Prescribing Tracleer®
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Tracleer® Dosage and Administration

Tracleer dosing

  • Initiate at 62.5 mg twice daily with or without food for four weeks; then increase to 125 mg twice daily.
    • Patients with low body weight (<40 kg) and >12 years old: initial and maintenance dose is 62.5 mg twice daily.
  • Reduce the dose or interrupt treatment and closely monitor patients developing aminotransferase elevations >3 x ULN.
  • Discontinue Tracleer (bosentan) 36 hours prior to initiation of ritonavir. Patients on ritonavir: initiate Tracleer at 62.5 mg once daily or every other day.

Tablets should be administered morning and evening with or without food. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset increased risk of hepatotoxicity.

Required monitoring—liver aminotransferase levels

Liver aminotransferase levels must be measured prior to initiation of treatment and monitored on a monthly basis.1

  • If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated.
  • 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 Tracleer should be stopped. There is no experience with reintroduction of Tracleer in these circumstances.

Tracleer should generally be avoided in patients with moderate or severe liver impairment.1 There are no specific data to guide dosing in hepatically impaired patients; caution should be exercised in patients with mildly impaired liver function.1

Prescribing Tracleer for females of childbearing potential

Initiate Tracleer in females of childbearing potential only after negative pregnancy test and only in females who are using two reliable methods of contraception.1

  • Females who have had tubal sterilization or Copper T 380A IUD or LNg-20 IUS inserted do not require other forms of contraception.
  • Effective contraception must be practiced throughout treatment and for one month after stopping Tracleer.
  • Pregnancy tests should be obtained monthly in females of childbearing potential taking Tracleer.

Drug-drug interactions1

  • Tracleer is contraindicated for use with cyclosporine A and 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 four 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 bosentan 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.
  • Tracleer has no significant interaction with iloprost.
  • Dose adjustments are not necessary with Tracleer and sildenafil.

Treatment discontinuation

Gradual dose reduction (62.5 mg twice daily for three to seven days) should be considered to avoid the potential for clinical deterioration as there is limited experience with abrupt discontinuation of Tracleer.1 No evidence for acute rebound has been observed.1

Indication and Important Safety Information Including Boxed Warning EXPAND COLLAPSE

INDICATION

Tracleer® (bosentan) is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%). Considerations for use: Patients with WHO class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of hepatotoxicity in WHO class II patients, which may preclude future use as their disease progresses.

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.

Hepatotoxicity

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.

Teratogenicity

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.

CONTRAINDICATIONS

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.

ADVERSE EVENTS

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%).

DRUG INTERACTIONS

  • 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.

MONITORING

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.