Dosage & Administration
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Tracleer Prescribing Information
Because of the risks of hepatotoxicity and birth defects, TRACLEER is available only through a restricted program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.3)] .
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 (2.4), Warnings and Precautions (5.1)] . 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 (2.4)] .
Elevations in aminotransferases require close attention [see Dosage and Administration (2.4)] . 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.
Embryo-Fetal Toxicity
TRACLEER is likely to cause major birth defects if used by pregnant females based on animal data [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)] . Therefore, pregnancy must be excluded before the start of treatment with TRACLEER. Throughout treatment and for one month after stopping TRACLEER, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, 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 (7.2)] . Obtain monthly pregnancy tests.
TRACLEER is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):
- in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO 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%) [see Clinical Studies (14.1)] .
- in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.
Required Monitoring
Healthcare professionals who prescribe TRACLEER must enroll in the Bosentan REMS Program and must comply with the required monitoring to minimize the risks associated with TRACLEER [see Warnings and Precautions (5.3)] .
Obtain a pregnancy test in females of reproductive potential prior to TRACLEER treatment, monthly during treatment and one month after stopping TRACLEER. Initiate treatment with TRACLEER in females of reproductive potential only after a negative pregnancy test [see Boxed Warning, Contraindications (4.1), Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)] .
Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Warnings and Precautions (5.1)] .
Recommended Dosage
Administer TRACLEER orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.
| Initial 4 weeks | Maintenance (after 4 weeks) | |
|---|---|---|
| Patients >12 years of age and >40 kg | 62.5 mg twice daily | 125 mg twice daily |
| Patients >12 years of age and <40 kg | 62.5 mg twice daily | 62.5 mg twice daily |
| Patients ≤12 years of age | ||
| ≥4–8 kg | 16 mg twice daily | 16 mg twice daily |
| >8–16 kg | 32 mg twice daily | 32 mg twice daily |
| >16–24 kg | 48 mg twice daily | 48 mg twice daily |
| >24–40 kg | 64 mg twice daily | 64 mg twice daily |
Administration
TRACLEER film-coated tablets and tablets for oral suspension (dispersible tablets) should be administered orally twice daily.
Disperse tablets for oral suspension, or dispersible tablet half, in a minimal amount of water immediately before administration.
Store divided dispersible tablet pieces at 20 ºC to 25 ºC (68 ºF to 77 ºF) in the opened blister for up to 7 days.
Dosage Adjustments for Aminotransferase Elevations
If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2.
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 bilirubin ≥2 ×Upper Limit of Normal (ULN). There is no experience with the reintroduction of TRACLEER in these circumstances.
| ALT/AST levels | Treatment and monitoring recommendations |
|---|---|
| >3 and ≤5 ×ULN | Confirm by another aminotransferase test; if confirmed,
|
| >5 and ≤8 ×ULN | Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values,
|
| >8 ×ULN | Stop treatment permanently. There is no experience with reintroduction of TRACLEER in these circumstances. |
Use with Ritonavir
Co-administration of TRACLEER in Patients on Ritonavir
In patients who have been receiving ritonavir for at least 10 days, start TRACLEER at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1)] .
Co-administration of Ritonavir in Patients on TRACLEER
Discontinue use of TRACLEER at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume TRACLEER at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1)] .
Use in Patients with Pre-existing Hepatic Impairment
Avoid initiation of TRACLEER in patients with aminotransferases >3 ×ULN. No dose adjustment is required in patients with mildly impaired liver function [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .
62.5 mg tablets: round, biconvex, orange-white tablets, debossed with identification marking "62,5"
125 mg tablets: oval, biconvex, orange-white tablets, debossed with identification marking "125"
32 mg tablets for oral suspension:
- quadrisected: clover-shaped, quadrisected, pale yellow to off-white tablets, debossed with identification marking "32" on the side opposite the quadrisection lines,
- bisected: round, pale yellow to off-white tablets, bisected on one side and debossed with identification marking "32" on the other side.
Pregnancy
Risk Summary
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 (4.1)] . There are limited data on TRACLEER use in pregnant women. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on a mg/m 2 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.
Data
Animal Data
Bosentan was teratogenic in rats given oral doses two times the MRHD (on a mg/m 2 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/m 2 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.
Lactation
Risk Summary
Data from a case report describe the presence of bosentan in human milk. There is insufficient information about the effects of bosentan on the breastfed infant and no information on the effects of bosentan 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
Pregnancy Testing
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.
Contraception
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 (7.2)] . 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 Boxed Warning] .
Infertility
Males
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 (5.6), Adverse Reactions (6.1), Nonclinical Toxicology (13.1)] .
Pediatric Use
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 (14.1)] . 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 (6.1), Pulmonary Arterial Hypertension (14.1)] .
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.
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 (C max 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 (2.6), Warnings and Precautions (5.1), Pharmacokinetics (12.3)] .
Renal Impairment
The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics (12.3)] .
Pregnancy
Use of TRACLEER is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2), Use in Specific Populations (8.1)] .
Use with Cyclosporine A
Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER and cyclosporine A is contraindicated [see Cytochrome P450 Drug Interactions (7.1)] .
Use with Glyburide
An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and TRACLEER is contraindicated [see Cytochrome P450 Drug Interactions (7.1)] .
Hypersensitivity
TRACLEER is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema [see Adverse Reactions (6.2), Description (11)] .