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Elevations in ALT or AST by more than 3 x ULN were observed in 11% of Tracleer treated patients (n = 658) compared to 2% of placebo-treated patients (n = 280). Threefold 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 x 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 x ULN) and increases in total bilirubin ( ≥ 2x 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 x 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 (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) 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 x 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].
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].
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Advise the patient that Tracleer is only available through a restricted access program called the Tracleer Access Program (T.A.P.)
As a component of the Tracleer REMS, prescribers must review the contents of the Tracleer Medication Guide with the patient before initiating Tracleer.
Instruct patients that the risks associated with Tracleer include:
Discuss with the patient the requirement to measure serum aminotransferases monthly.
- Serious birth defects if used by pregnant women
Educate and counsel female patients of child bearing potential about the need to use reliable methods of contraception during treatment with Tracleer and for one month after treatment discontinuation. Females of childbearing potential must have monthly pregnancy tests and must use two different forms of contraception while taking Tracleer and for one month after discontinuing Tracleer. Females who have a tubal ligation or a Copper T 380A IUD or LNg 20 IUS can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.
Advise the patient that Tracleer is available only from specialty pharmacies that are enrolled in Tracleer Access Program.
Patients must sign the Tracleer Enrollment for Patients and Prescribers form to confirm that they understand the risks of Tracleer.
Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the Tracleer REMS.
Other Risks Associated with Tracleer
Instruct patients that the risks associated with Tracleer also include the following:
Decreases in hemoglobin and hematocrit – advise patients of the importance of hemoglobin testing
Decreases in sperm count
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on a mg/m² basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan.
Reproductive and Developmental Toxicology
Bosentan was teratogenic in rats given oral doses ≥ 60 mg/kg/day. 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 of 60 and 300 mg/kg/day. Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, 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.
Impairment of Fertility/Testicular Function
The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.
Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m² basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 46 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).
Use In Specific Populations
Pregnancy Category X - Teratogenic Effects
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].
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.
Safety and efficacy in pediatric patients have not been established.
Clinical studies of Tracleer did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
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].
The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics].
Last reviewed on RxList: 10/16/2012
This monograph has been modified to include the generic and brand name in many instances.
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