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boxed warning
WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risk of hepatotoxicity, bosentan 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 )] . Hepatotoxicity In clinical studies, bosentan 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 bosentan in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan in these cases could not be excluded. In at least one case, the initial presentation (after > 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of bosentan. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping bosentan with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration ( 2.4 )] . Elevations in aminotransferases require close attention [see Dosage and Administration ( 2.4 )] . Bosentan should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult. 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 x ULN, treatment with bosentan should be stopped. There is no experience with the reintroduction of bosentan in these circumstances. Embryo-Fetal Toxicity Bosen...
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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 bosentan ( 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 x ULN were observed in 11% of bosentan-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 x ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. 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 x ULN) and increases in total bilirubin (≥ 2 x ULN) is a marker for potential serious hepatotoxicity. Elevations of AST or ALT associated with bosentan 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 bosentan. 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 bosentan 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 x ULN. Avoid initiation of bosentan in patients with elevated aminotransferases (> 3 x 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, con...
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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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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 bosentan 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 bosentan 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 bosentan 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 bosentan (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 bosentan was abnormal liver function. The adverse drug events that occurred in ≥ 3% of the bosentan-treated patients and were more common on bosentan in placebo-controlled trials in PAH at doses of 125 mg or 250 mg twice daily are shown in Table 3: Table 3 Adverse events * occurring in ≥ 3% of patients treated with Bosentan 125 mg to 250 mg twice daily and more common on Bosentan in placebo-controlled studies in pulmonary arterial hypertension * Note: only AEs with onset from start of treatment to 1 calendar da...
adverse reactions table
Table 3 Adverse events* occurring in ≥ 3% of patients treated with Bosentan 125 mg to 250 mg twice daily and more common on Bosentan in placebo-controlled studies in pulmonary arterial hypertension *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.**Respiratory Tract Infection combines the terms "Nasopharyngitis", "Upper Respiratory Tract Infection" and "Respiratory Tract Infection". Combined data from Study 351, BREATHE-1 and EARLY Adverse Event Bosentan n = 258 Placebo n = 172 No. % No. % Respiratory Tract Infection** 56 22% 30 17% Headache 39 15% 25 14% Edema 28 11% 16 9% Chest Pain 13 5% 8 5% Syncope 12 5% 7 4% Flushing 10 4% 5 3% Hypotension 10 4% 3 2% Sinusitis 9 4% 4 2% Arthralgia 9 4% 3 2% Serum Aminotransferases, abnormal 9 4% 3 2% Palpitations 9 4% 3 2% Anemia 8 3% - -