VIRAMUNE 50mg / 5ml oral suspension medication leaflet

Viramune 50 mg/5 mL oral suspension

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

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

Each mL of oral suspension contains 150 mg sucrose, 162 mg sorbitol, 1.8 mg of methylparahydroxybenzoate 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.

Oral suspension

White to off-white homogenous suspension.

Viramune is indicated in combination with other anti-retroviral medicinal products for the treatment of

HIV-1 infected adults, adolescents, and children of any age (see section 4.2).

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

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

Patients 16 years and older

The recommended dose for Viramune is 20 mL (200 mg) oral suspension once daily for the first14 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 additionalantiretroviral 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 misseddose as soon as possible. If a dose is missed and it is more than 8 hours later, the patient should onlytake the next dose at the usual time.

Patients experiencing rash during the 14-day lead-in period of 200 mg/day (4 mg/kg/day or150 mg/m2/day for paediatric patients) should not have their Viramune dose increased until the rashhas resolved. The isolated rash should be closely monitored (see section 4.4). The 200 mg once dailydosing regimen should not be continued beyond 28 days at which point in time an alternativetreatment 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 dosingregimen using the two week lead-in period.

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

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

For patients with renal dysfunction requiring dialysis an additional 200 mg dose of nevirapinefollowing each dialysis treatment is recommended. Patients with CLcr ≥ 20 mL/min do not require adose adjustment, see section 5.2.

Nevirapine should not be used in patients with severe hepatic impairment (Child-Pugh C, seesection 4.3). No dose adjustment is necessary in patients with mild to moderate hepatic impairment(see sections 4.4 and 5.2).

The total daily dose should not exceed 400 mg for any patient. Viramune may be dosed in paediatricpatients 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 is150 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 dosingon a body surface basis of 150 mg/m2:

BSA range (m2) Volume (mL)0.08-0.25 2.50.25-0.42 50.42-0.58 7.50.58-0.75 100.75-0.92 12.50.92-1.08 151.08-1.25 17.51.25+ 20() × ()

Mosteller Formula: (²) =

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

Weight Range (kg) for Weight Range (kg) for Volume (mL)patients < 8 yrs of age on a patients ≥ 8 years of age on abody weight basis receiving body weight basis receiving7 mg/kg. 4 mg/kg.1.79-5.36 3.13-9.38 2.55.36-8.93 9.38-15.63 58.93-12.50 15.63-21.88 7.512.50-16.07 21.88-28.12 1016.07-19.64 28.12-34.37 12.519.64-23.21 34.37-40.62 1523.21-26.79 40.62-46.88 17.526.79+ 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.

It is important that the entire measured dose of Viramune oral suspension is administered. This isassisted by the use of a dispensing syringe. If an alternative measuring device is used (e.g. adispensing cup or teaspoon for larger doses) it should be thoroughly rinsed with water and the rinseshould also be administered to the patient. Viramune may be taken with or without food.

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, rashaccompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due tonevirapine.

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

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

Coadministration with herbal preparations containing St. John’s wort (Hypericum perforatum) due tothe risk of decreased plasma concentrations and reduced clinical effects of nevirapine (see section 4.5).

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

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

The first 18 weeks of therapy with nevirapine are a critical period which requires closemonitoring of patients to disclose the potential appearance of severe and life-threatening skinreactions (including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis(TEN)) and serious hepatitis/hepatic failure. The greatest risk of hepatic and skin reactionsoccurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues past thisperiod 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 ofnevirapine therapy are associated with a greater risk of hepatic adverse reactions if the patienthas detectable plasma HIV-1 RNA - i.e. a concentration ≥ 50 copies/mL - at the initiation ofnevirapine. As serious and life threatening hepatotoxicity has been observed in controlled anduncontrolled studies predominantly in patients with a plasma HIV-1 viral load of 50 copies/mLor higher, nevirapine should not be initiated in adult females with CD4+ cell counts greater than250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3, who have adetectable plasma HIV-1 RNA unless the benefit outweighs the risk.

In some cases, hepatic injury has progressed despite discontinuation of treatment. Patientsdeveloping signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactionsmust discontinue nevirapine and seek medical evaluation immediately. Nevirapine must not berestarted 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).

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

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

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

Concomitant prednisone use (40 mg/day for the first 14 days of Viramune administration) has beenshown not to decrease the incidence of nevirapine-associated rash, and may be associated with anincrease 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 failureto follow the initial dosing of 200 mg daily (4 mg/kg or 150 mg/m2 for paediatric patients) during thelead-in period and a long delay between the initial symptoms and medical consultation. Womenappear 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 topromptly notify their physician of any rash and avoid delay between the initial symptoms and medicalconsultation. The majority of rashes associated with nevirapine occur within the first 6 weeks ofinitiation of therapy. Therefore, patients should be monitored carefully for the appearance of rashduring this period. Patients should be instructed that dose escalation is not to occur if any rash occursduring the two-week lead-in dosing period, until the rash resolves. The 200 mg once daily dosingregimen should not be continued beyond 28 days at which point in time an alternative treatmentshould be sought due to the possible risk of underexposure and resistance. Careful monitoring ofpaediatric patients is especially warranted, particularly in the first 18 weeks of treatment, since thesepatients 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 shoulddiscontinue the medicinal product and immediately seek medical evaluation. In these patientsnevirapine must not be restarted.

If patients present with a suspected nevirapine-associated rash, liver function tests should beperformed. Patients with moderate to severe elevations (ASAT or ALAT > 5 ULN) should bepermanently 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).

Severe and life-threatening hepatotoxicity, including fatal fulminant hepatitis, has occurred in patientstreated with nevirapine. The first 18 weeks of treatment is a critical period which requires closemonitoring. The risk of hepatic reactions is greatest in the first 6 weeks of therapy. However the riskcontinues 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 withnevirapine use.

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

Female gender and higher CD4+ counts at the initiation of nevirapine therapy in treatment-naïvepatients is associated with increased risk of hepatic adverse reactions. Women have a three fold higherrisk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), andtreatment-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 withnevirapine. In a retrospective review of predominantly patients with a plasma HIV-1 viral load of50 copies/mL or higher, women with CD4+ counts > 250 cells/mm3 had a 12 fold higher risk ofsymptomatic 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 plasmaand 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 withundetectable (i.e. < 50 copies/mL) plasma viral load.

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

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

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

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

Monitoring of hepatic tests should be done every two weeks during the first 2 months of treatment, atthe 3rd month and then regularly thereafter. Liver test monitoring should be performed if the patientexperiences 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 morefrequently 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 (seesection 4.3).

Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such asanorexia, nausea, jaundice, bilirubinuria, acholic stools, hepatomegaly or liver tenderness. Patientsshould be instructed to seek medical attention promptly if these occur.

If ASAT or ALAT increase to > 5 ULN during treatment, nevirapine should be immediatelystopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs orsymptoms of hepatitis, rash, constitutional symptoms or other findings suggestive of organdysfunction, it may be possible to reintroduce nevirapine, on a case by case basis, at the startingdose regimen of 200 mg/day for 14 days followed by 400 mg/day. In these cases, more frequentliver monitoring is required. If liver function abnormalities recur, nevirapine should bepermanently discontinued.

If clinical hepatitis occurs, characterised by anorexia, nausea, vomiting, icterus AND laboratoryfindings (such as moderate or severe liver function test abnormalities (excluding GGT)),nevirapine must be permanently stopped. Viramune must not be readministered to patients whohave required permanent discontinuation for clinical hepatitis due to nevirapine.

The safety and efficacy of Viramune has not been established in patients with significant underlyingliver 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 isadministered to patients with moderate hepatic dysfunction (Child-Pugh B). Patients with chronichepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severeand potentially fatal hepatic adverse reactions. In the case of concomitant antiviral therapy forhepatitis 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 increasedfrequency of liver function abnormalities during combination antiretroviral therapy and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, interruption or discontinuation of treatment must be considered.

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

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, includingopportunistic infections.

Hormonal methods of birth control other than Depo-medroxyprogesterone acetate (DMPA) should notbe used as the sole method of contraception in women taking Viramune, since nevirapine might lowerthe plasma concentrations of these medicinal products. For this reason, and to reduce the risk of HIVtransmission, barrier contraception (e.g. condoms) is recommended. Additionally, whenpostmenopausal hormone therapy is used during administration of nevirapine, its therapeutic effectshould be monitored.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished 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 overallimprovement in the total to HDL-cholesterol ratio. However, in the absence of specific studies, theclinical impact of these findings is not known. In addition, Viramune has not been shown to causeglucose disturbances.

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

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the timeof institution of combination antiretroviral therapy (CART), an inflammatory reaction toasymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, oraggravation of symptoms. Typically, such reactions have been observed within the first few weeks ormonths of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/orfocal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptomsshould 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 immunereactivation; however, the reported time to onset is more variable and these events can occur manymonths after initiation of treatment.

The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine isnot recommended. Furthermore, combining the following compounds with Viramune is notrecommended: efavirenz, ketoconazole, etravirine, rilpivirine, elvitegravir (in combination withcobicistat), atazanavir (in combination with ritonavir), fosamprenavir (if not co-administered with lowdose ritonavir) (see section 4.5).

Granulocytopenia is commonly associated with zidovudine. Therefore, patients who receivenevirapine and zidovudine concomitantly and especially paediatric patients and patients who receivehigher 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 parametersshould be carefully monitored.

Sucrose: Viramune oral suspension contains 150 mg of sucrose per mL. Patients with rare hereditaryproblems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiencyshould not take this medicine.

Sorbitol: Viramune oral suspension contains 162 mg of sorbitol per mL. Patients with hereditaryfructose intolerance (HFI) should not take/be given this medicinal product.

Methyl and propyl parahydroxybenzoates: Viramune oral suspension contains methylparahydroxybenzoate and propyl parahydroxybenzoate, which may cause allergic reaction (possiblydelayed).

Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurringwithin 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 metabolisedmedicinal products is recommended when taken in combination with nevirapine.

The absorption of nevirapine is not affected by food, antacids or medicinal products which areformulated 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 Interaction Recommendations concerningby therapeutic areas co-administration

ANTI-INFECTIVES

ANTIRETROVIRALS

NRTIs

Didanosine Didanosine AUC  1.08 Didanosine and Viramune can be100-150 mg BID (0.92-1.27) co-administered without dose

Didanosine Cmin ND adjustments.

Didanosine Cmax  0.98(0.79-1.21)

Emtricitabine Emtricitabine is not an inhibitor of Viramune and emtricitabine mayhuman CYP 450 enzymes. be coadministered without doseadjustments.

Abacavir In human liver microsomes, Viramune and abacavir may beabacavir did not inhibit cytochrome coadministered without dose

P450 isoforms. adjustments.

Lamivudine No changes to lamivudine apparent Lamivudine and Viramune can be150 mg BID clearance and volume of co-administered without dosedistribution, suggesting no adjustments.induction effect of nevirapine onlamivudine clearance.

Stavudine: Stavudine AUC  0.96 Stavudine and Viramune can be30/40 mg BID (0.89-1.03) co-administered without dose

Stavudine Cmin ND adjustments.

Stavudine Cmax  0.94 (0.86-1.03)

Nevirapine: compared to historicalcontrols, levels appeared to beunchanged.

Tenofovir Tenofovir plasma levels remain Tenofovir and Viramune can be co-300 mg QD unchanged when co-administered administered without dosewith nevirapine. adjustments.

Nevirapine plasma levels were notaltered by co-administration oftenofovir.

Zidovudine Zidovudine AUC  0.72 Zidovudine and Viramune can be100-200 mg TID (0.60-0.96) co-administered without dose

Zidovudine Cmin ND adjustments

Zidovudine Cmax  0.70 (0.49-1.04)

Granulocytopenia is commonly

Nevirapine: Zidovudine had no associated with zidovudine.

effect on its pharmacokinetics. Therefore, patients who receivenevirapine and zidovudineconcomitantly and especiallypaediatric patients and patientswho receive higher zidovudinedoses or patients with poor bonemarrow reserve, in particular thosewith advanced HIV disease, havean increased risk ofgranulocytopenia. In such patientshaematological parameters shouldbe carefully monitored.

NNRTIs

Efavirenz Efavirenz AUC  0.72 (0.66-0.86) It is not recommended to co-600 mg QD Efavirenz Cmin  0.68 (0.65-0.81) administer efavirenz and Viramune

Efavirenz Cmax  0.88 (0.77-1.01) (see section 4.4), because ofadditive toxicity and no benefit interms of efficacy over either

NNRTI alone (for results of 2NNstudy, see section 5.1).

Etravirine Concomitant use of etravirine with The concomitant administration ofnevirapine may cause a significant Viramune with NNRTIs is notdecrease in the plasma recommended (see section 4.4).concentrations of etravirine andloss of therapeutic effect ofetravirine.

Rilpivirine Interaction has not been studied. The concomitant administration of

Viramune with NNRTIs is notrecommended (see section 4.4).

PIs

Atazanavir/ritonavir Atazanavir/r 300/100 mg: It is not recommended to co-300/100 mg QD Atazanavir/r AUC  0.58 administer atazanavir/ritonavir and400/100 mg QD (0.48-0.71) Viramune (see section 4.4).

Atazanavir/r Cmin 0.28(0.20-0.40)

Atazanavir/r Cmax  0.72(0.60-0.86)

Atazanavir/r 400/100 mg:

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 300/100 mg withoutnevirapine)

Nevirapine AUC  1.25(1.17-1.34)

Nevirapine Cmin 1.32 (1.22-1.43)

Nevirapine Cmax  1.17 (1.09-1.25)

Darunavir/ritonavir Darunavir AUC  1.24 (0.97-1.57) Darunavir and Viramune can be400/100 mg BID Darunavir Cmin  1.02 (0.79-1.32) co-administered without dose

Darunavir Cmax  1.40 (1.14-1.73) adjustments.

Nevirapine AUC  1.27(1.12-1.44)

Nevirapine Cmin  1.47 (1.20-1.82)

Nevirapine Cmax  1.18 (1.02-1.37)

Fosamprenavir Amprenavir AUC  0.67 It is not recommended to co-1 400 mg BID (0.55-0.80) administer fosamprenavir and

Amprenavir Cmin  0.65 Viramune if fosamprenavir is not(0.49-0.85) co-administered with ritonavir (see

Amprenavir Cmax  0.75 section 4.4).

(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)

Fosamprenavir/ritonavir Amprenavir AUC  0.89 Fosamprenavir/ritonavir and700/100 mg BID (0.77-1.03) Viramune can be co-administered

Amprenavir Cmin  0.81 without dose adjustments(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)

Lopinavir/ritonavir Adult patients: An increase in the dose of(capsules) 400/100 mg Lopinavir AUC  0.73 (0.53-0.98) lopinavir/ritonavir to 533/133 mg

BID Lopinavir Cmin  0.54 (0.28-0.74) (4 capsules) or 500/125 mg

Lopinavir C  0.81 (0.62-0.95) (5 tablets with 100/25 mg each)maxtwice daily with food isrecommended in combination with

Viramune. Dose adjustment of

Viramune is not required when co-administered with lopinavir.

Lopinavir/ritonavir Paediatric patients: For children, increase of the dose(oral solution) Lopinavir AUC  0.78 (0.56-1.09) of lopinavir/ritonavir to300/75 mg/m2 BID 2

Lopinavir Cmin  0.45 (0.25-0.82) 300/75 mg/m twice daily with

Lopinavir Cmax  0.86 (0.64-1.16) food should be considered whenused in combination with

Viramune, particularly for patientsin whom reduced susceptibility tolopinavir/ritonavir is suspected.

Ritonavir Ritonavir AUC 0.92 (0.79-1.07) Ritonavir and Viramune can be co-600 mg BID Ritonavir Cmin  0.93 (0.76-1.14) administered without dose

Ritonavir Cmax  0.93 (0.78-1.07) adjustments.

Nevirapine: Co-administration ofritonavir does not lead to anyclinically relevant change innevirapine plasma levels.

Saquinavir/ritonavir The limited data available with Saquinavir/ritonavir and Viramunesaquinavir soft gel capsule boosted can be co-administered withoutwith ritonavir do not suggest any dose adjustments.clinically relevant interactionbetween saquinavir boosted withritonavir and nevirapine

Tipranavir/ritonavir No specific drug-drug interaction Tipranavir and Viramune can be500/200 mg BID study has been performed. co-administered without dose

The limited data available from a adjustments.phase IIa study in HIV-infectedpatients have shown a clinicallynon significant 20% decrease of

TPV Cmin.

ENTRY INHIBITORS

Enfuvirtide Due to the metabolic pathway no Enfuvirtide and Viramune can beclinically significant co-administered without dosepharmacokinetic interactions are adjustments.expected between enfuvirtide andnevirapine.

Maraviroc Maraviroc AUC  1.01 (0.6-1.55) Maraviroc and Viramune can be300 mg QD Maraviroc Cmin ND co-administered without dose

Maraviroc Cmax  1.54 (0.94-2.52) adjustments.

compared to historical controls

Nevirapine concentrations notmeasured, no effect is expected.

INTEGRASE INHIBITORS

Elvitegravir/ Interaction has not been studied. Coadministration of Viramunecobicistat Cobicistat, a cytochrome P450 3A with elvitegravir in combinationinhibitor significantly inhibits with cobicistat is not recommendedhepatic enzymes, as well as other (see section 4.4).metabolic pathways. Thereforecoadministration would likelyresult in altered plasma levels ofcobicistat and Viramune.

Raltegravir No clinical data available. Due to Raltegravir and Viramune can be400 mg BID the metabolic pathway of co-administered without doseraltegravir no interaction is adjustments.expected.

ANTIBIOTICS

Clarithromycin Clarithromycin AUC  0.69 Clarithromycin exposure was500 mg BID (0.62-0.76) significantly decreased, 14-OH

Clarithromycin Cmin  0.44 metabolite exposure increased.

(0.30-0.64) Because the clarithromycin active

Clarithromycin Cmax  0.77 metabolite has reduced activity(0.69-0.86) against Mycobacterium avium-intracellulare complex overall

Metabolite 14-OH clarithromycin activity against the pathogen may

AUC  1.42 (1.16-1.73) be altered. Alternatives to

Metabolite 14-OH clarithromycin clarithromycin, such as

Cmin  0 (0.68-1.49) azithromycin should be considered.

Metabolite 14-OH clarithromycin Close monitoring for hepatic

Cmax  1.47 (1.21-1.80) abnormalities is recommended

Nevirapine AUC  1.26

Nevirapine Cmin  1.28

Nevirapine Cmax  1.24compared to historical controls.

Rifabutin Rifabutin AUC  1.17 (0.98-1.40) No significant effect on rifabutin150 or 300 mg QD Rifabutin Cmin  1.07 (0.84-1.37) and Viramune mean PK parameters

Rifabutin Cmax  1.28 (1.09-1.51) is seen. Rifabutin and Viramunecan be co-administered without

Metabolite 25-O-desacetylrifabutin dose adjustments. However, due to

AUC  1.24 (0.84-1.84) the high interpatient variability

Metabolite 25-O-desacetylrifabutin some patients may experience large

C  1.22 (0.86-1.74) increases in rifabutin exposure andmin

Metabolite 25-O-desacetylrifabutin may be at higher risk for rifabutin

C  1.29 (0.98-1.68) toxicity. Therefore, caution shouldmaxbe used in concomitant

A clinically not relevant increase administration.

in the apparent clearance ofnevirapine (by 9%) compared tohistorical data was reported.

Rifampicin Rifampicin AUC  1.11 It is not recommended to co-600 mg QD (0.96-1.28) administer rifampicin and

Rifampicin Cmin ND Viramune (see section 4.4).

Rifampicin Cmax  1.06 Physicians needing to treat patients(0.91-1.22) co-infected with tuberculosis andusing a Viramune containing

Nevirapine AUC  0.42 regimen may consider co-

Nevirapine C  0.32 administration of rifabutin instead.min

Nevirapine Cmax  0.50compared to historical controls.

ANTIFUNGALS

Fluconazole Fluconazole AUC  0.94 Because of the risk of increased200 mg QD (0.88-1.01) exposure to Viramune, caution

Fluconazole Cmin  0.93 should be exercised if the(0.86-1.01) medicinal products are given

Fluconazole Cmax  0.92 concomitantly and patients should(0.85-0.99) be monitored closely.

Nevirapine: exposure: 100%compared with historical datawhere nevirapine was administeredalone.

Itraconazole Itraconazole AUC  0.39 A dose increase for itraconazole200 mg QD Itraconazole Cmin  0.13 should be considered when these

Itraconazole Cmax  0.62 two agents are administeredconcomitantly.

Nevirapine: there was nosignificant difference in nevirapinepharmacokinetic parameters.

Ketoconazole Ketoconazole AUC  0.28 It is not recommended to co-400 mg QD (0.20-0.40) administer ketoconazole and

Ketoconazole Cmin ND Viramune (see section 4.4).

Ketoconazole Cmax  0.56(0.42-0.73)

Nevirapine: plasma levels: 1.15-1.28 compared to historicalcontrols.

ANTIVIRALS FOR CHRONIC HEPATITIS B AND C

Adefovir Results of in vitro studies showed a Adefovir and Viramune may beweak antagonism of nevirapine by coadministered without doseadefovir (see section 5.1), this has adjustments.not been confirmed in clinicaltrials and reduced efficacy is notexpected. Adefovir did notinfluence any of the common CYPisoforms known to be involved inhuman drug metabolism and isexcreted renally. No clinicallyrelevant drug-drug interaction isexpected.

Entecavir Entecavir is not a substrate, Entecavir and Viramune may beinducer or an inhibitor of coadministered without dosecytochrome P450 (CYP450) adjustments.enzymes. Due to the metabolicpathway of entecavir, no clinicallyrelevant drug-drug interaction isexpected.

Interferons (pegylated Interferons have no known effect Interferons and Viramune may beinterferons alfa 2a and on CYP 3A4 or 2B6. No clinically coadministered without dosealfa 2b) adjustments.

relevant drug-drug interaction isexpected.

Ribavirin Results of in vitro studies showed a Ribavirin and Viramune may beweak antagonism of nevirapine by coadministered without doseribavirin (see section 5.1), this has adjustments.not been confirmed in clinicaltrials and reduced efficacy is notexpected. Ribavirin does notinhibit cytochrome P450 enzymes,and there is no evidence fromtoxicity studies that ribavirininduces liver enzymes. Noclinically relevant drug-druginteraction is expected.

Telbivudine Telbivudine is not a substrate, Telbivudine and Viramune may beinducer or inhibitor of the coadministered without dosecytochrome P450 (CYP450) adjustments.enzyme system. Due to themetabolic pathway of telbivudine,no clinically relevant drug-druginteraction is expected.

ANTACIDS

Cimetidine Cimetidine: no significant effect on Cimetidine and Viramune can becimetidine PK parameters is seen. co-administered without doseadjustments.

Nevirapine Cmin  1.07

ANTITHROMBOTICS

Warfarin The interaction between nevirapine Close monitoring ofand the antithrombotic agent anticoagulation levels is warranted.warfarin is complex, with thepotential for both increases anddecreases in coagulation time whenused concomitantly.

CONTRACEPTIVES

Depo- DMPA AUC  Viramune co-administration didmedroxyprogesterone DMPA Cmin  not alter the ovulation suppressionacetate (DMPA) DMPA Cmax  effects of DMPA. DMPA and150 mg every 3 months Viramune can be co-administered

Nevirapine AUC  1.20 without dose adjustments.

Nevirapine Cmax  1.20

Ethinyl estradiol (EE) EE AUC  0.80 (0.67-0.97) Oral hormonal contraceptives0.035 mg EE Cmin ND should not be used as the sole

EE Cmax  0.94 (0.79-1.12) method of contraception in women

Norethindrone (NET) NET AUC  0.81 (0.70-0.93) taking Viramune (see section 4.4).

1.0 mg QD NET C ND Appropriate doses for hormonalmin

NET Cmax  0.84 (0.73-0.97) contraceptives (oral or other formsof application) other than DMPAin combination with Viramunehave not been established withrespect to safety and efficacy.

ANALGESICS/OPIOIDS

Methadone Individual Methadone AUC  0.40 Methadone-maintained patients

Patient Dosing (0.31-0.51) beginning Viramune therapy

Methadone Cmin ND should be monitored for evidence

Methadone Cmax  0.58 (0.50-0.67) of withdrawal and methadone doseshould be adjusted accordingly.

HERBAL PRODUCTS

St. John’s Wort Serum levels of nevirapine can be Herbal preparations containing St.

reduced by concomitant use of the John’s Wort and Viramune mustherbal preparation St. John’s Wort not be co-administered (see(Hypericum perforatum). This is section 4.3). If a patient is alreadydue to induction of medicinal taking St. John’s Wort checkproduct metabolism enzymes nevirapine and if possible viraland/or transport proteins by St. levels and stop St. John’s Wort.

John’s Wort. Nevirapine levels may increase onstopping St. John’s Wort. The doseof Viramune may need adjusting.

The inducing effect may persist forat least 2 weeks after cessation oftreatment with St. John’s Wort.

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

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

Currently available data on pregnant women indicate no malformative or foeto/ neonatal toxicity. Todate no other relevant epidemiological data are available. No observable teratogenicity was detected inreproductive studies performed in pregnant rats and rabbits (see section 5.3). There are no adequateand well-controlled studies in pregnant women. Caution should be exercised when prescribingnevirapine 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 morecopies/mL), these conditions should be taken in consideration on therapeutic decision (seesection 4.4). There is not enough evidence to substantiate that the absence of an increased risk fortoxicity seen in pre-treated women initiating nevirapine with an undetectable viral load (less than50 copies/mL of HIV-1 in plasma) and CD4+ cell counts above 250 cells/mm3 also applies to pregnantwomen. All the randomised studies addressing this issue specifically excluded pregnant women, andpregnant women were under-represented in cohort studies as well as in meta-analyses.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

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

There are no specific studies about the ability to drive vehicles and use machinery.

However, patients should be advised that they may experience adverse reactions such as fatigue duringtreatment with Viramune. Therefore, caution should be recommended when driving a car or operatingmachinery. If patients experience fatigue they should avoid potentially hazardous tasks such as drivingor operating machinery.

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-Johnsonsyndrome/ toxic epidermal necrolysis, serious hepatitis/hepatic failure, and drug reaction witheosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such asfever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis,eosinophilia, granulocytopenia, and renal dysfunction. The first 18 weeks of treatment is a criticalperiod which requires close monitoring (see section 4.4).

The following adverse reactions which may be causally related to the administration of Viramune havebeen reported. The frequencies estimated are based on pooled clinical study data for adverse reactionsconsidered 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).

Common granulocytopenia

Uncommon anaemia

Common hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria)

Uncommon anaphylactic reaction

Rare drug reaction with eosinophilia and systemic symptoms

Common headache

Common nausea, vomiting, abdominal pain, diarrhoea

Common hepatitis (including severe and life-threatening hepatotoxicity) (1.9%)

Uncommon jaundice

Rare hepatitis fulminant (which may be fatal)

Very common rash (12.5%)

Uncommon Stevens-Johnson syndrome/ toxic epidermal necrolysis (which may be fatal)(0.2%), angioedema, urticaria

Uncommon arthralgia, myalgia

Common pyrexia, fatigue

Common liver function test abnormal (alanine aminotransferase increased; transaminasesincreased; aspartate aminotransferase increased; gamma-glutamyltransferaseincreased; hepatic enzyme increased; hypertransaminasaemia)

Uncommon blood phosphorus decreased; blood pressure increased

In study 1100.1090, from which the majority of related adverse events (n = 28) were received, patientson 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 inrandomised, controlled clinical studies. The frequency category was estimated from a statisticalcalculation based on the total number of patients exposed to nevirapine in randomised controlledclinical studies (n = 2 718).

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

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (seesection 4.4)

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

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).

The frequency of this is unknown (see section 4.4).

The most common clinical toxicity of nevirapine is rash, with Viramune attributable rash occurring in12.5% of patients in combination regimens in controlled studies.

Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with orwithout 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 reactionwith eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such asfever, 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 anddrug reaction with eosinophilia and systemic symptoms have been reported. The majority of severerashes occurred within the first 6 weeks of treatment and some required hospitalisation, with onepatient requiring surgical intervention (see section 4.4).

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

Based on clinical study experience of 361 paediatric patients the majority of which receivedcombination treatment with ZDV or/and ddI, the most frequently reported adverse events related tonevirapine were similar to those observed in adults. Granulocytopenia was more frequently observedin children. In an open-label clinical study (ACTG 180) granulocytopenia assessed as medicinalproduct-related occurred in 5/37 (13.5%) of patients. In ACTG 245, a double-blind placebo controlledstudy, the frequency of serious medicinal product-related granulocytopenia was 5/305 (1.6%). Isolatedcases of Stevens-Johnson syndrome or Stevens-Johnson/ toxic epidermal necrolysis transitionsyndrome have been reported in this population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known antidote for nevirapine overdose. Cases of Viramune overdose at doses rangingfrom 800 to 6 000 mg per day for up to 15 days have been reported. Patients have experiencedoedema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash,vertigo, vomiting, increase in transaminases and weight decrease. All of these effects subsidedfollowing discontinuation of nevirapine.

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

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

Nevirapine is a NNRTI of HIV-1. Nevirapine is a non-competitive inhibitor of the HIV-1 reversetranscriptase, but it does not have a biologically significant inhibitory effect on the HIV-2 reversetranscriptase or on eukaryotic DNA polymerases , , , or .

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 panelof 2 923 predominantly subtype B HIV-1 clinical isolates, the mean EC50 value was 90 nM. Similar

EC50 values are obtained when the antiviral activity of nevirapine is measured in peripheral bloodmononuclear cells, monocyte derived macrophages or lymphoblastoid cell line. Nevirapine had noantiviral 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 fusioninhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combinationwith the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, saquinavir and tipranavir, andthe NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. Theanti-HIV-1 activity of nevirapine was antagonized by the anti-HBV medicinal product adefovir and bythe anti-HCV medicinal product ribavirin in vitro.

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 uponthe virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture wasnot 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 andstavudine for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained oneor more of the following NNRTI resistance-associated substitutions:

Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.

Rapid emergence of HIV-strains which are cross-resistant to NNRTIs has been observed in vitro.

Cross resistance to efavirenz is expected after virologic failure with nevirapine. Depending onresistance testing results, an etravirine-containing regimen may be used subsequently. Cross-resistancebetween nevirapine and either HIV protease inhibitors, HIV integrase inhibitors or HIV entryinhibitors is unlikely because the enzyme targets involved are different. Similarly the potential forcross-resistance between nevirapine and NRTIs is low because the molecules have different bindingsites on the reverse transcriptase.

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

Studies in treatment-naïve patients2NN study

The double non-nucleoside study 2 NN was a randomised, open-label, multicentre prospective studycomparing 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 baselinewere assigned to Viramune 400 mg once daily, Viramune 200 mg twice daily, efavirenz 600 mg oncedaily, or Viramune (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine for48 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 fromweek 24 onwards, or disease progression.

Median age was 34 years and about 64% were male patients, median CD4+ cell count was 170 and190 cells per mm3 in the Viramune twice daily and efavirenz groups, respectively. There were nosignificant differences in demographic and baseline characteristics between the treatment groups.

The predetermined primary efficacy comparison was between the Viramune twice daily and theefavirenz 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 treatmentfailure including virological failure.

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

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

2NN Three-year follow-up-study

This is a retrospective multicentre study comparing the 3-year antiviral efficacy of Viramune andefavirenz 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 thestudy 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 studyendpoints 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 equivalencewithin a 10% range was demonstrated between Viramune 200 mg twice daily and efavirenz withrespect to treatment failure. Both, the primary (p = 0.92) and secondary endpoints showed nostatistically 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 forpatients 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-transcriptaseinhibitors and at least one PI and whose plasma HIV-1 RNA levels had been less than 200 c/mL for atleast the previous six months to switch from the PI to Viramune (155 patients), efavirenz (156), orabacavir (149).

The primary study endpoint was death, progression to the acquired immunodeficiency syndrome, or anincrease 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 accordingto an intention-to-treat analysis).

The overall incidence of adverse events was significantly lower (61 patients, or 41%) in the abacavirgroup 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 productbecause of adverse events.

Perinatal Transmission

Numerous studies have been performed examining the use of Viramune in regards to perinataltransmission, most notably HIVNET 012. This study demonstrated a significant reduction intransmission 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 beenassociated with the development of NNRTI resistance. Single dose nevirapine in mothers or infantsmay lead to reduced efficacy if an HIV treatment regimen using nevirapine is later instituted within6 months or less in these patients. Combination of other antiretrovirals with single-dose nevirapineattenuates the emergence of nevirapine resistance. Where other antiretroviral medicines are accessible,the single dose Viramune regimen should be combined with additional effective antiretroviralmedicines (as recommended in internationally recognized guidelines).

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

Results of a 48-week analysis of the South African study BI 1100.1368 confirmed that the 4/7 mg/kgand 150 mg/m2 nevirapine dose groups were well tolerated and effective in treating antiretroviral naivepaediatric patients. A marked improvement in the CD4+ cell percent was observed through Week 48for both dose groups. Also, both dosing regimens were effective in reducing the viral load. In this48-week study no unexpected safety findings were observed in either dosing group.

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

Absorption: Nevirapine is readily absorbed (> 90%) after oral administration in healthy volunteers andin adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-doseadministration was 93  9% (mean SD) for a 50 mg tablet and 91  8% for an oral solution. Peakplasma nevirapine concentrations of 2  0.4 µg/mL (7.5 µM) were attained by 4 hours following asingle 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increaselinearly in the dose range of 200 to 400 mg/day. Data reported in the literature from 20 HIV-infectedpatients 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. Otherpublished data support these conclusions. Long-term efficacy appears to be most likely in patientswhose nevirapine trough levels exceed 3.5 µg/mL.

Distribution: Nevirapine is lipophilic and is essentially nonionized at physiologic pH. Followingintravenous administration to healthy adults, the volume of distribution (Vdss) of nevirapine was1.21  0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readilycrosses the placenta and is found in breast milk. Nevirapine is about 60% bound to plasma proteins inthe plasma concentration range of 1-10 µg/mL. Nevirapine concentrations in human cerebrospinalfluid (n = 6) were 45% ( 5%) of the concentrations in plasma; this ratio is approximately equal to thefraction not bound to plasma protein.

Biotransformation and elimination: In vivo studies in humans and in vitro studies with human livermicrosomes have shown that nevirapine is extensively biotransformed via cytochrome P450(oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human livermicrosomes 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 amass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately91.4 ± 10.5% of the radiolabelled dose was recovered, with urine (81.3 ± 11.1%) representing theprimary route of excretion compared to faeces (10.1 ± 1.5%). Greater than 80% of the radioactivity inurine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites representthe 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 parentcompound; 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. Thepharmacokinetics of autoinduction is characterized by an approximately 1.5 to 2 fold increase in theapparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeksof dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminalphase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately25-30 hours following multiple dosing with 200-400 mg/day.

Renal impairment: The single-dose pharmacokinetics of nevirapine has been compared in 23 patientswith either mild (50 ≤ CLcr < 80 mL/min), moderate (30 ≤ CLcr < 50 mL/min) or severe renaldysfunction (CLcr < 30 mL/min), renal impairment or end-stage renal disease (ESRD) requiringdialysis, 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 overa one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites inplasma. 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 nevirapineclearance. Otherwise patients with CLcr ≥ 20 mL/min do not require an adjustment in nevirapinedosing.

Hepatic impairment: A steady state study comparing 46 patients withmild (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 forat least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years. Inthis study, the multiple dose pharmacokinetic disposition of nevirapine and the five oxidativemetabolites were not altered.

However, approximately 15% of these patients with hepatic fibrosis had nevirapine troughconcentrations above 9 000 ng/mL (2 fold the usual mean trough). Patients with hepatic impairmentshould 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 andmoderate 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 patientswith worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemiccirculation. Because nevirapine induces its own metabolism with multiple dosing, this single dosestudy may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics (seesection 4.4).

Gender and elderly

In the multinational 2NN study, a population pharmacokinetic substudy of 1 077 patients wasperformed that included 391 females. Female patients showed a 13.8% lower clearance of nevirapinethan did male patients. This difference is not considered clinically relevant. Since neither body weightnor Body Mass Index (BMI) had influence on the clearance of nevirapine, the effect of gender cannotbe explained by body size. Nevirapine pharmacokinetics in HIV-1 infected adults does not appear tochange with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). Nevirapine has not beenspecifically investigated in patients over the age of 65.

Data concerning the pharmacokinetics of nevirapine have been derived from two major sources: a48 week paediatric study in South Africa (BI 1100.1368) involving 123 HIV-1 positive, antiretroviralnaïve 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 groupdemonstrated that clearance of nevirapine increased with increasing age in a manner consistent withincreasing body surface area. Dosing of nevirapine at 150 mg/m2 BID (after a two-week lead in at150 mg/m2 QD) produced geometric mean or mean trough nevirapine concentrations between4-6 µg/mL (as targeted from adult data). In addition, the observed trough nevirapine concentrationswere 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 therange observed in adults and the remainder of the paediatric population, but were more variablebetween patients, particularly in the second month of age.

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

Carbomer

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Sorbitol

Sucrose

Polysorbate 80

Sodium hydroxide (for pH-adjustment)

Purified water

Not applicable.

3 years

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

This medicinal product does not require any special storage conditions.

White high density polyethylene (HDPE) bottle with two piece child-resistant closure (outer shellwhite polyethylene, inner shell polypropylene) with a polyethylene liner. Each bottle contains 240 mLof oral suspension.

Instructions for administration:

Viramune oral suspension should be shaken gently prior to administration. The required dose volumesshould be measured employing a dispensing syringe. Viramune oral suspension should be used within6 months after first opening of the bottle.

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

Boehringer Ingelheim International GmbH

Binger Strasse 17355216 Ingelheim am Rhein

Germany

EU/1/97/055/002

Date of first authorisation: 5 February 1998

Date of latest renewal: 20 December 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.