Ai Tai

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

Posology

Patients 16 years and older

The recommended dose of Ai Tai 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 Ai Tai dose increased until the rash has resolved.). 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 Ai Tai dosing for more than 7 days should restart the recommended dosing regimen using the two week lead-in period.

There are toxicities that require interruption of Ai Tai therapy.

Special populations

Elderly

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

Renal impairment

For patients with renal dysfunction requiring dialysis an additional 200 mg dose of Ai Tai following each dialysis treatment is recommended.

Hepatic impairment

Ai Tai should not be used in patients with severe hepatic impairment. No dose adjustment is necessary in patients with mild to moderate hepatic impairment.

Paediatric population

Ai Tai 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.

Children less than three years old

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

Method of administration

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

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

Posology

Patients 16 years and older

The recommended dose of Ai Tai 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 Ai Tai dose increased until the rash has resolved. The isolated rash should be closely monitored. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point in time an alternative treatment should be sought due to the possible risk of underexposure and resistance.

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

There are toxicities that require interruption of Ai Tai therapy.

Elderly

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

Renal impairment

For patients with renal dysfunction requiring dialysis an additional 200 mg dose of nevirapine following each dialysis treatment is recommended.

Hepatic impairment

Nevirapine should not be used in patients with severe hepatic impairment. No dose adjustment is necessary in patients with mild to moderate hepatic impairment.

Paediatric population

Ai Tai 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 Ai Tai oral suspension).

Children less than three years old.

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

Method of administration

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

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

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 Ai Tai therapy and had recurrence of liver function abnormalities upon readministration of Ai Tai.

Coadministration with herbal preparations containing St John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of Ai Tai.

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.

Coadministration with herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of nevirapine.

Ai Tai should only be used with at least two other antiretroviral agents.

Ai Tai 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 Ai Tai mainly during the first 6 weeks of therapy.

Ai Tai 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 Ai Tai use.

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

Patients should be instructed that a major toxicity of Ai Tai 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 Ai Tai 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 Ai Tai. 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 Ai Tai 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 Ai Tai containing regimens.

Female gender and higher CD4 counts at the initiation of Ai Tai 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 reactions (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 Ai Tai therapy are at higher risk for symptomatic hepatic reactions with Ai Tai. 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 Ai Tai requiring close monitoring during the first 18 weeks. They should be informed that occurrence of symptoms suggestive of hepatitis should lead them to discontinue Ai Tai 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 Ai Tai therapy and at appropriate intervals during therapy.

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

Asymptomatic elevations of liver enzymes are frequently described and are not necessarily a contraindication to use. 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 3^rd 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. Ai Tai must not be administered to patients with pre-treatment ASAT or ALAT> 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN.

Liver Disease

The safety and efficacy of Ai Tai has not been established in patients with significant underlying liver disorders. Ai Tai is contraindicated in patients with severe hepatic impairment. Pharmacokinetic results suggest caution should be exercised when Ai Tai 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 Ai Tai in the setting of post-exposure-prophylaxis (PEP), an unapproved use.).

Granulocytopenia is commonly associated with zidovudine. Therefore, patients who receive Ai Tai 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.

Ai Tai should only be used with at least two other antiretroviral agents.

Ai Tai 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.

Ai Tai 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 Ai Tai use.

Concomitant prednisone use (40 mg/day for the first 14 days of Ai Tai 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 hepatotoxicity, including fatal fulminant hepatitis, has occurred in patients treated with nevirapine. The first 18 weeks of treatment is a critical period which requires close monitoring. The risk of hepatic reactions is greatest in the first 6 weeks of therapy. However the risk continues past this period and monitoring should continue at frequent intervals throughout treatment.

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

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

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

Patients should be informed that hepatic reactions are a major toxicity of nevirapine requiring close monitoring during the first 18 weeks. They should be informed that occurrence of symptoms 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 3^rd 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.

Liver disease

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

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

Other warnings

Post-Exposure-Prophylaxis: Serious hepatotoxicity, including liver failure requiring transplantation, has been reported in HIV-uninfected individuals receiving multiple doses of Ai Tai in the setting of post-exposure-prophylaxis (PEP), an unapproved use. The use of Ai Tai 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 Ai Tai, since nevirapine might lower the plasma concentrations of these medicinal products. For this reason, and to reduce the risk of HIV transmission, barrier contraception (e.g., condoms) is recommended. Additionally, when postmenopausal hormone therapy is used during administration of nevirapine, its therapeutic effect should be monitored.

Weight and metabolic parameters:

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

In clinical studies, Ai Tai has been associated with an increase in HDL- cholesterol and an overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies, the clinical impact of these findings is not known. In addition, Ai Tai has not been shown to cause glucose disturbances.

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

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

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: Ai Tai 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.

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

However, patients should be advised that they may experience adverse reactions such as fatigue during treatment with Ai Tai. 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.

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

However, patients should be advised that they may experience adverse reactions such as fatigue during treatment with Ai Tai. 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.

Summary of the safety profile

The most frequently reported adverse reactions related to Ai Tai 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 Ai Tai have been reported. The frequencies estimated are based on pooled clinical study data for adverse reactions considered related to Ai Tai 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).

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 Ai Tai (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 Ai Tai in randomised controlled clinical studies (n=2,718).

Decreased blood phosphorus and increased blood pressure were observed in clinical studies with coadministration 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.

The following adverse reactions have also been reported when Ai Tai 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 Ai Tai is used in combination with other agents; however it is unlikely that these events are due to Ai Tai 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.

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.

Skin and subcutaneous tissues

The most common clinical toxicity of Ai Tai is rash, with Ai Tai 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 Ai Tai, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Fatal cases of SJS, TEN and 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.

Hepato-biliary

The most frequently observed laboratory test abnormalities are elevations in liver function tests (LFTs), including ALAT, ASAT, GGT, total bilirubin and alkaline phosphatase. Asymptomatic elevations of GGT levels are the most frequent. Cases of jaundice have been reported. Cases of hepatitis (severe and life-threatening hepatoxicity, including fatal fulminant hepatitis) have been reported in patients treated with Ai Tai. 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.

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 Ai Tai 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 medicinal product-related occurred in 5/37 (13.5%) of patients. In ACTG 245, a double-blind placebo controlled study, the frequency of serious medicinal product-related granulocytopenia was 5/305 (1.6%). Isolated cases of Stevens-Johnson syndrome or Stevens-Johnson/ toxic epidermal necrolysis transition syndrome have been reported in this population.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization 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.

Summary of the safety profile

The most frequently reported adverse reactions related to Ai Tai therapy, across all clinical studies, 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 Ai Tai have been reported. The frequencies estimated are based on pooled clinical study data for adverse reactions considered related to Ai Tai 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).

Description of selected adverse reactions

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

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

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

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

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.

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.

Skin and subcutaneous tissues

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

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

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

Hepato-biliary

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

Paediatric population

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

Reporting of suspected adverse reactions

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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

There is no known antidote for Ai Tai overdose. Cases of Ai Tai 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 Ai Tai.

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.

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

Paediatric population

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

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

Mechanism of action

Ai Tai is a NNRTI of HIV 1. Ai Tai 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 α, β, γ, or δ.

Antiviral activity in vitro

Ai Tai 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 Ai Tai is measured in peripheral blood mononuclear cells, monocyte derived macrophages or lymphoblastoid cell line. Ai Tai had no antiviral activity in cell culture against group O HIV-1 isolates or HIV-2 isolates.

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

Resistance

HIV-1 isolates with reduced susceptibility (100-250-fold) to Ai Tai 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 Ai Tai resistance in cell culture was not altered when selection included Ai Tai in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve patients receiving either Ai Tai (n=24) or Ai Tai and ZDV (n=14) were monitored in Phase I/II studies over 1 to >12 weeks. After 1 week of Ai Tai monotherapy, isolates from 3/3 patients had decreased susceptibility to Ai Tai in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C and G190A were detected in HIV-1 isolates from some patients as early as 2 weeks after therapy initiation. By week eight of Ai Tai monotherapy, 100% of the patients tested (n=24) had HIV-1 isolates with a>100-fold decrease in susceptibility to Ai Tai in cell culture compared to baseline, and had one or more of the Ai Tai-associated RT resistance mutations. Nineteen of these patients (80%) had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral naïve patients experiencing virologic failure (n=71) receiving Ai Tai 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 Ai Tai. Depending on resistance testing results, an etravirine-containing regimen may be used subsequently. Cross-resistance between Ai Tai 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 Ai Tai and NRTIs is low because the molecules have different binding sites on the reverse transcriptase.

Clinical results

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

Studies in treatment-naïve patients

2NN study

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

1216 antiretroviral-therapy naïve patients with plasma HIV-1 RNA> 5,000 copies/ml at baseline were assigned to Ai Tai 400 mg once daily, Ai Tai 200 mg twice daily, efavirenz 600 mg once daily, or Ai Tai (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 (new Centers for Disease Control and Prevention grade C event or death), or change of allocated treatment.

Median age was 34 years and about 64% were male patients, median CD4 cell count was 170 and 190 cells per mm³ in the Ai Tai 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 Ai Tai twice daily and the efavirenz treatment groups. Details of the primary efficacy comparison are given in table 1.

Table 1: Number of patients with treatment failure, components of treatment failure, and number of patients with plasma HIV-RNA concentration < 50 c/ml, at week 48 (Intention-To-Treat (ITT) Analysis).

* ART = antiretroviral therapy

Although, overall, treatment failure was numerically lower in the efavirenz group than in the Ai Tai-only groups, the findings of this study show no evidence that efavirenz is superior to Ai Tai twice daily in terms of treatment failure. However, equivalence within the 10% limits of these treatment groups was not shown even though the study was adequately powered for such an analysis. The Ai Tai twice daily regimen and the efavirenz regimen were not significantly different (p= 0.091) in terms of efficacy as measured by incidence of treatment failure. There was also no significant difference between Ai Tai twice daily and efavirenz regarding any components of treatment failure including virological failure.

The simultaneous use of Ai Tai (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 Ai Tai plus efavirenz did not have additional efficacy and caused more adverse events than each medicinal product separately, this regimen is not recommended.

Twenty per cent of patients assigned to Ai Tai 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 Ai Tai 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 Ai Tai twice daily and 4.5% for efavirenz. Of the patients with grade 3 or 4 liver-associated laboratory toxicity, the proportions coinfected with hepatitis B or hepatitis C virus were 6.7% and 20.0% in the Ai Tai twice daily group, 5.6% and 11.1% in the efavirenz group.

2NN Three-year follow-up-study

This is a retrospective multicentre study comparing the 3-year antiviral efficacy of Ai Tai 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.

Table 2 shows the main efficacy results of this study.

Table 2: Number of patients with treatment failure, components of treatment failure, and number of patients with plasma HIV-RNA concentration < 400 copies/ml, between week 49 to 144 (ITT analysis).

A durable response to Ai Tai for at least three years was documented in this study. Equivalence within a 10% range was demonstrated between Ai Tai 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 Ai Tai 200 mg twice daily.

Studies in treatment-experienced patients

NEFA study

The NEFA study is a controlled prospective randomised study which evaluated treatment options for patients who switch from protease inhibitor (PI) based regimen with undetectable load to either Ai Tai, 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 Ai Tai (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. The main results regarding the primary endpoint are given in table 3.

Table 3: Outcome of Therapy 12 months after switch from PI based therapy

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

The overall incidence of adverse events was significantly lower (61 patients, or 41%) in the abacavir group than in the Ai Tai 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 Ai Tai group (26 patients, or 17%) or the efavirenz group (27 patients, or 17%) discontinued the medicinal product because of adverse events (see table below).

* A grade 3 event was defined as severe, and a grade 4 event as life-threatening

** Systemic adverse events included hypersensitivity reactions

*** P=0.02 by the chi-square test

**** P=0.01 by the chi-square test

Perinatal Transmission

The HIVNET 012 study conducted in Kampala (Uganda) evaluated the efficacy of Ai Tai to prevent vertical transmission of HIV-1 infection. Mothers received only study antiretroviral therapy during these trials. Mother-infant pairs were randomised to receive oral Ai Tai (mother: 200 mg at the onset of labour; infant: 2 mg/kg within 72 hours of birth), or an ultra-short oral zidovudine regimen (mother: 600 mg at the onset of labour and 300 mg every 3 hours until delivery; infant: 4 mg/kg twice daily for 7 days). The cumulative HIV-1 infant infection rate at 14-16 weeks was 13.1% (n = 310) in the Ai Tai group, versus 25.1% (n = 308 in the ultra-short zidovudine group (p = 0.00063).

From a study in which infants of HIV infected mothers received either placebo or single dose Ai Tai, 30 HIV infected infants, 15 who have received placebo and 15 who have received Ai Tai, were subsequently treated with Ai Tai combined with other anti-retroviral drugs. Virologic failure after 6 months of treatment with Ai Tai combined with other anti-retroviral medicinal products occurred in significantly more infants who had previously received a single dose of Ai Tai (10 of 15) than in infants who had received placebo previously (1 of 15). This indicates that in infants previously treated with single-dose Ai Tai alone for prevention of mother to child transmission of HIV-1, the efficacy of Ai Tai as part of a combination therapy which they receive for their own health may be reduced.

In a study in which women who had received single dose Ai Tai for prevention of mother-to-child transmission were treated with Ai Tai combined with other anti-retroviral drugs for their own health, 29 of 123, or 24% experienced virologic failure, and five (38%) of 13 women with HIV-1 detected baseline resistance to Ai Tai experienced virologic failure. This indicates that in women previously treated with single-dose Ai Tai alone for prevention of mother to child transmission of HIV-1, the efficacy of Ai Tai as part of a combination therapy which the women receive for their own health may be reduced.

A blinded randomized clinical trial in women already taking antiretroviral therapy throughout pregnancy (PACTG 316) demonstrated no further reduction of vertical HIV-1 transmission when the mother and the child received a single Ai Tai dose during labour and after birth respectively. HIV-1 transmission rates were similarly low in both treatment groups (1.3% in the Ai Tai group, 1.4% in the placebo group). The vertical transmission decreased neither in women with HIV-1 RNA below the limit of quantification nor in women with HIV-1 RNA above the limit of quantification prior to partus. Of the 95 women who received intrapartum Ai Tai, 15% developed Ai Tai resistance mutations at 6 weeks post partus.

The clinical relevance of these data in European populations has not been established. Furthermore, in the case Ai Tai 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 Ai Tai 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.

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

Mechanism of action

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

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

Resistance

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

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

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

Cross-resistance

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

Clinical results

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

Studies in treatment-naïve patients

2NN study

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

1,216 antiretroviral-therapy naïve patients with plasma HIV-1 RNA > 5,000 copies/ml at baseline were assigned to Ai Tai 400 mg once daily, Ai Tai 200 mg twice daily, efavirenz 600 mg once daily, or Ai Tai (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 Ai Tai 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 Ai Tai twice daily and the efavirenz treatment groups.

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

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

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

2NN Three-year follow-up-study

This is a retrospective multicentre study comparing the 3-year antiviral efficacy of Ai Tai 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 Ai Tai for at least three years was documented in this study, and equivalence within a 10 % range was demonstrated between Ai Tai 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 Ai Tai 200 mg twice daily.

Studies in treatment-experienced patients

NEFA study

The NEFA study is a controlled prospective randomised study which evaluated treatment options for patients who switch from protease inhibitor (PI) based regimen with undetectable load to either Ai Tai, 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 Ai Tai (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 Ai Tai group, 6 % in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis).

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

Perinatal Transmission

Numerous studies have been performed examining the use of Ai Tai 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 Ai Tai group, versus 25.1 % (n = 308) in the ultra-short zidovudine group (p = 0.00063)). Monotherapy with Ai Tai 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 Ai Tai regimen should be combined with additional effective antiretroviral medicines (as recommended in internationally recognized guidelines).

The clinical relevance of these data in European populations has not been established. Furthermore, in the case Ai Tai 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.

Absorption: Ai Tai 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 Ai Tai concentrations of 2 ± 0.4 µg/ml (7.5 µM) were attained by 4 hours following a single 200 mg dose. Following multiple doses, Ai Tai 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 µg/ml (5.00-7.44) and C_min of 3.73 µg/ml (3.20-5.08) with an AUC of 109.0 h_*µg/ml (96.0-143.5) in patients taking 200 mg of Ai Tai bid. Other published data support these conclusions. Long-term efficacy appears to be most likely in patients whose Ai Tai trough levels exceed 3.5 µg/ml.

Distribution: Ai Tai is lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the volume of distribution (Vdss) of Ai Tai was 1.21 ± 0.09 l/kg, suggesting that Ai Tai is widely distributed in humans. Ai Tai readily crosses the placenta and is found in breast milk. Ai Tai is about 60% bound to plasma proteins in the plasma concentration range of 1-10 µg/ml. Ai Tai 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 Ai Tai is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of Ai Tai 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 Ai Tai 200 mg given twice daily followed by a single 50 mg dose of 14C-Ai Tai, 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 Ai Tai 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.

Ai Tai 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 Ai Tai 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 Ai Tai 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 Ai Tai has 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 Ai Tai. However, subjects with ESRD requiring dialysis exhibited a 43.5% reduction in Ai Tai AUC over a one-week exposure period. There was also accumulation of Ai Tai hydroxy-metabolites in plasma. The results suggest that supplementing Ai Tai therapy with an additional 200 mg dose of Ai Tai following each dialysis treatment would help offset the effects of dialysis on Ai Tai clearance. Otherwise patients with CLcr > 20 ml/min do not require an adjustment in Ai Tai 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 Ai Tai 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 Ai Tai and the five oxidative metabolites were not altered.

However, approximately 15% of these patients with hepatic fibrosis had Ai Tai 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 Ai Tai 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 Ai Tai 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 Ai Tai in the systemic circulation. Because Ai Tai induces its own metabolism with multiple dosing, this single dose study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics.

In the multinational 2NN study, a population pharmacokinetic substudy of 1,077 patients was performed that included 391 females. Female patients showed a 13.8% lower clearance of Ai Tai 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 Ai Tai, the effect of gender cannot be explained by body size. Ai Tai pharmacokinetics in HIV-1 infected adults does not appear to change with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). Ai Tai has not been specifically investigated in patients over the age of 65.

Paediatric population

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

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

Ai Tai tablets and oral suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg.

Absorption: Nevirapine is readily absorbed (> 90 %) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9 % (mean SD) for a 50 mg tablet and 91 ± 8 % for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 µg/ml (7.5 µM) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Data reported in the literature from 20 HIV-infected patients suggest a steady state C_max of 5.74 µg/ml (5.00-7.44) and C_min of 3.73 µg/ml (3.20-5.08) with an AUC of 109.0 h_*µg/ml (96.0-143.5) in patients taking 200 mg of nevirapine bid. Other published data support these conclusions. Long-term efficacy appears to be most likely in patients whose nevirapine trough levels exceed 3.5 µg/ml.

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

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

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

Renal impairment: The single-dose pharmacokinetics of nevirapine has been compared in 23 patients with either mild (50 ≤ CLcr < 80 ml/min), moderate (30 ≤ CLcr < 50 ml/min) or severe renal dysfunction (CLcr < 30 ml/min), renal impairment or end-stage renal disease (ESRD) requiring dialysis, and 8 patients with normal renal function (CLcr > 80 ml/min). Renal impairment (mild, moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine. However, patients with ESRD requiring dialysis exhibited a 43.5 % reduction in nevirapine AUC over a one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in plasma. The results suggest that supplementing nevirapine therapy with an additional 200 mg dose of Ai Tai following each dialysis treatment would help offset the effects of dialysis on nevirapine clearance. Otherwise patients with CLcr > 20 ml/min do not require an adjustment in nevirapine dosing.

Hepatic impairment:A steady state study comparing 46 patients with

mild (n=17: Ishak Score 1-2),

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

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

liver fibrosis as a measure of hepatic impairment was conducted.

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

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

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

Gender and elderly

In the multinational 2NN study, a population pharmacokinetic substudy of 1,077 patients was performed that included 391 females. Female patients showed a 13.8 % lower clearance of nevirapine than did male patients. This difference is not considered clinically relevant. Since neither body weight nor Body Mass Index (BMI) had influence on the clearance of nevirapine, the effect of gender cannot be explained by body size. Nevirapine pharmacokinetics in HIV-1 infected adults does not appear to change with age (range 19-68 years) or race (Black, Hispanic, or Caucasian). Nevirapine has not been specifically investigated in patients over the age of 65.

Paediatric population

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

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

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

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, Ai Tai induces hepatic tumours in rats and mice. These findings are most likely related to Ai Tai being a strong inducer of liver enzymes, and not due to a genotoxic mode of action. In reproductive toxicology studies, evidence of impaired fertility was seen in rats.

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.