Viramune 200mg Tablets

1. Name Of The Medicinal Product

Viramune 200 mg tablets

2. Qualitative And Quantitative Composition

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

Excipient: each tablet contains 318 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

White, oval, biconvex tablets. One side is embossed with the code “54 193”, with a single bisect separating the “54” and “193”. The opposite side is marked with the company symbol. The tablet should not be divided.

4. Clinical Particulars

4.1 Therapeutic Indications

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

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

4.2 Posology And Method Of Administration

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

Posology

Patients 16 years and older

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

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

Dose management considerations

Patients experiencing rash during the 14-day lead-in period of 200 mg/day should not have their Viramune dose increased until the rash has resolved. The isolated rash should be closely monitored (please refer to 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 Viramune 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

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

Viramune 200 mg tablets, following the dosing schedule described above, are suitable for larger children, particularly adolescents, below the age of 16 who weigh more than 50 kg or whose body surface area is above 1.25 m² according to the Mosteller formula. An oral suspension dosage form, which can be dosed according to body weight or body surface area, is available for children in this age group weighing less than 50 kg or whose body surface area is below 1.25 m² (please refer to the Summary of Product Characteristics of Viramune oral suspension).

Method of administration

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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

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

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

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

4.4 Special Warnings And Precautions For Use

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

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

The first 18 weeks of therapy with nevirapine are a critical period which requires close monitoring of patients to disclose the potential appearance of severe and life-threatening skin reactions (including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) and serious hepatitis/hepatic failure. The greatest risk of hepatic events and skin reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues past this period and monitoring should continue at frequent intervals. Female gender and higher CD4 counts (>250/mm3 in adult females and >400/mm3 in adult males) at the initiation of nevirapine therapy are associated with a greater risk of hepatic adverse events if the patient has detectable plasma HIV-1 RNA - i.e. a concentration In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Nevirapine must not be restarted following severe hepatic, skin or hypersensitivity reactions (see section 4.3). The dose must be strictly adhered to, especially the 14-days lead-in period (see section 4.2).

Cutaneous reactions

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

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

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

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

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

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

Any patient experiencing severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, or general malaise should discontinue the medicinal product and immediately seek medical evaluation. In these patients nevirapine must not be restarted. If patients present with a suspected nevirapine -associated rash, liver function tests should be performed. Patients with moderate to severe elevations (ASAT or ALAT > 5 ULN) should be permanently discontinued from nevirapine. If a hypersensitivity reaction occurs, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, nevirapine must be permanently stopped and not be re-introduced (see section 4.3).

Hepatic reactions

Severe and life-threatening 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-naïve 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-naïve patients of either gender with detectable HIV-1 RNA in plasma with higher CD4 counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review of predominantly patients with a plasma HIV-1 viral load of 50 copies/ml or higher, women with CD4 counts >250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse 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 nevirapine. Asymptomatic GGT elevations are not a contraindication to continue therapy.

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

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

Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such as anorexia, nausea, jaundice, bilirubinuria, acholic stools, hepatomegaly or liver tenderness. Patients should be instructed to seek medical attention promptly if these occur. If ASAT or ALAT increase to > 5 ULN during treatment, nevirapine should be immediately stopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs or symptoms of hepatitis, rash, constitutional symptoms or other findings suggestive of organ dysfunction, it may be possible to reintroduce nevirapine, on a case by case basis, at the starting dose regimen of 200 mg/day for 14 days followed by 400 mg/day. In these cases, more frequent liver monitoring is required. If liver function abnormalities recur, nevirapine should be permanently discontinued. If clinical hepatitis occurs, characterised by anorexia, nausea, vomiting, icterus AND laboratory findings (such as moderate or severe liver function test abnormalities (excluding GGT)), nevirapine must be permanently stopped. Viramune must not be readministered to patients who have required permanent discontinuation for clinical hepatitis due to nevirapine.

Liver disease

The safety and efficacy of Viramune has not been established in patients with significant underlying liver disorders. Viramune is contraindicated in patients with severe hepatic impairment (Child-Pugh C, see section 4.3). Pharmacokinetic results suggest caution should be exercised when nevirapine is administered to patients with moderate hepatic dysfunction (Child-Pugh B). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse 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 Viramune in the setting of post-exposure-prophylaxis (PEP), an unapproved use. The use of Viramune has not been evaluated within a specific study on PEP, especially in term of treatment duration and therefore, is strongly discouraged.

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

Combination therapy with nevirapine has not been shown to eliminate the risk of transmission of HIV-1 to others through sexual contact or contaminated blood.

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

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 medicinal product 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, Viramune has been associated with an increase in HDL- cholesterol and an overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies with nevirapine on modifying the cardiovascular risk in HIV infected patients, the clinical impact of these findings is not known. The selection of antiretroviral medicinal products 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 long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

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

The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine is not recommended (please also refer to section 4.5).

Lactose: Viramune tablets contain 636 mg of lactose per maximum recommended daily dose.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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

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

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

The interaction data is presented as geometric mean value with 90% confidence interval (90% CI) whenever these data were available. ND = Not Determined, ↑ = Increased,

Medicinal products by therapeutic areas	Interaction	Recommendations concerning co-administration
ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine 100-150 mg BID	Didanosine AUC ↔ 1.08 (0.92-1.27) Didanosine Cmin ND Didanosine Cmax↔ 0.98 (0.79-1.21)	Didanosine and Viramune can be co-administered without dose adjustments.
Lamivudine 150 mg BID	No changes to lamivudine apparent clearance and volume of distribution, suggesting no induction effect of nevirapine on lamivudine clearance.	Lamivudine and Viramune can be co-administered without dose adjustments.
Stavudine: 30/40 mg BID	Stavudine AUC ↔ 0.96 (0.89-1.03) Stavudine Cmin ND Stavudine Cmax ↔ 0.94 (0.86-1.03) Nevirapine: compared to historical controls, levels appeared to be unchanged.	Stavudine and Viramune can be co-administered without dose adjustments.
Tenofovir 300 mg QD	Tenofovir plasma levels remain unchanged when co-administered with Nevirapine. Nevirapine plasma levels were not altered by co-administration of tenofovir.	Tenofovir and Viramune can be co-administered without dose adjustments.
Zidovudine 100-200 mg TID	Zidovudine AUC Zidovudine Cmin ND Zidovudine Cmax Nevirapine: Zidovudine had no effect its pharmacokinetics.	Zidovudine and Viramune can be co-administered without dose adjustments
NNRTIs
Efavirenz 600 mg QD	Efavirenz AUC Efavirenz Cmin Efavirenz Cmax	It is not recommended to co-administer efavirenz and Viramune, because of additive toxicity and no benefit in terms of efficacy over either NNRTI alone.
PIs
Atazanavir/ritonavir 300/100 mg QD 400/100 mg QD	Atazanavir/r 300/100mg: Atazanavir/r AUC Atazanavir/r Cmin Atazanavir/r Cmax Atazanavir/r 400/100mg: Atazanavir/r AUC Atazanavir/r Cmin Atazanavir/r Cmax↔ 1.02 (0.85-1.24) (compared to 300/100mg without nevirapine) Nevirapine AUC ↑ 1.25 (1.17-1.34) Nevirapine Cmin↑ 1.32 (1.22-1.43) Nevirapine Cmax↑ 1.17 (1.09-1.25)	It is not recommended to co-administer atazanavir/ritonavir and Viramune.
Darunavir/ritonavir 400/100 mg BID	Darunavir AUC ↑ 1.24 (0.97-1.57) Darunavir Cmin ↔ 1.02 (0.79-1.32) Darunavir Cmax ↑ 1.40 (1.14-1.73) Nevirapine AUC ↑ 1.27 (1.12-1.44) Nevirapine Cmin↑ 1.47 (1.20-1.82) Nevirapine Cmax ↑ 1.18 (1.02-1.37)	Darunavir and Viramune can be co-administered without dose adjustments.
Fosamprenavir 1400 mg BID,	Amprenavir AUC Amprenavir Cmin Amprenavir Cmax Nevirapine AUC ↑ 1.29 (1.19-1.40) Nevirapine Cmin↑ 1.34 (1.21-1.49) Nevirapine Cmax↑ 1.25 (1.14-1.37)	It is not recommended to co-administer fosamprenavir and Viramune if fosamprenavir is not co-administered with ritonavir.
Fosamprenavir/ritonavir 700/100 mg BID	Amprenavir AUC ↔ 0.89 (0.77-1.03) Amprenavir Cmin Amprenavir Cmax↔ 0.97 (0.85-1.10) Nevirapine AUC ↑ 1.14 (1.05-1.24) Nevirapine Cmin↑ 1.22 (1.10-1.35) Nevirapine Cmax↑ 1.13 (1.03-1.24)	Fosamprenavir/ritonavir and Viramune can be co-administered without dose adjustments
Lopinavir/ritonavir (capsules) 400/100 mg BID	patients: Lopinavir AUC Lopinavir Cmin Lopinavir Cmax	An increase in the dose of lopinavir/ritonavir to 533/133 mg (4 capsules) or 500/125 mg (5 tablets with 100/25 mg each) twice daily with food is recommended in combination with Viramune. Dose adjustment of Viramune is not required when co-administered with lopinavir.
Lopinavir/ritonavir (oral solution) 300/75 mg/m2 BID	Paediatric patients: Lopinavir AUC Lopinavir Cmin Lopinavir Cmax	For children, increase of the dose of lopinavir/ritonavir to 300/75 mg/m2 twice daily with food should be considered when used in combination with Viramune, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Nelfinavir 750 mg TID	Nelfinavir AUC ↔ 1.06 (0.78-1.14) Cmin↔ 0.68 (0.50-1.5) Cmax↔ 1.06 (0.92-1.22) Nelfinavir metabolite M8: AUC Cmin Cmax Nevirapine: compared to historical controls, levels appeared to be unchanged.	Nelfinavir and Viramune can be co-administered without dose adjustments.
Ritonavir 600 mg BID	Ritonavir AUC↔ 0.92 (0.79-1.07) Ritonavir Cmin↔ 0.93 (0.76-1.14) Ritonavir Cmax↔ 0.93 (0.78-1.07) Nevirapine: Co-administration of ritonavir does not lead to any clinically relevant change in nevirapine plasma levels.	Ritonavir and Viramune can be co-administered without dose adjustments.
Saquinavir/ritonavir	The limited data available with saquinavir soft gel capsule boosted with ritonavir do not suggest any clinically relevant interaction between saquinavir boosted with ritonavir and Nevirapine	Saquinavir/ritonavir and Viramune can be co-administered without dose adjustments.
Tipranavir/ritonavir 500/200 mg BID	No specific drug-drug interaction study has been performed. The limited data available from a phase IIa study in HIV-infected patients have shown a clinically non significant 20% decrease of TPV Cmin.	Tipranavir and Viramune can be co-administered without dose adjustments.
ENTRY INHIBITORS
Enfuvirtide	Due to the metabolic pathway no clinically significant pharmacokinetic interactions are expected between enfuvirtide and nevirapine.	Enfuvirtide and Viramune can be co-administered without dose adjustments.
Maraviroc 300 mg QD	Maraviroc AUC ↔ 1.01 (0.6 -1.55) Maraviroc Cmin ND Maraviroc Cmax↔ 1.54 (0.94-2.52) compared to historical controls Nevirapine concentrations not measured, no effect is expected.	Maraviroc and Viramune can be co-administered without dose adjustments.
INTEGRASE INHIBITORS
Raltegravir 400 mg BID	No clinical data available. Due to the metabolic pathway of raltegravir no interaction is expected.	Raltegravir and Viramune can be co-administered without dose adjustments.
ANTIBIOTICS
Clarithromycin 500 mg BID	Clarithromycin AUC Clarithromycin Cmin Clarithromycin Cmax Metabolite 14-OH clarithromycin AUC ↑ 1.42 (1.16-1.73) Metabolite 14-OH clarithromycin Cmin↔ 0 (0.68-1.49) Metabolite 14-OH clarithromycin Cmax↑ 1.47 (1.21-1.80) Nevirapine AUC ↑ 1.26 Nevirapine Cmin↑ 1.28 Nevirapine Cmax↑ 1.24 compared to historical controls.	Clarithromycin exposure was significantly decreased, 14-OH metabolite exposure increased. Because the clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex overall activity against the pathogen may be altered. Alternatives to clarithromycin, such as azithromycin should be considered. Close monitoring for hepatic abnormalities is recommended
Rifabutin 150 or 300 mg QD	Rifabutin AUC ↑ 1.17 (0.98-1.40) Rifabutin Cmin↔ 1.07 (0.84-1.37) Rifabutin Cmax↑ 1.28 (1.09-1.51) Metabolite 25-O-desacetylrifabutin AUC ↑ 1.24 (0.84-1.84) Metabolite 25-O-desacetylrifabutin Cmin↑ 1.22 (0.86-1.74) Metabolite 25-O-desacetylrifabutin Cmax↑ 1.29 (0.98-1.68) A clinically not relevant increase in the apparent clearance of nevirapine (by 9%) compared to historical data was reported.	No significant effect on rifabutin and Viramune mean PK parameters is seen. Rifabutin and Viramune can be co-administered without dose adjustments. However, due to the high interpatient variability some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampicin 600 mg QD	Rifampicin AUC ↔ 1.11 (0.96-1.28) Rifampicin Cmin ND Rifampicin Cmax↔ 1.06 (0.91-1.22) Nevirapine AUC Nevirapine Cmin Nevirapine Cmax compared to historical controls.	It is not recommended to co-administer rifampicin and Viramune (see section 4.4). Physicians needing to treat patients co-infected with tuberculosis and using a Viramune containing regimen may consider co-administration of rifabutin instead.
ANTIFUNGALS
Fluconazole 200 mg QD	Fluconazole AUC ↔ 0.94 (0.88-1.01) Fluconazole Cmin↔ 0.93 (0.86-1.01) Fluconazole Cmax↔ 0.92 (0.85-0.99) Nevirapine: exposure: ↑100% compared with historical data where nevirapine was administered alone.	Because of the risk of increased exposure to Viramune, caution should be exercised if the medicinal products are given concomitantly and patients should be monitored closely.
Itraconazole 200 mg QD	Itraconazole AUC Itraconazole Cmin Itraconazole Cmax 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 Ketoconazole Cmin ND Ketoconazole Cmax Nevirapine: plasma levels: ↑ 1.15-1.28 compared to historical controls.	It is not recommended to co-administer ketoconazole and Viramune.
ANTACIDS
Cimetidine	Cimetidine: no significant effect on cimetidine PK parameters is seen. Nevirapine Cmin↑ 1.07	Cimetidine and Viramune can be co-administered without dose adjustments.
ANTITHROMBOTICS
Warfarin	The interaction between Nevirapine and the antithrombotic agent warfarin is complex, with the potential for both increases and decreases in coagulation time when used concomitantly.	Close monitoring of anticoagulation levels is warranted.
CONTRACEPTIVES
Depo-medroxyprogesterone acetate (DMPA) 150 mg every 3 months	DMPA AUC ↔ DMPA Cmin↔ DMPA Cmax↔ Nevirapine AUC ↑ 1.20 Nevirapine Cmax↑ 1.20	Viramune co-administration did not alter the ovulation suppression effects of DMPA. DMPA and Viramune can be co-administered without dose adjustments.
Ethinyl estradiol (EE) 0.035 mg	EE AUC EE Cmin ND EE Cmax↔ 0.94 (0.79 - 1.12)	Oral hormonal contraceptives should not be used as the sole method of contraception in women taking Viramune (see section 4.4). Appropriate doses for hormonal contraceptives (oral or other forms of application) other than DMPA in combination with Viramune have not been established with respect to safety and efficacy.
Norethindrone (NET) 1.0 mg QD	NET AUC NET Cmin ND NET Cmax
DRUG ABUSE
Methadone Individual Patient Dosing	Methadone AUC Methadone Cmin ND Methadone Cmax	Methadone-maintained patients beginning Viramune therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
HERBAL PRODUCTS
St. John's Wort	Serum levels of Nevirapine can be reduced by concomitant use of the herbal preparation St. John's Wort (Hypericum perforatum). This is due to induction of medicinal product metabolism enzymes and/or transport proteins by St. John's Wort.	Herbal preparations containing St. John's Wort and Viramune must not be co-administered (see section 4.3). If a patient is already taking St. John's Wort check nevirapine and if possible viral levels and stop St John's Wort. Nevirap