IMPORTANT SAFETY INFORMATION
Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted program called the Tracleer Access Program (T.A.P.), which is a component of the Tracleer Risk Evaluation and Mitigation Strategy (REMS). Under the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program, by calling T.A.P at 1-866-228-3546.
Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with Tracleer. In a setting of close monitoring, rare cases of liver failure and unexplained hepatic cirrhosis were observed after prolonged (>12 months) treatment. In general, avoid using Tracleer in patients with elevated aminotransferases (>3 x ULN) at baseline. Measure liver aminotransferases prior to initiation of treatment and then monthly. Discontinue Tracleer if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 x ULN.
Based on animal data, Tracleer is likely to cause major birth defects if used during pregnancy. Exclude pregnancy before and during treatment. To prevent pregnancy, females of childbearing potential must use 2 reliable forms of contraception during treatment and for 1 month after stopping Tracleer unless the patient has a tubal sterilization or Copper T 380A IUD or LNg-20 IUS inserted, in which case no other contraception is needed. Obtain monthly pregnancy tests.
Tracleer is contraindicated:
- In females who are or may become pregnant
- With cyclosporine A
- With glyburide
- In patients who are hypersensitive to bosentan or any component of Tracleer
WARNINGS AND PRECAUTIONS
In clinical trials, ALT/AST elevations (>3 x ULN) were observed in 11% of patients treated with Tracleer, accompanied by elevated bilirubin in a few cases. 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. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid using Tracleer in patients with moderate or severe liver impairment or elevated ALT/AST >3 x ULN prior to drug initiation.
If clinically significant fluid retention develops, with or without associated weight gain, the cause, such as Tracleer or underlying heart failure, must be determined. Patients may require treatment or Tracleer therapy may need to be discontinued.
Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether Tracleer should be discontinued.
Decreased sperm counts have been observed in patients receiving Tracleer. Preclinical data also suggest that Tracleer, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.
Treatment with Tracleer can cause a dose-related decrease in hemoglobin (Hgb) and hematocrit. Hgb should be checked after 1 and 3 months, and then every 3 months. Upon marked decrease in Hgb, determine the cause and need for specific treatment.
In Tracleer pivotal trials, the most common adverse events occurring more often in Tracleer-treated patients than in patients taking placebo were respiratory tract infection (22% vs 17%), headache (15% vs 14%), edema (11% vs 9%), chest pain (5% vs 5%), syncope (5% vs 4%), flushing (4% vs 3%), hypotension (4% vs 2%), sinusitis (4% vs 2%), arthralgia (4% vs 2%), serum aminotransferases abnormal (4% vs 2%), palpitations (4% vs 2%), and anemia (3% vs 0%).
- Tracleer is contraindicated for use with cyclosporine A and with glyburide.
- Tracleer is metabolized by CYP2C9 and CYP3A.
- Co-administration with agents that are metabolized by these pathways may affect plasma concentrations of one or both agents.
- When initiating lopinavir/ritonavir and other ritonavir-containing HIV regimens, dosage adjustment of Tracleer is necessary.
- When co-administered with simvastatin, or other statins that are CYP3A substrates, dosage adjustment of such statins may need to be considered.
- When co-administered with rifampicin, a CYP3A inducer, liver function should be monitored weekly for the first 4 weeks before reverting to normal monitoring.
- Co-administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals; caution should be exercised if they are used together.
- When co-administered with ketoconazole, a potent CYP3A inhibitor, no dose adjustment of Tracleer is necessary, but increased effects of Tracleer may need to be considered.
- There are no clinically relevant interactions between Tracleer and warfarin, digoxin, nimodipine, losartan, or sildenafil.
- Dose adjustments are not necessary when Tracleer and sildenafil are co-administered.
- Tracleer has no significant interaction with iloprost.
LIVER ENZYME ELEVATIONS
- Measure liver aminotransferases prior to initiation of treatment and then monthly.
- Use of Tracleer should generally be avoided in patients with elevated aminotransferases (>3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult.
- It is important to adhere strictly to the monthly monitoring schedule for the duration of treatment.
- Changes in aminotransferases may occur early or late in treatment.
- There have been rare postmarketing reports of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring; the contribution of Tracleer could not be excluded.
- For patients whose monthly LFTs are ≤3 x ULN, no change in monitoring schedule or dosage is required.
- For patients whose monthly LFTs are >3 x ULN, close monitoring and either dose reduction or treatment cessation are necessary.
It is important to adhere strictly to the monthly monitoring schedule for LFTs and, if applicable, pregnancy for the duration of treatment.
Please see full Prescribing Information, including BOXED WARNING about hepatotoxicity and teratogencity.