WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risks of hepatotoxicity and birth defects, bosentan tablets is available only through a restricted program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.3)]. Hepatotoxicity In clinical studies, bosentan tablets 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 tablets in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan tablets 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 tablets. 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 tablets 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 tablets 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 tablets should be stopped. There is no experience with the reintroduction of bosentan tablets in these circumstances. Embryo-Fetal Toxicity Bosentan tablets are likely to cause major birth defects if used by pregnant females based on animal data [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)] . Therefore, pregnancy must be excluded before the start of treatment with bosentan tablets. Throughout treatment and for one month after stopping bosentan tablets, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving bosentan tablets [see Drug Interactions (7.2)] . Obtain monthly pregnancy tests. WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Bosentan tablets are available only through a restricted distribution program called the Bosentan REMS Program because of these risks (5.3): Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with bosentan tablets (5.1). · Measure liver aminotransferases prior to initiation of treatment and then monthly (2.1, 5.1). · Discontinue bosentan tablets if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 x ULN (2.4, 5.1). Based on animal data, bosentan tablets are likely to cause major birth defects if used during pregnancy (4.1, 5.2, 8.1). · Must exclude pregnancy before and during treatment (2.1, 4.1, 8.1). · To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping bosentan tablets (4.1, 5.2, 8.1).
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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 tablets (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 tablets-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 tablets. The combination of hepatocellular injury (increases in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 2x ULN) is a marker for potential serious hepatotoxicity. Elevations of AST or ALT associated with bosentan tablets 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 tablets. 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 tablets 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 tablets 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, consider whether the benefits of bosentan tablets are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses. 5.2 Embryo-fetal Toxicity Based on data from animal reproduction studies, bosentan tablets may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test prior to bosentan tablets treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with bosentan tablets and for at least one month after the last dose [see Dosage and Administration (2), Use in Specific Populations (8.1, 8.3)] . Bosentan tablets are only available for females through a restricted program under REMS [see Warnings and Precautions (5.3)]. 5.3 Prescribing and Distribution Program for Bosentan Because of the risks of hepatotoxicity and birth defects, bosentan tablet is available only through a restricted program called the Bosentan REMS Program. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions (5.1, 5.2), Contraindications (4.1)] . Required components of the Bosentan REMS are: Healthcare professionals who prescribe bosentan tablets must review the prescriber educational materials, enroll in the Bosentan REMS Program and comply with its requirements. Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of reproductive potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly. To receive bosentan tablets, all patients must understand the risks and benefits, and complete a patient enrollment form. Pharmacies that dispense bosentan tablets must enroll in the program and agree to comply with the Bosentan REMS Program requirements. Further information about Bosentan REMS Program is available at www.BosentanREMSProgram.com or 1-866-359-2612. 5.4 Fluid Retention Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of bosentan tablets and other endothelin receptor antagonists. In PAH clinical trials with bosentan tablets, combined adverse events of fluid retention or edema were reported in 1.7% (placebo-corrected) of patients. In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting bosentan tablets. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure. If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as bosentan tablets or underlying heart failure, and the possible need for treatment or discontinuation of bosentan tablets [see Adverse Reactions (6.1), Clinical Studies (14.2)] . 5.5 Pulmonary Veno-Occlusive Disease If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether bosentan tablets should be discontinued. 5.6 Decreased Sperm Counts Decreased sperm counts have been observed in patients receiving bosentan tablets. Preclinical data also suggest that bosentan tablets, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)]. 5.7 Decreases in Hemoglobin and Hematocrit Treatment with bosentan tablets can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment [see Adverse Reactions (6.1)] .
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 (5.2)] · 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). To report SUSPECTED ADVERSE REACTIONS, contact 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 tablets 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 tablets 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 tablets 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 tablets (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 tablets was abnormal liver function. The adverse drug events that occurred in ≥3% of the bosentan tablets-treated patients and were more common on bosentan tablets in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3: Table 3: Adverse events * occurring in ≥3% of patients treated with bosentan tablets 125 to 250 mg twice daily and more common on bosentan tablets in placebo-controlled studies in pulmonary arterial hypertension Adverse Event Bosentan Tablets 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% - - * 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 Decreased Sperm Counts An open-label, single-arm, multicenter, safety study evaluated the effect on testicular function of bosentan tablets 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan tablets. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan tablets were discontinued and after 2 months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as bosentan tablets have an adverse effect on spermatogenesis. Decreases in Hemoglobin and Hematocrit Treatment with bosentan tablets can cause a dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment. The overall mean decrease in hemoglobin concentration for adult bosentan tablets-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan tablets treatment and hemoglobin levels stabilized by 4 to 12 weeks of bosentan tablets treatment. In placebo-controlled studies of all uses of bosentan tablets, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of bosentan tablets-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan tablets-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan tablets treatment. During the course of treatment, the hemoglobin concentration remained within normal limits in 68% of bosentan tablets-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. 6.2 Postmarketing Experience There have been several postmarketing reports of angioedema associated with the use of bosentan tablets. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing bosentan tablets. The following additional adverse reactions have been reported during the postapproval use of bosentan tablets. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to bosentan tablets exposure: Unexplained hepatic cirrhosis [see Boxed Warning] Liver failure [see Boxed Warning] Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4)] Thrombocytopenia Rash Jaundice Anemia requiring transfusion Neutropenia and leukopenia Nasal congestion