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boxed warning
WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risk of hepatotoxicity, TRACLEER is available only through a restricted program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS). Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.2) ] . WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. TRACLEER is available only through a restricted distribution program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS) because of the risk of hepatotoxicity ( 5.2 ): Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with TRACLEER ( 5.1 ). Measure liver aminotransferases prior to initiation of treatment and then monthly ( 2.1 , 5.1 ). Discontinue TRACLEER if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2×ULN ( 2.4 , 5.1 ). Based on animal data, TRACLEER may cause fetal harm if used during pregnancy ( 4.1 , 5.3 , 8.1 ). Females of reproductive potential: Exclude pregnancy before initiating treatment. Use effective contraception prior to initiation of treatment, during treatment and for one month after stopping TRACLEER ( 2.1 , 4.1 , 5.3 , 8.1 , 8.3 ). When pregnancy is detected, discontinue TRACLEER as soon as possible ( 5.3 ). Hepatotoxicity In clinical studies, TRACLEER caused at least 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) ] . In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy with TRACLEER in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of TRACLEER in these cases could not be excluded. In at least one case, the initial presentation (after >20 months of treatment) included pronounced elevations in aminotransferase...
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Fluid retention: May require intervention ( 5.4 ). Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing TRACLEER ( 5.5 ). Decreased sperm counts ( 5.6 ). Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter ( 5.7 ). 5.1 Hepatotoxicity ALT or AST >3 × ULN were observed in 11% of TRACLEER-treated patients (n=658) compared to 2% of placebo-treated patients (n=280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥3 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with TRACLEER. In a pooled analysis of four pediatric studies conducted in PAH (n=100), elevations in liver aminotransferases ≥3×ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3 × ULN) and increases in total bilirubin (≥2 × ULN) is a marker for potential serious hepatotoxicity. Elevations of AST or ALT associated with TRACLEER are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with TRACLEER. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see Dosage and Administration (2.1 , 2.4) ] . Discontinue TRACLEER if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥2 × ULN. Avoid initiation of TRACLEER in patients with elevated aminotransferases (>3 × ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning , Dosage and Administration (2.6) , Use in Specific Populations (8.6) ] . In WHO Functional Class II patients, consider wheth...
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adverse reactions
6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Boxed Warning , Warnings and Precautions (5.1) ] Embryo-fetal Toxicity [see Boxed Warning , Warnings and Precautions (5.3) ] Fluid Retention [see Warnings and Precautions (5.4) ] Common adverse reactions (≥3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia ( 6.1 ). Common adverse reactions (≥15%) for the dispersible tablet are upper respiratory tract infections and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Safety data on TRACLEER were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with PAH and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to TRACLEER in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years; and n=39 for more than 2 years). Exposure of PAH patients (n=328) to TRACLEER ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months). Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with PAH were more frequent on TRACLEER (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations >1% and occurring more often on TRACLEER was abnormal liver function. The adverse drug events that occurred in ≥3% of the TRACLEER-treated patients and were more common on TRACLEER in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3: Table 3: Adverse Events Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were...
adverse reactions table
Table 3: Adverse Events Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population.Occurring in ≥3% of Patients Treated with TRACLEER 125-250 mg Twice Daily and More Common on TRACLEER in Placebo-Controlled Studies in Pulmonary Arterial Hypertension Adverse EventTRACLEER n=258 Placebo n=172 No.%No.% Respiratory Tract Infection Respiratory Tract Infection combines the terms "Nasopharyngitis", "Upper Respiratory Tract Infection" and "Respiratory Tract Infection". Combined data from Study 351, BREATHE-1 and EARLY5622%3017% Headache3915%2514% Edema2811%169% Chest Pain135%85% Syncope125%74% Flushing104%53% Hypotension104%32% Sinusitis94%42% Arthralgia94%32% Serum Aminotransferases, abnormal94%32% Palpitations94%32% Anemia83%--
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