2NN study, see section 5.1).

Delavirdine Interaction has not been studied. The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

Etravirine Concomitant use of etravirine with 
nevirapine may cause a significant 
decrease in the plasma 
concentrations of etravirine and loss 
of therapeutic effect of etravirine.

The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

Rilpivirine Interaction has not been studied. The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

PIs



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Atazanavir/ritonavir 
300/100 mg QD
400/100 mg QD

Atazanavir/r 300/100mg:
Atazanavir/r AUC  0.58 (0.48-0.71)
Atazanavir/r Cmin 0.28 (0.20-0.40)
Atazanavir/r Cmax  0.72 (0.60-0.86)

Atazanavir/r 400/100mg:
Atazanavir/r AUC  0.81 (0.65-1.02) 
Atazanavir/r Cmin  0.41 (0.27-0.60)
Atazanavir/r Cmax  1.02 (0.85–
1.24)
(compared to 300/100mg without 
nevirapine)

Nevirapine AUC  1.25 (1.17-1.34)
Nevirapine Cmin 1.32 (1.22–1.43)
Nevirapine Cmax  1.17 (1.09-1.25)

It is not recommended to co-
administer atazanavir/ritonavir and 
Viramune (see section 4.4).

Darunavir/ritonavir 
400/100 mg BID 

Darunavir AUC  1.24 (0.97-1.57)
Darunavir Cmin  1.02 (0.79-1.32)
Darunavir Cmax  1.40 (1.14-1.73)

Nevirapine AUC  1.27 (1.12-1.44)
Nevirapine Cmin  1.47 (1.20-1.82)
Nevirapine Cmax  1.18 (1.02-1.37)

Darunavir and Viramune can be co-
administered without dose 
adjustments.

Fosamprenavir
1,400 mg BID

Amprenavir AUC  0.67 (0.55-0.80)
Amprenavir Cmin  0.65 (0.49-0.85)
Amprenavir Cmax  0.75 (0.63-0.89)

Nevirapine AUC  1.29 (1.19-1.40)
Nevirapine Cmin  1.34 (1.21-1.49)
Nevirapine Cmax  1.25 (1.14-1.37)

It is not recommended to co-
administer fosamprenavir and 
Viramune if fosamprenavir is not co-
administered with ritonavir (see 
section 4.4).

Fosamprenavir/ritona
vir 700/100 mg BID

Amprenavir AUC  0.89 (0.77-
1.03)
Amprenavir Cmin  0.81 (0.69-0.96)
Amprenavir Cmax  0.97 (0.85-1.10)

Nevirapine AUC  1.14 (1.05-1.24)
Nevirapine Cmin  1.22 (1.10-1.35)
Nevirapine Cmax  1.13 (1.03-1.24)

Fosamprenavir/ritonavir and 
Viramune can be co-administered 
without dose adjustments

Lopinavir/ritonavir 
(capsules) 
400/100 mg BID 

Adult patients: 
Lopinavir AUC  0.73 (0.53-0.98)
Lopinavir Cmin  0.54 (0.28-0.74)
Lopinavir Cmax  0.81 (0.62-0.95)

An increase in the dose of 
lopinavir/ritonavir to 533/133 mg (4 
capsules) or 500/125 mg (5 tablets 
with 100/25 mg each) twice daily 
with food is recommended in 
combination with Viramune. Dose 
adjustment of Viramune is not 
required when co-administered with 
lopinavir.



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Lopinavir/ritonavir 
(oral solution) 
300/75 mg/m2 BID

Paediatric patients: 
Lopinavir AUC  0.78 (0.56-1.09) 
Lopinavir Cmin  0.45 (0.25-0.82)
Lopinavir Cmax  0.86 (0.64-1.16) 

For children, increase of the dose of 
lopinavir/ritonavir to 300/75 mg/m2 

twice daily with food should be 
considered when used in combination 
with Viramune, particularly for 
patients in whom reduced 
susceptibility to lopinavir/ritonavir is 
suspected. 

Ritonavir
600 mg BID

Ritonavir AUC 0.92 (0.79-1.07)
Ritonavir Cmin  0.93 (0.76-1.14)
Ritonavir Cmax  0.93 (0.78-1.07)

Nevirapine: Co-administration of 
ritonavir does not lead to any 
clinically relevant change in 
nevirapine plasma levels.

Ritonavir and Viramune can be co-
administered without dose 
adjustments.

Saquinavir/ritonavir The limited data available with 
saquinavir soft gel capsule boosted 
with ritonavir do not suggest any 
clinically relevant interaction 
between saquinavir boosted with 
ritonavir and nevirapine

Saquinavir/ritonavir and Viramune
can be co-administered without dose 
adjustments. 

Tipranavir/ritonavir 
500/200 mg BID

No specific drug-drug interaction 
study has been performed.
The limited data available from a 
phase IIa study in HIV-infected 
patients have shown a clinically non 
significant 20% decrease of TPV 
Cmin. 

Tipranavir and Viramune can be co-
administered without dose 
adjustments.

ENTRY INHIBITORS
Enfuvirtide Due to the metabolic pathway no 

clinically significant 
pharmacokinetic interactions are 
expected between enfuvirtide and 
nevirapine.

Enfuvirtide and Viramune can be co-
administered without dose 
adjustments.

Maraviroc 
300 mg QD

Maraviroc AUC  1.01 (0.6 -1.55)
Maraviroc Cmin ND
Maraviroc Cmax  1.54 (0.94-2.52)
compared to historical controls 

Nevirapine concentrations not 
measured, no effect is expected.

Maraviroc and Viramune can be co-
administered without dose 
adjustments.

INTEGRASE INHIBITORS
Elvitegravir/
cobicistat 

Interaction has not been studied. 
Cobicistat, a cytochrome P450 3A 
inhibitor significantly inhibits 
hepatic enzymes, as well as other 
metabolic pathways. Therefore 
coadministration would likely result 

Coadministration of Viramune with 
elvitegravir in combination with 
cobicistat is not recommended (see 
section 4.4).



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in altered plasma levels of cobicistat 
and Viramune.

Raltegravir 
400 mg BID

No clinical data available. Due to the 
metabolic pathway of raltegravir no 
interaction is expected.

Raltegravir and Viramune can be co-
administered without dose 
adjustments.

ANTIBIOTICS
Clarithromycin 
500 mg BID

Clarithromycin AUC  0.69 (0.62-
0.76)
Clarithromycin Cmin  0.44 (0.30-
0.64)
Clarithromycin Cmax  0.77 (0.69-
0.86)

Metabolite 14-OH clarithromycin 
AUC  1.42 (1.16-1.73) 
Metabolite 14-OH clarithromycin 
Cmin  0 (0.68-1.49)
Metabolite 14-OH clarithromycin 
Cmax  1.47 (1.21-1.80)

Nevirapine AUC  1.26 
Nevirapine Cmin  1.28
Nevirapine Cmax  1.24 
compared to historical controls. 

Clarithromycin exposure was 
significantly decreased, 14-OH 
metabolite exposure increased. 
Because the clarithromycin active 
metabolite has reduced activity 
against Mycobacterium avium-
intracellulare complex overall 
activity against the pathogen may be 
altered. Alternatives to 
clarithromycin, such as azithromycin 
should be considered. Close 
monitoring for hepatic abnormalities 
is recommended

Rifabutin 
150 or 300 mg QD

Rifabutin AUC  1.17 (0.98-1.40)
Rifabutin Cmin  1.07 (0.84-1.37)
Rifabutin Cmax  1.28 (1.09-1.51)

Metabolite 25-O-desacetylrifabutin 
AUC  1.24 (0.84-1.84)
Metabolite 25-O-desacetylrifabutin
Cmin  1.22 (0.86-1.74)
Metabolite 25-O-desacetylrifabutin
Cmax  1.29 (0.98-1.68)

A clinically not relevant increase in 
the apparent clearance of nevirapine 
(by 9%) compared to historical data 
was reported. 

No significant effect on rifabutin and 
Viramune mean PK parameters is 
seen. Rifabutin and Viramune can be 
co-administered without dose 
adjustments. However, due to the 
high interpatient variability some 
patients may experience large 
increases in rifabutin exposure and 
may be at higher risk for rifabutin 
toxicity. Therefore, caution should be 
used in concomitant administration.

Rifampicin 
600 mg QD 

Rifampicin AUC  1.11 (0.96-1.28)
Rifampicin Cmin ND
Rifampicin Cmax  1.06 (0.91-1.22)

Nevirapine AUC  0.42
Nevirapine Cmin  0.32 
Nevirapine Cmax  0.50
compared to historical controls.

It is not recommended to co-
administer rifampicin and Viramune 
(see section 4.4). Physicians needing 
to treat patients co-infected with 
tuberculosis and using a Viramune 
containing regimen may consider co-
administration of rifabutin instead.

ANTIFUNGALS
Fluconazole Fluconazole AUC  0.94 (0.88- Because of the risk of increased 



13

200 mg QD 1.01)
Fluconazole Cmin  0.93 (0.86-1.01)
Fluconazole Cmax  0.92 (0.85-0.99)

Nevirapine: exposure: 100% 
compared with historical data where 
nevirapine was administered alone.

exposure to Viramune, caution 
should be exercised if the medicinal 
products are given concomitantly and 
patients should be monitored closely. 

Itraconazole 
200 mg QD

Itraconazole AUC  0.39
Itraconazole Cmin  0.13
Itraconazole Cmax  0.62

Nevirapine: there was no significant 
difference in nevirapine 
pharmacokinetic parameters.

A dose increase for itraconazole 
should be considered when these two 
agents are administered 
concomitantly.

Ketoconazole 
400 mg QD

Ketoconazole AUC  0.28 (0.20-
0.40)
Ketoconazole Cmin ND
Ketoconazole Cmax  0.56 (0.42-
0.73)

Nevirapine: plasma levels:  1.15-
1.28 compared to historical controls.

It is not recommended to co-
administer ketoconazole and 
Viramune (see section 4.4).

ANTIVIRALS FOR CHRONIC HEPATITIS B AND C
Adefovir Results of in vitro studies showed  a 

weak antagonism of nevirapine by 
adefovir (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Adefovir did not influence any of the 
common CYP isoforms known to be 
involved in human drug metabolism 
and is excreted renally. No clinically 
relevant drug-drug interaction is 
expected.

Adefovir and Viramune may be 
coadministered without dose 
adjustments.

Boceprevir Boceprevir is partly metabolized by 
CYP3A4/5. Co-administration of 
boceprevir with medicines that 
induce or inhibit CYP3A4/5 could 
increase or decrease exposure.  
Plasma trough concentrations of 
boceprevir were decreased when 
administered with an NNRTI with a 
similar metabolic pathway as 
nevirapine. The clinical outcome of 
this observed reduction of boceprevir 
trough concentrations has not been 
directly assessed. 

It is not recommended to 
coadminister boceprevir and 
Viramune (see section 4.4).

Entecavir Entecavir is not a substrate, inducer 
or an inhibitor of cytochrome P450 
(CYP450) enzymes. Due to the 
metabolic pathway of entecavir, no 

Entecavir and Viramune may be 
coadministered without dose 
adjustments.



14

clinically relevant drug-drug 
interaction is expected.

Interferons (pegylated 
interferons alfa 2a and 
alfa 2b)

Interferons have no known effect on 
CYP 3A4 or 2B6.  No clinically 
relevant drug-drug interaction is 
expected.

Interferons  and Viramune may be 
coadministered without dose 
adjustments.

Ribavirin Results of in vitro studies showed a 
weak antagonism of nevirapine by 
ribavirin (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Ribavirin does not inhibit 
cytochrome P450 enzymes, and there 
is no evidence from toxicity studies 
that ribavirin induces liver enzymes. 
No clinically relevant drug-drug 
interaction is expected. 

Ribavirin and Viramune may be 
coadministered without dose 
adjustments.

Telaprevir Telaprevir is metabolised in the liver 
by CYP3A and is a P-glycoprotein 
substrate. Other enzymes may be 
involved in the metabolism. Co-
administration of telaprevir and 
medicinal products that induce 
CYP3A and/or P-gp may decrease 
telaprevir plasma concentrations. No 
drug-drug interaction study of 
telaprevir with nevirapine has been 
conducted, however, interaction 
studies of telaprevir with an NNRTI 
with a similar metabolic pathway as 
nevirapine demonstrated reduced 
levels of both. Results of DDI 
studies of telaprevir with efavirenz 
indicate that caution should be 
exercised when co-administering 
telaprevir with P450 inducers. 

Caution should be exercised when 
co-administering telaprevir with 
nevirapine. 
If co-administered with Viramune, an 
adjustment in the telaprevir dose 
should be considered.

Telbivudine Telbivudine is not a substrate, 
inducer or inhibitor of the 
cytochrome P450 (CYP450) enzyme 
system. Due to the metabolic 
pathway of telbivudine, no clinically 
relevant drug-drug interaction is 
expected.

Telbivudine and Viramune may be 
coadministered without dose 
adjustments.

ANTACIDS
Cimetidine Cimetidine: no significant effect on 

cimetidine PK parameters is seen. 

Nevirapine Cmin  1.07

Cimetidine and Viramune can be co-
administered without dose 
adjustments. 

ANTITHROMBOTICS
Warfarin The interaction between nevirapine 

and the antithrombotic agent 
Close monitoring of anticoagulation 
levels is warranted.



15

warfarin is complex, with the 
potential for both increases and 
decreases in coagulation time when 
used concomitantly.

CONTRACEPTIVES
Depo-
medroxyprogesterone 
acetate (DMPA) 
150 mg every 3 
months

DMPA AUC 
DMPA Cmin 
DMPA Cmax 

Nevirapine AUC  1.20
Nevirapine Cmax  1.20

Viramune co-administration did not 
alter the ovulation suppression effects 
of DMPA. DMPA and Viramune can 
be co-administered without dose 
adjustments. 

Ethinyl estradiol (EE) 
0.035 mg 

EE AUC  0.80 (0.67 - 0.97) 
EE Cmin ND
EE Cmax  0.94 (0.79 - 1.12)

Oral hormonal contraceptives should 
not be used as the sole method of 
contraception in women taking 
Viramune (see section 4.4). 
Appropriate doses for hormonal 
contraceptives (oral or other forms of 
application) other than DMPA in 
combination with Viramune have not 
been established with respect to 
safety and efficacy.

Norethindrone (NET) 
1.0 mg QD

NET AUC  0.81 (0.70 - 0.93)
NET Cmin ND
NET Cmax  0.84 (0.73 - 0.97)

ANALGESICS/OPIOIDS
Methadone Individual
Patient Dosing

Methadone AUC  0.40 (0.31 - 0.51)
Methadone Cmin ND
Methadone Cmax  0.58 (0.50 - 0.67)

Methadone-maintained patients 
beginning Viramune therapy should 
be monitored for evidence of 
withdrawal and methadone dose 
should be adjusted accordingly.

HERBAL PRODUCTS
St. John's Wort Serum levels of nevirapine can be 

reduced by concomitant use of the 
herbal preparation St. John's Wort 
(Hypericum perforatum). This is due 
to induction of medicinal product 
metabolism enzymes and/or 
transport proteins by St. John’s 
Wort.

Herbal preparations containing St. 
John‘s Wort and Viramune must not 
be co-administered (see section 4.3). 
If a patient is already taking St. 
John‘s Wort check nevirapine and if 
possible viral levels and stop St. 
John‘s Wort. Nevirapine levels may 
increase on stopping St. John‘s Wort. 
The dose of Viramune may need 
adjusting. The inducing effect may 
persist for at least 2 weeks after 
cessation of treatment with St. John‘s 
Wort.

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.



16

4.6 Fertility, pregnancy and lactation

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

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

Breast-feeding
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.

4.7 Effects on ability to drive and use machines

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. 

4.8 Undesirable effects

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.

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 section 4.4).



17

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).

Blood and lymphatic system disorders
Common granulocytopenia
Uncommon anaemia

Immune system disorders
Common hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria)
Uncommon anaphylactic reaction  
Rare drug reaction with eosinophilia and systemic symptoms

Nervous system disorders
Common headache

Gastrointestinal disorders
Common nausea, vomiting, abdominal pain, diarrhoea

Hepatobiliary disorders
Common hepatitis (including severe and life-threatening hepatotoxicity) (1.9%)
Uncommon jaundice
Rare hepatitis fulminant (which may be fatal)

Skin and subcutaneous tissue disorders
Very common rash (12.5 %)
Uncommon Stevens-Johnson syndrome/ toxic epidermal necrolysis (which may be fatal) 

(0.2 %), angioedema, urticaria

Musculoskeletal and connective tissue disorders
Uncommon arthralgia, myalgia

General disorders and administration site conditions
Common pyrexia, fatigue

Investigations
Common liver function test abnormal (alanine aminotransferase increased; transaminases 

increased; aspartate aminotransferase increased; gamma-glutamyltransferase 
increased; hepatic enzyme increased; hypertransaminasaemia)

Uncommon blood phosphorus decreased ; blood pressure increased

Description of selected adverse reactions
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 %).

Anaphylactic 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).



18

Decreased blood phosphorus and increased blood pressure were observed in clinical studies with co-
administration of tenofovir/emtricitabine.

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (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 reaction
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 reaction 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 hepatotoxicity, 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).

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 



19

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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V.

4.9 Overdose

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 2 mg/kg/day. Mild isolated neutropenia and hyperlactataemia was observed, 
which spontaneously disappeared within one week without any clinical complications. One year later, 
the child’s development remained normal.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 , , , or .

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, saquinavir and tipranavir, and 
the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


20

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.

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. 

1,216 antiretroviral-therapy naïve patients with plasma HIV-1 RNA > 5,000 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. 

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. 

The nevirapine twice daily regimen and the efavirenz regimen were not significantly different 
(p=0.091) in terms of efficacy as measured by treatment failure, or any component of treatment failure 
including virological failure.
The simultaneous use of nevirapine (400 mg) plus efavirenz (800 mg) was associated with the highest 



21

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. 

A durable response to Viramune for at least three years was documented in this study, and 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. 

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.

Perinatal Transmission 

Numerous studies have been performed examining the use of Viramune in regards to perinatal 
transmission, most notably HIVNET 012. This study demonstrated a significant reduction in 
transmission using single dose nevirapine (13.1 % (n = 310) in the Viramune group, versus 25.1 % (n 
= 308) in the ultra-short zidovudine group (p = 0.00063)). Monotherapy with Viramune has been 



22

associated with the development of NNRTI resistance. Single dose nevirapine in mothers or infants 
may lead to reduced efficacy if an HIV treatment regimen using nevirapine is later instituted within 6 
months or less in these patients. Combination of other antiretrovirals with single-dose nevirapine 
attenuates the emergence of nevirapine resistance. Where other antiretroviral medicines are accessible, 
the single dose Viramune regimen should be combined with additional effective antiretroviral 
medicines (as recommended in internationally recognized guidelines).   

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.

5.2 Pharmacokinetic properties

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 Cmax of 5.74 µg/ml (5.00-7.44) and Cmin 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.



23

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The 
pharmacokinetics of autoinduction is characterised by an approximately 1.5 to 2 fold increase in the 
apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks 
of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal 
phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 
25-30 hours following multiple dosing with 200-400 mg/day.

Renal impairment: 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 impairment:A steady state study comparing 46 patients with 
mild (n=17: Ishak Score 1-2), 
moderate (n=20; Ishak Score 3-4), 
or severe (n=9; Ishak Score 5-6, Child-Pugh A in 8 pts., for 1 Child-Pugh score not applicable) 
liver fibrosis as a measure of hepatic impairment was conducted. 

The patients studied were receiving antiretroviral therapy containing Viramune 200 mg twice daily for 
at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years. In 
this study, the multiple dose pharmacokinetic disposition of nevirapine and the 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).

Gender and elderly
In the multinational 2NN study, a population pharmacokinetic substudy of 1,077 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 



24

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.

5.3 Preclinical safety data

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. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose
Lactose (as monohydrate)
Povidone K25
Sodium starch glycolate
Colloidal silicon dioxide
Magnesium stearate 

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Treatment initiation pack
Polyvinyl chloride (PVC)/aluminium foil push-through blister units (blister card of 7 tablets). 
Cartons containing 2 blister cards (14 tablets).



25

Maintenance packs
Polyvinyl chloride (PVC)/aluminium foil push-through blister units (blister card of 10 tablets). 
Cartons containing 6 or 12 blister cards (60 or 120 tablets). 

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein, Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/97/055/001 (60 tablets)
EU/1/97/055/003 (120 tablets)
EU/1/97/055/004 (14 tablets)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5 February 1998
Date of latest renewal: 20 December 2012

10. DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu


26

1. NAME OF THE MEDICINAL PRODUCT

Viramune 50 mg/5 ml oral suspension 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Each bottle contains 2.4 g of nevirapine (as hemihydrate) in 240 ml of Viramune oral suspension.

Excipients with known effect
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.
This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 
‘sodium-free’.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral suspension

White to off-white homogenous suspension.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 4.2).

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

4.2 Posology and method of administration

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 



27

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 (see 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.

There are toxicities that require interruption of Viramune therapy (see section 4.4).

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, 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).

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:

BSA range (m2) Volume (ml)
0.08 – 0.25 2.5
0.25 – 0.42 5
0.42 – 0.58 7.5
0.58 – 0.75 10
0.75 – 0.92 12.5
0.92 – 1.08 15
1.08 – 1.25 17.5
1.25+ 20

Mosteller Formula:    BSA (m2) =
3600

(kg) x Wt (cm)Height 

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.



28

Weight Range (kg) for 
patients < 8 yrs of age on 
a body weight basis 
receiving 7 mg/kg.

Weight Range (kg) for 
patients  8 years of age 
on a body weight basis 
receiving 4 mg/kg.

Volume (ml)

1.79 – 5.36 3.13 – 9.38 2.5
5.36 – 8.93 9.38 – 15.63 5
8.93 – 12.50 15.63 – 21.88 7.5
12.50 – 16.07 21.88 – 28.12 10
16.07 – 19.64 28.12 – 34.37 12.5
19.64 – 23.21 34.37 – 40.62 15
23.21 – 26.79 40.62– 46.88 17.5
26.79+ 46.88+ 20

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

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

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

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

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 (see section 4.5).

4.4 Special warnings and precautions for use

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.



29

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 evaluation immediately. Nevirapinemust 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).

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 



30

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.

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 evaluation. 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).

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. 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 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 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.



31

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.

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).

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 200 mg/day for 14 days followed by 400 mg/day. 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.

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.



32

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.

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 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 



33

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.

Hypersensitivity
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 hereditary 
fructose intolerance (HFI) should not take/be given this medicinal product.

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

4.5 Interaction with other medicinal products and other forms of interaction

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

Medicinal products 
by therapeutic areas

Interaction Recommendations concerning co-
administration

ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine 
100-150 mg BID

Didanosine AUC  1.08 (0.92-1.27)
Didanosine Cmin ND
Didanosine Cmax  0.98 (0.79-1.21)

Didanosine and Viramune can be co-
administered without dose 
adjustments.

Emtricitabine Emtricitabine is not an inhibitor of 
human CYP 450 enzymes.

Viramune and emtricitabine may be 
coadministered without dose 
adjustments.

Abacavir In human liver microsomes, abacavir 
did not inhibit cytochrome P450 
isoforms.

Viramune and abacavir may be 
coadministered without dose 
adjustments.

Lamivudine 
150 mg BID

No changes to lamivudine apparent 
clearance and volume of distribution, 

Lamivudine and Viramune can be co-
administered without dose 



34

suggesting no induction effect of 
nevirapine on lamivudine clearance.

adjustments.

Stavudine: 
30/40 mg BID 

Stavudine AUC  0.96 (0.89-1.03)
Stavudine Cmin ND
Stavudine Cmax  0.94 (0.86-1.03)

Nevirapine: compared to historical 
controls, levels appeared to be 
unchanged.

Stavudine and Viramune can be co-
administered without dose 
adjustments.

Tenofovir 
300 mg QD

Tenofovir plasma levels remain 
unchanged when co-administered 
with nevirapine. 

Nevirapine plasma levels were not 
altered by co-administration of 
tenofovir.

Tenofovir and Viramune can be co-
administered without dose 
adjustments.

Zidovudine 
100-200 mg TID

Zidovudine AUC  0.72 (0.60-0.96) 
Zidovudine Cmin ND
Zidovudine Cmax  0.70 (0.49-1.04)

Nevirapine: Zidovudine had no 
effect on its pharmacokinetics.

Zidovudine and Viramune can be co-
administered without dose 
adjustments

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.

NNRTIs
Efavirenz 
600 mg QD

Efavirenz AUC  0.72 (0.66-0.86)
Efavirenz Cmin  0.68 (0.65-0.81)
Efavirenz Cmax  0.88 (0.77-1.01)

It is not recommended to co-
administer efavirenz and Viramune
(see section 4.4), because of additive 
toxicity and no benefit in terms of 
efficacy over either NNRTI alone (for 
results of 2NN study, see section 5.1).

Delavirdine Interaction has not been studied. The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

Etravirine Concomitant use of etravirine with 
nevirapine may cause a significant 
decrease in the plasma 
concentrations of etravirine and loss 

The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).



35

of therapeutic effect of etravirine.
Rilpivirine Interaction has not been studied. The concomitant administration of 

Viramune with NNRTIs is not 
recommended (see section 4.4).

PIs

Atazanavir/ritonavir 
300/100 mg QD
400/100 mg QD

Atazanavir/r 300/100mg:
Atazanavir/r AUC  0.58 (0.48-0.71)
Atazanavir/r Cmin 0.28 (0.20-0.40)
Atazanavir/r Cmax  0.72 (0.60-0.86)

Atazanavir/r 400/100mg:
Atazanavir/r AUC  0.81 (0.65-1.02) 
Atazanavir/r Cmin  0.41 (0.27-0.60)
Atazanavir/r Cmax  1.02 (0.85–
1.24)
(compared to 300/100mg without 
nevirapine)

Nevirapine AUC  1.25 (1.17-1.34)
Nevirapine Cmin 1.32 (1.22–1.43)
Nevirapine Cmax  1.17 (1.09-1.25)

It is not recommended to co-
administer atazanavir/ritonavir and 
Viramune (see section 4.4).

Darunavir/ritonavir 
400/100 mg BID 

Darunavir AUC  1.24 (0.97-1.57)
Darunavir Cmin  1.02 (0.79-1.32)
Darunavir Cmax  1.40 (1.14-1.73)

Nevirapine AUC  1.27 (1.12-1.44)
Nevirapine Cmin  1.47 (1.20-1.82)
Nevirapine Cmax  1.18 (1.02-1.37)

Darunavir and Viramune can be co-
administered without dose 
adjustments.

Fosamprenavir
1,400 mg BID

Amprenavir AUC  0.67 (0.55-0.80)
Amprenavir Cmin  0.65 (0.49-0.85)
Amprenavir Cmax  0.75 (0.63-0.89)

Nevirapine AUC  1.29 (1.19-1.40)
Nevirapine Cmin  1.34 (1.21-1.49)
Nevirapine Cmax  1.25 (1.14-1.37)

It is not recommended to co-
administer fosamprenavir and 
Viramune if fosamprenavir is not co-
administered with ritonavir (see 
section 4.4).

Fosamprenavir/ritona
vir 700/100 mg BID

Amprenavir AUC  0.89 (0.77-
1.03)
Amprenavir Cmin  0.81 (0.69-0.96)
Amprenavir Cmax  0.97 (0.85-1.10)

Nevirapine AUC  1.14 (1.05-1.24)
Nevirapine Cmin  1.22 (1.10-1.35)
Nevirapine Cmax  1.13 (1.03-1.24)

Fosamprenavir/ritonavir and 
Viramune can be co-administered 
without dose adjustments

Lopinavir/ritonavir 
(capsules) 
400/100 mg BID 

Adult patients: 
Lopinavir AUC  0.73 (0.53-0.98)
Lopinavir Cmin  0.54 (0.28-0.74)
Lopinavir Cmax  0.81 (0.62-0.95)

An increase in the dose of 
lopinavir/ritonavir to 533/133 mg (4 
capsules) or 500/125 mg (5 tablets 
with 100/25 mg each) twice daily 



36

with food is recommended in 
combination with Viramune. Dose 
adjustment of Viramune is not 
required when co-administered with 
lopinavir.

Lopinavir/ritonavir 
(oral solution) 
300/75 mg/m2 BID

Paediatric patients: 
Lopinavir AUC  0.78 (0.56-1.09) 
Lopinavir Cmin  0.45 (0.25-0.82)
Lopinavir Cmax  0.86 (0.64-1.16) 

For children, increase of the dose of 
lopinavir/ritonavir to 300/75 mg/m2 

twice daily with food should be 
considered when used in combination 
with Viramune, particularly for 
patients in whom reduced 
susceptibility to lopinavir/ritonavir is 
suspected. 

Ritonavir
600 mg BID

Ritonavir AUC 0.92 (0.79-1.07)
Ritonavir Cmin  0.93 (0.76-1.14)
Ritonavir Cmax  0.93 (0.78-1.07)

Nevirapine: Co-administration of 
ritonavir does not lead to any 
clinically relevant change in 
nevirapine plasma levels.

Ritonavir and Viramune can be co-
administered without dose 
adjustments.

Saquinavir/ritonavir The limited data available with 
saquinavir soft gel capsule boosted 
with ritonavir do not suggest any 
clinically relevant interaction 
between saquinavir boosted with 
ritonavir and nevirapine

Saquinavir/ritonavir and Viramune
can be co-administered without dose 
adjustments. 

Tipranavir/ritonavir 
500/200 mg BID

No specific drug-drug interaction 
study has been performed.
The limited data available from a 
phase IIa study in HIV-infected 
patients have shown a clinically non 
significant 20% decrease of TPV 
Cmin. 

Tipranavir and Viramune can be co-
administered without dose 
adjustments.

ENTRY INHIBITORS
Enfuvirtide Due to the metabolic pathway no 

clinically significant 
pharmacokinetic interactions are 
expected between enfuvirtide and 
nevirapine.

Enfuvirtide and Viramune can be co-
administered without dose 
adjustments.

Maraviroc 
300 mg QD

Maraviroc AUC  1.01 (0.6 -1.55)
Maraviroc Cmin ND
Maraviroc Cmax  1.54 (0.94-2.52)
compared to historical controls 

Nevirapine concentrations not 
measured, no effect is expected.

Maraviroc and Viramune can be co-
administered without dose 
adjustments.



37

INTEGRASE INHIBITORS
Elvitegravir/
cobicistat 

Interaction has not been studied. 
Cobicistat, a cytochrome P450 3A 
inhibitor significantly inhibits 
hepatic enzymes, as well as other 
metabolic pathways. Therefore 
coadministration would likely result 
in altered plasma levels of cobicistat 
and Viramune.

Coadministration of Viramune with 
elvitegravir in combination with 
cobicistat is not recommended (see 
section 4.4).

Raltegravir 
400 mg BID

No clinical data available. Due to the 
metabolic pathway of raltegravir no 
interaction is expected.

Raltegravir and Viramune can be co-
administered without dose 
adjustments.

ANTIBIOTICS
Clarithromycin 
500 mg BID

Clarithromycin AUC  0.69 (0.62-
0.76)
Clarithromycin Cmin  0.44 (0.30-
0.64)
Clarithromycin Cmax  0.77 (0.69-
0.86)

Metabolite 14-OH clarithromycin 
AUC  1.42 (1.16-1.73) 
Metabolite 14-OH clarithromycin 
Cmin  0 (0.68-1.49)
Metabolite 14-OH clarithromycin 
Cmax  1.47 (1.21-1.80)

Nevirapine AUC  1.26 
Nevirapine Cmin  1.28
Nevirapine Cmax  1.24 
compared to historical controls. 

Clarithromycin exposure was 
significantly decreased, 14-OH 
metabolite exposure increased. 
Because the clarithromycin active 
metabolite has reduced activity 
against Mycobacterium avium-
intracellulare complex overall 
activity against the pathogen may be 
altered. Alternatives to 
clarithromycin, such as azithromycin 
should be considered. Close 
monitoring for hepatic abnormalities 
is recommended

Rifabutin 
150 or 300 mg QD

Rifabutin AUC  1.17 (0.98-1.40)
Rifabutin Cmin  1.07 (0.84-1.37)
Rifabutin Cmax  1.28 (1.09-1.51)

Metabolite 25-O-desacetylrifabutin 
AUC  1.24 (0.84-1.84)
Metabolite 25-O-desacetylrifabutin
Cmin  1.22 (0.86-1.74)
Metabolite 25-O-desacetylrifabutin
Cmax  1.29 (0.98-1.68)

A clinically not relevant increase in 
the apparent clearance of nevirapine 
(by 9%) compared to historical data 
was reported. 

No significant effect on rifabutin and 
Viramune mean PK parameters is 
seen. Rifabutin and Viramune can be 
co-administered without dose 
adjustments. However, due to the 
high interpatient variability some 
patients may experience large 
increases in rifabutin exposure and 
may be at higher risk for rifabutin 
toxicity. Therefore, caution should be 
used in concomitant administration.

Rifampicin 
600 mg QD 

Rifampicin AUC  1.11 (0.96-1.28)
Rifampicin Cmin ND
Rifampicin Cmax  1.06 (0.91-1.22)

It is not recommended to co-
administer rifampicin and Viramune 
(see section 4.4). Physicians needing 
to treat patients co-infected with 



38

Nevirapine AUC  0.42
Nevirapine Cmin  0.32 
Nevirapine Cmax  0.50
compared to historical controls.

tuberculosis and using a Viramune 
containing regimen may consider co-
administration of rifabutin instead.

ANTIFUNGALS
Fluconazole 
200 mg QD

Fluconazole AUC  0.94 (0.88-
1.01)
Fluconazole Cmin  0.93 (0.86-1.01)
Fluconazole Cmax  0.92 (0.85-0.99)

Nevirapine: exposure: 100% 
compared with historical data where 
nevirapine was administered alone.

Because of the risk of increased 
exposure to Viramune, caution 
should be exercised if the medicinal 
products are given concomitantly and 
patients should be monitored closely. 

Itraconazole 
200 mg QD

Itraconazole AUC  0.39
Itraconazole Cmin  0.13
Itraconazole Cmax  0.62

Nevirapine: there was no significant 
difference in nevirapine 
pharmacokinetic parameters.

A dose increase for itraconazole 
should be considered when these two 
agents are administered 
concomitantly.

Ketoconazole 
400 mg QD

Ketoconazole AUC  0.28 (0.20-
0.40)
Ketoconazole Cmin ND
Ketoconazole Cmax  0.56 (0.42-
0.73)

Nevirapine: plasma levels:  1.15-
1.28 compared to historical controls.

It is not recommended to co-
administer ketoconazole and 
Viramune (see section 4.4).

ANTIVIRALS FOR CHRONIC HEPATITIS B AND C
Adefovir Results of in vitro studies showed  a 

weak antagonism of nevirapine by 
adefovir (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Adefovir did not influence any of the 
common CYP isoforms known to be 
involved in human drug metabolism 
and is excreted renally. No clinically 
relevant drug-drug interaction is 
expected.

Adefovir and Viramune may be 
coadministered without dose 
adjustments.

Boceprevir Boceprevir is partly metabolized by 
CYP3A4/5. Co-administration of 
boceprevir with medicines that 
induce or inhibit CYP3A4/5 could 
increase or decrease exposure.  
Plasma trough concentrations of 
boceprevir were decreased when 
administered with an NNRTI with a 
similar metabolic pathway as 
nevirapine. The clinical outcome of 

It is not recommended to 
coadminister boceprevir and 
Viramune (see section 4.4).



39

this observed reduction of boceprevir 
trough concentrations has not been 
directly assessed. 

Entecavir Entecavir is not a substrate, inducer 
or an inhibitor of cytochrome P450 
(CYP450) enzymes. Due to the 
metabolic pathway of entecavir, no 
clinically relevant drug-drug 
interaction is expected.

Entecavir and Viramune may be 
coadministered without dose 
adjustments.

Interferons (pegylated 
interferons alfa 2a and 
alfa 2b)

Interferons have no known effect on 
CYP 3A4 or 2B6.  No clinically 
relevant drug-drug interaction is 
expected.

Interferons  and Viramune may be 
coadministered without dose 
adjustments.

Ribavirin Results of in vitro studies showed a 
weak antagonism of nevirapine by 
ribavirin (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Ribavirin does not inhibit 
cytochrome P450 enzymes, and there 
is no evidence from toxicity studies 
that ribavirin induces liver enzymes. 
No clinically relevant drug-drug 
interaction is expected. 

Ribavirin and Viramune may be 
coadministered without dose 
adjustments.

Telaprevir Telaprevir is metabolised in the liver 
by CYP3A and is a P-glycoprotein 
substrate. Other enzymes may be 
involved in the metabolism. Co-
administration of telaprevir and 
medicinal products that induce 
CYP3A and/or P-gp may decrease 
telaprevir plasma concentrations. No 
drug-drug interaction study of 
telaprevir with nevirapine has been 
conducted, however, interaction 
studies of telaprevir with an NNRTI 
with a similar metabolic pathway as 
nevirapine demonstrated reduced 
levels of both. Results of DDI 
studies of telaprevir with efavirenz 
indicate that caution should be 
exercised when co-administering 
telaprevir with P450 inducers. 

Caution should be exercised when 
co-administering telaprevir with 
nevirapine. 
If co-administered with Viramune, an 
adjustment in the telaprevir dose 
should be considered.

Telbivudine Telbivudine is not a substrate, 
inducer or inhibitor of the 
cytochrome P450 (CYP450) enzyme 
system. Due to the metabolic 
pathway of telbivudine, no clinically 
relevant drug-drug interaction is 
expected.

Telbivudine and Viramune may be 
coadministered without dose 
adjustments.



40

ANTACIDS
Cimetidine Cimetidine: no significant effect on 

cimetidine PK parameters is seen. 

Nevirapine Cmin  1.07

Cimetidine and Viramune can be co-
administered without dose 
adjustments. 

ANTITHROMBOTICS
Warfarin The interaction between nevirapine

and the antithrombotic agent 
warfarin is complex, with the 
potential for both increases and 
decreases in coagulation time when 
used concomitantly.

Close monitoring of anticoagulation 
levels is warranted.

CONTRACEPTIVES
Depo-
medroxyprogesterone 
acetate (DMPA) 
150 mg every 3 
months

DMPA AUC 
DMPA Cmin 
DMPA Cmax 

Nevirapine AUC  1.20
Nevirapine Cmax  1.20

Viramune co-administration did not 
alter the ovulation suppression effects 
of DMPA. DMPA and Viramune can 
be co-administered without dose 
adjustments. 

Ethinyl estradiol (EE) 
0.035 mg 

EE AUC  0.80 (0.67 - 0.97) 
EE Cmin ND
EE Cmax  0.94 (0.79 - 1.12)

Oral hormonal contraceptives should 
not be used as the sole method of 
contraception in women taking 
Viramune (see section 4.4). 
Appropriate doses for hormonal 
contraceptives (oral or other forms of 
application) other than DMPA in 
combination with Viramune have not 
been established with respect to 
safety and efficacy.

Norethindrone (NET) 
1.0 mg QD

NET AUC  0.81 (0.70 - 0.93)
NET Cmin ND
NET Cmax  0.84 (0.73 - 0.97)

ANALGESICS/OPIOIDS
Methadone Individual
Patient Dosing

Methadone AUC  0.40 (0.31 - 0.51)
Methadone Cmin ND
Methadone Cmax  0.58 (0.50 - 0.67)

Methadone-maintained patients 
beginning Viramune therapy should 
be monitored for evidence of 
withdrawal and methadone dose 
should be adjusted accordingly.

HERBAL PRODUCTS
St. John's Wort Serum levels of nevirapine can be 

reduced by concomitant use of the 
herbal preparation St. John's Wort 
(Hypericum perforatum). This is due 
to induction of medicinal product 
metabolism enzymes and/or 
transport proteins by St. John’s 
Wort.

Herbal preparations containing St. 
John‘s Wort and Viramune must not 
be co-administered (see section 4.3). 
If a patient is already taking St. 
John‘s Wort check nevirapine and if 
possible viral levels and stop St. 
John‘s Wort. Nevirapine levels may 
increase on stopping St. John‘s Wort. 
The dose of Viramune may need 
adjusting. The inducing effect may 
persist for at least 2 weeks after 
cessation of treatment with St. John‘s 
Wort.



41

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.

4.6 Fertility, pregnancy and lactation

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

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

Breast-feeding
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.

4.7 Effects on ability to drive and use machines

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. 

4.8 Undesirable effects

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.



42

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 section 4.4).

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).

Blood and lymphatic system disorders
Common granulocytopenia
Uncommon anaemia

Immune system disorders
Common hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria)
Uncommon anaphylactic reaction
Rare drug reaction with eosinophilia and systemic symptoms

Nervous system disorders
Common headache

Gastrointestinal disorders
Common nausea, vomiting, abdominal pain, diarrhoea

Hepatobiliary disorders
Common hepatitis (including severe and life-threatening hepatotoxicity) (1.9%)
Uncommon jaundice
Rare hepatitis fulminant (which may be fatal)

Skin and subcutaneous tissue disorders
Very common rash (12.5 %)
Uncommon Stevens-Johnson syndrome/ toxic epidermal necrolysis (which may be fatal) 

(0.2 %), angioedema, urticaria

Musculoskeletal and connective tissue disorders
Uncommon arthralgia, myalgia

General disorders and administration site conditions
Common pyrexia, fatigue

Investigations
Common liver function test abnormal (alanine aminotransferase increased; transaminases 

increased; aspartate aminotransferase increased; gamma-glutamyltransferase 
increased; hepatic enzyme increased; hypertransaminasaemia)

Uncommon blood phosphorus decreased; blood pressure increased



43

Description of selected adverse reactions
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 %).

Anaphylactic 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).

Decreased blood phosphorus and increased blood pressure were observed in clinical studies with co-
administration of tenofovir/emtricitabine.

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (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 reaction
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 reaction 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). 



44

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 hepatotoxicity, 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).

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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V.

4.9 Overdose

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 2 mg/kg/day. Mild isolated neutropenia and hyperlactataemia was observed, 
which spontaneously disappeared within one week without any clinical complications. One year later, 
the child’s development remained normal. 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 , , , or .

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


45

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, 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.

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. 

1,216 antiretroviral-therapy naïve patients with plasma HIV-1 RNA > 5,000 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. 



46

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. 

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. 

The nevirapine twice daily regimen and the efavirenz regimen were not significantly different (p= 
0.091) in terms of efficacy as measured by treatment failure, or any component 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. 

A durable response to Viramune for at least three years was documented in this study, and 
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. 
At 12 months, the Kaplan–Meier estimates of the likelihood of reaching the endpoint were 10 % in the 



47

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.

Perinatal Transmission

Numerous studies have been performed examining the use of Viramune in regards to perinatal 
transmission, most notably HIVNET 012. This study demonstrated a significant reduction in 
transmission using single dose nevirapine (13.1 % (n = 310) in the Viramune group, versus 25.1 % (n 
= 308) in the ultra-short zidovudine group (p = 0.00063)). Monotherapy with Viramune has been 
associated with the development of NNRTI resistance. Single dose nevirapine in mothers or infants 
may lead to reduced efficacy if an HIV treatment regimen using nevirapine is later instituted within 6 
months or less in these patients. Combination of other antiretrovirals with single-dose nevirapine 
attenuates the emergence of nevirapine resistance. Where other antiretroviral medicines are accessible, 
the single dose Viramune regimen should be combined with additional effective antiretroviral 
medicines (as recommended in internationally recognized guidelines).

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.

5.2 Pharmacokinetic properties

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 Cmax of 5.74 µg/ml (5.00-7.44) and Cmin 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.



48

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.

Renal impairment: 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 impairment: A steady state study comparing 46 patients with 
mild (n=17: Ishak Score 1-2), 
moderate (n=20; Ishak Score 3-4), 
or severe (n=9; Ishak Score 5-6, Child-Pugh A in 8 pts., for 1 Child-Pugh score not applicable) 
liver fibrosis as a measure of hepatic impairment was conducted. 

The patients studied were receiving antiretroviral therapy containing Viramune 200 mg twice daily for 
at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years. In 
this study, the multiple dose pharmacokinetic disposition of nevirapine and the 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 



49

4.4).

Gender and elderly
In the multinational 2NN study, a population pharmacokinetic substudy of 1,077 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.

5.3 Preclinical safety data

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. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Carbomer
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Sorbitol
Sucrose
Polysorbate 80
Sodium hydroxide (for pH-adjustment)
Purified water

6.2 Incompatibilities

Not applicable.



50

6.3 Shelf life

3 years

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

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal and other handling

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein, 
Germany



51

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/97/055/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5 February 1998
Date of latest renewal: 20 December 2012

10. DATE OF REVISION OF THE TEXT

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



52

1. NAME OF THE MEDICINAL PRODUCT

Viramune 100 mg prolonged-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 100 mg of nevirapine (as anhydrous). 

Excipient with known effect
Each prolonged-release tablet contains 100 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Prolonged-release tablet

Yellow, round and biconvex prolonged-release tablets. The prolonged-release tablets are 
approximately 9 mm in diameter, debossed with V01 on one side and company symbol on the other 
side. The prolonged-release tablet should not be divided.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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

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

4.2 Posology and method of administration

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) 



53

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
BSA (m2) Viramune prolonged-release tablets dose (mg)
0.58-0.83 200 (2 x 100 mg)
0.84-1.16 300 (3 x 100 mg)
≥ 1.17 400 (1 x 400 mg)

Mosteller Formula:   BSA (m2) =
3600

(kg) x Wt (cm)Height 

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. 

Weight Range (kg) for 
patients < 8 yrs of age 

Weight Range (kg) for patients 
 8 years of age 

Viramune prolonged-release tablets 
dose (mg)

12.5-17.8 17.9 to 31.2 200 (2 x 100 mg)

17.9-24.9 31.3 to 43.7 300 (3 x 100 mg)

25 and above 43.8 and above 400 (1 x 400 mg)

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. 

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 



54

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).

Elderly
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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

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

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

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 (see section 4.5).

4.4 Special warnings and precautions for use

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.



55

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 evaluation 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).

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 



56

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.

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 evaluation. 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).

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 
evaluation, which should include liver function tests.



57

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).

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.

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.



58

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.

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 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 



59

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 compared to 400 mg prolonged-release tablets 
and therefore, 100 mg prolonged-release tablets should not 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, total lactase deficiency or glucose-
galactose malabsorption should not take this medicine.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

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

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

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



60

Medicinal products 
by therapeutic areas

Interaction Recommendations concerning co-
administration

ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine 
100-150 mg BID

Didanosine AUC  1.08 (0.92-1.27)
Didanosine Cmin ND
Didanosine Cmax  0.98 (0.79-1.21)

Didanosine and Viramune can be co-
administered without dose 
adjustments.

Emtricitabine Emtricitabine is not an inhibitor of 
human CYP 450 enzymes.

Viramune and emtricitabine may be 
coadministered without dose 
adjustments.

Abacavir In human liver microsomes, abacavir 
did not inhibit cytochrome P450 
isoforms.

Viramune and abacavir may be 
coadministered without dose 
adjustments.

Lamivudine 
150 mg BID

No changes to lamivudine apparent 
clearance and volume of distribution, 
suggesting no induction effect of 
nevirapine on lamivudine clearance.

Lamivudine and Viramune can be co-
administered without dose 
adjustments.

Stavudine: 
30/40 mg BID 

Stavudine AUC  0.96 (0.89-1.03)
Stavudine Cmin ND
Stavudine Cmax  0.94 (0.86-1.03)

Nevirapine: compared to historical 
controls, levels appeared to be 
unchanged.

Stavudine and Viramune can be co-
administered without dose 
adjustments.

Tenofovir 
300 mg QD

Tenofovir plasma levels remain 
unchanged when co-administered 
with nevirapine. 

Nevirapine plasma levels were not 
altered by co-administration of 
tenofovir.

Tenofovir and Viramune can be co-
administered without dose 
adjustments.

Zidovudine 
100-200 mg TID

Zidovudine AUC  0.72 (0.60-0.96) 
Zidovudine Cmin ND
Zidovudine Cmax  0.70 (0.49-1.04)

Nevirapine: Zidovudine had no 
effect on its pharmacokinetics.

Zidovudine and Viramune can be co-
administered without dose 
adjustments

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 



61

monitored.

NNRTIs
Efavirenz 
600 mg QD

Efavirenz AUC  0.72 (0.66-0.86)
Efavirenz Cmin  0.68 (0.65-0.81)
Efavirenz Cmax  0.88 (0.77-1.01)

It is not recommended to co-
administer efavirenz and Viramune
(see section 4.4), because of additive 
toxicity and no benefit in terms of 
efficacy over either NNRTI alone (for 
results of 2NN study, see section 5.1
Viramune immediate-release 
formulations).

Delavirdine Interaction has not been studied. The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

Etravirine Concomitant use of etravirine with 
nevirapine may cause a significant 
decrease in the plasma 
concentrations of etravirine and loss 
of therapeutic effect of etravirine.

The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

Rilpivirine Interaction has not been studied. The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

PIs

Atazanavir/ritonavir 
300/100 mg QD
400/100 mg QD

Atazanavir/r 300/100mg:
Atazanavir/r AUC  0.58 (0.48-0.71)
Atazanavir/r Cmin 0.28 (0.20-0.40)
Atazanavir/r Cmax  0.72 (0.60-0.86)

Atazanavir/r 400/100mg:
Atazanavir/r AUC  0.81 (0.65-1.02) 
Atazanavir/r Cmin  0.41 (0.27-0.60)
Atazanavir/r Cmax  1.02 (0.85–
1.24)
(compared to 300/100mg without 
nevirapine)

Nevirapine AUC  1.25 (1.17-1.34)
Nevirapine Cmin 1.32 (1.22–1.43)
Nevirapine Cmax  1.17 (1.09-1.25)

It is not recommended to co-
administer atazanavir/ritonavir and 
Viramune (see section 4.4).

Darunavir/ritonavir 
400/100 mg BID 

Darunavir AUC  1.24 (0.97-1.57)
Darunavir Cmin  1.02 (0.79-1.32)
Darunavir Cmax  1.40 (1.14-1.73)

Nevirapine AUC  1.27 (1.12-1.44)
Nevirapine Cmin  1.47 (1.20-1.82)
Nevirapine Cmax  1.18 (1.02-1.37)

Darunavir and Viramune can be co-
administered without dose 
adjustments.



62

Fosamprenavir
1400 mg BID

Amprenavir AUC  0.67 (0.55-0.80)
Amprenavir Cmin  0.65 (0.49-0.85)
Amprenavir Cmax  0.75 (0.63-0.89)

Nevirapine AUC  1.29 (1.19-1.40)
Nevirapine Cmin  1.34 (1.21-1.49)
Nevirapine Cmax  1.25 (1.14-1.37)

It is not recommended to co-
administer fosamprenavir and 
Viramune if fosamprenavir is not co-
administered with ritonavir (see 
section 4.4).

Fosamprenavir/ritona
vir 700/100 mg BID

Amprenavir AUC  0.89 (0.77-
1.03)
Amprenavir Cmin  0.81 (0.69-0.96)
Amprenavir Cmax  0.97 (0.85-1.10)

Nevirapine AUC  1.14 (1.05-1.24)
Nevirapine Cmin  1.22 (1.10-1.35)
Nevirapine Cmax  1.13 (1.03-1.24)

Fosamprenavir/ritonavir and 
Viramune can be co-administered 
without dose adjustments

Lopinavir/ritonavir 
(capsules) 
400/100 mg BID 

Adult patients: 
Lopinavir AUC  0.73 (0.53-0.98)
Lopinavir Cmin  0.54 (0.28-0.74)
Lopinavir Cmax  0.81 (0.62-0.95)

An increase in the dose of 
lopinavir/ritonavir to 533/133 mg (4 
capsules) or 500/125 mg (5 tablets 
with 100/25 mg each) twice daily 
with food is recommended in 
combination with Viramune. Dose 
adjustment of Viramune is not 
required when co-administered with 
lopinavir.

Lopinavir/ritonavir 
(oral solution) 
300/75 mg/m2 BID

Paediatric patients: 
Lopinavir AUC  0.78 (0.56-1.09) 
Lopinavir Cmin  0.45 (0.25-0.82)
Lopinavir Cmax  0.86 (0.64-1.16) 

For children, increase of the dose of 
lopinavir/ritonavir to 300/75 mg/m2 

twice daily with food should be 
considered when used in combination 
with Viramune, particularly for 
patients in whom reduced 
susceptibility to lopinavir/ritonavir is 
suspected. 

Ritonavir
600 mg BID

Ritonavir AUC 0.92 (0.79-1.07)
Ritonavir Cmin  0.93 (0.76-1.14)
Ritonavir Cmax  0.93 (0.78-1.07)

Nevirapine: Co-administration of 
ritonavir does not lead to any 
clinically relevant change in 
nevirapine plasma levels.

Ritonavir and Viramune can be co-
administered without dose 
adjustments.

Saquinavir/ritonavir The limited data available with 
saquinavir soft gel capsule boosted 
with ritonavir do not suggest any 
clinically relevant interaction 
between saquinavir boosted with 
ritonavir and nevirapine.

Saquinavir/ritonavir and Viramune 
can be co-administered without dose 
adjustments. 

Tipranavir/ritonavir 
500/200 mg BID

No specific drug-drug interaction 
study has been performed.
The limited data available from a 

Tipranavir and Viramune can be co-
administered without dose 
adjustments.



63

phase IIa study in HIV-infected 
patients have shown a clinically non 
significant 20% decrease of TPV 
Cmin.. 

ENTRY INHIBITORS
Enfuvirtide Due to the metabolic pathway no 

clinically significant 
pharmacokinetic interactions are 
expected between enfuvirtide and 
nevirapine.

Enfuvirtide and Viramune can be co-
administered without dose 
adjustments.

Maraviroc 
300 mg QD

Maraviroc AUC  1.01 (0.6 -1.55)
Maraviroc Cmin ND
Maraviroc Cmax  1.54 (0.94-2.52)
compared to historical controls 

Nevirapine concentrations not 
measured, no effect is expected.

Maraviroc and Viramune can be co-
administered without dose 
adjustments.

INTEGRASE INHIBITORS
Elvitegravir/
cobicistat 

Interaction has not been studied. 
Cobicistat, a cytochrome P450 3A 
inhibitor significantly inhibits 
hepatic enzymes, as well as other 
metabolic pathways. Therefore 
coadministration would likely result 
in altered plasma levels of cobicistat 
and Viramune.

Coadministration of Viramune with 
elvitegravir in combination with 
cobicistat is not recommended (see 
section 4.4).

Raltegravir 
400 mg BID

No clinical data available. Due to the 
metabolic pathway of raltegravir no 
interaction is expected.

Raltegravir and Viramune can be co-
administered without dose 
adjustments.

ANTIBIOTICS
Clarithromycin 
500 mg BID

Clarithromycin AUC  0.69 (0.62-
0.76)
Clarithromycin Cmin  0.44 (0.30-
0.64)
Clarithromycin Cmax  0.77 (0.69-
0.86)

Metabolite 14-OH clarithromycin 
AUC  1.42 (1.16-1.73) 
Metabolite 14-OH clarithromycin 
Cmin  0 (0.68-1.49)
Metabolite 14-OH clarithromycin 
Cmax  1.47 (1.21-1.80)

Nevirapine AUC  1.26 
Nevirapine Cmin  1.28
Nevirapine Cmax  1.24 
compared to historical controls. 

Clarithromycin exposure was 
significantly decreased, 14-OH 
metabolite exposure increased. 
Because the clarithromycin active 
metabolite has reduced activity 
against Mycobacterium avium-
intracellulare complex overall 
activity against the pathogen may be 
altered. Alternatives to 
clarithromycin, such as azithromycin 
should be considered. Close 
monitoring for hepatic abnormalities 
is recommended



64

Rifabutin 
150 or 300 mg QD

Rifabutin AUC  1.17 (0.98-1.40)
Rifabutin Cmin  1.07 (0.84-1.37)
Rifabutin Cmax  1.28 (1.09-1.51)

Metabolite 25-O-desacetylrifabutin 
AUC  1.24 (0.84-1.84)
Metabolite 25-O-desacetylrifabutin
Cmin  1.22 (0.86-1.74)
Metabolite 25-O-desacetylrifabutin
Cmax  1.29 (0.98-1.68)

A clinically not relevant increase in 
the apparent clearance of nevirapine 
(by 9%) compared to historical data 
was reported. 

No significant effect on rifabutin and 
Viramune mean PK parameters is 
seen. Rifabutin and Viramune can be 
co-administered without dose 
adjustments. However, due to the 
high interpatient variability some 
patients may experience large 
increases in rifabutin exposure and 
may be at higher risk for rifabutin 
toxicity. Therefore, caution should be 
used in concomitant administration.

Rifampicin 
600 mg QD 

Rifampicin AUC  1.11 (0.96-1.28)
Rifampicin Cmin ND
Rifampicin Cmax  1.06 (0.91-1.22)

Nevirapine AUC  0.42
Nevirapine Cmin  0.32 
Nevirapine Cmax  0.50
compared to historical controls.

It is not recommended to co-
administer rifampicin and Viramune 
(see section 4.4). Physicians needing 
to treat patients co-infected with 
tuberculosis and using a Viramune 
containing regimen may consider co-
administration of rifabutin instead.

ANTIFUNGALS
Fluconazole 
200 mg QD

Fluconazole AUC  0.94 (0.88-
1.01)
Fluconazole Cmin  0.93 (0.86-1.01)
Fluconazole Cmax  0.92 (0.85-0.99)

Nevirapine: exposure: 100% 
compared with historical data where 
nevirapine was administered alone.

Because of the risk of increased 
exposure to Viramune, caution 
should be exercised if the medicinal 
products are given concomitantly and 
patients should be monitored closely. 

Itraconazole 
200 mg QD

Itraconazole AUC  0.39
Itraconazole Cmin  0.13
Itraconazole Cmax  0.62

Nevirapine: there was no significant 
difference in nevirapine 
pharmacokinetic parameters.

A dose increase for itraconazole 
should be considered when these two 
agents are administered 
concomitantly.

Ketoconazole 
400 mg QD

Ketoconazole AUC  0.28 (0.20-
0.40)
Ketoconazole Cmin ND
Ketoconazole Cmax  0.56 (0.42-
0.73)

Nevirapine: plasma levels:  1.15-
1.28 compared to historical controls.

It is not recommended to co-
administer ketoconazole and 
Viramune (see section 4.4).

ANTIVIRALS FOR CHRONIC HEPATITIS B AND C
Adefovir Results of in vitro studies showed  a 

weak antagonism of nevirapine by 
Adefovir and Viramune may be 
coadministered without dose 



65

adefovir (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Adefovir did not influence any of the 
common CYP isoforms known to be 
involved in human drug metabolism 
and is excreted renally. No clinically 
relevant drug-drug interaction is 
expected.

adjustments.

Boceprevir Boceprevir is partly metabolized by 
CYP3A4/5. Co-administration of 
boceprevir with medicines that 
induce or inhibit CYP3A4/5 could 
increase or decrease exposure.  
Plasma trough concentrations of 
boceprevir were decreased when 
administered with an NNRTI with a 
similar metabolic pathway as 
nevirapine. The clinical outcome of 
this observed reduction of boceprevir 
trough concentrations has not been 
directly assessed. 

It is not recommended to
coadminister boceprevir and 
Viramune (see section 4.4).

Entecavir Entecavir is not a substrate, inducer 
or an inhibitor of cytochrome P450 
(CYP450) enzymes. Due to the 
metabolic pathway of entecavir, no 
clinically relevant drug-drug 
interaction is expected.

Entecavir and Viramune may be 
coadministered without dose 
adjustments.

Interferons (pegylated 
interferons alfa 2a and 
alfa 2b)

Interferons have no known effect on 
CYP 3A4 or 2B6.  No clinically 
relevant drug-drug interaction is 
expected.

Interferons  and Viramune may be 
coadministered without dose 
adjustments.

Ribavirin Results of in vitro studies showed a 
weak antagonism of nevirapine by 
ribavirin (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Ribavirin does not inhibit 
cytochrome P450 enzymes, and there 
is no evidence from toxicity studies 
that ribavirin induces liver enzymes. 
No clinically relevant drug-drug 
interaction is expected. 

Ribavirin and Viramune may be 
coadministered without dose 
adjustments.

Telaprevir Telaprevir is metabolised in the liver 
by CYP3A and is a P-glycoprotein 
substrate. Other enzymes may be 
involved in the metabolism. Co-
administration of telaprevir and 
medicinal products that induce 
CYP3A and/or P-gp may decrease
telaprevir plasma concentrations. No 

Caution should be exercised when 
co-administering telaprevir with 
nevirapine. 
If co-administered with Viramune, an 
adjustment in the telaprevir dose 
should be considered.



66

drug-drug interaction study of 
telaprevir with nevirapine has been 
conducted, however, interaction 
studies of telaprevir with an NNRTI 
with a similar metabolic pathway as 
nevirapine demonstrated reduced 
levels of both. Results of DDI 
studies of telaprevir with efavirenz 
indicate that caution should be 
exercised when co-administering 
telaprevir with P450 inducers. 

Telbivudine Telbivudine is not a substrate, 
inducer or inhibitor of the 
cytochrome P450 (CYP450) enzyme 
system. Due to the metabolic 
pathway of telbivudine, no clinically 
relevant drug-drug interaction is 
expected.

Telbivudine and Viramune may be 
coadministered without dose 
adjustments.

ANTACIDS
Cimetidine Cimetidine: no significant effect on 

cimetidine PK parameters is seen. 

Nevirapine Cmin  1.07

Cimetidine and Viramune can be co-
administered without dose 
adjustments. 

ANTITHROMBOTICS
Warfarin The interaction between nevirapine 

and the antithrombotic agent 
warfarin is complex, with the 
potential for both increases and 
decreases in coagulation time when 
used concomitantly.

Close monitoring of anticoagulation 
levels is warranted.

CONTRACEPTIVES
Depo-
medroxyprogesterone 
acetate (DMPA) 
150 mg every 3 
months

DMPA AUC 
DMPA Cmin 
DMPA Cmax 

Nevirapine AUC  1.20
Nevirapine Cmax  1.20

Viramune co-administration did not 
alter the ovulation suppression effects 
of DMPA. DMPA and Viramune can 
be co-administered without dose 
adjustments. 

Ethinyl estradiol (EE) 
0.035 mg 

EE AUC  0.80 (0.67 - 0.97) 
EE Cmin ND
EE Cmax  0.94 (0.79 - 1.12)

Oral hormonal contraceptives should 
not be used as the sole method of 
contraception in women taking 
Viramune (see section 4.4). 
Appropriate doses for hormonal 
contraceptives (oral or other forms of 
application) other than DMPA in 
combination with Viramune have not 
been established with respect to 
safety and efficacy.

Norethindrone (NET) 
1.0 mg QD

NET AUC  0.81 (0.70 - 0.93)
NET Cmin ND
NET Cmax  0.84 (0.73 - 0.97)

ANALGESICS/OPIOIDS
Methadone Individual
Patient Dosing

Methadone AUC  0.40 (0.31 - 0.51)
Methadone Cmin ND

Methadone-maintained patients 
beginning Viramune therapy should 



67

Methadone Cmax  0.58 (0.50 - 0.67) be monitored for evidence of 
withdrawal and methadone dose 
should be adjusted accordingly.

HERBAL PRODUCTS
St. John's Wort Serum levels of nevirapine can be 

reduced by concomitant use of the 
herbal preparation St. John's Wort 
(Hypericum perforatum). This is due 
to induction of medicinal product 
metabolism enzymes and/or 
transport proteins by St. John’s 
Wort.

Herbal preparations containing St. 
John‘s Wort and Viramune must not 
be co-administered (see section 4.3). 
If a patient is already taking St. 
John‘s Wort check nevirapine and if 
possible viral levels and stop St. 
John‘s Wort. Nevirapine levels may 
increase on stopping St. John‘s Wort. 
The dose of Viramune may need 
adjusting. The inducing effect may 
persist for at least 2 weeks after 
cessation of treatment with St. John‘s 
Wort.

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.

4.6 Fertility, pregnancy and lactation

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

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

Breast-feeding
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.



68

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

The nevirapine 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 section 4.4).

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

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

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

Blood and lymphatic system disorders
Uncommon granulocytopenia
Rare anaemia

Immune system disorders
Uncommon hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria), drug reaction

with eosinophilia and systemic symptoms, anaphylactic reaction

Nervous system disorders
Common headache

Gastrointestinal disorders
Common abdominal pain, nausea, diarrhoea
Uncommon vomiting



69

Hepatobiliary disorders
Uncommon jaundice, hepatitis fulminant (which may be fatal)
Rare hepatitis (incl. severe and life-threatening hepatotoxicity)(0.09%)

Skin and subcutaneous tissue disorders
Common rash (6.7 %)
Uncommon Stevens-Johnson Syndrome/toxic epidermal necrolysis (which may be fatal) 

(0.2 %), angioedema, urticaria

Musculoskeletal and connective tissue disorders
Uncommon arthralgia, myalgia

General disorders and administration site conditions
Common fatigue, pyrexia

Investigations
Uncommon liver function test abnormal (alanine aminotransferase increased; transaminases 

increased; aspartate aminotransferase increased; gamma-glutamyltransferase 
increased; hepatic enzyme increased; hypertransaminasaemia), blood phosphorus 
decreased, blood pressure increased

Table 2: Maintenance phase of Viramune prolonged-release 

Blood and lymphatic system disorders
Uncommon anaemia, granulocytopenia

Immune system disorders
Uncommon hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria), drug reaction

with eosinophilia and systemic symptoms, anaphylactic reaction

Nervous system disorders
Common headache

Gastrointestinal disorders
Common abdominal pain, nausea, vomiting, diarrhoea

Hepatobiliary disorders
Common hepatitis (incl. severe and life-threatening hepatotoxicity) (1.6 %)
Uncommon jaundice, hepatitis fulminant (which may be fatal)

Skin and subcutaneous tissue disorders
Common rash (5.7 %)
Uncommon Stevens-Johnson Syndrome/toxic epidermal necrolysis (which may be fatal) 

(0.6 %), angioedema, urticaria

Musculoskeletal and connective tissue disorders
Uncommon arthralgia, myalgia

General disorders and administration site conditions
Common fatigue
Uncommon pyrexia



70

Investigations
Common liver function test abnormal (alanine aminotransferase increased; transaminases 

increased; aspartate aminotransferase increased; gamma-glutamyltransferase 
increased; hepatic enzyme increased; hypertransaminasaemia), blood phosphorus 
decreased, blood pressure increased

Description of selected adverse reactions
The following adverse reactions were identified in other nevirapine studies or by post-marketing 
surveillance but not observed in the randomised, controlled clinical study 1100.1486. 
As granulocytopenia, drug reaction with eosinophilia and systemic symptoms, anaphylactic reaction, 
jaundice, hepatitis fulminant (which may be fatal), urticaria, decreased blood phosphorus and 
increased blood pressure during the lead-in phase with Viramune immediate release were not seen in 
study 1100.1486 the frequency category was estimated from a statistical calculation based on the total 
number of patients exposed to nevirapine immediate-release in the lead-in phase of the randomised 
controlled clinical study 1100.1486 (n= 1,068).
Accordingly, as anaemia, granulocytopenia, anaphylactic reaction, jaundice, Stevens-Johnson 
Syndrome/toxic epidermal necrolysis (which may be fatal), angioedema, decreased blood phosphorus
and increased blood pressure during maintenance phase with Viramune prolonged-release tablets were 
not seen in study 1100.1486 the frequency category was estimated from a statistical calculation based 
on the total number of patients exposed to nevirapine prolonged-release in the maintenance phase of 
the randomised controlled clinical study 1100.1486 (n= 505).

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4).

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

Skin and subcutaneous tissues

The most common clinical toxicity of nevirapine is rash. Rashes are usually mild to moderate, 
maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face 
and extremities. Hypersensitivity (incl. anaphylactic reaction, angioedema and urticaria) has been 
reported. Rashes occur alone or in the context of drug reaction 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 reaction with eosinophilia and systemic symptoms have been reported. The majority of severe 



71

rashes occurred within the first 6 weeks of treatment and some required hospitalisation, with one 
patient requiring surgical intervention (see section 4.4). 

In study 1100.1486 (VERxVE) antiretroviral-naïve patients received a lead-in dose of Viramune 
200 mg immediate-release once daily for 14 days (n=1068) and then were randomised to receive either 
Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. 
All patients received tenofovir + emtricitabine as background therapy. Safety data included all the 
patient visits up to the point in time when the last patient completed 144 weeks in the trial. This also 
includes safety data for patient visits in the post-week 144 open label extension (which patients in 
either treatment group who completed the 144 week blinded phase could enter). Severe or life-
threatening rash considered related to nevirapine treatment occurred in 1.1 % of patients during the 
lead-in phase with Viramune immediate-release. Severe rash occurred in 1.4 % and 0.2 % of the 
Viramune immediate-release and Viramune prolonged-release groups respectively during the 
randomised phase. No life-threatening (Grade 4) rash events considered related to Viramune were 
reported during the randomised phase of this study. Six cases of Stevens-Johnson Syndrome were 
reported in the study; all but one occurred within the first 30 days of nevirapine treatment. 

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

Hepato-biliary

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

In study 1100.1486 (VERxVE) treatment-naïve patients received a lead-in dose of Viramune 200 mg 
immediate-release once daily for 14 days and then were randomised to receive either Viramune 
200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. All patients 
received tenofovir + emtricitabine as background therapy. Patients were enrolled with CD4 counts 
<250 cells/mm3 for women and <400 cells/mm3 for men. Data on potential symptoms of hepatic 
events were prospectively collected in this study. The safety data include all patient visits up to the 
time of the last patient’s completion of study week 144. The incidence of symptomatic hepatic events 
during the Viramune immediate-release lead-in phase was 0.5 %. After the lead-in period the 
incidence of symptomatic hepatic events was 2.4 % in the Viramune immediate-release group and 
1.6% in the Viramune prolonged-release group. Overall, there was a comparable incidence of 
symptomatic hepatic events among men and women enrolled in VERxVE.

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

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



72

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V.

4.9 Overdose

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

Paediatric population

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 , , , or .

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, 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.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


73

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.

Genotypic analysis of isolates from antiretroviral naïve patients experiencing virologic failure (n=71) 
receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and 
stavudine for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained one 
or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, 
K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.

Genotypic analysis was performed on isolates from 86 antiretroviral naïve patients who discontinued 
the VERxVE study (1100.1486) after experiencing virologic failure (rebound, partial response) or due 
to an adverse event or who had transient increase in viral load during the course of the study. The 
analysis of these samples of patients receiving Viramune immediate-release twice daily or Viramune
prolonged-release once daily in combination with tenofovir and emtricitabine showed that isolates 
from 50 patients contained resistance mutations expected with a nevirapine-based regimen. Of these 
50 patients, 28 developed resistance to efavirenz and 39 developed resistance to etravirine (the most 
frequently emergent resistance mutation being Y181C). There were no differences based on the 
formulation taken (immediate-release twice daily or prolonged-release once daily).

The observed mutations at failure were those expected with a nevirapine-based regimen. Two new 
substitutions on codons previously associated with nevirapine resistance were observed: one patient 
with Y181I in the Viramune prolonged-release group and one patient with Y188N in the Viramune
immediate-release group; resistance to nevirapine was confirmed by phenotype.

Cross-resistance

Rapid emergence of HIV-strains which are cross-resistant to NNRTIs has been observed in vitro. 
Cross resistance to delavirdine and efavirenz is expected after virologic failure with nevirapine. 
Depending on resistance testing results, an etravirine-containing regimen may be used subsequently. 
Cross-resistance between nevirapine and either HIV protease inhibitors, HIV integrase inhibitors or 
HIV entry inhibitors is unlikely because the enzyme targets involved are different. Similarly the 
potential for cross-resistance between nevirapine and NRTIs is low because the molecules have 
different binding sites on the reverse transcriptase.

Clinical results

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

Clinical studies with prolonged-release tablets

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



74

Treatment-naïve patients
VERxVE (study 1100.1486) is a phase 3 study in which treatment-naïve patients received Viramune
200 mg immediate-release once daily for 14 days and then were randomised to receive either 
Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. 
All patients received tenofovir + emtricitabine as background therapy. Randomisation was stratified 
by screening HIV-1 RNA level (<100,000 copies/ml and >100,000 copies/ml). Selected demographic 
and baseline disease characteristics are displayed in Table 1.

Table 1: Demographic and Baseline Disease Characteristics in study 1100.1486

Viramune
immediate-release

Viramune
prolonged-release

n=508* n=505

Gender 

- Male 85 % 85 %

- Female 15 % 15 %

Race 

- White 74 % 77 %

- Black 22 % 19 %

- Asian 3 % 3 %

- Other** 1 % 2 %

Region

- North America 30 % 28 %

- Europe 50 % 51 %

- Latin America 10 % 12 %

- Africa 11 % 10 %

Baseline Plasma HIV-1 RNA (log10 copies/ml)

- Mean (SD) 4.7 (0.6) 4.7 (0.7)

- <100,000 66 % 67 %

- >100,000 34 % 33 %

Baseline CD4 count (cells/mm3)

- Mean (SD) 228 (86) 230 (81)

HIV-1 subtype

- B 71 % 75 %
- Non-B 29 % 24 %

* Includes 2 patients who were randomised but never received blinded medicinal products. 
** Includes American Indians/Alaska natives and Hawaiian/Pacific islanders.

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



75

Table 2: Outcomes at week 48 in study 1100.1486*

Viramune
immediate-release

n=506

Viramune
prolonged-release

n=505

Virologic responder (HIV-1 RNA <50 copies/ml) 75.9 % 81.0 %

Virologic failure
5.9 % 3.2 %

- Never suppressed through week 48 2.6 % 1.0 %

- Rebound 3.4 % 2.2 %

Discontinued medicinal product prior to week 48 18.2 % 15.8 %

- Death 0.6 % 0.2 %

- Adverse events 8.3 % 6.3 %

- Other** 9.3 % 9.4 %

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

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

At week 48, mean change from baseline in CD4 cell count was 184 cells/mm3 and 197 cells/mm3 for 
the groups receiving Viramune immediate-release and Viramune prolonged-release respectively.

Table 3 shows outcomes at 48-weeks in study 1100.1486 (after randomization) by baseline viral load.

Table 3: Outcomes at 48 weeks in study 1100.1486 by baseline viral load*
Number with response/total number (%) Difference in %

(95 % CI)Viramune
immediate-release

Viramune
prolonged-release

Baseline HIV−1 viral load 
stratum (copies/ml)
- < 100,000 240/303 (79.2 %) 267/311 (85.0 %) 6.6 (0.7, 12.6)
- >100,000 144/203 (70.9 %) 142/194 (73.2 %) 2.3 (−6.6, 11.1)
Total 384/506 (75.9 %) 409/505 (81.0 %) 4.9 (−0.1, 10.0)**
* Includes patients who received at least one dose of blinded medicinal product after randomisation. 
Patients who discontinued treatment during the lead-in period are excluded.
** Based on Cochran’s statistic with continuity correction for the variance calculation

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

Lipids, Change from baseline
Changes from baseline in fasting lipids are shown in Table 4.



76

Table 4: Summary of lipid laboratory values at baseline (screening) and week 48 - study 
1100.1486

Viramune
immediate-release

Viramune
prolonged-release

Baseline
(mean)
n=503

Week 48
(mean)
n=407

Percent
change

*

n=406

Baseline
(mean)
n=505

Week 48
(mean)
n=419

Percent 
change

*

n=419
LDL (mg/dL) 98.8 110.0 +9 98.3 109.5 +7
HDL (mg/dL) 38.8 52.2 +32 39.0 50.0 +27
Total cholesterol. (mg/dL) 163.8 186.5 +13 163.2 183.8 +11
Total cholesterol/HDL 4.4 3.8 -14 4.4 3.9 -12
Triglycerides (mg/dL) 131.2 124.5 -9 132.8 127.5 -7

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

Patients switching from Viramune immediate-release to Viramune prolonged-release
TRANxITION (study 1100.1526) is a Phase 3 study to evaluate safety and antiviral activity in patients 
switching from Viramune immediate-release to Viramune prolonged-release. In this open-label study, 
443 patients already on an antiviral regimen containing Viramune 200 mg immediate-release twice 
daily with HIV-1 RNA < 50 copies/ml were randomised in a 2:1 ratio to Viramune 400 mg prolonged-
release once daily or Viramune 200 mg immediate-release twice daily. Approximately half of the 
patients had tenofovir + emtricitabine as their background therapy, with the remaining patients 
receiving abacavir sulfate + lamivudine or zidovudine + lamivudine. Approximately half of the 
patients had at least 3 years of prior exposure to Viramune immediate-release prior to entering study
1100.1526. 

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

Paediatric population
Results of a 48-week analysis of the South African study BI 1100.1368 confirmed that the 4/7 mg/kg 
and 150 mg/m2 nevirapine dose groups were well tolerated and effective in treating antiretroviral naive 
paediatric patients. A marked improvement in the CD4+ cell percent was observed through Week 48 
for both dose groups. Also, both dosing regimens were effective in reducing the viral load. In this 48-
week study no unexpected safety findings were observed in either dosing group.

5.2 Pharmacokinetic properties

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

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

The pharmacokinetics of Viramune prolonged-release has also been studied in a multiple dose 
pharmacokinetics study (study 1100.1489) in 24 HIV-1 infected patients who switched from chronic 
Viramune immediate-release therapy to Viramune prolonged-release. The nevirapine AUC0-24,ss and 



77

Cmin,ss measured after 19 days of fasted dosing of Viramune 400 mg prolonged-release tablets once 
daily were approximately 80 % and 90 %, respectively, of the AUC0-24,ss and Cmin,ss measured when 
patients were dosed with Viramune 200 mg immediate-release tablets twice daily. The geometric 
mean nevirapine Cmin,ss was 2,770 ng/ml.

When Viramune prolonged-release was dosed with a high fat meal, the nevirapine AUC0-24,ss and Cmin,ss
were approximately 94 % and 98 %, respectively, of the AUC0-24,ss and Cmin,ss measured when patients 
were dosed with Viramune immediate-release tablets. The difference in nevirapine pharmacokinetics 
observed when Viramune prolonged-release tablets are dosed under fasted or fed conditions is not 
considered clinically relevant. Viramune prolonged-release tablets can be taken with or without food.

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.

Distribution: Nevirapine is lipophilic and is essentially nonionized at physiologic pH. Following 
intravenous administration to healthy adults, the volume of distribution (Vdss) of nevirapine was 1.21 
 0.09 l/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the 
placenta and is found in breast milk. Nevirapine is about 60 % bound to plasma proteins in the plasma 
concentration range of 1-10 µg/ml. Nevirapine concentrations in human cerebrospinal fluid (n = 6) 
were 45 % ( 5 %) of the concentrations in plasma; this ratio is approximately equal to the fraction not 
bound to plasma protein.

Biotransformation and elimination: In vivo studies in humans and in vitro studies with human liver 
microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 
(oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver 
microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome 
P450 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a 
mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 
200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 
10.5 % of the radiolabelled dose was recovered, with urine (81.3  11.1 %) representing the primary 
route of excretion compared to faeces (10.1  1.5 %). Greater than 80 % of the radioactivity in urine 
was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 
metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent 
the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (< 
5%) of the radioactivity in urine (representing < 3 % of the total dose) was made up of parent 
compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The 
pharmacokinetics of autoinduction is characterised by an approximately 1.5 to 2 fold increase in the 
apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks 
of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal 
phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 
25-30 hours following multiple dosing with 200-400 mg/day.

Renal impairment: The single-dose pharmacokinetics of nevirapine immediate-release has been 
compared in 23 patients with either mild (50  CLcr  80 ml/min), moderate (30  CLcr  50 ml/min) 
or severe renal dysfunction (CLcr  30 ml/min), renal impairment or end-stage renal disease (ESRD) 
requiring dialysis, and 8 patients with normal renal function (CLcr  80 ml/min). Renal impairment 
(mild, moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine. 
However, patients with ESRD requiring dialysis exhibited a 43.5 % reduction in nevirapine AUC over 
a one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in 
plasma. The results suggest that supplementing nevirapine therapy for adults with an additional 
200 mg immediate-release tablet following each dialysis treatment would help offset the effects of 



78

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

Hepatic impairment: A steady state study comparing 46 patients with 
mild (n=17: Ishak Score 1-2), 
moderate (n=20; Ishak Score 3-4), 
or severe (n=9; Ishak Score 5-6, Child-Pugh A in 8 pts., for 1 Child-Pugh score not applicable) 
liver fibrosis as a measure of hepatic impairment was conducted. 

The patients studied were receiving antiretroviral therapy containing Viramune 200 mg immediate-
release tablets twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median 
duration of therapy of 3.4 years. In this study, the multiple dose pharmacokinetic disposition of 
nevirapine and the five oxidative metabolites were not altered.

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

In a single dose pharmacokinetic study of 200 mg Viramune immediate-release tablets in 
HIV-negative patients with mild and moderate hepatic impairment (Child-Pugh A, n=6; Child-Pugh B, 
n=4), a significant increase in the AUC of nevirapine was observed in one Child-Pugh B patient with 
ascites suggesting that patients with worsening hepatic function and ascites may be at risk of 
accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism 
with multiple dosing, this single dose study may not reflect the impact of hepatic impairment on 
multiple dose pharmacokinetics (see section 4.4). Viramune prolonged-release tablets have not been 
evaluated in patients with hepatic impairment and Viramune immediate-release should be used.

Gender 
In the multinational 2NN study with Viramune immediate-release, a population pharmacokinetic 
substudy of 1077 patients was performed that included 391 females. Female patients showed a 13.8 % 
lower clearance of nevirapine than did male patients. This difference is not considered clinically 
relevant. Since neither body weight nor Body Mass Index (BMI) had influence on the clearance of 
nevirapine, the effect of gender cannot be explained by body size.

The effects of gender on the pharmacokinetics of Viramune prolonged-release have been investigated 
in study 1100.1486. Female patients tend to have higher (approximately 20 – 30 %) trough 
concentrations in both Viramune prolonged-release and Viramune immediate-release treatment 
groups. 

Elderly
Nevirapine pharmacokinetics in HIV-1 infected adults does not appear to change with age (range 18 -
68 years). Nevirapine has not been specifically investigated in patients over the age of 65. Black 
patients (n=80/group) in study 1100.1486 showed approximately 30 % higher trough concentrations 
than Caucasian patients (250-325 patients/group) in both the Viramune immediate-release and 
Viramune prolonged-release treatment groups over 48 weeks of treatment at 400 mg/day.

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



79

Pharmacokinetic data on 33 patients (age range 0.77 – 13.7 years) in the intensive sampling group 
demonstrated that clearance of nevirapine increased with increasing age in a manner consistent with 
increasing body surface area. Dosing of nevirapine at 150 mg/m2 BID (after a two-week lead in at 
150 mg/m2 QD) produced geometric mean or mean trough nevirapine concentrations between 4-
6 µg/ml (as targeted from adult data). In addition, the observed trough nevirapine concentrations were 
comparable between the two methods.

The consolidated analysis of Paediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 
377, and 403 allowed for the evaluation of paediatric patients less than 3 months of age (n=17) 
enrolled in these PACTG studies. The plasma nevirapine concentrations observed were within the 
range observed in adults and the remainder of the paediatric population, but were more variable 
between patients, particularly in the second month of age.

The pharmacokinetics of Viramune prolonged-release was assessed in study 1100.1518. Eighty-five 
patients (3 to < 18 years) received weight or body surface area dose-adjusted Viramune immediate-
release for a minimum of 18 weeks and then were switched to Viramune prolonged-release tablets (2 x 
100 mg, 3 x 100 mg or 1 x 400 mg once daily) in combination with other antiretrovirals for 10 days. 
The observed geometric mean ratios of Viramune prolonged-release to Viramune immediate-release 
were ~90 % for Cmin,ss and AUCss with 90 % confidence intervals within 80 %-125 %; the ratio for 
Cmax,ss was lower and consistent with a once-daily prolonged-release dosage form. Geometric mean 
steady-state plasma Viramune prolonged-release pre-dose trough concentrations were 3,880 ng/ml, 
3,310 ng/ml and 5,350 ng/ml in age groups 3 to <6 years, 6 to <12 years, and 12 to <18 years of age, 
respectively. Overall, the exposure in children was similar to that observed in adults receiving 
Viramune prolonged-release in study 1100.1486. 

In single dose, parallel group bioavailability studies (studies 1100.1517 and 1100.1531), the Viramune 
50 and 100 mg prolonged-release tablets exhibited extended release characteristics of prolonged 
absorption and lower maximal concentrations, similar to the findings when a 400 mg prolonged-
release tablet was compared to the Viramune immediate-release 200 mg tablet. Dividing a 200 mg 
total dose into four 50 mg doses rather than two 100 mg doses produced a 7-11 % greater overall 
absorption, but with comparable medicinal product release rates. The observed pharmacokinetic 
difference between the 50 mg and 100 mg Viramune prolonged-release tablets is not clinically 
relevant, and the 50 mg prolonged-release tablet can be used as an alternative to the slightly larger 
100 mg tablet.

5.3 Preclinical safety data

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. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose (as monohydrate)
Hypromellose
Iron oxide yellow
Magnesium stearate



80

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

The medicinal product should be used within 2 months of opening.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Maintenance packs:
High density polyethylene (HDPE) plastic bottle, with a plastic cap and an induction foil seal liner. 
Bottles contain 90 prolonged-release tablets.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein, Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/97/055/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5 February 1998
Date of latest renewal: 20 December 2012

10. DATE OF REVISION OF THE TEXT

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



81

1. NAME OF THE MEDICINAL PRODUCT

Viramune 400 mg prolonged-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect
Each prolonged-release tablet contains 400 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Prolonged-release tablet

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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

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

4.2 Posology and method of administration

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

Posology

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

Patients currently on a Viramune immediate-release twice daily regimen:
Patients already on a regimen of Viramune immediate-release twice daily in combination with other 
antiretroviral agents can be switched to Viramune 400 mg prolonged-release tablets once daily in 



82

combination with other antiretroviral agents without a lead-in period of Viramune immediate-release.

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

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

Paediatric population
Children three years and older and adolescents

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

 are  8 years of age and weigh 43.8 kg or more or
 are < 8 years of age and weigh 25 kg or more or
 have a body surface area of 1.17 m2 or above according to the Mosteller formula. 

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

Children less than three years old

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

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

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

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

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

There are toxicities that require interruption of Viramune therapy (see section 4.4).

Elderly
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.



83

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

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

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

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 (see section 4.5).

4.4 Special warnings and precautions for use

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.



84

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 evaluation 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).

Cutaneous reactions

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

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

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

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

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



85

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

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

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 evaluation. 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).

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 



86

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 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).

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 one immediate-release 200 mg Viramune tablet daily for 14 days followed by 
one Viramune 400 mg prolonged-release tablet 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.

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.



87

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.

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 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.



88

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.

Lactose: Viramune prolonged-release tablets contain 400 mg of lactose per maximum recommended 
daily dose.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-
galactose malabsorption should not take this medicine.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

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

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

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

Medicinal products 
by therapeutic areas

Interaction Recommendations concerning co-
administration

ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine 
100-150 mg BID

Didanosine AUC  1.08 (0.92-1.27)
Didanosine Cmin ND
Didanosine Cmax  0.98 (0.79-1.21)

Didanosine and Viramune can be co-
administered without dose 
adjustments.

Emtricitabine Emtricitabine is not an inhibitor of 
human CYP 450 enzymes.

Viramune and emtricitabine may be 
coadministered without dose 
adjustments.



89

Abacavir In human liver microsomes, abacavir 
did not inhibit cytochrome P450 
isoforms.

Viramune and abacavir may be 
coadministered without dose 
adjustments.

Lamivudine 
150 mg BID

No changes to lamivudine apparent 
clearance and volume of distribution, 
suggesting no induction effect of 
nevirapine on lamivudine clearance.

Lamivudine and Viramune can be co-
administered without dose 
adjustments.

Stavudine: 
30/40 mg BID 

Stavudine AUC  0.96 (0.89-1.03)
Stavudine Cmin ND
Stavudine Cmax  0.94 (0.86-1.03)

Nevirapine: compared to historical 
controls, levels appeared to be 
unchanged.

Stavudine and Viramune can be co-
administered without dose 
adjustments.

Tenofovir 
300 mg QD

Tenofovir plasma levels remain 
unchanged when co-administered 
with nevirapine. 

Nevirapine plasma levels were not 
altered by co-administration of 
tenofovir.

Tenofovir and Viramune can be co-
administered without dose 
adjustments.

Zidovudine 
100-200 mg TID

Zidovudine AUC  0.72 (0.60-0.96) 
Zidovudine Cmin ND
Zidovudine Cmax  0.70 (0.49-1.04)

Nevirapine: Zidovudine had no 
effect on its pharmacokinetics.

Zidovudine and Viramune can be co-
administered without dose 
adjustments

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.

NNRTIs
Efavirenz 
600 mg QD

Efavirenz AUC  0.72 (0.66-0.86)
Efavirenz Cmin  0.68 (0.65-0.81)
Efavirenz Cmax  0.88 (0.77-1.01)

It is not recommended to co-
administer efavirenz and Viramune
(see section 4.4), because of additive 
toxicity and no benefit in terms of 
efficacy over either NNRTI alone (for 
results of 2NN study, see section 5.1
Viramune immediate-release 
formulations).

Delavirdine Interaction has not been studied. The concomitant administration of 



90

Viramune with NNRTIs is not 
recommended (see section 4.4).

Etravirine Concomitant use of etravirine with 
nevirapine may cause a significant 
decrease in the plasma 
concentrations of etravirine and loss 
of therapeutic effect of etravirine.

The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

Rilpivirine Interaction has not been studied. The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4).

PIs

Atazanavir/ritonavir 
300/100 mg QD
400/100 mg QD

Atazanavir/r 300/100mg:
Atazanavir/r AUC  0.58 (0.48-0.71)
Atazanavir/r Cmin 0.28 (0.20-0.40)
Atazanavir/r Cmax  0.72 (0.60-0.86)

Atazanavir/r 400/100mg:
Atazanavir/r AUC  0.81 (0.65-1.02) 
Atazanavir/r Cmin  0.41 (0.27-0.60)
Atazanavir/r Cmax  1.02 (0.85–
1.24)
(compared to 300/100mg without 
nevirapine)

Nevirapine AUC  1.25 (1.17-1.34)
Nevirapine Cmin 1.32 (1.22–1.43)
Nevirapine Cmax  1.17 (1.09-1.25)

It is not recommended to co-
administer atazanavir/ritonavir and 
Viramune (see section 4.4).

Darunavir/ritonavir 
400/100 mg BID 

Darunavir AUC  1.24 (0.97-1.57)
Darunavir Cmin  1.02 (0.79-1.32)
Darunavir Cmax  1.40 (1.14-1.73)

Nevirapine AUC  1.27 (1.12-1.44)
Nevirapine Cmin  1.47 (1.20-1.82)
Nevirapine Cmax  1.18 (1.02-1.37)

Darunavir and Viramune can be co-
administered without dose 
adjustments.

Fosamprenavir
1400 mg BID

Amprenavir AUC  0.67 (0.55-0.80)
Amprenavir Cmin  0.65 (0.49-0.85)
Amprenavir Cmax  0.75 (0.63-0.89)

Nevirapine AUC  1.29 (1.19-1.40)
Nevirapine Cmin  1.34 (1.21-1.49)
Nevirapine Cmax  1.25 (1.14-1.37)

It is not recommended to co-
administer fosamprenavir and 
Viramune if fosamprenavir is not co-
administered with ritonavir (see 
section 4.4).

Fosamprenavir/ritona
vir 700/100 mg BID

Amprenavir AUC  0.89 (0.77-
1.03)
Amprenavir Cmin  0.81 (0.69-0.96)
Amprenavir Cmax  0.97 (0.85-1.10)

Fosamprenavir/ritonavir and 
Viramune can be co-administered 
without dose adjustments



91

Nevirapine AUC  1.14 (1.05-1.24)
Nevirapine Cmin  1.22 (1.10-1.35)
Nevirapine Cmax  1.13 (1.03-1.24)

Lopinavir/ritonavir 
(capsules) 
400/100 mg BID 

Adult patients: 
Lopinavir AUC  0.73 (0.53-0.98)
Lopinavir Cmin  0.54 (0.28-0.74)
Lopinavir Cmax  0.81 (0.62-0.95)

An increase in the dose of 
lopinavir/ritonavir to 533/133 mg (4 
capsules) or 500/125 mg (5 tablets 
with 100/25 mg each) twice daily 
with food is recommended in 
combination with Viramune. Dose 
adjustment of Viramune is not 
required when co-administered with 
lopinavir.

Lopinavir/ritonavir 
(oral solution) 
300/75 mg/m2 BID

Paediatric patients: 
Lopinavir AUC  0.78 (0.56-1.09) 
Lopinavir Cmin  0.45 (0.25-0.82)
Lopinavir Cmax  0.86 (0.64-1.16) 

For children, increase of the dose of 
lopinavir/ritonavir to 300/75 mg/m2 

twice daily with food should be 
considered when used in combination 
with Viramune, particularly for 
patients in whom reduced 
susceptibility to lopinavir/ritonavir is 
suspected. 

Ritonavir
600 mg BID

Ritonavir AUC 0.92 (0.79-1.07)
Ritonavir Cmin  0.93 (0.76-1.14)
Ritonavir Cmax  0.93 (0.78-1.07)

Nevirapine: Co-administration of 
ritonavir does not lead to any 
clinically relevant change in 
nevirapine plasma levels.

Ritonavir and Viramune can be co-
administered without dose 
adjustments.

Saquinavir/ritonavir The limited data available with 
saquinavir soft gel capsule boosted 
with ritonavir do not suggest any 
clinically relevant interaction 
between saquinavir boosted with 
ritonavir and nevirapine.

Saquinavir/ritonavir and Viramune 
can be co-administered without dose 
adjustments. 

Tipranavir/ritonavir 
500/200 mg BID

No specific drug-drug interaction 
study has been performed.
The limited data available from a 
phase IIa study in HIV-infected 
patients have shown a clinically non 
significant 20 % decrease of TPV 
Cmin. 

Tipranavir and Viramune can be co-
administered without dose 
adjustments.

ENTRY INHIBITORS
Enfuvirtide Due to the metabolic pathway no 

clinically significant 
pharmacokinetic interactions are 
expected between enfuvirtide and 
nevirapine.

Enfuvirtide and Viramune can be co-
administered without dose 
adjustments.

Maraviroc Maraviroc AUC  1.01 (0.6 -1.55) Maraviroc and Viramune can be co-



92

300 mg QD Maraviroc Cmin ND
Maraviroc Cmax  1.54 (0.94-2.52)
compared to historical controls 

Nevirapine concentrations not 
measured, no effect is expected.

administered without dose 
adjustments.

INTEGRASE INHIBITORS
Elvitegravir/
cobicistat 

Interaction has not been studied. 
Cobicistat, a cytochrome P450 3A 
inhibitor significantly inhibits 
hepatic enzymes, as well as other 
metabolic pathways. Therefore 
coadministration would likely result 
in altered plasma levels of cobicistat 
and Viramune.

Coadministration of Viramune with 
elvitegravir in combination with 
cobicistat is not recommended (see 
section 4.4).

Raltegravir 
400 mg BID

No clinical data available. Due to the 
metabolic pathway of raltegravir no 
interaction is expected.

Raltegravir and Viramune can be co-
administered without dose 
adjustments.

ANTIBIOTICS
Clarithromycin 
500 mg BID

Clarithromycin AUC  0.69 (0.62-
0.76)
Clarithromycin Cmin  0.44 (0.30-
0.64)
Clarithromycin Cmax  0.77 (0.69-
0.86)

Metabolite 14-OH clarithromycin 
AUC  1.42 (1.16-1.73) 
Metabolite 14-OH clarithromycin 
Cmin  0 (0.68-1.49)
Metabolite 14-OH clarithromycin 
Cmax  1.47 (1.21-1.80)

Nevirapine AUC  1.26 
Nevirapine Cmin  1.28
Nevirapine Cmax  1.24 
compared to historical controls. 

Clarithromycin exposure was 
significantly decreased, 14-OH 
metabolite exposure increased. 
Because the clarithromycin active 
metabolite has reduced activity 
against Mycobacterium avium-
intracellulare complex overall 
activity against the pathogen may be 
altered. Alternatives to 
clarithromycin, such as azithromycin 
should be considered. Close 
monitoring for hepatic abnormalities 
is recommended

Rifabutin 
150 or 300 mg QD

Rifabutin AUC  1.17 (0.98-1.40)
Rifabutin Cmin  1.07 (0.84-1.37)
Rifabutin Cmax  1.28 (1.09-1.51)

Metabolite 25-O-desacetylrifabutin 
AUC  1.24 (0.84-1.84)
Metabolite 25-O-desacetylrifabutin
Cmin  1.22 (0.86-1.74)
Metabolite 25-O-desacetylrifabutin
Cmax  1.29 (0.98-1.68)

A clinically not relevant increase in 
the apparent clearance of nevirapine 

No significant effect on rifabutin and 
Viramune mean PK parameters is 
seen. Rifabutin and Viramune can be 
co-administered without dose 
adjustments. However, due to the 
high interpatient variability some 
patients may experience large 
increases in rifabutin exposure and 
may be at higher risk for rifabutin 
toxicity. Therefore, caution should be 
used in concomitant administration.



93

(by 9 %) compared to historical data 
was reported. 

Rifampicin 
600 mg QD 

Rifampicin AUC  1.11 (0.96-1.28)
Rifampicin Cmin ND
Rifampicin Cmax  1.06 (0.91-1.22)

Nevirapine AUC  0.42
Nevirapine Cmin  0.32 
Nevirapine Cmax  0.50
compared to historical controls.

It is not recommended to co-
administer rifampicin and Viramune 
(see section 4.4). Physicians needing 
to treat patients co-infected with 
tuberculosis and using a Viramune 
containing regimen may consider co-
administration of rifabutin instead.

ANTIFUNGALS
Fluconazole 
200 mg QD

Fluconazole AUC  0.94 (0.88-
1.01)
Fluconazole Cmin  0.93 (0.86-1.01)
Fluconazole Cmax  0.92 (0.85-0.99)

Nevirapine: exposure: 100% 
compared with historical data where 
nevirapine was administered alone.

Because of the risk of increased 
exposure to Viramune, caution 
should be exercised if the medicinal 
products are given concomitantly and 
patients should be monitored closely. 

Itraconazole 
200 mg QD

Itraconazole AUC  0.39
Itraconazole Cmin  0.13
Itraconazole Cmax  0.62

Nevirapine: there was no significant 
difference in nevirapine 
pharmacokinetic parameters.

A dose increase for itraconazole 
should be considered when these two 
agents are administered 
concomitantly.

Ketoconazole 
400 mg QD

Ketoconazole AUC  0.28 (0.20-
0.40)
Ketoconazole Cmin ND
Ketoconazole Cmax  0.56 (0.42-
0.73)

Nevirapine: plasma levels:  1.15-
1.28 compared to historical controls.

It is not recommended to co-
administer ketoconazole and 
Viramune (see section 4.4).

ANTIVIRALS FOR CHRONIC HEPATITIS B AND C
Adefovir Results of in vitro studies showed  a 

weak antagonism of nevirapine by 
adefovir (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Adefovir did not influence any of the 
common CYP isoforms known to be 
involved in human drug metabolism 
and is excreted renally. No clinically 
relevant drug-drug interaction is 
expected.

Adefovir and Viramune may be 
coadministered without dose 
adjustments.

Boceprevir Boceprevir is partly metabolized by 
CYP3A4/5. Co-administration of 
boceprevir with medicines that 
induce or inhibit CYP3A4/5 could 

It is not recommended to 
coadminister boceprevir and 
Viramune (see section 4.4).



94

increase or decrease exposure.  
Plasma trough concentrations of 
boceprevir were decreased when 
administered with an NNRTI with a 
similar metabolic pathway as 
nevirapine. The clinical outcome of 
this observed reduction of boceprevir 
trough concentrations has not been 
directly assessed. 

Entecavir Entecavir is not a substrate, inducer 
or an inhibitor of cytochrome P450 
(CYP450) enzymes. Due to the 
metabolic pathway of entecavir, no 
clinically relevant drug-drug 
interaction is expected.

Entecavir and Viramune may be 
coadministered without dose 
adjustments.

Interferons (pegylated 
interferons alfa 2a and 
alfa 2b)

Interferons have no known effect on 
CYP 3A4 or 2B6.  No clinically 
relevant drug-drug interaction is 
expected.

Interferons  and Viramune may be 
coadministered without dose 
adjustments.

Ribavirin Results of in vitro studies showed a 
weak antagonism of nevirapine by 
ribavirin (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Ribavirin does not inhibit 
cytochrome P450 enzymes, and there 
is no evidence from toxicity studies 
that ribavirin induces liver enzymes. 
No clinically relevant drug-drug 
interaction is expected. 

Ribavirin and Viramune may be 
coadministered without dose 
adjustments.

Telaprevir Telaprevir is metabolised in the liver 
by CYP3A and is a P-glycoprotein 
substrate. Other enzymes may be 
involved in the metabolism. Co-
administration of telaprevir and 
medicinal products that induce 
CYP3A and/or P-gp may decrease 
telaprevir plasma concentrations. No 
drug-drug interaction study of 
telaprevir with nevirapine has been 
conducted, however, interaction 
studies of telaprevir with an NNRTI 
with a similar metabolic pathway as 
nevirapine demonstrated reduced 
levels of both. Results of DDI 
studies of telaprevir with efavirenz 
indicate that caution should be 
exercised when co-administering 
telaprevir with P450 inducers. 

Caution should be exercised when 
co-administering telaprevir with 
nevirapine. 
If co-administered with Viramune, an 
adjustment in the telaprevir dose 
should be considered.

Telbivudine Telbivudine is not a substrate, 
inducer or inhibitor of the 
cytochrome P450 (CYP450) enzyme 

Telbivudine and Viramune may be 
coadministered without dose 
adjustments.



95

system. Due to the metabolic 
pathway of telbivudine, no clinically 
relevant drug-drug interaction is 
expected.

ANTACIDS
Cimetidine Cimetidine: no significant effect on

cimetidine PK parameters is seen. 

Nevirapine Cmin  1.07

Cimetidine and Viramune can be co-
administered without dose 
adjustments. 

ANTITHROMBOTICS
Warfarin The interaction between nevirapine 

and the antithrombotic agent 
warfarin is complex, with the 
potential for both increases and 
decreases in coagulation time when 
used concomitantly.

Close monitoring of anticoagulation 
levels is warranted.

CONTRACEPTIVES
Depo-
medroxyprogesterone 
acetate (DMPA) 
150 mg every 3 
months

DMPA AUC 
DMPA Cmin 
DMPA Cmax 

Nevirapine AUC  1.20
Nevirapine Cmax  1.20

Viramune co-administration did not 
alter the ovulation suppression effects 
of DMPA. DMPA and Viramune can 
be co-administered without dose 
adjustments. 

Ethinyl estradiol (EE) 
0.035 mg 

EE AUC  0.80 (0.67 - 0.97) 
EE Cmin ND
EE Cmax  0.94 (0.79 - 1.12)

Oral hormonal contraceptives should 
not be used as the sole method of 
contraception in women taking 
Viramune (see section 4.4). 
Appropriate doses for hormonal 
contraceptives (oral or other forms of 
application) other than DMPA in 
combination with Viramune have not 
been established with respect to 
safety and efficacy.

Norethindrone (NET) 
1.0 mg QD

NET AUC  0.81 (0.70 - 0.93)
NET Cmin ND
NET Cmax  0.84 (0.73 - 0.97)

ANALGESICS/OPIOIDS
Methadone Individual
Patient Dosing

Methadone AUC  0.40 (0.31 - 0.51)
Methadone Cmin ND
Methadone Cmax  0.58 (0.50 - 0.67)

Methadone-maintained patients 
beginning Viramune therapy should 
be monitored for evidence of 
withdrawal and methadone dose 
should be adjusted accordingly.

HERBAL PRODUCTS
St. John's Wort Serum levels of nevirapine can be 

reduced by concomitant use of the 
herbal preparation St. John's Wort 
(Hypericum perforatum). This is due 
to induction of medicinal product 
metabolism enzymes and/or 
transport proteins by St. John’s 
Wort.

Herbal preparations containing St. 
John‘s Wort and Viramune must not 
be co-administered (see section 4.3). 
If a patient is already taking St. 
John‘s Wort check nevirapine and if 
possible viral levels and stop St. 
John‘s Wort. Nevirapine levels may 
increase on stopping St. John‘s Wort. 
The dose of Viramune may need 



96

adjusting. The inducing effect may 
persist for at least 2 weeks after 
cessation of treatment with St. John‘s 
Wort.

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.

4.6 Fertility, pregnancy and lactation

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

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

Breast-feeding
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.

4.7 Effects on ability to drive and use machines

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



97

4.8 Undesirable effects

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

The nevirapine 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 section 4.4).

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

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

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

Blood and lymphatic system disorders
Uncommon granulocytopenia
Rare anaemia

Immune system disorders
Uncommon hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria), drug reaction

with eosinophilia and systemic symptoms, anaphylactic reaction

Nervous system disorders
Common headache

Gastrointestinal disorders
Common abdominal pain, nausea, diarrhoea
Uncommon vomiting

Hepatobiliary disorders
Uncommon jaundice, hepatitis fulminant (which may be fatal)
Rare hepatitis (incl. severe and life-threatening hepatotoxicity)(0.09 %)

Skin and subcutaneous tissue disorders
Common rash (6.7 %)
Uncommon Stevens-Johnson Syndrome/toxic epidermal necrolysis (which may be fatal) 

(0.2 %), angioedema, urticaria

Musculoskeletal and connective tissue disorders
Uncommon arthralgia, myalgia



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General disorders and administration site conditions
Common fatigue, pyrexia

Investigations
Uncommon liver function test abnormal (alanine aminotransferase increased; transaminases 

increased; aspartate aminotransferase increased; gamma-glutamyltransferase 
increased; hepatic enzyme increased; hypertransaminasaemia), blood phosphorus 
decreased, blood pressure increased

Table 2: Maintenance phase of Viramune prolonged-release 

Blood and lymphatic system disorders
Uncommon anaemia, granulocytopenia

Immune system disorders
Uncommon hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria), drug reaction

with eosinophilia and systemic symptoms, anaphylactic reaction

Nervous system disorders
Common headache

Gastrointestinal disorders
Common abdominal pain, nausea, vomiting, diarrhoea

Hepatobiliary disorders
Common hepatitis (incl. severe and life-threatening hepatotoxicity) (1.6%)
Uncommon jaundice, hepatitis fulminant (which may be fatal)

Skin and subcutaneous tissue disorders
Common rash (5.7 %)
Uncommon Stevens-Johnson Syndrome/toxic epidermal necrolysis (which may be fatal) 

(0.6 %), angioedema, urticaria

Musculoskeletal and connective tissue disorders
Uncommon arthralgia, myalgia

General disorders and administration site conditions
Common fatigue
Uncommon pyrexia

Investigations
Common liver function test abnormal (alanine aminotransferase increased; transaminases 

increased; aspartate aminotransferase increased; gamma-glutamyltransferase 
increased; hepatic enzyme increased; hypertransaminasaemia), blood phosphorus 
decreased, blood pressure increased

Description of selected adverse reactions
The following adverse reactions were identified in other nevirapine studies or by post-marketing 
surveillance but not observed in the randomised, controlled clinical study 1100.1486. 
As granulocytopenia, drug reaction with eosinophilia and systemic symptoms, anaphylactic reaction, 
jaundice, hepatitis fulminant (which may be fatal), urticaria, decreased blood phosphorus and 
increased blood pressure during the lead-in phase with Viramune immediate release were not seen in 
study 1100.1486 the frequency category was estimated from a statistical calculation based on the total 
number of patients exposed to nevirapine immediate-release in the lead-in phase of the randomised 
controlled clinical study 1100.1486 (n= 1,068).



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Accordingly, as anaemia, granulocytopenia, anaphylactic reaction, jaundice, Stevens-Johnson 
Syndrome/toxic epidermal necrolysis (which may be fatal), angioedema, decreased blood phosphorus
and increased blood pressure during maintenance phase with Viramune prolonged-release tablets were 
not seen in study 1100.1486 the frequency category was estimated from a statistical calculation based 
on the total number of patients exposed to nevirapine prolonged-release in the maintenance phase of 
the randomised controlled clinical study 1100.1486 (n= 505).

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4).

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

Skin and subcutaneous tissues

The most common clinical toxicity of nevirapine is rash. Rashes are usually mild to moderate, 
maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face 
and extremities. Hypersensitivity (incl. anaphylactic reaction, angioedema and urticaria) has been 
reported. Rashes occur alone or in the context of drug reaction 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 reaction with eosinophilia and systemic symptoms have been reported. The majority of severe 
rashes occurred within the first 6 weeks of treatment and some required hospitalisation, with one 
patient requiring surgical intervention (see section 4.4). 

In study 1100.1486 (VERxVE) antiretroviral-naïve patients received a lead-in dose of Viramune 
200 mg immediate-release once daily for 14 days (n=1068) and then were randomised to receive either 
Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. 
All patients received tenofovir + emtricitabine as background therapy. Safety data included all the 
patient visits up to the point in time when the last patient completed 144 weeks in the trial. This also 
includes safety data for patient visits in the post-week 144 open label extension (which patients in 
either treatment group who completed the 144 week blinded phase could enter). Severe or life-
threatening rash considered related to nevirapine treatment occurred in 1.1 % of patients during the 
lead-in phase with Viramune immediate-release. Severe rash occurred in 1.4 % and 0.2 % of the 
Viramune immediate-release and Viramune prolonged-release groups respectively during the 
randomised phase. No life-threatening (Grade 4) rash events considered related to Viramune were 
reported during the randomised phase of this study.Six cases of Stevens-Johnson Syndrome were 



100

reported in the study; all but one occurred within the first 30 days of nevirapine treatment. 

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

Hepato-biliary

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

In study 1100.1486 (VERxVE) treatment-naïve patients received a lead-in dose of Viramune 200 mg 
immediate-release once daily for 14 days and then were randomised to receive either Viramune 
200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. All patients 
received tenofovir + emtricitabine as background therapy. Patients were enrolled with CD4 counts 
<250 cells/mm3 for women and <400 cells/mm3 for men. Data on potential symptoms of hepatic 
events were prospectively collected in this study. The safety data include all patient visits up to the 
time of the last patient’s completion of study week 144. The incidence of symptomatic hepatic events 
during the Viramune immediate-release lead-in phase was 0.5 %. After the lead-in period the 
incidence of symptomatic hepatic events was 2.4 % in the Viramune immediate-release group and 
1.6 % in the Viramune prolonged-release group. Overall, there was a comparable incidence of 
symptomatic hepatic events among men and women enrolled in VERxVE.

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

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V.

4.9 Overdose

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


101

Paediatric population

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 , , , or .

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, 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.

Genotypic analysis of isolates from antiretroviral naïve patients experiencing virologic failure (n=71) 
receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and 
stavudine for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained one 
or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, 
K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.

Genotypic analysis was performed on isolates from 86 antiretroviral naïve patients who discontinued 
the VERxVE study (1100.1486) after experiencing virologic failure (rebound, partial response) or due 
to an adverse event or who had transient increase in viral load during the course of the study. The 
analysis of these samples of patients receiving Viramune immediate-release twice daily or Viramune



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prolonged-release once daily in combination with tenofovir and emtricitabine showed that isolates 
from 50 patients contained resistance mutations expected with a nevirapine-based regimen. Of these 
50 patients, 28 developed resistance to efavirenz and 39 developed resistance to etravirine (the most 
frequently emergent resistance mutation being Y181C). There were no differences based on the 
formulation taken (immediate-release twice daily or prolonged-release once daily).

The observed mutations at failure were those expected with a nevirapine-based regimen. Two new 
substitutions on codons previously associated with nevirapine resistance were observed: one patient 
with Y181I in the Viramune prolonged-release group and one patient with Y188N in the Viramune
immediate-release group; resistance to nevirapine was confirmed by phenotype.

Cross-resistance

Rapid emergence of HIV-strains which are cross-resistant to NNRTIs has been observed in vitro. 
Cross resistance to delavirdine and efavirenz is expected after virologic failure with nevirapine. 
Depending on resistance testing results, an etravirine-containing regimen may be used subsequently. 
Cross-resistance between nevirapine and either HIV protease inhibitors, HIV integrase inhibitors or 
HIV entry inhibitors is unlikely because the enzyme targets involved are different. Similarly the 
potential for cross-resistance between nevirapine and NRTIs is low because the molecules have 
different binding sites on the reverse transcriptase.

Clinical results

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

Clinical studies with prolonged-release tablets

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

Treatment-naïve patients
VERxVE (study 1100.1486) is a phase 3 study in which treatment-naïve patients received Viramune
200 mg immediate-release once daily for 14 days and then were randomised to receive either 
Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. 
All patients received tenofovir + emtricitabine as background therapy. Randomisation was stratified 
by screening HIV-1 RNA level (<100,000 copies/ml and >100,000 copies/ml). Selected demographic 
and baseline disease characteristics are displayed in Table 1.



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Table 1: Demographic and Baseline Disease Characteristics in study 1100.1486
Viramune

immediate-release
Viramune

prolonged-release
n=508* n=505

Gender 

- Male 85 % 85 %

- Female 15 % 15 %

Race 

- White 74 % 77 %

- Black 22 % 19 %

- Asian 3 % 3 %

- Other** 1 % 2 %

Region

- North America 30 % 28 %

- Europe 50 % 51 %

- Latin America 10 % 12 %

- Africa 11 % 10 %

Baseline Plasma HIV-1 RNA (log10 copies/ml)

- Mean (SD) 4.7 (0.6) 4.7 (0.7)

- <100,000 66 % 67 %

- >100,000 34 % 33 %

Baseline CD4 count (cells/mm3)

- Mean (SD) 228 (86) 230 (81)

HIV-1 subtype

- B 71 % 75 %
- Non-B 29 % 24 %

* Includes 2 patients who were randomised but never received blinded medicinal products. 
** Includes American Indians/Alaska natives and Hawaiian/Pacific islanders.

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

Table 2: Outcomes at week 48 in study 1100.1486*
Viramune

immediate-release
n=506

Viramune
prolonged-release

n=505

Virologic responder (HIV-1 RNA <50 copies/ml) 75.9 % 81.0 %

Virologic failure
5.9 % 3.2 %

- Never suppressed through week 48 2.6 % 1.0 %

- Rebound 3.4 % 2.2 %

Discontinued medicinal product prior to week 48 18.2 % 15.8 %

- Death 0.6 % 0.2 %

- Adverse events 8.3 % 6.3 %

- Other** 9.3 % 9.4 %

* Includes patients who received at least one dose of blinded medicinal product after randomisation. 



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Patients who discontinued treatment during the lead-in period are excluded.
** Includes lost to follow-up, consent withdrawn, noncompliance, lack of efficacy, pregnancy, and 
other.

At week 48, mean change from baseline in CD4 cell count was 184 cells/mm3 and 197 cells/mm3 for 
the groups receiving Viramune immediate-release and Viramune prolonged-release respectively.

Table 3 shows outcomes at 48-weeks in study 1100.1486 (after randomization) by baseline viral load.

Table 3: Outcomes at 48 weeks in study 1100.1486 by baseline viral load*
Number with response/total number (%) Difference in %

(95 % CI)Viramune
immediate-release

Viramune
prolonged-release

Baseline HIV−1 viral load 
stratum (copies/ml)
- < 100,000 240/303 (79.2 %) 267/311 (85.0 %) 6.6 (0.7, 12.6)
- >100,000 144/203 (70.9 %) 142/194 (73.2 %) 2.3 (−6.6, 11.1)
Total 384/506 (75.9 %) 409/505 (81.0 %) 4.9 (−0.1, 10.0)**
* Includes patients who received at least one dose of blinded medicinal product after randomisation. 
Patients who discontinued treatment during the lead-in period are excluded.
** Based on Cochran’s statistic with continuity correction for the variance calculation

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

Lipids, Change from baseline
Changes from baseline in fasting lipids are shown in Table 4.

Table 4: Summary of lipid laboratory values at baseline (screening) and week 48 - study 
1100.1486

Viramune
immediate-release

Viramune
prolonged-release

Baseline
(mean)
n=503

Week 48
(mean)
n=407

Percent 
change

*

n=406

Baseline
(mean)
n=505

Week 48
(mean)
n=419

Percent 
change

*

n=419
LDL (mg/dL) 98.8 110.0 +9 98.3 109.5 +7
HDL (mg/dL) 38.8 52.2 +32 39.0 50.0 +27
Total cholesterol. (mg/dL) 163.8 186.5 +13 163.2 183.8 +11
Total cholesterol/HDL 4.4 3.8 -14 4.4 3.9 -12
Triglycerides (mg/dL) 131.2 124.5 -9 132.8 127.5 -7

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

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



105

receiving abacavir sulfate + lamivudine or zidovudine + lamivudine. Approximately half of the 
patients had at least 3 years of prior exposure to Viramune immediate-release prior to entering study
1100.1526. 

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

Paediatric population
Results of a 48-week analysis of the South African study BI 1100.1368 confirmed that the 4/7 mg/kg 
and 150 mg/m2 nevirapine dose groups were well tolerated and effective in treating antiretroviral naive 
paediatric patients. A marked improvement in the CD4+ cell percent was observed through Week 48 
for both dose groups. Also, both dosing regimens were effective in reducing the viral load. In this 48-
week study no unexpected safety findings were observed in either dosing group.

5.2 Pharmacokinetic properties

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

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

The pharmacokinetics of Viramune prolonged-release has also been studied in a multiple dose 
pharmacokinetics study (study 1100.1489) in 24 HIV-1 infected patients who switched from chronic 
Viramune immediate-release therapy to Viramune prolonged-release. The nevirapine AUC0-24,ss and 
Cmin,ss measured after 19 days of fasted dosing of Viramune 400 mg prolonged-release tablets once 
daily were approximately 80 % and 90 %, respectively, of the AUC0-24,ss and Cmin,ss measured when 
patients were dosed with Viramune 200 mg immediate-release tablets twice daily. The geometric 
mean nevirapine Cmin,ss was 2,770 ng/ml.

When Viramune prolonged-release was dosed with a high fat meal, the nevirapine AUC0-24,ss and Cmin,ss
were approximately 94 % and 98 %, respectively, of the AUC0-24,ss and Cmin,ss measured when patients 
were dosed with Viramune immediate-release tablets. The difference in nevirapine pharmacokinetics 
observed when Viramune prolonged-release tablets are dosed under fasted or fed conditions is not 
considered clinically relevant. Viramune prolonged-release tablets can be taken with or without food.

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.

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.



106

Biotransformation and elimination: In vivo studies in humans and in vitro studies with human liver 
microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 
(oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver 
microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome 
P450 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a 
mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 
200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 
10.5 % of the radiolabelled dose was recovered, with urine (81.3  11.1 %) representing the primary 
route of excretion compared to faeces (10.1  1.5 %). Greater than 80 % of the radioactivity in urine 
was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 
metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent 
the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (< 
5 %) of the radioactivity in urine (representing < 3 % of the total dose) was made up of parent 
compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The 
pharmacokinetics of autoinduction is characterised by an approximately 1.5 to 2 fold increase in the 
apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks 
of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal 
phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 
25-30 hours following multiple dosing with 200-400 mg/day.

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

Hepatic impairment:A steady state study comparing 46 patients with 
mild (n=17: Ishak Score 1-2), 
moderate (n=20; Ishak Score 3-4), 
or severe (n=9; Ishak Score 5-6, Child-Pugh A in 8 pts., for 1 Child-Pugh score not applicable) 
liver fibrosis as a measure of hepatic impairment was conducted. 

The patients studied were receiving antiretroviral therapy containing Viramune 200 mg immediate-
release tablets twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median 
duration of therapy of 3.4 years. In this study, the multiple dose pharmacokinetic disposition of 
nevirapine and the five oxidative metabolites were not altered.

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

In a single dose pharmacokinetic study of 200 mg Viramune immediate-release tabletsof in HIV-
negative patients with mild and moderate hepatic impairment (Child-Pugh A, n=6; Child-Pugh B, 



107

n=4), a significant increase in the AUC of nevirapine was observed in one Child-Pugh B patient with 
ascites suggesting that patients with worsening hepatic function and ascites may be at risk of 
accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism 
with multiple dosing, this single dose study may not reflect the impact of hepatic impairment on 
multiple dose pharmacokinetics (see section 4.4). Viramune prolonged-release tablets have not been 
evaluated in patients with hepatic impairment and Viramune immediate-release should be used.

Gender
In the multinational 2NN study with Viramune immediate-release, a population pharmacokinetic 
substudy of 1077 patients was performed that included 391 females. Female patients showed a 13.8 % 
lower clearance of nevirapine than did male patients. This difference is not considered clinically 
relevant. Since neither body weight nor Body Mass Index (BMI) had influence on the clearance of 
nevirapine, the effect of gender cannot be explained by body size.

The effects of gender on the pharmacokinetics of Viramune prolonged-release have been investigated 
in study 1100.1486. Female patients tend to have higher (approximately 20 – 30 %) trough 
concentrations in both Viramune prolonged-release and Viramune immediate-release treatment 
groups. 

Elderly
Nevirapine pharmacokinetics in HIV-1 infected adults does not appear to change with age (range 18 -
68 years). Nevirapine has not been specifically investigated in patients over the age of 65. Black 
patients (n=80/group) in study 1100.1486 showed approximately 30% higher trough concentrations 
than Caucasian patients (250-325 patients/group) in both the Viramune immediate-release and 
Viramune prolonged-release treatment groups over 48 weeks of treatment at 400 mg/day.

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

Pharmacokinetic data on 33 patients (age range 0.77 – 13.7 years) in the intensive sampling group 
demonstrated that clearance of nevirapine increased with increasing age in a manner consistent with 
increasing body surface area. Dosing of nevirapine at 150 mg/m2 BID (after a two-week lead in at 
150 mg/m2 QD) produced geometric mean or mean trough nevirapine concentrations between 4-
6 µg/ml (as targeted from adult data). In addition, the observed trough nevirapine concentrations were 
comparable between the two methods.

The consolidated analysis of Paediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 
377, and 403 allowed for the evaluation of paediatric patients less than 3 months of age (n=17) 
enrolled in these PACTG studies. The plasma nevirapine concentrations observed were within the 
range observed in adults and the remainder of the paediatric population, but were more variable 
between patients, particularly in the second month of age.

The pharmacokinetics of Viramune prolonged-release was assessed in study 1100.1518. Eighty-five 
patients (3 to < 18 years) received weight or body surface area dose-adjusted Viramune immediate-
release for a minimum of 18 weeks and then were switched to Viramune prolonged-release tablets (2 x 
100 mg, 3 x 100 mg or 1 x 400 mg once daily) in combination with other antiretrovirals for 10 days. 
The observed geometric mean ratios of Viramune prolonged-release to Viramune immediate-release 
were ~90 % for Cmin,ss and AUCss with 90% confidence intervals within 80 %-125 %; the ratio for 
Cmax,ss was lower and consistent with a once-daily prolonged-release dosage form. Geometric mean 
steady-state plasma Viramune prolonged-release pre-dose trough concentrations were 3,880 ng/ml, 
3,310 ng/ml and 5,350 ng/ml in age groups 3 to <6 years, 6 to <12 years, and 12 to <18 years of age, 
respectively. Overall, the exposure in children was similar to that observed in adults receiving 
Viramune prolonged-release in study 1100.1486. 



108

In single dose, parallel group bioavailability studies (studies 1100.1517 and 1100.1531), the Viramune 
50 and 100 mg prolonged-release tablets exhibited extended release characteristics of prolonged 
absorption and lower maximal concentrations, similar to the findings when a 400 mg prolonged-
release tablet was compared to the Viramune immediate-release 200 mg tablet. Dividing a 200 mg 
total dose into four 50 mg doses rather than two 100 mg doses produced a 7-11 % greater overall 
absorption, but with comparable medicinal product release rates. The observed pharmacokinetic 
difference between the 50 mg and 100 mg Viramune prolonged-release tablets is not clinically 
relevant, and the 50 mg prolonged-release tablet can be used as an alternative to the slightly larger 
100 mg tablet. 

5.3 Preclinical safety data

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. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose (as monohydrate)
Hypromellose
Iron oxide yellow
Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

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

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Maintenance packs:
Polyvinyl chloride (PVC)/aluminium foil push through blister units. Cartons containing 30 prolonged-
release tablets or 90 prolonged-release tablets.
or
High density polyethylene (HDPE) plastic bottle, with a plastic cap and an induction foil seal liner. 
Bottles contain 30 prolonged-release tablets.

6.6 Special precautions for disposal

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



109

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein, Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/97/055/007 (30 tablets, bottle)
EU/1/97/055/008 (30 tablets, blister)
EU/1/97/055/009 (90 tablets, blister)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 5 February 1998
Date of latest renewal: 20 December 2012

10. DATE OF REVISION OF THE TEXT

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



110

ANNEX II

A. MANUFACTURERS RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT



111

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers responsible for batch release

Viramune 200 mg Tablets

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173 - 55216 Ingelheim am Rhein
Germany

Boehringer Ingelheim Ellas A.E.
5th km Paiania-Markopoulo
194 00 Koropi
Greece

Viramune 50 mg/5 ml Oral suspension and Viramune 400 mg and 100 mg prolonged-release tablets

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173 – 55216 Ingelheim am Rhein
Germany

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT  

 Risk management plan (RMP)

The marketing authorization holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2. of the 
marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency. 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.



112

ANNEX III

LABELLING AND PACKAGE LEAFLET



113

A. LABELLING



114

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

BLISTER CARTON LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 200 mg tablets
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 200 mg of nevirapine (as anhydrous)

3. LIST OF EXCIPIENTS

Excipients: includes lactose (see leaflet for further information)

4. PHARMACEUTICAL FORM AND CONTENTS

60 tablets
120 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



115

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/97/055/001 [60 tablets]
EU/1/97/055/003 [120 tablets]

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Viramune 200 mg

17. UNIQUE IDENTIFIER –  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER –  HUMAN READABLE DATA

PC {number} [product code]
SN {number} [serial number]
NN {number} [national reimbursement number or other national number identifying the medicinal
product]



116

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

BLISTER CARTON LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 200 mg tablets
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 200 mg of nevirapine (as anhydrous)

3. LIST OF EXCIPIENTS

Excipients: includes lactose (see leaflet for further information)

4. PHARMACEUTICAL FORM AND CONTENTS

Treatment initiation pack containing 14 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



117

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/97/055/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Viramune 200 mg

17. UNIQUE IDENTIFIER –  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER –  HUMAN READABLE DATA

PC {number} [product code]
SN {number} [serial number]
NN {number} [national reimbursement number or other national number identifying the medicinal
product]



118

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

1. NAME OF THE MEDICINAL PRODUCT

Viramune 200 mg tablets
nevirapine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP 

4. BATCH NUMBER

Lot

5. OTHER



119

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

BOTTLE CARTON LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 50 mg/5 ml oral suspension
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Excipients: includes sucrose, sorbitol, methyl parahydroxybenzoate, propyl parahydroxybenzoate (see 
leaflet for further information)

4. PHARMACEUTICAL FORM AND CONTENTS

240 ml oral suspension

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use
Shake gently before use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
To be used within 6 months after opening the bottle

9. SPECIAL STORAGE CONDITIONS



120

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/055/002 

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Viramune 50 mg/5 ml

17. UNIQUE IDENTIFIER –  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER –  HUMAN READABLE DATA

PC {number} [product code]
SN {number} [serial number]
NN {number} [national reimbursement number or other national number identifying the medicinal
product]



121

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 50 mg/5 ml oral suspension
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Excipients: includes sucrose, sorbitol, methyl parahydroxybenzoate, propyl parahydroxybenzoate (see 
leaflet for further information)

4. PHARMACEUTICAL FORM AND CONTENTS

240 ml oral suspension

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use
Shake gently before use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
To be used within 6 months after opening the bottle

9. SPECIAL STORAGE CONDITIONS



122

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/055/002 

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE



123

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

BOTTLE CARTON LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 100 mg prolonged-release tablets
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 100 mg of nevirapine (as anhydrous)

3. LIST OF EXCIPIENTS

Excipients: includes lactose (see leaflet for further information)

4. PHARMACEUTICAL FORM AND CONTENTS

90 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use
Once daily
Swallow whole, do not chew, divide or crush

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Use within 2 months after 1st opening

9. SPECIAL STORAGE CONDITIONS



124

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/055/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

viramune 100 mg prolonged-release tablets

17. UNIQUE IDENTIFIER –  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER –  HUMAN READABLE DATA

PC {number} [product code]
SN {number} [serial number]
NN {number} [national reimbursement number or other national number identifying the medicinal
product]



125

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 100 mg prolonged-release tablets
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 100 mg of nevirapine (as anhydrous)

3. LIST OF EXCIPIENTS

Contains lactose

4. PHARMACEUTICAL FORM AND CONTENTS

90 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use
Once daily
Swallow whole, do not chew, divide or crush

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Use within 2 months after 1st opening

9. SPECIAL STORAGE CONDITIONS



126

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/055/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE



127

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

BOTTLE CARTON LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 400 mg prolonged-release tablets
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Excipients: includes lactose (see leaflet for further information)

4. PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use
Once daily
Swallow whole, do not chew, divide or crush

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Use within 2 months after 1st opening

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



128

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/055/007

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

viramune 400 mg prolonged-release tablets

17. UNIQUE IDENTIFIER –  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER –  HUMAN READABLE DATA

PC {number} [product code]
SN {number} [serial number]
NN {number} [national reimbursement number or other national number identifying the medicinal
product]



129

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 400 mg prolonged-release tablets
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Contains lactose

4. PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use
Once daily
Swallow whole, do not chew, divide or crush

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Use within 2 months after 1st opening

9. SPECIAL STORAGE CONDITIONS



130

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/055/007

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE



131

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

BLISTER CARTON LABEL

1. NAME OF THE MEDICINAL PRODUCT

Viramune 400 mg prolonged-release tablets
nevirapine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Excipients: includes lactose (see leaflet for further information)

4. PHARMACEUTICAL FORM AND CONTENTS

30 prolonged-release tablets
90 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Oral use
Once daily
Swallow whole, do not chew, divide or crush

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS



132

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/97/055/008 [30 prolonged-release]
EU/1/97/055/009 [90 prolonged-release]

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

viramune 400 mg prolonged-release tablets

17. UNIQUE IDENTIFIER –  2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER –  HUMAN READABLE DATA

PC {number} [product code]
SN {number} [serial number]
NN {number} [national reimbursement number or other national number identifying the medicinal
product]



133

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

1. NAME OF THE MEDICINAL PRODUCT

Viramune 400 mg prolonged-release tablets
nevirapine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP 

4. BATCH NUMBER

Lot

5. OTHER



134

B. PACKAGE LEAFLET



135

Package leaflet: Information for the user

Viramune 200 mg
tablets

nevirapine

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Viramune is and what it is used for
2. What you need to know before you take Viramune
3. How to take Viramune
4. Possible side effects
5. How to store Viramune
6. Contents of the pack and other information

1. What Viramune is and what it is used for 

Viramune belongs to a group of medicines called antiretrovirals, used in the treatment of Human 
Immunodeficiency Virus (HIV-1) infection.

The active substance of your medicine is called nevirapine. Nevirapine belongs to a class of anti-HIV 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Reverse transcriptase is an 
enzyme that HIV needs in order to multiply. Nevirapine stops reverse transcriptase from working. By 
stopping reverse transcriptase from working, Viramune helps control HIV-1 infection. 

Viramune is indicated for the treatment of HIV-1 infected adults, adolescents, and children of any age. 
You must take Viramune together with other antiretroviral medicines. Your doctor will recommend 
the best medicines for you.

If Viramune has been prescribed for your child, please note that all information in this leaflet is 
addressed to your child (in this case please read “your child” instead of “you”).

2. What you need to know before you take Viramune 

Do not take Viramune
- if you are allergic to nevirapine or any of the other ingredients of this medicine (listed in section 

6 ).
- if you have taken Viramune before and had to stop the treatment because you suffered from:

- severe skin rash 
- skin rash with other symptoms for example:

- fever
- blistering
- mouth sores
- inflammation of the eye
- swelling of the face



136

- general swelling
- shortness of breath
- muscle or joint pain
- general feelings of illness
- abdominal pain

- hypersensitivity (allergic) reactions 
- inflammation of the liver (hepatitis)

- if you have severe liver disease 
- if you have had to stop Viramune treatment in the past because of changes in your liver function
- if you are taking a medicine containing the herbal substance St. John’s Wort (Hypericum 

perforatum). This herbal substance may stop Viramune from working properly.

Warnings and precautions 
Talk to your doctor or pharmacist before taking Viramune.
During the first 18 weeks of treatment with Viramune it is very important that you and your 
doctor watch out for signs of liver or skin reactions. These can become severe and even life 
threatening. You are at greatest risk of such a reaction during the first 6 weeks of treatment.

If you experience severe rash or hypersensitivity (allergic reactions that may appear in the 
form of rash) accompanied by other side effects such as 

- fever, 
- blistering, 
- mouth sores, 
- inflammation of the eye, 
- swelling of the face, 
- general swelling,
- shortness of breath, 
- muscle or joint pain, 
- general feelings of illness, 
- or abdominal pain

YOU SHOULD DISCONTINUE TAKING VIRAMUNE AND YOU MUST CONTACT your 
doctor IMMEDIATELY as such reactions can be potentially life-threatening or lead to death.
If you ever have only mild rash symptoms without any other reaction please inform your 
doctor immediately, who will advise you whether you should stop taking Viramune.

If you experience symptoms suggesting damage of the liver, such as 
- loss of appetite, 
- feeling sick (nausea), 
- vomiting, 
- yellow skin (jaundice), 
- abdominal pain

you should discontinue taking Viramune and must contact your doctor immediately.

If you develop severe liver, skin or hypersensitivity reactions whilst taking Viramune, NEVER 
TAKE VIRAMUNE again without referring to your doctor.
You must take the dose of Viramune as prescribed by your doctor. This is especially important 
within the first 14 days of treatment (see more information in “How to take Viramune”).

The following patients are at increased risk of developing liver problems:
- women
- infected with hepatitis B or C
- abnormal liver function tests
- treatment-naïve patients with higher CD4 cell counts at the start of Viramune therapy (women 

more than 250 cells/mm³, men more than 400 cells/mm³)
- pre-treated patients with detectable HIV-1 plasma viral load and higher CD4 cell counts at the 

start of Viramune therapy (women more than 250 cells/mm³, men more than 400 cells/mm³)



137

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection (AIDS 
defining illness), signs and symptoms of inflammation from previous infections may occur soon after 
anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the 
body’s immune response, enabling the body to fight infections that may have been present with no 
obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection. Autoimmune disorders may occur many months after the start of 
treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

Changes of body fat may occur in patients receiving combination antiretroviral therapy. Contact your 
doctor if you notice changes in body fat (see section 4 “Possible side effects”). 

Some patients taking combination antiretroviral therapy may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe weakness of the 
immune system and higher body mass index may be some of the many risk factors for developing this 
disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and 
shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

If you are taking nevirapine and zidovudine concomitantly please inform your doctor since he might 
need to check your white blood cells.
Do not take Viramune after an exposure to HIV unless you have been diagnosed with HIV and 
instructed to do so by your doctor. Viramune is not a cure for HIV infection. Therefore, you may 
continue to develop infections and other illnesses associated with HIV infection. You should therefore 
remain in regular contact with your doctor. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your doctor the 
precautions needed to avoid infecting other people.

Prednisone should not be used to treat a rash related to Viramune.

If you are taking oral contraceptives (e.g. „pill“) or other hormonal methods of birth control during 
treatment with Viramune, you should use a barrier contraception (e.g. condoms) in addition to prevent 
pregnancy and further HIV transmission. 
If you are receiving post-menopausal hormone therapy, ask your doctor for advice before taking this 
medicine.

If you are taking or are prescribed rifampicin to treat tuberculosis please inform your doctor before 
taking this medicine with Viramune. 

Children and adolescents
Viramune tablets can be taken by:
- children 16 years of age or older
- children under 16 years of age who:

- weigh 50 kg or more 
- or have a body surface area above 1.25 square metres. 

For smaller children an oral suspension liquid form is available.

Other medicines and Viramune
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. Inform your doctor about all other medicines you are taking before you start taking 



138

Viramune. Your doctor might need to monitor whether your other medicines are still working and 
adjust doses. Carefully read the package leaflet of all other HIV medicinal products you are taking in 
combination with Viramune.

It is particularly important that you tell your doctor if you are taking or have recently taken:

- St. John’s Wort (Hypericum perforatum, medicine to treat depression)
- rifampicin (medicine to treat tuberculosis)
- rifabutin (medicine to treat tuberculosis)
- macrolides e.g. clarithromycin (medicine to treat bacterial infections)
- fluconazole (medicine to treat fungal infections)
- ketoconazole (medicine to treat fungal infections)
- itraconazole (medicine to treat fungal infections)
- methadone (medicine used for treatment of opiate addicts)
- warfarin (medicine to reduce blood clotting)
- hormonal contraceptives (e.g. the “pill”)
- atazanavir (another medicine to treat HIV-infection)
- lopinavir/ritonavir (another medicine to treat HIV-infection)
- fosamprenavir (another medicine to treat HIV-infection)
- efavirenz (another medicine to treat HIV-infection)
- etravirine (another medicine to treat HIV-infection)
- rilpivirine (another medicine to treat HIV-infection)
- delavirdine (another medicine to treat HIV-infection)
- zidovudine (another medicine to treat HIV-infection)
- boceprevir (medicine to treat hepatitis C)
- telaprevir (medicine to treat hepatitis C)
- elvitegravir/cobicistat (another medicine to treat HIV-infection)

Your doctor will carefully monitor the effect of Viramune and any of these medicines if you are taking 
them together. 

If you are undergoing kidney dialysis, your doctor may consider a dose adjustment of Viramune. This 
is because Viramune can be partly washed out of your blood by dialysis. 

Taking Viramune with food and drink
There are no restrictions on taking Viramune with food and drink.

Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

You should stop breast-feeding if you are taking Viramune. It is in general recommended that you do 
not breast-feed if you have HIV infection because it is possible that your baby can become infected 
with HIV through your breast milk.

Driving and using machines
You may experience fatigue when taking Viramune. Use caution when engaging in activities such as 
driving, using any tools or machines. If you experience fatigue you should avoid potentially hazardous 
tasks such as driving or using any tools or machines.

Viramune contains lactose and sodium
Viramune tablets contain lactose (milk sugar).
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.
Viramune tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 



139

‘sodium-free’.

3. How to take Viramune 

You should not use Viramune on its own. You must take it with at least two other antiretroviral 
medicines. Your doctor will recommend the best medicines for you.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

Dose:

The dose is one 200 mg tablet per day for the first 14 days of treatment (“lead-in” period). After 14 
days, the usual dose is one 200 mg tablet twice a day. 

It is very important that you take only one Viramune tablet a day for the first 14 days (“lead-in” 
period). If you have any rash during this period, do not increase the dose but consult your doctor.

The 14-day ”lead-in” period has been shown to lower the risk of skin rash.

As Viramune must always be taken together with other HIV antiretroviral medicines, you should 
follow the instructions for your other medicines carefully. These are supplied in the package leaflets 
for those medicines.

Viramune is also available in liquid form as an oral suspension. This is particularly suitable if:
- you have problems swallowing tablets
- or you are a child weighing less than 50 kg
- or you are a child having a body surface area less than 1.25 square metres (your doctor will 

work out your surface area).

You should continue to take Viramune for as long as instructed by your doctor.

As explained in ‘Warnings and precautions’, above, your doctor will monitor you with liver tests or 
for undesirable effects such as rash. Depending on the outcome your doctor may decide to interrupt or 
stop your Viramune treatment. Your doctor might then decide to restart you on a lower dose.

Only take Viramune tablets by mouth. Do not chew your tablets. You may take Viramune with or 
without food.

If you take more Viramune than you should
Do not take more Viramune than prescribed by your doctor and described in this leaflet. There is at 
present little information on the effects of Viramune overdose. Consult your doctor if you have taken 
more Viramune than you should. 

If you forget to take Viramune
Try not to miss a dose. If you notice that you have missed a dose within 8 hours of when it was due, 
take the missed dose as soon as possible. If it has been more than 8 hours since the dose was due only
take the next dose at the usual time.

If you stop taking Viramune
Taking all doses at the appropriate times:
- greatly increases the effectiveness of your combination antiretroviral medicines 



140

- reduces the chances of your HIV infection becoming resistant to your antiretroviral medicines.

It is important that you continue taking Viramune correctly, as described above, unless your doctor 
instructs you to stop.

If you stop taking Viramune for more than 7 days your doctor will instruct you to start the 14 day 
'lead-in' period (described above) once again, before returning to the twice daily dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects 

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

As mentioned in ‘Warnings and precautions', above, the most important side effects of Viramune
are severe and life threatening skin reactions and serious liver damage. These reactions occur 
mainly in the first 18 weeks of treatment with Viramune. This is therefore an important period
which requires close monitoring by your doctor.

If you ever observe any rash symptoms, inform your doctor immediately.

When rash occurs it is normally mild to moderate. However, in some patients a rash, which appears as 
a blistering skin reaction, can be severe or life-threatening (Stevens-Johnson syndrome and toxic 
epidermal necrolysis) and deaths have been recorded. Most of the cases of both severe rash and 
mild/moderate rash occur in the first six weeks of treatment. 

If rash occurs and you also feel sick, you must stop treatment and visit your doctor immediately.

Hypersensitivity (allergic) reactions can occur. Such reactions may appear in the form of anaphylaxis 
(a severe form of allergic reaction) with symptoms such as:
- rash
- swelling of the face
- difficulty breathing (bronchial spasm)
- anaphylactic shock
Hypersensitivity reactions can also occur as rash with other side effects such as:
- fever
- blistering of your skin 
- mouth sores
- inflammation of the eye
- swelling of the face
- general swelling
- shortness of breath
- muscle or joint pain
- a reduction in the numbers of your white blood cells (granulocytopenia)
- general feelings of illness
- severe problems with liver or kidneys (liver or kidney failure). 

Tell your doctor immediately if you experience rash and any of the other side effects of a 
hypersensitivity (allergic) reaction. Such reactions can be life-threatening.

Abnormal liver functioning has been reported with the use of Viramune. This includes some cases of 



141

inflammation of the liver (hepatitis), which can be sudden and intense (fulminant hepatitis), and liver 
failure, which can be both fatal.

Tell your doctor if you experience any of the following clinical symptoms of liver damage:
- loss of appetite
- feeling sick (nausea)
- vomiting
- yellow skin (jaundice)
- abdominal pain 

The side effects described below have been experienced by patients given Viramune:

Very common (may affect more than 1 in 10 people):
- rash

Common (may affect up to 1 in 10 people):
- decreased numbers of white blood cells (granulocytopenia)
- allergic reactions (hypersensitivity) 
- headache
- feeling sick (nausea)
- vomiting
- abdominal pain
- loose stools (diarrhoea)
- inflammation of the liver (hepatitis)
- feeling tired (fatigue)
- fever
- abnormal liver function tests

Uncommon (may affect up to 1 in 100 people):
- allergic reaction characterized by rash, swelling of the face, difficulty breathing (bronchial 

spasm) or anaphylactic shock
- decreased numbers of red blood cells (anaemia)
- yellow skin (jaundice)
- severe and life-threatening skin rashes (Stevens-Johnson syndrome/ toxic epidermal necrolysis)
- hives (urticaria)
- fluid under the skin (angioedema)
- joint pain (arthralgia)
- muscle pain (myalgia)
- decreased blood phosphorus
- increased blood pressure

Rare (may affect up to 1 in 1000 people):
- sudden and intense inflammation of the liver (fulminant hepatitis)
- drug reaction with systemic symptoms (drug reaction with eosinophilia and systemic symptoms)

The following events have also been reported when Viramune has been used in combination with 
other antiretroviral agents: 
- decreased numbers of red blood cells or platelets
- inflammation of the pancreas
- decrease in or abnormal skin sensations 
These events are commonly associated with other antiretroviral agents and may be expected to occur 
when Viramune is used in combination with other agents; however, it is unlikely that these events are 
due to treatment with Viramune.

Additional side effects in children and adolescents
A reduction in white blood cells (granulocytopenia) can occur, which is more common in children. A 



142

reduction in red blood cells (anaemia), which may be related to nevirapine therapy, is also more 
commonly observed in children. As with rash symptoms, please inform your doctor of any side 
effects.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Viramune 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
“EXP”. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

6. Contents of the pack and other information 

What Viramune contains

- The active substance is nevirapine. Each tablet contains 200 mg nevirapine.
- The other ingredients are:

microcrystalline cellulose, 
lactose (as monohydrate), 
povidone K25, 
sodium starch glycolate, 
colloidal silicon dioxide and 
magnesium stearate.

What Viramune looks like and contents of the pack

White, oval, biconvex tablets. One side is marked with the code “54 193”, with a single bisect 
separating the “54” and “193”. The opposite side is marked with the company symbol. The score line 
is not intended for breaking the tablet.
Viramune tablets are supplied in blisters, with 14, 60 or 120 tablets per carton. Not all pack sizes may 
be marketed.

Viramune is also available as an oral suspension.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


143

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

or

Boehringer Ingelheim Ellas A.E.
5th km Paiania-Markopoulo
194 00 Koropi
Greece



144

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel.: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +35 31 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG 
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel.: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00



145

Ísland
Vistor hf.
Tel: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in {MM/YYYY}

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu



146

Package leaflet: Information for the user
Viramune 50 mg/5 ml oral suspension

nevirapine

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Viramune is and what it is used for
2. What you need to know before you take Viramune
3. How to take Viramune
4. Possible side effects
5. How to store Viramune
6. Contents of the pack and other information

1. What Viramune is and what it is used for 

Viramune belongs to a group of medicines called antiretrovirals, used in the treatment of Human 
Immunodeficiency Virus (HIV-1) infection.

The active substance of your medicine is called nevirapine. Nevirapine belongs to a class of anti-HIV 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Reverse transcriptase is an 
enzyme that HIV needs in order to multiply. Nevirapine stops reverse transcriptase from working. By 
stopping reverse transcriptase from working, Viramune helps control HIV-1 infection.

Viramune is indicated for the treatment of HIV-1 infected adults, adolescents, and children of any age. 
You must take Viramune together with other antiretroviral medicines. Your doctor will recommend 
the best medicines for you.

If Viramune has been prescribed for your child, please note that all information in this leaflet is 
addressed to your child (in this case please read “your child” instead of “you”).

2. What you need to know before you take Viramune 

Do not take Viramune
- if you are allergic to nevirapine or any of the other ingredients of this medicine (listed in section 

6 ).
- if you have taken Viramune before and had to stop the treatment because you suffered from:

- severe skin rash 
- skin rash with other symptoms for example:

- fever
- blistering
- mouth sores
- inflammation of the eye
- swelling of the face
- general swelling
- shortness of breath



147

- muscle or joint pain
- general feelings of illness
- abdominal pain

- hypersensitivity (allergic) reactions 
- inflammation of the liver (hepatitis)

- if you have severe liver disease 
- if you have had to stop Viramune treatment in the past because of changes in your liver function
- if you are taking a medicine containing the herbal substance St. John’s Wort (Hypericum 

perforatum). This herbal substance may stop Viramune from working properly.

Warnings and precautions 
Talk to your doctor or pharmacist before taking Viramune.
During the first 18 weeks of treatment with Viramune it is very important that you and your 
doctor watch out for signs of liver or skin reactions. These can become severe and even life 
threatening. You are at greatest risk of such a reaction during the first 6 weeks of treatment.

If you experience severe rash or hypersensitivity (allergic reactions that may appear in the 
form of rash) accompanied by other side effects such as 
- fever, 
- blistering, 
- mouth sores, 
- inflammation of the eye, 
- swelling of the face, 
- general swelling,
- shortness of breath, 
- muscle or joint pain, 
- general feelings of illness, 
- or abdominal pain
YOU SHOULD DISCONTINUE TAKING VIRAMUNE AND YOU MUST CONTACT your 
doctor IMMEDIATELY as such reactions can be potentially life-threatening or lead to death.

If you ever have only mild rash symptoms without any other reaction please inform your 
doctor immediately, who will advise you whether you should stop taking Viramune.

If you experience symptoms suggesting damage of the liver, such as 
- loss of appetite, 
- feeling sick (nausea), 
- vomiting, 
- yellow skin (jaundice), 
- abdominal pain

you should discontinue taking Viramune and must contact your doctor immediately.

If you develop severe liver, skin or hypersensitivity reactions whilst taking Viramune, NEVER 
TAKE VIRAMUNE again without referring to your doctor.
You must take the dose of Viramune as prescribed by your doctor. This is especially important 
within the first 14 days of treatment (see more information in “How to take Viramune”).

The following patients are at increased risk of developing liver problems:
- women
- infected with hepatitis B or C
- abnormal liver function tests
- treatment-naïve patients with higher CD4 cell counts at the start of Viramune therapy (women 

more than 250 cells/mm³, men more than 400 cells/mm³)
- pre-treated patients with detectable HIV-1 plasma viral load and higher CD4 cell counts at the 

start of Viramune therapy (women more than 250 cells/mm³, men more than 400 cells/mm³)

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection (AIDS-



148

defining illness), signs and symptoms of inflammation from previous infections may occur soon after 
anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the 
body’s immune response, enabling the body to fight infections that may have been present with no 
obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection. Autoimmune disorders may occur many months after the start of 
treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

Changes of body fat may occur in patients receiving combination antiretroviral therapy. Contact your 
doctor if you notice changes in body fat (see section 4 “Possible side effects”). 

Some patients taking combination antiretroviral therapy may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe weakness of the 
immune system and higher body mass index may be some of the many risk factors for developing this 
disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and 
shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

If you are taking nevirapine and zidovudine concomitantly please inform your doctor since he might 
need to check your white blood cells.Do not take Viramune after an exposure to HIV unless you have 
been diagnosed with HIV and instructed to do so by your doctor. Viramune is not a cure for HIV 
infection. Therefore, you may continue to develop infections and other illnesses associated with HIV 
infection. You should, therefore, remain in regular contact with your doctor. You can still pass on HIV 
when taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss 
with your doctor the precautions needed to avoid infecting other people.

Prednisone should not be used to treat a rash related to Viramune.

If you are taking oral contraceptives (e.g. „pill“) or other hormonal methods of birth control during 
treatment with Viramune, you should use a barrier contraception (e.g. condoms) in addition to prevent 
pregnancy and further HIV transmission. 
If you are receiving post-menopausal hormone therapy, ask your doctor for advice before taking this 
medicine.

If you are taking or are prescribed rifampicin to treat tuberculosis please inform your doctor before 
taking this medicine with Viramune. 

Children and adolescents:
Viramune oral suspension can be taken by children of all age groups. Always follow the exact 
instructions given by your child’s doctor. 
Viramune is also available as tablets. Viramune tablets can be taken by:
- children 16 years of age or older 
- children under 16 years of age who:

- weigh 50 kg or more 
- or have a body surface area above 1.25 square metres.

Other medicines and Viramune
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. Inform your doctor about all other medicines you are taking before you start taking 
Viramune. Your doctor might need to monitor whether your other medicines are still working and 
adjust doses. Carefully read the package leaflet of all other HIV medicinal products you are taking in 
combination with Viramune.



149

It is particularly important that you tell your doctor if you are taking or have recently taken:
- St. John’s Wort (Hypericum perforatum, medicine to treat depression)
- rifampicin (medicine to treat tuberculosis)
- rifabutin (medicine to treat tuberculosis)
- macrolides e.g. clarithromycin (medicine to treat bacterial infections)
- fluconazole (medicine to treat fungal infections)
- ketoconazole (medicine to treat fungal infections)
- itraconazole (medicine to treat fungal infections)
- methadone (medicine used for treatment of opiate addicts)
- warfarin (medicine to reduce blood clotting)
- hormonal contraceptives (e.g. the “pill”)
- atazanavir (another medicine to treat HIV-infection)
- lopinavir/ritonavir (another medicine to treat HIV-infection)
- fosamprenavir (another medicine to treat HIV-infection)
- efavirenz (another medicine to treat HIV-infection)
- etravirine (another medicine to treat HIV-infection)
- rilpivirine (another medicine to treat HIV-infection)
- delavirdine (another medicine to treat HIV-infection)
- zidovudine (another medicine to treat HIV-infection)
- boceprevir (medicine to treat hepatitis C)
- telaprevir (medicine to treat hepatitis C)
- elvitegravir/cobicistat (another medicine to treat HIV-infection)

Your doctor will carefully monitor the effect of Viramune and any of these medicines if you are taking 
them together. 

If you are undergoing kidney dialysis, your doctor may consider a dose adjustment of Viramune. This 
is because Viramune can be partly washed out of your blood by dialysis.

Taking Viramune with food and drink
There are no restrictions on taking Viramune with food and drink.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking this medicine.

You should stop breast-feeding if you are taking Viramune. It is in general recommended that you do 
not breast-feed if you have HIV infection because it is possible that your baby can become infected 
with HIV through your breast milk.

Driving and using machines
You may experience fatigue when taking Viramune. Use caution when engaging in activities such as 
driving, using any tools or machines. If you experience fatigue you should avoid potentially hazardous 
tasks such as driving or using any tools or machines.

Viramune contains sucrose, sorbitol, methyl parahydroxybenzoate, propyl 
parahydroxybenzoate and sodium
Viramune oral suspension contains 150 mg sucrose per ml. This should be taken into account in 
patients with diabetes mellitus. If you have been told by your doctor that you have an intolerance to 
some sugars, contact your doctor before taking this medicinal product. May be harmful to the teeth.
Viramune oral suspension contains 162 mg sorbitol per ml. Sorbitol is a source of fructose. If your 
doctor has told you that you (or your child) have an intolerance to some sugars or you have been 
diagnosed with hereditary fructose intolerance (HFI), a rare genetic disorder in which a person cannot
break down fructose, talk to your doctor before you (or your child) take or receive this medicine.



150

Viramune oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. 
These excipients can cause allergic reactions over time.

Viramune oral suspension contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’.

3. How to take Viramune 

You should not use Viramune on its own. You must take it with at least two other antiretroviral 
medicines. Your doctor will recommend the best medicines for you.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

The usual dose is the same for all adults (20 ml).
Your child’s doctor will calculate the dose for your child. The calculation will include your child's age 
and body weight, or body surface area. Make sure that your child's doctor clearly tells you what dose 
you must give to your child. 

For adults

The dose for adults is 20 ml (200 mg) once a day for the first 14 days of treatment (”lead in” period). 
After 14 days, the usual dose is 20 ml (200 mg) twice a day.

It is very important that you take only 20 ml of Viramune a day for the first 14 days (“lead-in” period). 
If you have any rash during this period, do not increase the dose but consult your doctor.

Viramune is also available as 200 mg tablets for adults (16 years of age and older).

For children

The dose for children is 4 mg/kg body weight or 150 mg/m2 body surface area once a day for the first 
14 days of treatment (“lead-in period”). Thereafter your child will be switched to a twice daily dosing 
schedule and your child’s doctor will decide the right dose based either on your child’s weight or body 
surface area. 

It is very important that your child takes Viramune only once a day for the first 14 days (“lead-in” 
period). If your child develops any rash during this period, do not increase the dose but consult your 
child’s doctor.

Viramune is also available as 200 mg tablets for older children, particularly adolescents, weighing 
more than 50 kg or having a body surface of more than 1.25 m2. Your child's doctor will inform you 
exactly of the correct dose for your child. Your child’s doctor will continually check your child’s 
weight or body surface area to ensure the correct dose. 
If you are uncertain please be sure to ask your child’s doctor or pharmacist.

Measure the exact dose using the measuring syringe and adapter supplied as follows:

1. Shake the bottle gently.
2. Open the bottle.
3. Fit the plastic adapter onto the open bottle neck by first pressing and then screwing the 

adapter. Make sure that the adapter is fitted tightly.
4. Insert the syringe into the adapter. Make sure that the syringe is tightly inserted.
5. Turn the bottle upside down and gently draw out the required amount of Viramune oral 



151

suspension.
6. The most that you can withdraw is 5 ml at a time. If you need a higher dose, repeat steps 4-5 

above.

The bottle can be kept sealed with the lid of the plastic adapter.

If you are an adult and choose to use another measuring device (e.g. cup or teaspoon) please make sure 
that you take the whole dose. This is because some Viramune can remain in the cup or spoon.

The 14-day ”lead-in” period has been shown to lower the risk of skin rash.

As Viramune must always be taken together with other HIV antiretroviral medicines, you should 
follow the instructions for your other medicines carefully. These are supplied in the package leaflets 
for those medicines.

You should continue to take Viramune for as long as instructed by your doctor.

As explained in 'Warnings and precautions’, above, your doctor will monitor you with liver tests or 
for undesirable effects such as rash. Depending on the outcome your doctor may decide to interrupt or 
stop Viramune treatment. Your doctor might then decide to restart you on a lower dose.

Viramune oral suspension is in a liquid suspension form and should only be taken by mouth. Shake the 
bottle well before you take your medicine. 

If you take more Viramune than you should
Do not take more Viramune than prescribed by your doctor and described in this leaflet. There is at 
present little information on the effects of Viramune overdose. Consult your doctor if you have taken 
more Viramune than you should. 

If you forget to take Viramune
Try not to miss a dose. If you notice that you have missed a dose within 8 hours of when it was due, 
take the missed dose as soon as possible. If it has been more than 8 hours since the dose was due only
take the next dose at the usual time.

If you stop taking Viramune
Taking all doses at the appropriate times:
- greatly increases the effectiveness of your combination antiretroviral medicines 
- reduces the chances of your HIV infection becoming resistant to your antiretroviral medicines. 

It is important that you continue taking Viramune correctly, as described above, unless your doctor 
instructs you to stop.

If you stop taking Viramune for more than 7 days your doctor will instruct you to start the 14-day 'lead 
in' period (described above) once again, before returning to the twice daily dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.



152

As mentioned in 'Warnings and precautions', above, the most important side effects of Viramune
are severe and life threatening skin reactions and serious liver damage. These reactions occur 
mainly in the first 18 weeks of treatment with Viramune. This is therefore an important period 
which requires close monitoring by your doctor.

If you ever observe any rash symptoms, inform your doctor immediately. 

When rash occurs it is normally mild to moderate. However, in some patients a rash, which appears as 
a blistering skin reaction, can be severe or life-threatening (Stevens-Johnson syndrome and toxic 
epidermal necrolysis) and deaths have been recorded. Most of the cases of both severe rash and 
mild/moderate rash occur in the first six weeks of treatment.

If rash occurs and you also feel sick, you must stop treatment and visit your doctor immediately. Pay 
special attention to any rashes that your child develops. Although these may appear normal (for 
example nappy rash), they might be rashes due to Viramune. If in doubt ask your child's doctor.

Hypersensitivity (allergic) reactions can occur. Such reactions may appear in the form of anaphylaxis 
(a severe form of allergic reaction) with symptoms such as: 
- rash
- swelling of the face
- difficulty breathing (bronchial spasm), 
- anaphylactic shock
Hypersensitivity reactions can also occur as rash with other side effects such as:
- fever
- blistering of your skin
- mouth sores
- inflammation of the eye
- swelling of the face
- general swelling
- shortness of breath 
- muscle or joint pain
- a reduction in the number of your white blood cells (granulocytopaenia)
- general feelings of illness
- severe problems with liver or kidneys (liver or kidney failure).

Tell your doctor immediately if you experience rash and any of the other side effects of a 
hypersensitivity (allergic) reaction. Such reactions can be life-threatening.

Abnormal liver functioning has been reported with the use of Viramune. This includes some cases of 
inflammation of the liver (hepatitis), which can be sudden and intense (fulminant hepatitis), and liver 
failure, which can be both fatal.

Tell your doctor if you experience any of the following clinical symptoms of liver damage:
- loss of appetite
- feeling sick (nausea)
- vomiting
- yellow skin (jaundice)
- abdominal pain.

The side effects described below have been experienced by patients given Viramune:

Very common (may affect more than 1 in 10 people):
- rash

Common (may affect up to 1 in 10 people):
- decreased number of white blood cells (granulocytopenia)



153

- allergic reactions (hypersensitivity)
- headache
- feeling sick (nausea)
- vomiting
- abdominal pain
- loose stools (diarrhoea)
- inflammation of the liver (hepatitis)
- feeling tired (fatigue)
- fever
- abnormal liver function tests 

Uncommon (may affect up to 1 in 100 people):
- allergic reaction characterized by rash, swelling of the face, difficulty breathing (bronchial 

spasm) or anaphylactic shock
- decreased numbers of red blood cells (anaemia)
- yellow skin (jaundice)
- severe and life-threatening skin rashes (Stevens-Johnson syndrome/ toxic epidermal necrolysis)
- hives (urticaria)
- fluid under the skin (angioedema)
- joint pain (arthralgia)
- muscle pain (myalgia)
- decreased blood phosphorus
- increased blood pressure

Rare (may affect up to 1 in 1000 people):
- sudden and intense inflammation of the liver (fulminant hepatitis)
- drug reaction with systemic symptoms (drug reaction with eosinophilia and systemic symptoms)

The following events have also been reported when Viramune has been used in combination with 
other antiretroviral agents:
- decreased numbers of red blood cells or platelets
- inflammation of the pancreas
- decrease in or abnormal skin sensations.
These events are commonly associated with other antiretroviral agents and may be expected to occur 
when Viramune is used in combination with other agents; however, it is unlikely that these events are 
due to treatment with Viramune.

Additional side effects in children and adolescents
A reduction in white blood cells (granulocytopenia) can occur, which is more common in children. A 
reduction in red blood cells (anaemia), which may be related to nevirapine therapy, is also more 
commonly observed in children. As with rash symptoms, please inform your doctor of any side 
effects.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Viramune 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
“EXP”. The expiry date refers to the last day of that month. 
Viramune should be used within 6 months of opening the bottle.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


154

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Viramune contains

- The active substance is nevirapine. Each 5 ml contains 50 mg of the active substance nevirapine 
(as hemihydrate).

- The other ingredients are:
carbomer, 
methyl parahydroxybenzoate, 
propyl parahydroxybenzoate, 
sorbitol, 
sucrose, 
polysorbate 80, 
sodium hydroxide and 
water.

What Viramune looks like and contents of the pack

Viramune oral suspension is a white to off-white homogenous suspension.
Viramune oral suspension is supplied in plastic bottles of suspension for oral use, with 240 ml 
suspension per bottle. A plastic measuring syringe is included for measuring the correct dose.

Viramune is also supplied as 200 mg tablets for older children and adults.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany



155

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel.: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +35 31 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG 
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel.: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00



156

Ísland
Vistor hf.
Tel: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in {MM/YYYY}

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu

http://www.ema.europa.eu


157

Package leaflet: Information for the user

Viramune 100 mg prolonged-release tablets

nevirapine

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Viramune is and what it is used for
2. What do you need to know before you take Viramune
3. How to take Viramune
4. Possible side effects
5. How to store Viramune
6. Contents of the pack and other information

1. What Viramune is and what it is used for

Viramune belongs to a group of medicines called antiretrovirals, used in the treatment of Human 
Immunodeficiency Virus (HIV-1) infection.

The active substance of your medicine is called nevirapine. Nevirapine belongs to a class of anti-HIV 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Reverse transcriptase is an 
enzyme that HIV needs in order to multiply. Nevirapine stops reverse transcriptase from working. By 
stopping reverse transcriptase from working, Viramune helps control HIV-1 infection. 

Viramune is indicated for the treatment of HIV-1 infected adolescents and children three years and 
above and able to swallow tablets. You must take Viramune together with other antiretroviral 
medicines. Your doctor will recommend the best medicines for you.

Viramune prolonged-release tablets should only be used after a two-week treatment with another type 
of Viramune (immediate-release tablets or suspension) unless you are currently on Viramune and are 
switching to the prolonged-release form.

If Viramune has been prescribed for your child, please note that all information in this leaflet is 
addressed to your child (please read “your child” instead of “you”).

2. What you need to know before you take Viramune

Do not take Viramune
- if you are allergic to nevirapine or any of the other ingredients of this medicine (listed in section 

6 ).
- if you have taken Viramune before and had to stop the treatment because you suffered from:

- severe skin rash 
- skin rash with other symptoms for example:

- fever



158

- blistering
- mouth sores
- inflammation of the eye
- swelling of the face
- general swelling
- shortness of breath
- muscle or joint pain
- general feelings of illness
- abdominal pain

- hypersensitivity (allergic) reactions 
- inflammation of the liver (hepatitis)

- if you have severe liver disease 
- if you have had to stop Viramune treatment in the past because of changes in your liver function
- if you are taking a medicine containing the herbal substance St. John’s Wort (Hypericum 

perforatum). This herbal substance may stop Viramune from working properly.

Warnings and precautions
Talk to your doctor or pharmacist before taking Viramune.
During the first 18 weeks of treatment with Viramune it is very important that you and your 
doctor watch out for signs of liver or skin reactions. These can become severe and even life 
threatening. You are at greatest risk of such a reaction during the first 6 weeks of treatment.

If you experience severe rash or hypersensitivity (allergic reactions that may appear in the 
form of rash) accompanied by other side effects such as 

- fever,
- blistering, 
- mouth sores, 
- inflammation of the eye, 
- swelling of the face, 
- general swelling,
- shortness of breath, 
- muscle or joint pain, 
- general feelings of illness, 
- or abdominal pain

YOU SHOULD DISCONTINUE TAKING VIRAMUNE AND YOU MUST CONTACT your 
doctor IMMEDIATELY as such reactions can be potentially life-threatening or lead to death.
If you ever have only mild rash symptoms without any other reaction please inform your 
doctor immediately, who will advise you whether you should stop taking Viramune.

If you experience symptoms suggesting damage of the liver, such as 
- loss of appetite, 
- feeling sick (nausea), 
- vomiting, 
- yellow skin (jaundice), 
- abdominal pain

you should discontinue taking Viramune and must contact your doctor immediately.

If you develop severe liver, skin or hypersensitivity reactions whilst taking Viramune, NEVER 
TAKE VIRAMUNE again without referring to your doctor.
You must take the dose of Viramune as prescribed by your doctor. This is especially important 
within the first 14 days of treatment (see more information in “How to take Viramune”).

The following patients are at increased risk of developing liver problems:
- women
- infected with hepatitis B or C
- abnormal liver function tests



159

- treatment-naïve patients with higher CD4 cell counts at the start of Viramune therapy (women 
more than 250 cells/mm³, men more than 400 cells/mm³)

- pre-treated patients with detectable HIV-1 plasma viral load and higher CD4 cell counts at the 
start of Viramune therapy (women more than 250 cells/mm³, men more than 400 cells/mm³)

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection (AIDS 
defining illness), signs and symptoms of inflammation from previous infections may occur soon after 
anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the 
body’s immune response, enabling the body to fight infections that may have been present with no 
obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection. Autoimmune disorders may occur many months after the start of 
treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

Changes of body fat may occur in patients receiving combination antiretroviral therapy. Contact your 
doctor if you notice changes in body fat (see section 4 “Possible side effects”). 

Some patients taking combination antiretroviral therapy may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe weakness of the 
immune system and higher body mass index may be some of the many risk factors for developing this 
disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and 
shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

If you are taking nevirapine and zidovudine concomitantly please inform your doctor since he might 
need to check your white blood cells.

Do not take Viramune after an exposure to HIV unless you have been diagnosed with HIV and 
instructed to do so by your doctor. Viramune is not a cure for HIV infection. Therefore, you may 
continue to develop infections and other illnesses associated with HIV infection. You should therefore 
remain in regular contact with your doctor. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your doctor the 
precautions needed to avoid infecting other people.

Prednisone should not be used to treat a rash related to Viramune.

If you are taking oral contraceptives (e.g. „pill“) or other hormonal methods of birth control during 
treatment with Viramune, you should use a barrier contraception (e.g. condoms) in addition to prevent 
pregnancy and further HIV transmission. 
If you are receiving post-menopausal hormone therapy, ask your doctor for advice before taking this 
medicine.

If you are taking or are prescribed rifampicin to treat tuberculosis please inform your doctor before 
taking this medicine with Viramune. 

Viramune prolonged-release tablets or parts of tablets may occasionally be passed and seen in the 
stool (faeces). These may look like whole tablets, but have not been found to affect the efficacy of 
nevirapine. Inform your doctor if you find tablet pieces in your faeces.

Children and adolescents
Viramune 100 mg prolonged-release tablets can be taken by children three years of age and above. 
Always follow the exact instructions given by your child’s doctor. 



160

For smaller children starting from birth an oral suspension liquid form is available. 

Other medicines and Viramune
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. Inform your doctor about all other medicines you are taking before you start taking 
Viramune. Your doctor might need to monitor whether your other medicines are still working and 
adjust doses. Carefully read the package leaflet of all other HIV medicines you are taking in 
combination with Viramune.

It is particularly important that you tell your doctor if you are taking or have recently taken:

- St. John’s Wort (Hypericum perforatum, medicine to treat depression)
- rifampicin (medicine to treat tuberculosis)
- rifabutin (medicine to treat tuberculosis)
- macrolides e.g. clarithromycin (medicine to treat bacterial infections)
- fluconazole (medicine to treat fungal infections)
- ketoconazole (medicine to treat fungal infections)
- itraconazole (medicine to treat fungal infections)
- methadone (medicine used for treatment of opiate addicts)
- warfarin (medicine to reduce blood clotting)
- hormonal contraceptives (e.g. the “pill”)
- atazanavir (another medicine to treat HIV-infection)
- lopinavir/ritonavir (another medicine to treat HIV-infection)
- fosamprenavir (another medicine to treat HIV-infection)
- efavirenz (another medicine to treat HIV-infection)
- etravirine (another medicine to treat HIV-infection)
- rilpivirine (another medicine to treat HIV-infection)
- delavirdine (another medicine to treat HIV-infection)
- zidovudine (another medicine to treat HIV-infection)
-     boceprevir (medicine to treat hepatitis C)
-     telaprevir (medicine to treat hepatitis C)
- elvitegravir/cobicistat (another medicine to treat HIV-infection)

Your doctor will carefully monitor the effect of Viramune and any of these medicines if you are taking 
them together. 

Taking Viramune with food and drink
There are no restrictions on taking Viramune with food and drink.

Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking this medicine.

You should stop breast-feeding if you are taking Viramune. It is in general recommended that you do 
not breast-feed if you have HIV infection because it is possible that your baby can become infected 
with HIV through your breast milk.

Driving and using machines
You may experience fatigue when taking Viramune. Use caution when engaging in activities such as 
driving, using any tools or machines. If you experience fatigue you should avoid potentially hazardous 
tasks such as driving or using any tools or machines.

Viramune contains lactose
Viramune prolonged-release tablets contain lactose (milk sugar).
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 



161

before taking this medicinal product. 

3. How to take Viramune

You should not use Viramune on its own. You must take it with at least two other antiretroviral 
medicines. Your doctor will recommend the best medicines for you.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

Dosage:

For adults

Viramune 100 mg prolonged-release tablets should not be used by adults. Instead Viramune 400 mg 
prolonged-release tablets should be used after the lead-in period.

For children

Viramune prolonged-release tablets are only to be used for children three years of age and above. For 
younger children starting from birth an oral suspension is available.

Your child’s doctor will calculate the dose for your child. The calculation will include your child's age 
and body weight, or body surface area. Make sure that your child's doctor clearly tells you what dose 
you must give to your child. 

The dose for children is 4 mg/kg body weight or 150 mg/m2 body surface area once a day for the first 
14 days of treatment (“lead-in period”) with Viramune oral suspension. Thereafter your child will be 
switched to Viramune prolonged-release tablets once a day and your child’s doctor will decide the 
right dose and prolonged-release tablet strength based either on your child’s weight or body surface 
area. 

It is very important that your child takes Viramune oral suspension only once a day for the first 14 
days (“lead-in” period). If your child develops any rash during this period, do not start taking 
Viramune prolonged-release tablets but consult your child’s doctor.

Your child’s doctor will continually check your child’s age, weight or body surface area to ensure the
correct dose. If you are uncertain please be sure to ask your child’s doctor.

The 14-day”lead-in” period has been shown to lower the risk of skin rash.

Patients who are already on immediate-release tablets or oral suspension can switch to prolonged-
release tablets without lead-in period.

As Viramune must always be taken together with other HIV antiretroviral medicines, you should 
follow the instructions for your other medicines carefully. These are supplied in the package leaflets 
for those medicines.

Viramune is also available as 400 mg prolonged-release tablets for a once daily usage after the lead-in 
phase for children depending on their age and body weight (body surface area). Your child's doctor 
will inform you of the correct dose for your child. 

You should continue to take Viramune for as long as instructed by your doctor.



162

As explained in ‘Warnings and precautions’, above, your doctor will monitor you with liver tests or 
for undesirable effects such as rash. Depending on the outcome your doctor may decide to interrupt or 
stop your Viramune treatment. Your doctor might then decide to restart you on a lower dose.

If you have a renal or hepatic dysfunction of any degree please use only Viramune 200 mg tablets or 
Viramune 50 mg/5 ml oral suspension.

Only take Viramune prolonged-release tablets by mouth. Do not chew your prolonged-release tablets. 
You may take Viramune with or without food.

If you take more Viramune than you should
Do not take more Viramune than prescribed by your doctor and described in this leaflet. There is at 
present little information on the effects of Viramune overdose. Consult your doctor if you have taken 
more Viramune than you should. 

If you forget to take Viramune
Try not to miss a dose. If you notice you missed a dose within 12 hours of when it was due, take the 
missed dose as soon as possible. If it has been more than 12 hours since the dose was due only take the 
next dose at the usual time. 

If you stop taking Viramune
Taking all doses at the appropriate times:
- greatly increases the effectiveness of your combination antiretroviral medicines 
- reduces the chances of your HIV infection becoming resistant to your antiretroviral medicines.

It is important that you continue taking Viramune correctly, as described above, unless your doctor 
instructs you to stop.

If you stop taking Viramune for more than 7 days your doctor will instruct you to start the 14 day 
'lead-in' period with Viramune oral suspension (described above) once again, before returning to the 
once daily dose with Viramune prolonged-release tablets.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

As mentioned in ‘Warnings and precautions', above, the most important side effects of Viramune
are severe and life threatening skin reactions and serious liver damage. These reactions occur 
mainly in the first 18 weeks of treatment with Viramune. This is therefore an important period 
which requires close monitoring by your doctor.

If you ever observe any rash symptoms, inform your doctor immediately.

When rash occurs it is normally mild to moderate. However, in some patients a rash, which appears as 
a blistering skin reaction, can be severe or life-threatening (Stevens-Johnson syndrome and toxic 
epidermal necrolysis) and deaths have been recorded. Most of the cases of both severe rash and 
mild/moderate rash occur in the first six weeks of treatment. 

If rash occurs and you also feel sick, you must stop treatment and visit your doctor immediately.



163

Hypersensitivity (allergic) reactions can occur. Such reactions may appear in the form of anaphylaxis 
(a severe form of allergic reaction) with symptoms such as:
- rash
- swelling of the face
- difficulty breathing (bronchial spasm)
- anaphylactic shock
Hypersensitivity reactions can also occur as rash with other side effects such as:
- fever
- blistering of your skin 
- mouth sores
- inflammation of the eye
- swelling of the face
- general swelling
- shortness of breath
- muscle or joint pain
- a reduction in the numbers of your white blood cells (granulocytopenia)
- general feelings of illness
- severe problems with liver or kidneys (liver or kidney failure). 

Tell your doctor immediately if you experience rash and any of the other side effects of a 
hypersensitivity (allergic) reaction. Such reactions can be life-threatening.

Abnormal liver functioning has been reported with the use of Viramune. This includes some cases of 
inflammation of the liver (hepatitis), which can be sudden and intense (fulminant hepatitis), and liver 
failure, which can be both fatal.

Tell your doctor if you experience any of the following clinical symptoms of liver damage:
- loss of appetite
- feeling sick (nausea)
- vomiting
- yellow skin (jaundice)
- abdominal pain 

The side effects described below have been experienced by patients given Viramune 200 mg tablets 
during the 14 day lead-in phase:

Common (may affect up to 1 in 10 people):
- rash
- fever
- headache
- abdominal pain
- feeling sick (nausea)
- loose stools (diarrhoea)
- feeling tired (fatigue)

Uncommon (may affect up to 1 in 100 people):
- allergic reactions (hypersensitivity) 
- allergic reaction characterized by rash, swelling of the face, difficulty breathing (bronchial 

spasm) or anaphylactic shock 
- drug reaction with systemic symptoms (drug reaction with eosinophilia and systemic symptoms)
- sudden and intense inflammation of the liver (fulminant hepatitis)
- severe and life-threatening skin rashes (Stevens Johnson Syndrome/toxic epidermal necrolysis)
- yellow skin (jaundice)
- hives (urticaria)
- fluid under the skin (angioneurotic oedema)



164

- vomiting
- muscle pain (myalgia)
- joint pain (arthralgia)
- decreased numbers of white blood cells (granulocytopenia)
- abnormal liver function tests
- decreased blood phosphorus
- increased blood pressure

Rare (may affect up to 1 in 1000 people):
- inflammation of the liver (hepatitis)
- decreased numbers of red blood cells (anaemia)

The side effects described below have been experienced by patients given Viramune prolonged-release 
tablets once daily in the maintenance phase:

Common (may affect up to 1 in 10 people):
- rash
- headache
- abdominal pain
- feeling sick (nausea)
- inflammation of the liver (hepatitis)
- feeling tired (fatigue)
- abnormal liver function tests
- fever
- vomiting 
- loose stools (diarrhoea)

Uncommon (may affect up to 1 in 100 people):
- allergic reactions (hypersensitivity) 
- allergic reaction characterized by rash, swelling of the face, difficulty breathing (bronchial 

spasm) or anaphylactic shock 
- drug reaction with systemic symptoms (drug reaction with eosinophilia and systemic symptoms)
- sudden and intense inflammation of the liver (fulminant hepatitis)
- severe and life-threatening skin rashes (Stevens Johnson Syndrome/toxic epidermal necrolysis)
- decreased numbers of red blood cells (anaemia)
- decreased numbers of white blood cells (granulocytopenia)
- yellow skin (jaundice)
- hives (urticaria)
- fluid under the skin (angioneurotic oedema)
- muscle pain (myalgia)
- joint pain (arthralgia)
- decreased blood phosphorus
- increased blood pressure

The following events have also been reported when Viramune has been used in combination with 
other antiretroviral agents: 
- decreased numbers of red blood cells or platelets
- inflammation of the pancreas
- decrease in or abnormal skin sensations 
These events are commonly associated with other antiretroviral agents and may be expected to occur 
when Viramune is used in combination with other agents; however, it is unlikely that these events are 
due to treatment with Viramune.

Additional side effects in children and adolescents
A reduction in white blood cells (granulocytopenia) can occur, which is more common in children. A 
reduction in red blood cells (anaemia), which may be related to nevirapine therapy, is also more 



165

commonly observed in children. As with rash symptoms, please inform your doctor of any side 
effects.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Viramune

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the carton and on bottle after “EXP”. 
The expiry date refers to the last day of that month.
Viramune should be used within 2 months of opening the bottle.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

6. Contents of the pack and other information

What Viramune contains

- The active substance is nevirapine. Each prolonged-release tablet contains 100 mg nevirapine.
- The other ingredients are lactose (as monohydrate), hypromellose, iron oxide yellow and 

magnesium stearate.

What Viramune looks like and contents of the pack

Viramune 100 mg prolonged-release tablets are yellow, round and biconvex. The prolonged-release
tablets are approximately 9 mm in diameter, debossed with V01 on one side and the company logo on 
the other side. Viramune 100 mg prolonged-release tablets are supplied in bottles with 90 prolonged-
release tablets. 

Viramune is also available as an oral suspension, tablets or as prolonged-release tablets with higher 
strength.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


166

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel.: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +35 31 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG 
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel.: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00



167

Ísland
Vistor hf.
Tel: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in {MM/YYYY}

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu

http://www.ema.europa.eu


168

Package leaflet: Information for the user

Viramune 400 mg prolonged-release tablets
nevirapine

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Viramune is and what it is used for
2. What you need to know before you take Viramune
3. How to take Viramune
4. Possible side effects
5. How to store Viramune
6. Contents of the pack and other information

1. What Viramune is and what it is used for 

Viramune belongs to a group of medicines called antiretrovirals, used in the treatment of Human 
Immunodeficiency Virus (HIV-1) infection.

The active substance of your medicine is called nevirapine. Nevirapine belongs to a class of anti-HIV 
medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Reverse transcriptase is an 
enzyme that HIV needs in order to multiply. Nevirapine stops reverse transcriptase from working. By 
stopping reverse transcriptase from working, Viramune helps control HIV-1 infection. 

Viramune is indicated for the treatment of HIV-1 infected adults, adolescents and children three years 
and above and able to swallow tablets. You must take Viramune together with other antiretroviral 
medicines. Your doctor will recommend the best medicines for you.

Viramune prolonged-release tablets should only be used after a two-week treatment with another type 
of Viramune (immediate-release tablets or suspension) unless you are currently on Viramune and are 
switching to the prolonged-release form.

2. What you need to know before you take Viramune 

Do not take Viramune
- if you are allergic to nevirapine or any of the other ingredients of this medicine (listed in section 

6 ).
- if you have taken Viramune before and had to stop the treatment because you suffered from:

- severe skin rash 
- skin rash with other symptoms for example:

- fever
- blistering
- mouth sores
- inflammation of the eye
- swelling of the face



169

- general swelling
- shortness of breath
- muscle or joint pain
- general feelings of illness
- abdominal pain

- hypersensitivity (allergic) reactions 
- inflammation of the liver (hepatitis)

- if you have severe liver disease 
- if you have had to stop Viramune treatment in the past because of changes in your liver function
- if you are taking a medicine containing the herbal substance St. John’s Wort (Hypericum 

perforatum). This herbal substance may stop Viramune from working properly.

Warnings and precautions 
Talk to your doctor or pharmacist before taking Viramune.
During the first 18 weeks of treatment with Viramune it is very important that you and your 
doctor watch out for signs of liver or skin reactions. These can become severe and even life 
threatening. You are at greatest risk of such a reaction during the first 6 weeks of treatment.

If you experience severe rash or hypersensitivity (allergic reactions that may appear in the 
form of rash) accompanied by other side effects such as 

- fever, 
- blistering, 
- mouth sores, 
- inflammation of the eye, 
- swelling of the face, 
- general swelling,
- shortness of breath, 
- muscle or joint pain, 
- general feelings of illness, 
- or abdominal pain

YOU SHOULD DISCONTINUE TAKING VIRAMUNE AND YOU MUST CONTACT your 
doctor IMMEDIATELY as such reactions can be potentially life-threatening or lead to death.
If you ever have only mild rash symptoms without any other reaction please inform your 
doctor immediately, who will advise you whether you should stop taking Viramune.

If you experience symptoms suggesting damage of the liver, such as 
- loss of appetite, 
- feeling sick (nausea), 
- vomiting, 
- yellow skin (jaundice), 
- abdominal pain

you should discontinue taking Viramune and must contact your doctor immediately.

If you develop severe liver, skin or hypersensitivity reactions whilst taking Viramune, NEVER 
TAKE VIRAMUNE again without referring to your doctor.
You must take the dose of Viramune as prescribed by your doctor. This is especially important 
within the first 14 days of treatment (see more information in “How to take Viramune”).

The following patients are at increased risk of developing liver problems:
- women
- infected with hepatitis B or C
- abnormal liver function tests
- treatment-naïve patients with higher CD4 cell counts at the start of Viramune therapy (women 

more than 250 cells/mm³, men more than 400 cells/mm³)
- pre-treated patients with detectable HIV-1 plasma viral load and higher CD4 cell counts at the 

start of Viramune therapy (women more than 250 cells/mm³, men more than 400 cells/mm³)



170

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection (AIDS 
defining illness), signs and symptoms of inflammation from previous infections may occur soon after 
anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the 
body’s immune response, enabling the body to fight infections that may have been present with no 
obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection. Autoimmune disorders may occur many months after the start of 
treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

Changes of body fat may occur in patients receiving combination antiretroviral therapy. Contact your 
doctor if you notice changes in body fat (see section 4 “Possible side effects”). 

Some patients taking combination antiretroviral therapy may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe weakness of the 
immune system and higher body mass index may be some of the many risk factors for developing this 
disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and 
shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

If you are taking nevirapine and zidovudine concomitantly please inform your doctor since he might 
need to check your white blood cells.

Do not take Viramune after an exposure to HIV unless you have been diagnosed with HIV and 
instructed to do so by your doctor. Viramune is not a cure for HIV infection. Therefore, you may 
continue to develop infections and other illnesses associated with HIV infection. You should therefore 
remain in regular contact with your doctor. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your doctor the 
precautions needed to avoid infecting other people.

Prednisone should not be used to treat a rash related to Viramune.

If you are taking oral contraceptives (e.g. „pill“) or other hormonal methods of birth control during 
treatment with Viramune, you should use a barrier contraception (e.g. condoms) in addition to prevent 
pregnancy and further HIV transmission. 
If you are receiving post-menopausal hormone therapy, ask your doctor for advice before taking this 
medicine.

If you are taking or are prescribed rifampicin to treat tuberculosis please inform your doctor before 
taking this medicine with Viramune. 

Viramune prolonged-release tablets or parts of tablets may occasionally be passed and seen in the 
stool (faeces). These may look like whole tablets, but have not been found to affect the efficacy of 
nevirapine. Inform your doctor if you find tablet pieces in your faeces.

Children and adolescents
Viramune 400 mg prolonged-release tablets can be taken by children if they:

- are  8 years of age and weigh 43.8 kg or more
- are older than 3 years of age and below 8 years of age and weigh 25 kg or more
- have a body surface area of 1.17 square metres or above. 

For smaller children smaller prolonged-release tablets or an oral suspension liquid form are available.



171

Other medicines and Viramune
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. Inform your doctor about all other medicines you are taking before you start taking 
Viramune. Your doctor might need to monitor whether your other medicines are still working and 
adjust doses. Carefully read the package leaflet of all other HIV medicines you are taking in 
combination with Viramune.

It is particularly important that you tell your doctor if you are taking or have recently taken:

- St. John’s Wort (Hypericum perforatum, medicine to treat depression)
- rifampicin (medicine to treat tuberculosis)
- rifabutin (medicine to treat tuberculosis)
- macrolides e.g. clarithromycin (medicine to treat bacterial infections)
- fluconazole (medicine to treat fungal infections)
- ketoconazole (medicine to treat fungal infections)
- itraconazole (medicine to treat fungal infections)
- methadone (medicine used for treatment of opiate addicts)
- warfarin (medicine to reduce blood clotting)
- hormonal contraceptives (e.g. the “pill”)
- atazanavir (another medicine to treat HIV-infection)
- lopinavir/ritonavir (another medicine to treat HIV-infection)
- fosamprenavir (another medicine to treat HIV-infection)
- efavirenz (another medicine to treat HIV-infection)
- etravirine (another medicine to treat HIV-infection)
- rilpivirine (another medicine to treat HIV-infection)
- delavirdine (another medicine to treat HIV-infection)
- zidovudine (another medicine to treat HIV-infection)
- boceprevir (medicine to treat hepatitis C)
-     telaprevir (medicine to treat hepatitis C)
- elvitegravir/cobicistat (another medicine to treat HIV-infection)

Your doctor will carefully monitor the effect of Viramune and any of these medicines if you are taking 
them together. 

Taking Viramune with food and drink
There are no restrictions on taking Viramune with food and drink.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking this medicine.

You should stop breast-feeding if you are taking Viramune. It is in general recommended that you do 
not breast-feed if you have HIV infection because it is possible that your baby can become infected 
with HIV through your breast milk.

Driving and using machines
You may experience fatigue when taking Viramune. Use caution when engaging in activities such as 
driving, using any tools or machines. If you experience fatigue you should avoid potentially hazardous 
tasks such as driving or using any tools or machines.

Viramune contains lactose
Viramune prolonged-release tablets contain lactose (milk sugar).
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product. 



172

3. How to take Viramune 

You should not use Viramune on its own. You must take it with at least two other antiretroviral 
medicines. Your doctor will recommend the best medicines for you.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

Dosage:

Adults:
The dose is one 200 mg Viramune tablet per day for the first 14 days of treatment (“lead-in” period). 
A separate treatment initiation pack with 200 mg Viramune tablets is available for this lead-in period. 
After 14 days, the usual dose is one 400 mg prolonged-release tablet once a day. 

It is very important that you take only one Viramune tablet a day for the first 14 days (“lead-in” 
period). If you have any rash during this period, do not start taking Viramune prolonged-release tablets 
but consult your doctor.

The 14-day ”lead-in” period has been shown to lower the risk of skin rash.

Patients who are already on immediate-release tablets or oral suspension can switch to prolonged-
release tablets without lead-in period.

As Viramune must always be taken together with other HIV antiretroviral medicines, you should 
follow the instructions for your other medicines carefully. These are supplied in the package leaflets 
for those medicines.

Viramune is also available as smaller prolonged-release tablets (for children 3 years of age and above 
after the lead-in period) or as an oral suspension (for all age groups).

You should continue to take Viramune for as long as instructed by your doctor.

As explained in ‘Warnings and precautions’, above, your doctor will monitor you with liver tests or 
for undesirable effects such as rash. Depending on the outcome your doctor may decide to interrupt or 
stop your Viramune treatment. Your doctor might then decide to restart you on a lower dose.

If you have a renal or hepatic dysfunction of any degree please use only Viramune 200 mg tablets or 
Viramune 50 mg/5 ml oral suspension.

Only take Viramune prolonged-release tablets by mouth. Do not chew your prolonged-release tablets. 
You may take Viramune with or without food.

If you take more Viramune than you should
Do not take more Viramune than prescribed by your doctor and described in this leaflet. There is at 
present little information on the effects of Viramune overdose. Consult your doctor if you have taken 
more Viramune than you should. 

If you forget to take Viramune
Try not to miss a dose. If you notice you missed a dose within 12 hours of when it was due, take the 
missed dose as soon as possible. If it has been more than 12 hours since the dose was due only take the 
next dose at the usual time. 



173

If you stop taking Viramune
Taking all doses at the appropriate times:
- greatly increases the effectiveness of your combination antiretroviral medicines 
- reduces the chances of your HIV infection becoming resistant to your antiretroviral medicines.

It is important that you continue taking Viramune correctly, as described above, unless your doctor 
instructs you to stop.

If you stop taking Viramune for more than 7 days your doctor will instruct you to start the 14 day 
'lead-in' period with Viramune tablets (described above) once again, before returning to the once daily 
dose with Viramune prolonged-release tablets.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

As mentioned in ‘Warnings and precautions', above, the most important side effects of Viramune
are severe and life threatening skin reactions and serious liver damage. These reactions occur 
mainly in the first 18 weeks of treatment with Viramune. This is therefore an important period 
which requires close monitoring by your doctor.

If you ever observe any rash symptoms, inform your doctor immediately.

When rash occurs it is normally mild to moderate. However, in some patients a rash, which appears as 
a blistering skin reaction, can be severe or life-threatening (Stevens-Johnson syndrome and toxic 
epidermal necrolysis) and deaths have been recorded. Most of the cases of both severe rash and 
mild/moderate rash occur in the first six weeks of treatment. 

If rash occurs and you also feel sick, you must stop treatment and visit your doctor immediately.

Hypersensitivity (allergic) reactions can occur. Such reactions may appear in the form of anaphylaxis 
(a severe form of allergic reaction) with symptoms such as:
- rash
- swelling of the face
- difficulty breathing (bronchial spasm)
- anaphylactic shock
Hypersensitivity reactions can also occur as rash with other side effects such as:
- fever
- blistering of your skin 
- mouth sores
- inflammation of the eye
- swelling of the face
- general swelling
- shortness of breath
- muscle or joint pain
- a reduction in the numbers of your white blood cells (granulocytopenia)
- general feelings of illness
- severe problems with liver or kidneys (liver or kidney failure). 



174

Tell your doctor immediately if you experience rash and any of the other side effects of a 
hypersensitivity (allergic) reaction. Such reactions can be life-threatening.

Abnormal liver functioning has been reported with the use of Viramune. This includes some cases of 
inflammation of the liver (hepatitis), which can be sudden and intense (fulminant hepatitis), and liver 
failure, which can be both fatal.

Tell your doctor if you experience any of the following clinical symptoms of liver damage:
- loss of appetite
- feeling sick (nausea)
- vomiting
- yellow skin (jaundice)
- abdominal pain 

The side effects described below have been experienced by patients given Viramune 200 mg tablets 
during the 14 day lead-in phase:

Common (may affect up to 1 in 10 people):
- rash
- fever
- headache
- abdominal pain
- feeling sick (nausea)
- loose stools (diarrhoea)
- feeling tired (fatigue)

Uncommon (may affect up to 1 in 100 people):
- allergic reactions (hypersensitivity) 
- allergic reaction characterized by rash, swelling of the face, difficulty breathing (bronchial 

spasm) or anaphylactic shock 
- drug reaction with systemic symptoms (drug reaction with eosinophilia and systemic symptoms)
- sudden and intense inflammation of the liver (fulminant hepatitis)
- severe and life-threatening skin rashes (Stevens Johnson Syndrome/toxic epidermal necrolysis)
- yellow skin (jaundice)
- hives (urticaria)
- fluid under the skin (angioneurotic oedema)
- vomiting
- muscle pain (myalgia)
- joint pain (arthralgia)
- decreased numbers of white blood cells (granulocytopenia)
- abnormal liver function tests
- decreased blood phosphorus
- increased blood pressure

Rare (may affect up to 1 in 1000 people):
- inflammation of the liver (hepatitis)
- decreased numbers of red blood cells (anaemia)

The side effects described below have been experienced by patients given Viramune prolonged-release 
tablets once daily in the maintenance phase:

Common (may affect up to 1 in 10 people):
- rash
- headache
- abdominal pain



175

- feeling sick (nausea)
- inflammation of the liver (hepatitis)
- feeling tired (fatigue)
- abnormal liver function tests
- fever
- vomiting 
- loose stools (diarrhoea)

Uncommon (may affect up to 1 in 100 people):
- allergic reactions (hypersensitivity) 
- allergic reaction characterized by rash, swelling of the face, difficulty breathing (bronchial 

spasm) or anaphylactic shock 
- drug reaction with systemic symptoms (drug reaction with eosinophilia and systemic symptoms)
- sudden and intense inflammation of the liver (fulminant hepatitis)
- severe and life-threatening skin rashes (Stevens Johnson Syndrome/toxic epidermal necrolysis)
- decreased numbers of red blood cells (anaemia)
- decreased numbers of white blood cells (granulocytopenia)
- yellow skin (jaundice)
- hives (urticaria)
- fluid under the skin (angioneurotic oedema)
- muscle pain (myalgia)
- joint pain (arthralgia)
- decreased blood phosphorus
- increased blood pressure

The following events have also been reported when Viramune has been used in combination with 
other antiretroviral agents: 
- decreased numbers of red blood cells or platelets
- inflammation of the pancreas
- decrease in or abnormal skin sensations 
These events are commonly associated with other antiretroviral agents and may be expected to occur 
when Viramune is used in combination with other agents; however, it is unlikely that these events are 
due to treatment with Viramune.

Additional side effects in children and adolescents
A reduction in white blood cells (granulocytopenia) can occur, which is more common in children. A 
reduction in red blood cells (anaemia), which may be related to nevirapine therapy, is also more 
commonly observed in children. As with rash symptoms, please inform your doctor of any side 
effects.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Viramune 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the carton and on the blister or bottle
after “EXP”. The expiry date refers to the last day of that month.
Viramune should be used within 2 months of opening the bottle.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


176

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

6. Contents of the pack and other information

What Viramune contains

- The active substance is nevirapine. Each prolonged-release tablet contains 400 mg nevirapine.
- The other ingredients are lactose (as monohydrate), hypromellose, iron oxide yellow and 

magnesium stearate.

What Viramune looks like and contents of the pack

Yellow, oval, biconvex prolonged-release tablets. The prolonged-release tablets are about 9.3 x 
19.1 mm, debossed with V04 on one side and the company symbol on the other side. Viramune 400 
mg prolonged-release tablets are supplied in blisters, with 30 or 90 prolonged-release tablets per 
carton. Alternatively, 30 Viramune 400 mg prolonged-release tablets are supplied in bottles. Not all 
pack size may be marketed.

Viramune is also available as an oral suspension, tablets or as prolonged-release tablets with lower 
strength.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
Germany



177

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder.

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel.: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +35 31 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG 
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp. z o.o.
Tel.: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00



178

Ísland
Vistor hf.
Tel: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in {MM/YYYY}

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu

http://www.ema.europa.eu

	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET