Bosentan - Warnings and Precautions
The following warnings and precautions are taken directly from the US FDA-approved drug label for Bosentan. This is the same information dispensing pharmacists read.
\u26a0\ufe0f Boxed Warning (Highest FDA Alert)
WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risk of hepatotoxicity, bosentan tablets are 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 ]. 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 , Warnings and Precautions ] . 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 tablets. This case reinforces the importance of strict adherence to
5 WARNINGS AND PRECAUTIONS Fluid retention: May require intervention .
Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing bosentan .
Decreased sperm counts .
Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter .
5.1 Hepatotoxicity ALT or AST >3xULN 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 ≥3xULN 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 >3xULN) and increases in total bilirubin (≥2xULN) 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 ≥2xULN.
Avoid initiation of bosentan in patients with elevated aminotransferases (>3xULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning , D osage and Administration , Use in Specific Populations ] .
In WHO Functional Class II patients, consider whether the benefits of bosentan are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses.
Bosentan is only available through a restricted program under REMS [see Warnings and Precautions ].
5.2 Bosentan REMS Because of the risks of hepatotoxicity, bosentan tablets are available only through a restricted program called the Bosentan REMS.
As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning , Warnings and Precautions ] .
Required components of the Bosentan REMS are: Healthcare professionals who prescribe bosentan tablets must review the prescriber educational materials, enroll in the Bosentan REMS and comply with its requirements.
Healthcare professionals must review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly.
To receive bosentan tablets, all patients must understand the risks and benefits, and complete a patient enrollment form with their prescriber.
Pharmacies that dispense bosentan tablets must enroll in the program and agree to comply with the Bosentan REMS requirements.
Further information about bosentan tablets and the Bosentan REMS is available at www.BosentanREMSProgram.com or 1-866-359-2612.
5.3 Embryo-Fetal Toxicity Based on data from animal reproduction studies, bosentan may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant.
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