İHALE DÜNYASI
İHALE DÜNYASI
VIRAMUNE is the brand name for nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds. The chemical name of nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one. Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C 15 H 14 N 4 O. Nevirapine has the following structural formula: VIRAMUNE Tablets are for oral administration. Each tablet contains 200 mg of nevirapine and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. VIRAMUNE Oral Suspension is for oral administration. Each 5 mL of VIRAMUNE suspension contains 50 mg of nevirapine (as nevirapine hemihydrate). The suspension also contains the following excipients: carbomer 934P, methylparaben, propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide and purified water. Chemical Structure
VIRAMUNE is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on one principal clinical trial (BI 1090) that demonstrated prolonged suppression of HIV-1 RNA and two smaller supportive studies, one of which (BI 1046) is described below. Additional important information regarding the use of VIRAMUNE for the treatment of HIV-1 infection: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, VIRAMUNE should not be initiated in adult females with CD4 + cell counts greater than 250 cells/mm 3 or in adult males with CD4 + cell counts greater than 400 cells/mm 3 unless the benefit outweighs the risk [ see Boxed Warning and Warnings and Precautions (5.1) ]. The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash [ see Dosage and Administration (2.4) and Warnings and Precautions (5.2) ]. If rash persists beyond the 14-day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once-daily dosing regimen should not be continued beyond 28 days, at which point an alternative regimen should be sought. VIRAMUNE is an NNRTI indicated for combination antiretroviral treatment of HIV-1 infection (1) Important Considerations: Initiation of treatment is not recommended in the following populations unless the benefits outweigh the risks (1 , 5.1) adult females with CD4 + cell counts >250 cells/mm 3 adult males with CD4 + cell counts >400 cells/mm 3 The 14-day lead-in period must be strictly followed; it may reduce the frequency of rash (2.4 , 5.2)
Any patient experiencing rash during the 14-day lead-in period should not increase dose until the rash has resolved. The lead-in dosing regimen should not be continued beyond 28 days (2.4) If dosing interrupted for >7 days, restart 14-day lead-in dosing (2.4) *Total daily dose should not exceed 400 mg for any patient. Adults (?16 yrs) Pediatric* (>15 days) First 14 days 200 mg once daily 150 mg/m 2 once daily After 14 days 200 mg twice daily 150 mg/m 2 twice daily 2.1 Adults The recommended dose for VIRAMUNE is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The lead-in period has been observed to decrease the incidence of rash. For concomitantly administered antiretroviral therapy, the manufacturer's recommended dosage and monitoring should be followed. 2.2 Pediatric Patients The recommended oral dose for pediatric patients 15 days and older is 150 mg/m 2 once daily for 14 days followed by 150 mg/m 2 twice daily thereafter. The total daily dose should not exceed 400 mg for any patient. Table 1 Calculation of the Volume of VIRAMUNE Oral Suspension (50 mg/5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m 2 BSA range (m 2 ) Volume (mL) 0.06 - 0.12 1.25 0.12 - 0.25 2.5 0.25 - 0.42 5 0.42 - 0.58 7.5 0.58 - 0.75 10 0.75 - 0.92 12.5 0.92 - 1.08 15 1.08 - 1.25 17.5 1.25+ 20 VIRAMUNE suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of 5 mL or less. If a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient. Formula Image 2.3 Monitoring of Patients Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with VIRAMUNE. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation, and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE treatment [ see Warnings and Precautions (5) ]. In some cases, hepatic injury has progressed despite discontinuation of treatment. 2.4 Dosage Adjustment Patients with Rash VIRAMUNE should be discontinued if a patient experiences severe rash or any rash accompanied by constitutional findings [ see Boxed Warning , Warnings and Precautions (5.2) , and Patient Counseling Information (17.1) ]. A patient experiencing mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients) should not have their VIRAMUNE dose increased until the rash has resolved [ see Warnings and Precautions (5.2) and Patient Counseling Information (17.1) ]. The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought. Patients with Hepatic Events If a clinical (symptomatic) hepatic event occurs, VIRAMUNE should be permanently discontinued. Do not restart VIRAMUNE after recovery [ see Warnings and Precautions (5.1) ]. Patients with Dose Interruption Patients who interrupt VIRAMUNE dosing for more than 7 days should restart the recommended dosing, using one 200 mg tablet daily (150 mg/m 2 /day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (150 mg/m 2 twice daily for pediatric patients). Patients on Dialysis An additional 200 mg dose of VIRAMUNE following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [ see Clinical Pharmacology (12.3) ]. Patients with CrCL ?20 mL/min do not require an adjustment in VIRAMUNE dosing.
VIRAMUNE is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ]. Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment (4 , 5.1 , 8.7)
The most common adverse reaction is rash. In adults the incidence of rash is 14.8% vs 5.9% with placebo, with Grade 3/4 rash occurring in 1.5% of patients (6.1) In pediatric patients the incidence of rash (all causality) was 21% (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials in Adults The most serious adverse reactions associated with VIRAMUNE are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [ see Boxed Warning and Warnings and Precautions (5.1 , 5.2) ]. Hepatic Reaction In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4.0% (range 0% to 11.0%) of patients who received VIRAMUNE and 1.2% of patients in control groups. Female gender and higher CD4 + cell counts (>250 cells/mm 3 in women and >400 cells/mm 3 in men) place patients at increased risk of these events [ see Boxed Warning and Warnings and Precautions (5.1) ]. Asymptomatic transaminase elevations (AST or ALT >5X ULN) were observed in 5.8% (range 0% to 9.2%) of patients who received VIRAMUNE and 5.5% of patients in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT. Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in patients receiving VIRAMUNE than in controls (see Table 3 ). Skin Reaction The most common clinical toxicity of VIRAMUNE is rash, which can be severe or life-threatening [ see Boxed Warning and Warnings and Precautions (5.2) ]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13.3% of patients receiving VIRAMUNE compared to 5.8% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 1.5% of VIRAMUNE recipients compared to 0.1% of subjects receiving placebo. Women tend to be at higher risk for development of VIRAMUNE-associated rash [ see Boxed Warning and Warnings and Precautions (5.2) ]. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment-related, adverse experiences of moderate or severe intensity observed in >2% of patients receiving VIRAMUNE in placebo-controlled trials are shown in Table 2. Table 2 Percentage of Patients with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials 1 Background therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4 + cell counts <200 cells/mm 3 . 2 Background therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some patients. Patients had CD4 + cell count ?200 cells/mm 3 . Trial 1090 1 Trials 1037, 1038, 1046 2 VIRAMUNE Placebo VIRAMUNE Placebo (n=1121) (n=1128) (n=253) (n=203) Median exposure (weeks) 58 52 28 28 Any adverse event 14.5% 11.1% 31.6% 13.3% Rash 5.1 1.8 6.7 1.5 Nausea 0.5 1.1 8.7 3.9 Granulocytopenia 1.8 2.8 0.4 0 Headache 0.7 0.4 3.6 0.5 Fatigue 0.2 0.3 4.7 3.9 Diarrhea 0.2 0.8 2.0 0.5 Abdominal pain 0.1 0.4 2.0 0 Myalgia 0.2 0 1.2 2.0 Laboratory Abnormalities Liver enzyme test abnormalities (AST, ALT) were observed more frequently in patients receiving VIRAMUNE than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue VIRAMUNE therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing VIRAMUNE and control regimens (see Table 3). Table 3 Percentage of Adult Patients with Laboratory Abnormalities 1 Background therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4 + cell counts <200 cells/mm 3 . 2 Background therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some patients. Patients had CD4 + cell count > 200 cells/mm 3 . Trial 1090 1 Trials 1037, 1038, 1046 2 VIRAMUNE Placebo VIRAMUNE Placebo Laboratory Abnormality (n=1121) (n=1128) (n=253) (n=203) Blood Chemistry SGPT (ALT) >250 U/L 5.3 4.4 14.0 4.0 SGOT (AST) >250 U/L 3.7 2.5 7.6 1.5 Bilirubin >2.5 mg/dL 1.7 2.2 1.7 1.5 Hematology Hemoglobin <8.0 g/dL 3.2 4.1 0 0 Platelets <50,000/mm 3 1.3 1.0 0.4 1.5 Neutrophils <750/mm 3 13.3 13.5 3.6 1.0 6.2 Clinical Trials in Pediatric Patients Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of VIRAMUNE (n=305) in which pediatric patients received combination treatment with VIRAMUNE. In this trial two patients were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of VIRAMUNE (n=37) in which patients were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these patients in trial BI 1100.892). The most frequently reported adverse events related to VIRAMUNE in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE. Cases of allergic reaction, including one case of anaphylaxis, were also reported. The safety of VIRAMUNE was also examined in BI Trial 1100.1368, an open-label, randomized clinical study performed in South Africa in which 123 HIV-1 infected treatment-naive patients between 3 months and 16 years of age received combination treatment with VIRAMUNE oral suspension, lamivudine and zidovudine for 48 weeks [ see Use In Specific Populations (8.4) and Clinical Pharmacology (12.3) ]. Rash (all causality) was reported in 21% of the patients, 4 (3%) of whom discontinued drug due to rash. All 4 patients experienced the rash early in the course of therapy (<4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (8.9%), anemia (7.3%) and hepatotoxicity (2.4%) [ see Use in Specific Populations (8.4) and Clinical Studies (14.2) ]. Safety information on use of VIRAMUNE in combination therapy in pediatric patients 2 weeks to <3 months of age was assessed in 36 patients from the BI 1100.1222 (PACTG 356) study. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults. 6.3 Post-Marketing Surveillance In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of VIRAMUNE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: fever, somnolence, drug withdrawal [ see Drug Interactions (7) ], redistribution/accumulation of body fat [ see Warnings and Precautions (5.6) ] Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities [ see Warnings and Precautions (5.1) ] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported with the use of VIRAMUNE. In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.
The most serious adverse reactions associated with VIRAMUNE are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. The first 18 weeks of therapy with VIRAMUNE are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE treatment. In addition, the 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash [ see Dosage and Administration (2.1) ]. Hepatitis and hepatic failure (5) Stevens-Johnson syndrome (5) Toxic epidermal necrolysis (5) Hypersensitivity reactions (5) 5.1 Hepatotoxicity and Hepatic Impairment Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with VIRAMUNE. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11.0%) of patients who received VIRAMUNE and 1.2% of patients in control groups. The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the VIRAMUNE groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the patients with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with VIRAMUNE use. Patients with signs or symptoms of hepatitis must be advised to discontinue VIRAMUNE and immediately seek medical evaluation, which should include liver enzyme tests. Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible [ see Boxed Warning , Dosage and Administration (2.3) , and Patient Counseling Information (17.1) ]. If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, VIRAMUNE should be permanently discontinued. Do not restart VIRAMUNE after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment. The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 + cell counts. In general, during the first 6 weeks of treatment, women have a three-fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4 + cell counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4 + cell counts >250 cells/mm 3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4 + cell counts <250 cells/mm 3 (11.0% versus 0.9%). An increased risk was observed in men with CD4 + cell counts >400 cells/mm 3 (6.3% versus 1.2% for men with CD4 + cell counts <400 cells/mm 3 ). However, all patients, regardless of gender, CD4 + cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 + cell counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT. In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of VIRAMUNE in the setting of post-exposure prophylaxis, an unapproved use. Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, patients with either hepatic fibrosis or cirrhosis should be monitored carefully for evidence of drug-induced toxicity. Nevirapine should not be administered to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Contraindications (4) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ]. 5.2 Skin Reactions Severe and life-threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with VIRAMUNE use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 1.5% of VIRAMUNE recipients compared to 0.1% of placebo subjects. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue VIRAMUNE and seek medical evaluation immediately [ see Boxed Warning and Patient Counseling Information (17.1) ]. Do not restart VIRAMUNE following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction. If patients present with a suspected VIRAMUNE-associated rash, transaminases should be measured immediately. Patients with rash-associated transaminase elevations should be permanently discontinued from VIRAMUNE [ see Warnings and Precautions (5.1) ]. Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients), which has been shown to reduce the frequency of rash. VIRAMUNE should be discontinued if a patient experiences severe rash or any rash accompanied by constitutional findings. A patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients) should not have their VIRAMUNE dose increased until the rash has resolved. The total duration of the once-daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought [ see Dosage and Administration (2.4) ]. Patients should be monitored closely if isolated rash of any severity occurs. Delay in stopping VIRAMUNE treatment after the onset of rash may result in a more serious reaction. Women appear to be at higher risk than men of developing rash with VIRAMUNE. In a clinical trial, concomitant prednisone use (40 mg/day for the first 14 days of VIRAMUNE administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of VIRAMUNE therapy. Therefore, use of prednisone to prevent VIRAMUNE-associated rash is not recommended. 5.3 Resistance VIRAMUNE must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing VIRAMUNE, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than VIRAMUNE are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop [ see Clinical Pharmacology (12.4) ]. 5.4 Drug Interactions See Table 4 for listings of established and potential drug interactions [ see Drug Interactions (7) ]. Concomitant use of St. John's wort ( Hypericum perforatum ) or St. John's wort-containing products and VIRAMUNE is not recommended. Co-administration of St. John's wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including VIRAMUNE, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of VIRAMUNE and lead to loss of virologic response and possible resistance to VIRAMUNE or to the class of NNRTIs. Co-administration of VIRAMUNE and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy. 5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRAMUNE. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. 5.6 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. --- BOXED WARNING: WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with VIRAMUNE. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4 + cell counts at initiation of therapy place patients at increased risk; women with CD4 + cell counts >250 cells/mm 3 , including pregnant women receiving VIRAMUNE in combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with VIRAMUNE use can occur in both genders, all CD4 + cell counts and at any time during treatment. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue VIRAMUNE and seek medical evaluation immediately [ see Warnings and Precautions (5.1) ]. SKIN REACTIONS: Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with VIRAMUNE. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue VIRAMUNE and seek medical evaluation immediately. Transaminase levels should be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed [ see Warnings and Precautions (5.2) ]. MONITORING: Patients must be monitored intensively during the first 18 weeks of therapy with VIRAMUNE to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events. Do not restart VIRAMUNE following severe hepatic, skin or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment. WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS See full prescribing information for complete boxed warning. Fatal and non-fatal hepatotoxicity (5.1) Fatal and non-fatal skin reactions (5.2) Discontinue immediately if experiencing: Signs or symptoms of hepatitis (5.1) Increased transaminases combined with rash or other systemic symptoms (5.1) Severe skin or hypersensitivity reactions (5.2) Any rash with systemic symptoms (5.2) Monitoring during the first 18 weeks of therapy is essential. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events (5) .
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology , Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 4. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when co-administering these drugs. The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently. Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction. Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment Atazanavir/Ritonavir ? Atazanavir ? Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. Clarithromycin ? Clarithromycin ? 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Efavirenz ? Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ]. Ethinyl estradiol and Norethindrone ? Ethinyl estradiol ? Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. Fluconazole ?Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Fosamprenavir ? Amprenavir ? Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/Ritonavir ? Amprenavir ? Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. Indinavir ? Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. Ketoconazole ? Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Lopinavir/Ritonavir ?Lopinavir Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with nevirapine with no dose adjustment in antiretroviral-naive patients. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected. Methadone ? Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Nelfinavir ?Nelfinavir M8 Metabolite ?Nelfinavir C min The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. Rifabutin ?Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, 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. Rifampin ? Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. Saquinavir/ritonavir The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. Potential Drug Interactions: Drug Class Examples of Drugs Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased. Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased. Ergot alkaloids Ergotamine Plasma concentrations may be decreased. Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased. Motility agents Cisapride Plasma concentrations may be decreased. Opiate agonists Fentanyl Plasma concentrations may be decreased. Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. Co-administration of VIRAMUNE can alter the concentrations of other drugs and other drugs may alter the concentration of nevirapine. The potential for drug interactions must be considered prior to and during therapy (7 , 12.3)