Silkay Warnings

Bosentan is associated with transaminase elevations (ALT or AST ≥3 times ULN), and in a small numer of cases may occur with elevations in bilirubin. Monitor transaminases at baseline then monthly thereafter. Adjust dosage if elevations in liver enzymes occur without symptoms of hepatic injury or elevated bilirubin. In the postmarketing surveillance (with close monitoring), there have been rare cases of unexplained hepatic cirrhosis after prolonged therapy (>12 months) patients with multiple comorbidities and drug therapies. There have also been cases of hepatic failure. Treatment should be stopped in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting abdominal pain, and/or fever) or elevated bilirubin (≥2 times ULN); safety of reintroduction is unknown. Avoid use in patients with base line serum transaminases >3 times ULN at baseline (monitoring for hepatotoxicity may be more difficult) or moderate-to-severe hepatic impairment. The combination of hepatocellular injury (transaminase elevations >3 times ULN) and bilirubin increased ≥2 times ULN are a marker for potential serious hepatotoxicity. Transaminase elevations are dose dependent, generally asymptomatic, occur both early and late in therapy, progress slowly, and are usually reversible after treatment interruption or discontinuation. Transaminase elevations may also spontaneously reverse while continuing bosentan treatment. Consider the benefits of treatment versus the risk of hepatotoxicity when initiating therapy in patients with WHO Class II symptoms.
May cause birth defects (based on animal data); use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during therapy and for 1 month after stopping treatment. Hormonal contraceptives (oral, injectable, transdermal, or implantable) should not be used as the sole means of contraception because they may not be effective in patients receiving bosentan. Patients with an intrauterine device (IUD) or tubal ligation do not need additional contraceptive measures.
Dose-related decreases in hematocrit/hemoglobin may be observed, usually within the first few weeks of therapy with subsequent stabilization of levels by 4 to 12 weeks of treatment. Monitor hemoglobin prior to initiation, after 1 and 3 months, and every 3 months thereafter. Significant decreases in hemoglobin require further evaluation to determine the cause and specific management. Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). If clinically significant fluid retention develops (with or without weight gain), further evaluation is necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with underlying heart failure due to potential complications from fluid retention. In a scientific statement from the American Heart Association, bosentan has been determined to be an agent that may exacerbate underlying myocardial dysfunction. If signs of pulmonary edema occur, consider possibility of pulmonary veno-occlusive disease; may require discontinuation of bosentan. Hypersensitivity reactions, including rash and angioedema have been observed. Decreased sperm counts have been observed in men during treatment; bosentan may have an adverse effect on spermatogenesis. Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy.