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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nevirapine Mylan 200 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200 mg of nevirapine anhydrous.

Excipient with known effect:

Each 200 mg tablet contains 464 mg of lactose monohydrate .

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

A white to off-white oval, biconvex tablet of 19 mm debossed with “NE” and “200” on one side of the tablet, separated by a score line and debossed with “M” on the other side, with a score line.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nevirapine Mylan is indicated in combination with other anti-retroviral medicinal products for treatment of HIV-1 infected adults, adolescents, and children of any age (see section 4.4).

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

4.2 Posology and method of administration

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

Posology

Patients 16 years and older

The recommended dose of Nevirapine Mylan is one 200 mg tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily, in combination with at least two additional antiretroviral agents.

If a dose is recognised as missed within 8 hours of when it was due, the patient should take the missed dose as soon as possible. If a dose is missed and it is more than 8 hours later, the patient should only take the next dose at the usual time.

Dose management considerations

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

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

For toxicities that require interruption of nevirapine therapy, see section 4.4.

Special populations Renal impairment

For patients with renal dysfunction requiring dialysis an additional 200 mg dose of nevirapine following each dialysis treatment is recommended. Patients with CLcr > 20 ml/min do not require a dose adjustment, see section 5.2.

Hepatic impairment

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

Elderly

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

Paediatric population

Nevirapine Mylan 200 mg tablets, following the dosing schedule described above, are suitable for larger children, particularly adolescents, below the age of 16 who weigh more than 50 kg or whose body surface area is above 1.25 m² according to the Mosteller formula.

An oral suspension dosage form, which can be dosed according to body weight or body surface area, is available for children in this age group weighing less than 50 kg or whose body surface area is below 1.25 m² (please refer to a Summary of Product Characteristics of nevirapine oral suspension).

Method of administration

For oral use.

The tablets shall be taken with liquid, and should not be crushed or chewed. This medicine may be taken with or without food.

An oral suspension dosage form is available for patients who have difficulty swallowing tablets (please refer to a Summary of Products Characteristics of nevirapine oral suspension).

4.3 Contraindications

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

Nevirapine must not be re-administered to patients who have required permanent discontinuation for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to nevirapine.

Nevirapine must not be used in patients with severe hepatic impairment (Child-Pugh C) or pretreatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN.

Nevirapine must not be re-administered in patients who previously had ASAT or ALAT > 5 ULN during nevirapine therapy and had recurrence of liver function abnormalities upon readministration of nevirapine (see section 4.4).

Herbal preparations containing St John's Wort (Hypericum perforatum) must not be used while taking Nevirapine Mylan due to the risk of decreased plasma concentrations and reduced clinical effects of nevirapine (see section 4.5).

4.4 Special warnings and precautions for use

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

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

Cutaneous reactions

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

The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of nevirapine, nevirapine must not be restarted in this patient at any time.

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

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

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

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

Patients should be instructed that a major toxicity of nevirapine is rash. They should be advised to promptly notify their physician of any rash and avoid delay between the initial symptoms and medical consultation. The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Therefore, patients should be monitored carefully for the appearance of rash during this period. Patients should be instructed that dose escalation is not to occur if any rash occurs during the two-week lead-in dosing period, until the rash resolves. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point in time an alternative treatment should be sought due to the possible risk of underexposure and resistance.

Hepatic reactions

Severe and life-threatening hepatoxicity, including fatal fulminant hepatitis, has occurred in patients treated with nevirapine. The first 18 weeks of treatment is a critical period which requires close monitoring. The risk of hepatic events is greatest in the first 6 weeks of therapy. However the risk continues past this period and monitoring should continue at frequent intervals throughout treatment.

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

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

Female gender and higher CD4 counts at the initiation of nevirapine therapy in treatment-naive patients is associated with increased risk of hepatic adverse events. Women have a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and treatment-naive patients of either gender with detectable HIV-1 RNA in plasma with higher CD4 counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review of predominantly patients with a plasma HIV-1 viral load of 50 copies/ml or higher, women with CD4 counts >250 cells/mm³ had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts < 250 cells/mm³ (11.0% versus 0.9%). An increased risk was observed in men with detectable HIV-1 RNA in plasma and CD4 counts > 400 cells/mm³ (6.3% versus 1.2% for men with CD4 counts < 400 cells/mm³). This increased risk for toxicity based on CD4 count thresholds has not been detected in patients with undetectable (i.e. < 50 copies/ml) plasma viral load.

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

Liver monitoring

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

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

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

Monitoring of hepatic tests should be done every two weeks during the first 2 months of treatment, at the 3rd month and then regularly thereafter. Liver test monitoring should be performed if the patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity.

If ASAT or ALAT > 2.5 ULN before or during treatment, then liver tests should be monitored more frequently during regular clinic visits. Nevirapine must not be administered to patients with pre-treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN (see section 4.3).

Liver Disease

The safety and efficacy of nevirapine has not been established in patients with significant underlying liver disorders. Nevirapine is contraindicated in patients with severe hepatic impairment (Child-Pugh C, see section 4.3). Pharmacokinetic results suggest caution should be exercised when nevirapine is administered to patients with moderate hepatic dysfunction (Child-Pugh B). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In the case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Other warnings

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

Combination therapy with nevirapine is not a curative treatment of patients infected with HIV-1; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Hormonal methods of birth control other than Depo-medroxyprogesterone acetate (DMPA) should not be used as the sole method of contraception in women taking nevirapine, since nevirapine might lower the plasma concentrations of these medications. For this reason, and to reduce the risk of HIV transmission, barrier contraception (e.g., condoms) is recommended. Additionally, when postmenopausal hormone therapy is used during administration of nevirapine, its therapeutic effect should be monitored.

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

In clinical studies, nevirapine has been associated with an increase in HDL- cholesterol and an overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies with nevirapine on modifying the cardiovascular risk in HIV infected patients, the clinical impact of these findings is not known. The selection of antiretroviral drugs must be guided primarily by their antiviral efficacy.

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

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine is not recommended. Furthermore, combining the following compounds with nevirapine is not recommended: efavirenz, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (in combination with cobicistat), atazanavir (in combination with ritonavir), boceprevir; fosamprenavir (if not co-administered with low dose ritonavir) (see section 4.5).

Granulocytopenia is commonly associated with zidovudine. Therefore, patients who receive nevirapine and zidovudine concomitantly and especially paediatric patients and patients who receive higher zidovudine doses or patients with poor bone marrow reserve, in particular those with advanced HIV disease, have an increased risk of granulocytopenia. In such patients haematological parameters should be carefully monitored.

Lactose: Nevirapine Mylan tablets contain 464 mg of lactose per maximum recommended daily dose.

Patients with rare hereditary problems of galactose intolerance the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

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

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

Medicinal products by therapeutic areas	Interaction	Recommendations concerning coadministration
ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine 100 mg - 150 mg BID	Didanosine AUC <->■ 1.08 (0.921.27) Didanosine Cmin ND Didanosine Cmax <->■ 0.98 (0.791.21)	Didanosine and nevirapine can be co-administered without dose adjustments.
Emtricitabine	Emtricitabine is not an inhibitor of human CYP 450 enzymes.	Nevirapine and emtricitabine may be co-administered without dose adjustments.
Abacavir	In human liver microsomes, abacavir did not inhibit cytochrome P450 isoforms.	Nevirapine and abacavir may be co-administered without dose adjustments.
Lamivudine 150 mg BID	No changes to lamivudine apparent clearance and volume of distribution, suggesting no induction effect of nevirapine on lamivudine clearance.	Lamivudine and nevirapine can be co-administered without dose adjustments.
Stavudine: 30/40 mg BID	Stavudine AUC ^ 0.96 (0.89-1.03) Stavudine Cmin ND Stavudine Cmax <->■ 0.94 (0.86-1.03) Nevirapine: compared to historical controls, levels appeared to be unchanged.	Stavudine and nevirapine can be coadministered without dose adjustments.

Tenofovir 300 mg QD	Tenofovir plasma levels remain unchanged when co-administered with nevirapine. Nevirapine plasma levels were not altered by co-administration of tenofovir.	Tenofovir and nevirapine can be coadministered without dose adjustments.
Zidovudine	Zidovudine J.AUC 0.72 (0.60-	Zidovudine and nevirapine can be
	0.96)	co-administered without dose
100-200 mg TID	Zidovudine Cmin ND	adjustments Granulocytopenia is commonly
	Zidovudine Cmax J.0.70 (0.49-1.04)	associated with zidovudine. Therefore, patients who receive nevirapine and zidovudine concomitantly and especially
	Nevirapine: Zidovudine had no	paediatric patients and patients who
	effect its pharmacokinetics.	receive higher zidovudine doses or patients with poor bone marrow reserve, in particular those with advanced HIV disease, have an increased risk of granulocytopenia. In such patients haematological parameters should be carefully monitored.
NNRTIs
Efavirenz	Efavirenz AUC J.0.72 (0.66-0.86)	It is not recommended to coadminister efavirenz and nevirapine
600 mg QD	Efavirenz Cmin J.0.68 (0.65-0.81)	(see section 4.4), because of additive toxicity and no benefit in
	Efavirenz Cmax J.0.88 (0.77-1.01)	terms of efficacy over either NNRTI alone alone (for results of 2NN study, see section 5.1).
Delavirdine	Interaction has not been studied.	The concomitant administration of nevirapine with NNRTIs is not recommended (see section 4.4).
Etravirine	Concomitant use of etravirine with	The concomitant administration of
	nevirapine may cause a significant	nevirapine with NNRTIs is not
	decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine.	recommended (see section 4.4).
Rilpivirine	Interaction has not been studied.	The concomitant administration of nevirapine with NNRTIs is not recommended (see section 4.4).

PIs
Atazanavir/ritonavir	Atazanavir/r 300/100mg :	It is not recommended to co-
300/100 mg QD		administer atazanavir/ritonavir and
400/100 mg QD	Atazanavir/r AUC | 0.58 (0.48-0.71) Atazanavir/r Cmm J, 0.28 (0.20-0.40) Atazanavir/r Cmax J.0.72 (0.60-0.86) Atazanavir/r 400/100mg: Atazanavir/r AUC J, 0.81 (0.65-1.02) Atazanavir/r Cmm J, 0.41 (0.27-0.60) Atazanavir/r Cmax <->■ 1.02 (0.85-1.24) (compared to 300/100mg without nevirapine) Nevirapine AUC f 1.25 (1.17-1.34) Nevirapine Cmin j 1.32 (1.22-1.43) Nevirapine Cmaxt 1.17 (1.09-1.25)	nevirapine (see section 4.4).
Darunavir/ritonavir 400/100	Darunavir AUC f 1.24 (0.97-1.57)	Darunavir and nevirapine can be co-
mg BID		administered without dose
	Darunavir Cmin <->■ 1.02 (0.79-1.32) Darunavir Cmax j 1.40 (1.14-1.73) Nevirapine AUC f 1.27 (1.12-1.44) Nevirapine Cmm"f 1 47 (1.20-1.82) Nevirapine Cmax t 1 18 (1.02-1.37)	adjustments.
Fosamprenavir	Amprenavir AUC J, 0.67 (0.55-0.80)	It is not recommended to coadminister fosamprenavir and
1400 mg BID	Amprenavir Cmin J.0.65 (0.49-0.85)	nevirapine if fosamprenavir is not co-administered with ritonavir (see
	Amprenavir Cmax J.0.75 (0.63-0.89) Nevirapine AUC f 1.29 (1.19-1.40) Nevirapine Cmint 1.34 (1.21-1.49) Nevirapine Cmaxt 1.25 (1.14-1.37)	section 4.4).
Fosamprenavir/ritonavir	Amprenavir AUC <->■ 0.89 (0.77-1.03)	Fosamprenavir/ritonavir and
700/100 mg BID		nevirapine can be co-administered
	Amprenavir Cmin J, 0.81 (0.69-0.96) Amprenavir Cma^^-*- 0.97 (0.85-1.10) Nevirapine AUC f 1.14 (1.05-1.24) Nevirapine Cmint 1.22 (1.10-1.35) Nevirapine Cmaxt 1.13 (1.03-1.24)	without dose adjustments

Lopinavir/ritonavir (capsules) 400/100 mg BID	Adult patients : Lopinavir AUC | 0.73 (0.53-0.98) Lopinavir Cmm J, 0.54 (0.28-0.74) Lopinavir Cmax J, 0.81 (0.62-0.95)	An increase in the dose of lopinavir/ritonavir to 533/133 mg (4 capsules) or 500/125 mg (5 tablets with 100/25 mg each) twice daily with food is recommended in combination with nevirapine. Dose adjustment of nevirapine is not required when co-administered with lopinavir.
Lopinavir/ritonavir (oral solution) 300/75 mg/m2 BID	Paediatric patients : Lopinavir AUC | 0.78 (0.56-1.09) Lopinavir Cmm J, 0.45 (0.25-0.82) Lopinavir Cmax J, 0.86 (0.64-1.16)	For children, increase of the dose of lopinavir/ritonavir to 300/75 mg/m2 twice daily with food should be considered when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Ritonavir 600 mg BID	Ritonavir AUC^ 0.92 (0.79-1.07) Ritonavir Cmm^ 0.93 (0.76-1.14) Ritonavir Cmax <->■ 0.93 (0.78-1.07)	Ritonavir and nevirapine can be coadministered without dose adjustments.
	Nevirapine: Co-administration of ritonavir does not lead to any clinically relevant change in nevirapine plasma levels.
Saquinavir/ritonavir	The limited data available with saquinavir soft gel capsule boosted with ritonavir do not suggest any clinically relevant interaction between saquinavir boosted with ritonavir and nevirapine	Saquinavir/ritonavir and nevirapine can be co-administered without dose adjustments.
Tipranavir/ritonavir 500/200 mg BID	No specific drug-drug interaction study has been performed. The limited data available from a phase IIa study in HIV-infected patients have shown a clinically non significant 20% decrease of TPV Cmin.	Tipranavir and nevirapine can be co-administered without dose adjustments
ENTRY INHIBITORS
Enfuvirtide	Due to the metabolic pathway no clinically significant pharmacokinetic interactions are expected between enfuvirtide and nevirapine.	Enfuvirtide and nevirapine can be co-administered without dose adjustments.
Maraviroc 300 mg QD	Maraviroc AUC ^ 1.01 (0.6 -1.55) Maraviroc Cmin ND Maraviroc Cmax^-> 1.54 (0.94-2.52) compared to historical controls	Maraviroc and nevirapine can be co-administered without dose adjustments.
	Nevirapine concentrations not measured, no effect is expected.
INTEGRASE INHIBITORS

Elvitegravir/ cobicistat	Interaction has not been studied. Cobicistat, a cytochrome P450 3A inhibitor significantly inhibits hepatic enzymes, as well as other metabolic pathways. Therefore co-administration would likely result in altered plasma levels of cobicistat and nevirapine.	Co-administration of nevirapine with elvitegravir in combination with cobicistat is not recommended (see section 4.4).
Raltegravir 400 mg BID	No clinical data available. Due to the metabolic pathway of raltegravir no interaction is expected.	Raltegravir and nevirapine can be co-administered without dose adjustments.
ANTIBIOTICS
Clarithromycin 500 mg BID	Clarithromycin AUC J, 0.69 (0.620.76) Clarithromycin Cmin J, 0.44 (0.30-0.64) Clarithromycin Cmax J, 0.77 (0.69-0.86) Metabolite 14-OH clarithromycin AUC f 1.42 (1.16-1.73) Metabolite 14-OH clarithromycin Cmin ^ 0 (0.68-1.49) Metabolite 14-OH clarithromycin Cmax! 1.47 (1.21-1.80) Nevirapine AUC f 1.26 Nevirapine Cmm"f 1.28 Nevirapine Cmax"f 1.24 compared to historical controls.	Clarithromycin exposure was significantly decreased, 14-OH metabolite exposure increased. Because the clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex overall activity against the pathogen may be altered. Alternatives to clarithromycin, such as azithromycin should be considered. Close monitoring for hepatic abnormalities is recommended

Rifabutin	Rifabutin AUC t 1.17 (0.98-1.40)	No significant effect on rifabutin and nevirapine mean PK parameters
150 or 300 mg QD	Rifabutin Cmm^ 1.07 (0.84-1.37)	is seen. Rifabutin and nevirapine can be co-administered without
	Rifabutin CmaxT 1.28 (1.09-1.51)	dose adjustments. However, due to the high interpatient variability some patients may experience large
	Metabolite 25-O-desacetylrifabutin	increases in rifabutin exposure and may be at higher risk for rifabutin
	AUC f 1.24 (0.84-1.84)	toxicity. Therefore, caution should be used in concomitant
	Metabolite 25-O-desacetylrifabutin	administration.
	Cminf 1.22 (0.86-1.74)
	Metabolite 25-O-desacetylrifabutin
	Cmaxf 1.29 (0.98-1.68)
	A clinically not relevant increase in the apparent clearance of nevirapine (by 9%) compared to historical data was reported.
Rifampicin	Rifampicin AUC ^ 1.11 (0.96-1.28)	It is not recommended to coadminister rifampicin and
600 mg QD	Rifampicin Cmin ND	nevirapine (see section 4.4). Physicians needing to treat patients
	Rifampicin Cmax^-> 1.06 (0.91-1.22)	co-infected with tuberculosis and using a nevirapine containing
	Nevirapine AUC J, 0.42	regimen may consider coadministration of rifabutin instead.
	Nevirapine CminJ, 0.32
	Nevirapine Cmax J.0.50
	compared to historical controls.
ANTIFUNGALS
Fluconazole	Fluconazole AUC ^ 0.94 (0.88-1.01)	Because of the risk of increased exposure to nevirapine, caution
200 mg QD	Fluconazole Cmin^ 0.93 (0.86-1.01)	should be exercised if the medicinal products are given concomitantly
	Fluconazole Cmax^-> 0.92 (0.85-0.99)	and patients should be monitored closely
	Nevirapine: exposure: '['100% compared with historical data where nevirapine was administered alone.

Itraconazole 200 mg QD	Itraconazole AUC J, 0.39 Itraconazole Cmin J, 0.13 Itraconazole Cmax J, 0.62 Nevirapine: there was no significant difference in nevirapine pharmacokinetic parameters.	A dose increase for itraconazole should be considered when these two agents are administered concomitantly.
Ketoconazole 400 mg QD	Ketoconazole AUC J, 0.28 (0.200.40) Ketoconazole Cmin ND Ketoconazole Cmax J, 0.56 (0.420.73) Nevirapine: plasma levels: j 1.151.28 compared to historical controls.	It is not recommended to coadminister ketoconazole and nevirapine (see section 4.4).
ANTIVIRALS FOR CHRONIC HEPATITIS B AND C
Adefovir	Results of in vitro studies showed a weak antagonism of nevirapine by adefovir (see section 5.1), this has not been confirmed in clinical trials and reduced efficacy is not expected. Adefovir did not influence any of the common CYP isoforms known to be involved in human drug metabolism and is excreted renally. No clinically relevant drug-drug interaction is expected.	Adefovir and nevirapine may be coadministered without dose adjustments.
Boceprevir	Boceprevir is partly metabolised by CYP3A4/5. Co-administration of boceprevir with medicines that induce or inhibit CYP3A4/5 could increase or decrease exposure. Plasma trough concentrations of boceprevir were decreased when administered with an NNRTI with a similar metabolic pathway as nevirapine. The clinical outcome of this observed reduction of boceprevir trough concentrations has not been directly assessed	It is not recommended to coadminister boceprevir and nevirapine (see section 4.4).
Entecavir	Entecavir is not a substrate, inducer or an inhibitor of cytochrome P450 (CYP450) enzymes. Due to the metabolic pathway of entecavir, no clinically relevant drug-drug interaction is expected.	Entecavir and nevirapine may be co-administered without dose adjustments.
Interferons (pegylated interferons alfa 2a and alfa 2b)	Interferons have no known effect on CYP 3A4 or 2B6. No clinically relevant drug-drug interaction is expected.	Interferons and nevirapine may be co-administered without dose adjustments.

Ribavirin	Results of in vitro studies showed a weak antagonism of nevirapine by ribavirin (see section 5.1), this has not been confirmed in clinical trials and reduced efficacy is not expected. Ribavirin does not inhibit cytochrome P450 enzymes, and there is no evidence from toxicity studies that ribavirin induces liver enzymes. No clinically relevant drug-drug interaction is expected.	Ribavirin and nevirapine may be co-administered without dose adjustments.
Telaprevir	Telaprevir is metabolised in the liver by CYP3A and is a P-glycoprotein substrate. Other enzymes may be involved in the metabolism. Co- administration of telaprevir and medicinal products that induce CYP3A and/or P-gp may decrease telaprevir plasma concentrations. No drug-drug interaction study of telaprevir with nevirapine has been conducted, however, interaction studies of telaprevir with an NNRTI with a similar metabolic pathway as nevirapine demonstrated reduced levels of both. Results of DDI studies of telaprevir with efavirenz indicate that caution should be exercised when coadministering telaprevir with P450 inducers.	Caution should be exercised when co-administering telaprevir with nevirapine. If co-administered with nevirapine an adjustment in the telaprevir dose should be considered.
Telbivudine	Telbivudine is not a substrate, inducer or inhibitor of the cytochrome P450 (CYP450) enzyme system. Due to the metabolic pathway of telbivudine, no clinically relevant drug-drug interaction is expected.	Telbivudine and nevirapine may be co-administered without dose adjustments.
ANTACIDS
Cimetidine	Cimetidine: no significant effect on cimetidine PK parameters is seen.	Cimetidine and nevirapine can be co-administered without dose adjustments.
	Nevirapine Cmm| 1.07
ANTITHROMBOTICS
Warfarin	The interaction between nevirapine and the antithrombotic agent warfarin is complex, with the potential for both increases and decreases in coagulation time when used concomitantly.	Close monitoring of anticoagulation levels is warranted
CONTRACEPTIVES

Depo-medroxyprogesterone acetate (DMPA) 150 mg every 3 months	DMPA AUC ^ DMPA Cmm^ DMPA Cmax^	Nevirapine co-administration did not alter the ovulation suppression effects of DMPA. DMPA and nevirapine can be co-administered without dose adjustments.
	Nevirapine AUC f 1.20
	Nevirapine Cmaxt 1.20
Ethinyl estradiol (EE) 0.035 mg	EE AUC 0.80 (0.67 - 0.97) EE Cmin ND EE Cmax^ 0.94 (0.79 - 1.12)	Oral hormonal contraceptives should not be used as the sole method of contraception in women taking nevirapine (see section 4.4). Appropriate doses for hormonal
Norethindrone (NET) 1.0 mg QD	NET AUCJ, 0.81 (0.70 - 0.93) NET Cmn ND NET Cmax |0.84 (0.73 - 0.97)	contraceptives (oral or other forms of application) other than DMPA in combination with nevirapine have not been established with respect to safety and efficacy.
ANALGESICS/OPIOIDS
Methadone Individual Patient Dosing	Methadone AUC f 0.40 (0.31 -0.51) Methadone Cmin ND Methadone Cmax J, 0.58 (0.50 -0.67)	Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
HERBAL PRODUCTS
St. John's Wort	Serum levels of nevirapine can be reduced by concomitant use of the herbal preparation St. John's Wort (Hypericum perforatum). This is due to induction of drug metabolism enzymes and/or transport proteins by St. John's Wort.	Herbal preparations containing St. John's Wort and nevirapine must not be co-administered (see section 4.3). If a patient is already taking St. John's Wort check nevirapine and if possible viral levels and stop St John's Wort. Nevirapine levels may increase on stopping St John's Wort. The dose of nevirapine may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St. John's Wort.

Other information:

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should not use oral contraceptives as the sole method for birth control, since nevirapine might lower the plasma concentrations of these medications (see sections 4.4 & 4.5).

Pregnancy

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

Breast-feeding

Nevirapine readily crosses the placenta and is found in breast milk.

It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV and that, mothers should discontinue breast-feeding if they are receiving nevirapine

Fertility

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

4.7 Effects on ability to drive and use machines

No specific studies on the effects on the ability to drive and use machines have been performed.

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

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions related to nevirapine therapy, across all clinical trials, were rash, allergic reactions, hepatitis, abnormal liver function tests, nausea, vomiting, diarrhoea, abdominal pain, fatigue, fever, headache and myalgia.

Tabulated summary of adverse reactions

The following adverse reactions which may be causally related to the administration of nevirapine have been reported. The frequencies estimated are based on pooled clinical trial data for events considered related to nevirapine 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), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Common: granulocytopenia Uncommon: anaemia Immune system disorders

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

Uncommon: anaphylactic reaction

Rare: drug rash with eosinophilia and systemic symptoms

Nervous system disorders

Common: headache

Gastrointestinal disorders

Common: nausea, vomiting, abdominal pain, diarrhoea Hepatobiliary disorders

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

Uncommon j aundice

Rare: hepatitis fulminant (which may be fatal)

Skin and subcutaneous tissue

Very common: rash (12.5%)

Uncommon: Severe cutaneous adverse reactions (SCARs): Stevens Johnson Syndrome and toxic epidermal necrolysis (which may be fatal) (0.2%), angioedema, urticaria (see section 4.4).

Musculoskeletal and connective tissue disorders

Uncommon: arthralgia, myalgia

General disorders and administration site conditions

Common: pyrexia, fatigue

Investigations

Common: liver function tests abnormal (alanine amino transferase increased; transaminases increased; aspartate aminotransferase increased; gamma-glutamyltransferase increased; hepatic enzyme increased; hypertransaminasaemia)

Uncommon: blood phosphorus decreased; blood pressure increased

Description of selected adverse reactions

In study 1100.1090, from which the majority of related adverse events (n=28) were received, patients on placebo had a higher incidence of events of granulocytopenia (3.3%) than patients on nevirapine (2.5%).

Anaphylactic reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical studies. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to nevirapine in randomised controlled clinical studies (n= 2,718).

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

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV infected patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

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

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

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

Skin and subcutaneous tissue

The most common clinical toxicity of nevirapine is rash, with nevirapine attributable rash occurring in 12.5% of patients in combination regimens in controlled studies.

Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Hypersensitivity (anaphylactic reaction, angioedema and urticaria) have been reported. Rashes occur alone or in the context of drug rash with eosinophilia and systemic symptoms, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lympadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction.

Severe and life-threatening skin reactions have occurred in patients treated with nevirapine, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Fatal cases of SJS, TEN and a drug rash with eosinophilia and systemic symptoms have been reported. The majority of severe rashes occurred within the first 6 weeks of treatment and some required hospitalisation, with one patient requiring surgical intervention (see section 4.4).

Hepatobiliary

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

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov .uk/yellowcard

4.9 Overdose

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

Paediatric population

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, NNRTI (non-nucleoside reverse transcriptase inhibitors),

ATC code J05AG01.

Mechanism of action

Nevirapine is a NNRTI of HIV-1. Nevirapine is a non-competitive inhibitor of the HIV -1 reverse transcriptase, but it does not have a biologically significant inhibitory effect on the HIV-2 reverse transcriptase or on eukaryotic DNA polymerases a, P, y, or 8.

Antiviral activity in vitro

Nevirapine had a median EC₅₀ value (50% inhibitory concentration) of 63 nM against a panel of group M HIV-1 isolates from clades A, B, C, D, F, G, and H, and circulating recombinant forms (CRF), CRF01_AE, CRF02_AG and CRF12_BF replicating in human embryonic kidney 293 cells. In a panel of 2,923 predominantly subtype B HIV-1 clinical isolates, the mean EC₅₀ value was 90nM. Similar EC₅₀ values are obtained when the antiviral activity of nevirapine is measured in peripheral blood mononuclear cells, monocyte derived macrophages or lymphoblastoid cell line. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates or HIV-2 isolates.

Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity in vitro (see section 4.5) and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in vitro.

Resistance

HIV-1 isolates with reduced susceptibility (100-250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV -1 RT gene Y181C and/or V106A depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Genotypic analysis of isolates from antiretroviral naive patients experiencing virologic failure (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained one or more of the following NNRTI resistance-associated substitutions:

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

Cross-resistance

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

Clinical efficacy and safetyresults

Nevirapine has been evaluated in both treatment-naive and treatment-experienced patients. Studies in treatment naive patients

2NN study

The double non-nucleoside study 2 NN was a randomised, open-label, multicentre prospective study comparing the NNRTIs nevirapine, efavirenz and both drugs given together.

1216 antiretroviral-therapy naive patients with plasma HIV-1 RNA> 5000 copies/ml at baseline were assigned to nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine for 48 weeks.

The primary endpoint, treatment failure, was defined as less than 1 log₁₀ decline in plasma HIV-1 RNA in the first 12 weeks, or two consecutive measurements of more than 50 copies/ ml from week 24 onwards, or disease progression.

Median age was 34 years and about 64% were male patients, median CD4 cell count was 170 and 190 cells per mm³ in the nevirapine twice daily and efavirenz groups, respectively. There were no significant differences in demographic and baseline characteristics between the treatment groups.

The predetermined primary efficacy comparison was between the nevirapine twice daily and the efavirenz treatment groups.

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

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

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

2NN Three-year follow-up-study

This is a retrospective multi-centre study comparing the 3-year antiviral efficacy of nevirapine and efavirenz in combination with stavudine and lamivudine in 2NN patients from week 49 to week 144.

Patients who participated in the 2NN study and were still under active follow-up at week 48 when the study closed and were still being treated at the study clinic, were asked to participate in this study. Primary study endpoints (percentage of patients with treatment failures) and secondary study endpoints as well as backbone therapy were similar to the original 2NN study.

A durable response to nevirapine for at least three years was documented in this study and equivalence within a 10% range was demonstrated between nevirapine 200 mg twice daily and efavirenz with respect to treatment failure. Both, the primary (p = 0.92) and secondary endpoints showed no statistically significant differences between efavirenz and nevirapine 200 mg twice daily.

Studies in treatment experienced patients

NEFA study

The NEFA trial is a controlled prospective randomised study which evaluated treatment options for patients who switch from protease inhibitor (PI) based regimen with undetectable load to either nevirapine, efavirenz or abacavir.

The study randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one PI and whose plasma HIV-1 RNA levels had been less than 200 c/ml for at least the previous six months to switch from the PI to nevirapine (155 patients), efavirenz (156), or abacavir (149).

The primary study endpoint was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per millilitre.

At 12 months, the Kaplan-Meier estimates of the likelihood of reaching the endpoint were 10 % in the nevirapine group, 6 % in the efavirenz group, and 13 % in the abacavir group (P=0.10 according to an intention-to-treat analysis).

The overall incidence of adverse events was significantly lower (61 patients, or 41%) in the abacavir group than in the nevirapine group (83 patients, or 54%) or the efavirenz group (89 patients, or 57%). Significantly fewer patients in the abacavir group (9 patients, or 6%) than in the nevirapine group (26 patients, or 17%) or the efavirenz group (27 patients, or 17%) discontinued the study medication because of adverse events.

Perinatal Transmission

Numerous studies have been performed examining the use of nevirapine in regards to perinatal transmission, most notably HIVNET 012. This study demonstrated a significant reduction in transmission using single dose nevirapine 13.1% (n = 310) in the nevirapine group, versus 25.1%

(n = 308) in the ultra-short zidovudine group (p = 0.00063). Monotherapy with nevirapine has been associated with the development of NNRTI resistance. Single dose nevirapine in mothers or infants may lead to reduced efficacy if an HIV treatment regimen using nevirapine is later instituted within 6 months or less in these patients. Combination of other antiretrovirals with single-dose nevirapine attenuates the emergence of nevirapine resistance. Where other antiretroviral medicines are accessible, the single dose nevirapine regimen should be combined with additional effective antiretroviral medicines (as recommended in internationally recognised guidelines).

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

Paediatric population

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

5.2 Pharmacokinetic properties

Absorption

Nevirapine is readily absorbed (> 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 pg/ml (7.5 pM) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Data reported in the literature from 20 HIV infected patients suggest a steady state C_max of 5.74 pg/ml (5.00-7.44) and C_min of 3.73 pg/ml (3.205.08) with an AUC of 109.0 h*pg/ml (96.0-143.5) in patients taking 200 mg of nevirapine bid. Other published data support these conclusions. Long-term efficacy appears to be most likely in patients whose nevirapine trough levels exceed 3.5 pg/ml.

Distribution

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

Biotransformation and elimination

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 isozymes from the CYP3A family, although other isozymes may have a secondary role. In a mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of _J4C-nevirapine, approximately 91.4 ± 10.5% of the radiolabelled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to faeces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (< 5%) of the radioactivity in urine (representing < 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

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

Special populations:

Renal dysfunction

The single-dose pharmacokinetics of nevirapine have been compared in 23 subjects with either mild (50 < CLcr < 80 ml/min), moderate (30 < CLcr < 50 ml/min) or severe renal dysfunction (CLcr < 30 ml/min), renal impairment or end-stage renal disease (ESRD) requiring dialysis, and 8 subjects 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, subjects with ESRD requiring dialysis exhibited a 43.5% reduction in nevirapine AUC over a one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in plasma. The results suggest that supplementing nevirapine therapy with an additional 200 mg dose of nevirapine following each dialysis treatment would help offset the effects of dialysis on nevirapine clearance. Otherwise patients with CLcr > 20 ml/min do not require an adjustment in nevirapine dosing.

Hepatic dysfunction: A steady state study comparing 46 patients with

-    mild (n=17: Ishak Score 1-2),

-    moderate (n=20; Ishak Score 3-4),

-    or severe (n=9; Ishak Score 5-6, Child-Pugh A in 8 pts., for 1 Child-Pugh score not applicable)

liver fibrosis as a measure of hepatic impairment was conducted.

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

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

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

Gender and older people

In the multinational 2NN study, a population pharmacokinetic substudy of 1077 patients was performed that included 391 females. Female patients showed a 13.8% lower clearance of nevirapine than did male patients. This difference is not considered clinically relevant. Since neither body weight nor Body Mass Index (BMI) had influence on the clearance of nevirapine, the effect of gender cannot be explained by body size. Nevirapine pharmacokinetics in HIV-1 infected adults do not appear to change with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). Nevirapine has not been specifically investigated in patients over the age of 65.

Paediatric population

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

Pharmacokinetic data on 33 patients (age range 0.77 - 13.7 years) in the intensive sampling group demonstrated that clearance of nevirapine increased with increasing age in a manner consistent with increasing body surface area. Dosing of nevirapine at 150 mg/m²BID (after a two-week lead in at 150 mg/m² QD) produced geometric mean or mean trough nevirapine concentrations between 4-6 pg/ml (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the two methods.

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

5.3 Preclinical safety data

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Microcrystalline cellulose (E460) Povidone (E1201) (K30)

Sodium starch glycolate (Type A) Silica colloidal anhydrous (E551)

Magnesium stearate (E572)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/Aluminium Blisters of 14, 14 x 1 (unit dose blister), 30, 60, 60 x 1 (unit dose blister), 100, 120, 200 and HDPE bottle with a child-resistant polypropylene screw cap containing 60 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

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

7    MARKETING AUTHORISATION HOLDER

Mylan S.A.S

117 allee des Parcs, 69 800 Saint Priest France

8    MARKETING AUTHORISATION NUMBER(S)

PL 33302/0023

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/08/2011

10    DATE OF REVISION OF THE TEXT

30/09/2015