Included as part of the "PRECAUTIONS" Section
ALT or AST > 3 x 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 x ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with Tracleer. In a pooled analysis of four pediatric studies conducted in PAH (n =100), elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of patients. 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.
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.
Avoid initiation of Tracleer in patients with elevated aminotransferases (> 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see BOX WARNING, DOSAGE AND ADMINISTRATION, Use In Specific Populations].
In WHO Functional Class II patients, consider whether the benefits of Tracleer are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses.
Based on data from animal reproduction studies, Tracleer may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test prior to Tracleer treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with Tracleer and for at least one month after the last dose [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Tracleer is only available for females through a restricted program under REMS [see Prescribing And Distribution Program For Tracleer].
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 REMS Program. As a component of the Tracleer REMS, prescribers, patients, and pharmacies must enroll in the program [see BOX WARNING, Hepatotoxicity, Embryo-Fetal Toxicity, CONTRAINDICATIONS].
Required components of the Tracleer REMS are:
- Healthcare professionals who prescribe Tracleer must review the prescriber educational materials, enroll in the Tracleer REMS Program 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 reproductive 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.
- Pharmacies that dispense Tracleer must enroll in the program and agree to comply with the Tracleer REMS Program requirements.
Further information about Tracleer and the Tracleer REMS Program is available at www.Tracleerrems.com or 1-866-228-3546.
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% (placebocorrected) 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, Clinical Studies].
Pulmonary Veno-Occlusive Disease
If signs of pulmonary edema occur, consider the possibility of associated pulmonary venoocclusive 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, similar to 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
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Advise the patient that Tracleer is only available through a restricted access program called the Tracleer REMS Program.
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.
Educate and counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with Tracleer and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use two different forms of contraception while taking Tracleer and for one month after discontinuing Tracleer [see Use In Specific Populations].
Females who have intrauterine devices (IUD) or tubal sterilization 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.
Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.
Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.
Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected.
Advise the patient that Tracleer is available only from specialty pharmacies that are enrolled in the Tracleer REMS Program.
Patients must sign the Tracleer Patient Enrollment and Consent Form to confirm that they understand the risks of Tracleer.
Advise women not to breastfeed during treatment with TRACLEER [see Use In Specific Populations].
Advise males of reproductive potential that TRACLEER may impair fertility [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, Use In Specific Populations and Nonclinical Toxicology].
Tracleer dispersible tablets contain phenylalanine, a component of aspartame. Each dispersible tablet contains 1.87 mg of phenylalanine.
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
Advise patients that Tracleer dispersible tablets should not be split into quarters.
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.
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 4-6 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
Based on data from animal reproduction studies, Tracleer may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy [see CONTRAINDICATIONS]. There are limited data on Tracleer use in pregnant women. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2times the maximum recommended human dose (MRHD) on a mg/m2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see Animal Data]. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Bosentan was teratogenic in rats given oral doses two times the 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 embryo-fetal toxicity is a class effect of these drugs.
There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from Tracleer, advise women not to breastfeed during treatment with Tracleer.
Females And Males Of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to initiating Tracleer, monthly during treatment and one month after stopping treatment with 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 reproductive potential using Tracleer must use two acceptable methods of contraception during treatment and for 1 month after treatment with Tracleer. Patients may choose one highly effective form of contraception (intrauterine devices (IUD) or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see BOX WARNING].
Decreased sperm counts have been observed in patients receiving Tracleer. Based on these findings and findings in animals, Tracleer may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, Nonclinical Toxicology].
The efficacy of Tracleer in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with Tracleer. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with Tracleer [see Pulmonary Arterial Hypertension]. Safety in pediatric patients is supported by data from 100 pediatric patients treated with Tracleer for a median of 17 months [see Clinical Studies Experience, Pulmonary Arterial Hypertension].
Juvenile Animal Toxicity Data
In a juvenile rat toxicity study, rats were treated from Day 4 postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen. The NOAEL was 4 times (at Day 4 postpartum) and 2 times (Day 69 postpartum) the human therapeutic exposure, respectively.
No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, 7 times the therapeutic exposure in children with PAH.
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 have 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 were 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