VIRAMUNE 400mg prolonged tablets medication leaflet

Viramune 400 mg prolonged-release tablets

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

Each prolonged-release tablet contains 400 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Prolonged-release tablet

Yellow, oval, biconvex prolonged-release tablets. The prolonged-release tablets are about9.3 × 19.1 mm, debossed with V04 on one side and the company symbol on the other side. Theprolonged-release tablet should not be divided.

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 (seesection 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 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.

The recommended dose of Viramune for patients initiating nevirapine therapy is one 200 mgimmediate-release tablet daily for the first 14 days (this lead-in period should be used because it hasbeen found to lessen the frequency of rash), followed by one 400 mg prolonged-release tablet oncedaily, 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 otherantiretroviral agents can be switched to Viramune 400 mg prolonged-release tablets once daily incombination 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 concomitantlyadministered 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 themissed dose as soon as possible. If a dose is missed and it is more than 12 hours later, the patientshould only take the next dose at the usual time.

According to paediatric dose recommendations Viramune 400 mg prolonged-release tablets can bealso 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.

The safety and efficacy of Viramune prolonged-release tablets in children aged less than 3 years hasnot been established. No data are available.

For patients less than 3 years and for all other age, weight and BSA groups, an immediate-release oralsuspension dosage form is available (please refer to the respective Summary of Product

Characteristics).

The total daily dose at any time during treatment should not exceed 400 mg for any patient. Patientsshould 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 initiatetreatment with Viramune prolonged-release tablets until the rash has resolved. The isolated rashshould be closely monitored (see section 4.4). The 200 mg once daily Viramune immediate-releaselead-in dosing 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 of Viramune immediate-release.

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.

In adult patients with renal dysfunction requiring dialysis an additional 200 mg dose of nevirapineimmediate-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 renaldysfunction who are undergoing dialysis it is recommended that following each dialysis treatmentpatients receive an additional dose of Viramune oral suspension or immediate-release tabletsrepresenting 50% of the recommended daily dose of Viramune oral suspension or immediate-releasetablets 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.

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). Viramune prolonged-release tablets have not been studied in patients withhepatic impairment and Viramune immediate-release should be used.

The prolonged-release tablets shall be taken with liquid, and should not be broken or chewed.

Viramune can 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 immediate-releaseadministration) has been shown not to decrease the incidence of nevirapine-associated rash, and maybe associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapinetherapy.

Some risk factors for developing serious cutaneous reactions have been identified; they include failureto follow the initial dosing of 200 mg daily during the lead-in period and a long delay between theinitial symptoms and medical consultation. Women appear to be at higher risk than men of developingrash, 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 they should not begin Viramune prolonged-release tablets until anyrash 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 continuedbeyond 28 days at which point in time an alternative treatment should be sought due to the possiblerisk 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 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. In a retrospective analysis ofpooled clinical studies with Viramune immediate-release tablets, women had a three fold higher riskthan 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 atinitiation 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 reactionscompared to women with CD4+ counts < 250 cells/mm3 (11.0% versus 0.9%). An increased risk wasobserved 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 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.

For patients already on a regimen of Viramune immediate-release twice daily who switch to Viramuneprolonged-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 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 one immediate-release 200 mg Viramune tablet daily for 14 days followed byone Viramune 400 mg prolonged-release tablet daily. In these cases, more frequent livermonitoring is required. If liver function abnormalities recur, nevirapine should be permanentlydiscontinued.

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.

Lactose: Viramune prolonged-release tablets contain 400 mg lactose per maximum recommendeddaily 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.

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

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 Viramuneimmediate-release formulations).

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 Cmax  0.81 (0.62-0.95) (5 tablets with 100/25 mg each)twice 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

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

Metabolite 14-OH clarithromycin Close monitoring for hepatic

C  1.47 (1.21-1.80) abnormalities is recommendedmax

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 C  1.28 (1.09-1.51) is seen. Rifabutin and Viramunemaxcan 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 Cmin  0.32 administration of rifabutin instead.

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 C  0.62 two agents are administeredmaxconcomitantly.

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) relevant drug-drug interaction is adjustments.

expected.

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 C  0.84 (0.73-0.97) contraceptives (oral or other formsmaxof 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, patientsshould be advised that they may experience adverse reactions such as fatigue during treatment withnevirapine. Therefore, caution should be recommended when driving a car or operating machinery. Ifpatients experience fatigue they should avoid potentially hazardous tasks such as driving or operatingmachinery.

The most frequently reported adverse reactions related to Viramune prolonged-release therapy intreatment 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, abdominalpain, diarrhoea and pyrexia. There are no new adverse drug reactions for Viramune prolonged-releasetablets that have not been previously identified for Viramune immediate-release tablets and oralsuspension.

The nevirapine postmarketing experience has shown that the most serious adverse reactions are

Stevens-Johnson syndrome/toxic epidermal necrolysis, serious hepatitis/hepatic failure, and drugreaction with eosinophilia and systemic symptoms, characterised by rash with constitutional symptomssuch 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 criticalperiod which requires close monitoring (see section 4.4).

The following adverse reactions which may be causally related to the administration of Viramuneprolonged-release tablets have been reported. The frequencies given below are based on crudeincidence 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 ofclinical study 1100.1486 with 1 068 patients exposed to Viramune on a backbone oftenofovir/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

Uncommon granulocytopenia

Rare anaemia

Uncommon hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria), drug reactionwith eosinophilia and systemic symptoms, anaphylactic reaction

Common headache

Common abdominal pain, nausea, diarrhoea

Uncommon vomiting

Uncommon jaundice, hepatitis fulminant (which may be fatal)

Rare hepatitis (incl. severe and life-threatening hepatotoxicity)(0.09%)

Common rash (6.7%)

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

Uncommon arthralgia, myalgia

Common fatigue, pyrexia

Uncommon liver function test abnormal (alanine aminotransferase increased; transaminasesincreased; aspartate aminotransferase increased; gamma-glutamyltransferaseincreased; hepatic enzyme increased; hypertransaminasaemia), blood phosphorusdecreased, blood pressure increased

Table 2: Maintenance phase of Viramune prolonged-release

Uncommon anaemia, granulocytopenia

Uncommon hypersensitivity (incl. anaphylactic reaction, angioedema, urticaria), drug reactionwith eosinophilia and systemic symptoms, anaphylactic reaction

Common headache

Common abdominal pain, nausea, vomiting, diarrhoea

Common hepatitis (incl. severe and life-threatening hepatotoxicity) (1.6%)

Uncommon jaundice, hepatitis fulminant (which may be fatal)

Common rash (5.7%)

Uncommon Stevens-Johnson Syndrome/toxic epidermal necrolysis (which may be fatal)(0.6%), angioedema, urticaria

Uncommon arthralgia, myalgia

Common fatigue

Uncommon pyrexia

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

The following adverse reactions were identified in other nevirapine studies or by post-marketingsurveillance 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 andincreased blood pressure during the lead-in phase with Viramune immediate release were not seen instudy 1100.1486 the frequency category was estimated from a statistical calculation based on the totalnumber of patients exposed to nevirapine immediate-release in the lead-in phase of the randomisedcontrolled 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 phosphorusand increased blood pressure during maintenance phase with Viramune prolonged-release tablets werenot seen in study 1100.1486 the frequency category was estimated from a statistical calculation basedon the total number of patients exposed to nevirapine prolonged-release in the maintenance phase ofthe randomised controlled clinical study 1100.1486 (n = 505).

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. Rashes are usually mild to moderate,maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, faceand extremities. Hypersensitivity (incl. anaphylactic reaction, angioedema and urticaria) has beenreported. Rashes occur alone or in the context of drug reaction with eosinophilia and systemicsymptoms, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia andlympadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, andrenal 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).

In study 1100.1486 (VERxVE) antiretroviral-naïve patients received a lead-in dose of Viramune200 mg immediate-release once daily for 14 days (n = 1 068) and then were randomised to receiveeither Viramune 200 mg immediate-release twice daily or Viramune 400 mg prolonged-release oncedaily. All patients received tenofovir + emtricitabine as background therapy. Safety data included allthe patient visits up to the point in time when the last patient completed 144 weeks in the trial. Thisalso includes safety data for patient visits in the post-week 144 open label extension (which patients ineither 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 thelead-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 therandomised phase. No life-threatening (Grade 4) rash events considered related to Viramune werereported during the randomised phase of this study. Six cases of Stevens-Johnson Syndrome werereported 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 dailytreatment for at least 18 weeks were randomised to either receive Viramune 400 mg prolonged-releaseonce 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.

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).

In study 1100.1486 (VERxVE) treatment-naïve patients received a lead-in dose of Viramune 200 mgimmediate-release once daily for 14 days and then were randomised to receive either Viramune200 mg immediate-release twice daily or Viramune 400 mg prolonged-release once daily. All patientsreceived 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 hepaticevents were prospectively collected in this study. The safety data include all patient visits up to thetime of the last patient’s completion of study week 144. The incidence of symptomatic hepatic eventsduring the Viramune immediate-release lead-in phase was 0.5%. After the lead-in period the incidenceof 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 hepaticevents among men and women enrolled in VERxVE.

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

Based on clinical study experience with Viramune immediate-release tablets and oral suspension of361 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 inadults. 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%) ofpatients. In ACTG 245, a double-blind placebo controlled study, the frequency of serious medicinalproduct-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 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 overdose with Viramune immediate-release at doses ranging from 800 to 6 000 mg per day for up to 15 days have been reported. Patientshave experienced oedema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonaryinfiltrates, rash, vertigo, vomiting, increase in transaminases and weight decrease. All of these effectssubsided following 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.

Genotypic analysis was performed on isolates from 86 antiretroviral naïve patients who discontinuedthe VERxVE study (1100.1486) after experiencing virologic failure (rebound, partial response) or dueto an adverse event or who had transient increase in viral load during the course of the study. Theanalysis of these samples of patients receiving Viramune immediate-release twice daily or Viramuneprolonged-release once daily in combination with tenofovir and emtricitabine showed that isolatesfrom 50 patients contained resistance mutations expected with a nevirapine-based regimen. Of these50 patients, 28 developed resistance to efavirenz and 39 developed resistance to etravirine (the mostfrequently emergent resistance mutation being Y181C). There were no differences based on theformulation taken (immediate-release twice daily or prolonged-release once daily).

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

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-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 thepotential for cross-resistance between nevirapine and NRTIs is low because the molecules havedifferent binding sites on the reverse transcriptase.

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

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 patientsand on 24-week data from a randomised, open-label study in patients who transitioned from Viramuneimmediate-release tablets administered twice daily to Viramune prolonged-release tabletsadministered once daily (TRANxITION - study 1100.1526).

VERxVE (study 1100.1486) is a phase 3 study in which treatment-naïve patients received Viramune200 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 stratifiedby screening HIV-1 RNA level (≤ 100 000 copies/mL and > 100 000 copies/mL). Selecteddemographic and baseline disease characteristics are displayed in Table 1.

Table 1: Demographic and Baseline Disease Characteristics in study 1100.1486

Viramune Viramuneimmediate-release prolonged-releasen = 508* n = 505

- Male 85% 85%

- Female 15% 15%

- 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 allpatients who were randomised after the 14 day lead-in with Viramune immediate-release and receivedat least one dose of blinded medicinal product.

Table 2: Outcomes at week 48 in study 1100.1486*

Viramune Viramuneimmediate-release prolonged-releasen = 506 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. Patientswho 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 forthe 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%

Viramune Viramune (95% CI)immediate-release prolonged-release

Baseline HIV−1 viral loadstratum (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. Patientswho 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 whostopped treatment during the lead in phase and two patients randomized but never treated withrandomized dose. The numerator 793 is the number of patients who were treatment responders at48 weeks (384 from immediate-release and 409 from prolonged-release treatment groups).

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 Viramuneimmediate-release prolonged-release

Baseline Week 48 Percent Baseline Week 48 Percent(mean) (mean) change* (mean) (mean) change*n = 503 n = 407 n = 406 n = 505 n = 419 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 andweek 48 values and is not a simple difference of the baseline and week 48 mean values, respectively.

TRANxITION (study 1100.1526) is a Phase 3 study to evaluate safety and antiviral activity in patientsswitching 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 twicedaily with HIV-1 RNA < 50 copies/mL were randomised in a 2:1 ratio to Viramune 400 mgprolonged-release once daily or Viramune 200 mg immediate-release twice daily. Approximately halfof the patients had tenofovir + emtricitabine as their background therapy, with the remaining patientsreceiving abacavir sulfate + lamivudine or zidovudine + lamivudine. Approximately half of thepatients had at least 3 years of prior exposure to Viramune immediate-release prior to enteringstudy 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.

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.

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 whendosed 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 was2 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 dosepharmacokinetics 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 oncedaily were approximately 80% and 90%, respectively, of the AUC0-24,ss and Cmin,ss measured whenpatients were dosed with Viramune 200 mg immediate-release tablets twice daily. The geometricmean 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,sswere approximately 94% and 98%, respectively, of the AUC0-24,ss and Cmin,ss measured when patientswere dosed with Viramune immediate-release tablets. The difference in nevirapine pharmacokineticsobserved when Viramune prolonged-release tablets are dosed under fasted or fed conditions is notconsidered 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.

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 characterised 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 immediate-release has beencompared 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 renaldisease (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 thepharmacokinetics 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 ofnevirapine hydroxy-metabolites in plasma. The results suggest that supplementing nevirapine therapyfor adults with an additional 200 mg immediate-release tablet following each dialysis treatment wouldhelp offset the effects of dialysis on nevirapine clearance. Otherwise patients with CLcr ≥ 20 mL/mindo not require an adjustment in nevirapine dosing. In paediatric patients with renal dysfunction whoare undergoing dialysis it is recommended following each dialysis treatment patients receive anadditional dose of Viramune oral suspension or immediate-release tablets representing 50% of therecommended daily dose of Viramune oral suspension or immediate-release tablets, which would helpoffset the effects of dialysis on nevirapine clearance. Viramune prolonged-release tablets have notbeen studied in patients with renal dysfunction and Viramune immediate-release should be used.

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 immediate-release tablets twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a medianduration of therapy of 3.4 years. In this study, the multiple dose pharmacokinetic disposition ofnevirapine and the five oxidative metabolites 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 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 Bpatient with ascites suggesting that patients with worsening hepatic function and ascites may be at riskof accumulating nevirapine in the systemic circulation. Because nevirapine induces its ownmetabolism with multiple dosing, this single dose study may not reflect the impact of hepaticimpairment on multiple dose pharmacokinetics (see section 4.4). Viramune prolonged-release tabletshave not been evaluated in patients with hepatic impairment and Viramune immediate-release shouldbe used.

In the multinational 2NN study with Viramune immediate-release, a population pharmacokineticsubstudy 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 clinicallyrelevant. Since neither body weight nor Body Mass Index (BMI) had influence on the clearance ofnevirapine, the effect of gender cannot be explained by body size.

The effects of gender on the pharmacokinetics of Viramune prolonged-release have been investigatedin study 1100.1486. Female patients tend to have higher (approximately 20-30%) troughconcentrations in both Viramune prolonged-release and Viramune immediate-release treatmentgroups.

Nevirapine pharmacokinetics in HIV-1 infected adults does not appear to change with age (range18-68 years). Nevirapine has not been specifically investigated in patients over the age of 65. Blackpatients (n = 80/group) in study 1100.1486 showed approximately 30% higher trough concentrationsthan 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.

Data concerning the pharmacokinetics of nevirapine has 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.

The pharmacokinetics of Viramune prolonged-release was assessed in study 1100.1518. Eighty-fivepatients (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 × 100 mg, 3 × 100 mg or 1 × 400 mg once daily) in combination with other antiretrovirals for10 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 ratiofor Cmax,ss was lower and consistent with a once-daily prolonged-release dosage form. Geometric meansteady-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 ofage, 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 Viramune50 and 100 mg prolonged-release tablets exhibited extended release characteristics of prolongedabsorption 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.

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.

Lactose (as monohydrate)

Hypromellose

Iron oxide yellow

Magnesium stearate

Not applicable.

3 years

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

This medicinal product does not require any special storage conditions.

Polyvinyl chloride (PVC)/aluminium foil push-through blister units. Cartons containing30 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.

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/1/97/055/007 (30 tablets, bottle)

EU/1/97/055/008 (30 tablets, blister)

EU/1/97/055/009 (90 tablets, blister)

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.