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Tracleer (Bosentan) - Warnings and Precautions

 
 



WARNING: RISKS OF HEPATOTOXICITY and TERATOGENICITY

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.). T.A.P. 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. [see Warnings and Precautions].

Hepatotoxicity

In clinical studies, Tracleer 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 Tracleer in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of Tracleer 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 Tracleer. 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 Tracleer with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration].

Elevations in aminotransferases require close attention [see Dosage and Administration]. Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × 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 × ULN, treatment with Tracleer should be stopped. There is no experience with the reintroduction of Tracleer in these circumstances.

Teratogenicity

Tracleer is likely to cause major birth defects if used by pregnant females based on animal data [see Use in Specific Populations]. Therefore, pregnancy must be excluded before the start of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of childbearing potential must use two reliable methods of contraception 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. 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 Tracleer [see Drug Interactions]. Obtain monthly pregnancy tests.

 

WARNINGS AND PRECAUTIONS

Hepatotoxicity

Elevations in ALT or AST by more than 3 × ULN were observed in 11% of Tracleer-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 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with Tracleer. The combination of hepatocellular injury (increases in aminotransferases of > 3 × ULN) and increases in total bilirubin (≥ 2× ULN) is a marker for potential serious hepatotoxicity.

Elevations of AST or ALT associated with Tracleer 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 Tracleer.

Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see Dosage and Administration]. Discontinue Tracleer 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 × ULN.

Prescribing and Distribution Program for Tracleer

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.) As a component of the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program. [see Boxed Warning and Contraindications].

Required components of the Tracleer REMS are:

  • Healthcare professionals who prescribe Tracleer must review the prescriber educational materials, enroll in T.A.P. and comply with its requirements.
  • Healthcare professionals must review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and for females of childbearing potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.
  • To receive Tracleer, all patients must understand the risks and benefits, complete a patient enrollment form, and be re-enrolled annually by their prescriber.
  • Pharmacies that dispense Tracleer must enroll in the program and agree to comply with the T.A.P. requirements.

Further information about Tracleer and T.A.P. is available at www.tracleerrems.com or 1-866-228-3546.

Patients with Pre-existing Hepatic Impairment

Tracleer is not recommended in patients with moderate or severe liver impairment. In addition, initiation of Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning, Dosage and Administration Use in Specific Populations].

Fluid Retention

Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of Tracleer and other endothelin receptor antagonists. In PAH clinical trials with Tracleer, combined adverse events of fluid retention or edema were reported in 1.7 percent (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 Tracleer. 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 Tracleer or underlying heart failure, and the possible need for treatment or discontinuation of Tracleer. [see Adverse Reactions and Clinical Studies].

Pulmonary Veno-Occlusive Disease

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

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 [see Adverse Reactions, Nonclinical Toxicology].

Decreases in Hemoglobin and Hematocrit

Treatment with Tracleer 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 ].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X: Teratogenic Effects [see Contraindications]

Use of Tracleer is contraindicated in females who are or may become pregnant. While there are no adequate and well-controlled studies in pregnant females, animal studies show that Tracleer is likely to cause major birth defects when administered during pregnancy. Bosentan caused teratogenic effects in animals including malformations of the head, mouth, face, and large blood vessels. If Tracleer is used during pregnancy or if a patient becomes pregnant while taking Tracleer, the patient should be apprised of the potential hazard to the fetus.

Females of childbearing potential should have a negative pregnancy test before starting treatment with Tracleer. The prescriber should not dispense a prescription for Tracleer without documenting a negative urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse. Follow-up urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Tracleer. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus.

Drug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using Tracleer and should not be used as a patient's only contraceptive method [see Drug Interactions]. Females of childbearing potential using Tracleer must use two reliable forms of contraception unless she has a tubal sterilization or has a Copper T 380A IUD or LNg 20 IUS. In these cases, no additional contraception is needed. Contraception should be continued until one month after completing Tracleer therapy. Females of childbearing potential using Tracleer should seek contraception counseling from a gynecologist or other expert as needed.

Bosentan was teratogenic in rats given oral doses two times the maximum recommended human dose [MRHD] (on a mg/ m2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs [see Nonclinical Toxicology].

Nursing mothers

It is not known whether bosentan is excreted into human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from bosentan, a decision should be made to discontinue nursing or to discontinue Tracleer, taking into account the importance of Tracleer to the mother.

Pediatric use

Safety and efficacy in pediatric patients have not been established.

Geriatric use

Clinical studies of Tracleer did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

Hepatic Impairment

Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (Cmax and AUC) of bosentan. The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. Tracleer should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan was not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) [see Dosage and Administration, Warnings and Precautions, Pharmacokinetics].

Renal Impairment

The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics].

Page last updated: 2012-10-31

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