FULL PRESCRIBING INFORMATION
WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY
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.
1 INDICATIONS AND USAGE
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.
2 DOSAGE AND ADMINISTRATION
2.1 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)] .
2.2 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 |
2.3 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 20ºC to 25ºC (68ºF to 77ºF) in the opened blister for up to 7 days.
2.4 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. |
2.5 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)] .
2.6 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)] .
3 DOSAGE FORMS AND STRENGTHS
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.
4 CONTRAINDICATIONS
4.1 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)] .
4.2 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)] .
4.3 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)] .
4.4 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)] .
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
ALT or AST >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. 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 ×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 (2.1, 2.4)] . 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.
Avoid initiation of TRACLEER 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 (2.6), Use in Specific Populations (8.6)] .
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.
5.2 Embryo-fetal Toxicity
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 (2), Use in Specific Populations (8.1, 8.3)] .
TRACLEER is only available for females through a restricted program under REMS [see Warnings and Precautions (5.3)] .
5.3 Prescribing and Distribution Program for Bosentan
Because of the risks of hepatotoxicity and birth defects, TRACLEER is available only through a restricted program called the Bosentan REMS Program. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions (5.1, 5.2), Contraindications (4.1)] .
Required components of the Bosentan REMS are:
- Healthcare professionals who prescribe TRACLEER must review the prescriber educational materials, enroll in the Bosentan 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, and complete a patient enrollment form.
- Pharmacies that dispense TRACLEER must enroll in the program and agree to comply with the Bosentan REMS Program requirements.
Further information about TRACLEER and the Bosentan REMS Program is available at www.BosentanREMSProgram.com or 1-866-359-2612.
5.4 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% (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 (6.1), Clinical Studies (14.2)] .
5.5 Pulmonary Veno-Occlusive Disease
If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether TRACLEER should be discontinued.
5.6 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 (6.1), Nonclinical Toxicology (13.1)] .
5.7 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)] .
6 ADVERSE REACTIONS
The following important adverse reactions are described elsewhere in the labeling:
- Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]
- Embryo-fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.2)]
- Fluid Retention [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Safety data on TRACLEER were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with PAH and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to TRACLEER in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years; and n=39 for more than 2 years). Exposure of PAH patients (n=328) to TRACLEER ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months).
Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with PAH were more frequent on TRACLEER (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations >1% and occurring more often on TRACLEER was abnormal liver function.
The adverse drug events that occurred in ≥3% of the TRACLEER-treated patients and were more common on TRACLEER in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3:
| Adverse Event | TRACLEER
n=258 | Placebo
n=172 |
||
|---|---|---|---|---|
| No. | % | No. | % | |
|
||||
| Respiratory Tract Infection † | 56 | 22% | 30 | 17% |
| Headache | 39 | 15% | 25 | 14% |
| Edema | 28 | 11% | 16 | 9% |
| Chest Pain | 13 | 5% | 8 | 5% |
| Syncope | 12 | 5% | 7 | 4% |
| Flushing | 10 | 4% | 5 | 3% |
| Hypotension | 10 | 4% | 3 | 2% |
| Sinusitis | 9 | 4% | 4 | 2% |
| Arthralgia | 9 | 4% | 3 | 2% |
| Serum Aminotransferases, abnormal | 9 | 4% | 3 | 2% |
| Palpitations | 9 | 4% | 3 | 2% |
| Anemia | 8 | 3% | - | - |
TRACLEER was evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH.
Decreased Sperm Counts
An open-label, single-arm, multicenter, safety study evaluated the effect on testicular function of TRACLEER 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with TRACLEER. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. TRACLEER was discontinued and after 2 months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as TRACLEER have an adverse effect on spermatogenesis.
Decreases in Hemoglobin and Hematocrit
Treatment with TRACLEER can cause a dose-related decrease in hemoglobin and hematocrit. 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.
The overall mean decrease in hemoglobin concentration for adult TRACLEER-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of TRACLEER treatment and hemoglobin levels stabilized by 4–12 weeks of TRACLEER treatment. In placebo-controlled studies of all uses of TRACLEER, marked decreases in hemoglobin (>15% decrease from baseline resulting in values <11 g/dL) were observed in 6% of TRACLEER-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients.
A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of TRACLEER-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of TRACLEER treatment.
During the course of treatment, the hemoglobin concentration remained within normal limits in 68% of TRACLEER-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis.
In a pooled analysis of pediatric patients (N=100) with PAH treated with TRACLEER, a decrease in hemoglobin levels to <10 g/dL from baseline was reported in 11% of patients. There was no decrease to <8 g/dL.
6.2 Postmarketing Experience
There have been several postmarketing reports of angioedema associated with the use of TRACLEER. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing TRACLEER.
The following additional adverse reactions have been reported during the postapproval use of TRACLEER. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to TRACLEER exposure:
- Unexplained hepatic cirrhosis [see Boxed Warning]
- Liver failure [see Boxed Warning]
- Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4)]
- Thrombocytopenia
- Rash
- Jaundice
- Anemia requiring transfusion
- Neutropenia and leukopenia
- Nasal congestion
7 DRUG INTERACTIONS
7.1 Cytochrome P450 Drug Interactions
Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see Pharmacokinetics (12.3)] . Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with TRACLEER will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with TRACLEER is not recommended.
Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when TRACLEER is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, TRACLEER is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.
Figure 1. CYP3A induction-mediated effect of bosentan on other drugs
Figure 2. Effect of other drugs on bosentan
7.2 Hormonal Contraceptives
Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking TRACLEER [see Use in Specific Populations (8.3)] .
An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.
8 USE IN SPECIFIC POPULATIONS
8.1 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.
8.2 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.
8.3 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)] .
8.4 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.
8.5 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.
8.6 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)] .
8.7 Renal Impairment
The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics (12.3)] .
10 OVERDOSAGE
Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.
In the postmarketing period, there was one reported overdose of 10,000 mg of TRACLEER taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support.
Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.
11 DESCRIPTION
TRACLEER ® is the proprietary name for bosentan, an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula:
Bosentan has a molecular weight of 569.64 and a molecular formula of C 27H 29N 5O 6S∙H 2O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive.
TRACLEER is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, ethylcellulose, glyceryl behenate, hydroxypropylmethylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, povidone, pregelatinized starch, sodium starch glycolate, talc, titanium dioxide, and triacetin. Each TRACLEER 62.5 mg tablet contains 64.54 mg of bosentan monohydrate, equivalent to 62.5 mg of anhydrous bosentan. Each TRACLEER 125 mg tablet contains 129.08 mg of bosentan monohydrate, equivalent to 125 mg of anhydrous bosentan.
TRACLEER is also available as a 32 mg tablet for oral suspension and contains the following excipients: acesulfame potassium, aspartame (E951), calcium hydrogen phosphate anhydrous, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, silica colloidal anhydrous, tartaric acid, and tutti frutti flavor. Each dispersible tablet contains 1.87 mg of phenylalanine. Each dispersible tablet contains 33.045 mg of bosentan monohydrate, equivalent to 32 mg anhydrous bosentan.
12 CLINICAL PHARMACOLOGY
12.3 Pharmacokinetics
General
After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about twice as high in adult patients with PAH as it is in healthy adult subjects.
In a relative bioavailability study in healthy adults, the peak plasma concentration and area under the plasma concentration-time curve for bosentan are on an average 14% and 11%, respectively, lower following administration of the oral dispersible tablet compared to the film-coated tablet.
Absorption
The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food.
Bosentan is highly bound (>98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. The volume of distribution is about 18 L.
Elimination
Metabolism
Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10%–20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50–65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3–5 days.
Specific Populations
Pediatrics
The average plasma exposure to bosentan at steady state (AUC ss) in pediatric patients with PAH aged 3 to 15 years treated with 31.25, 62.5 or 125 mg (approximately 2 mg/kg) film-coated tablet twice daily is 37% lower than that observed in adult patients with PAH receiving 125 mg film-coated tablet twice daily. Following administration of 4 mg/kg twice daily doses of dispersible tablet in patients with PAH aged 2 to 11 years, the average systemic exposure to bosentan at steady state is similar to that observed with 2 mg/kg. The average exposure to bosentan in these pediatric patients was approximately half the exposure in adult patients treated with 125 mg film-coated tablets twice daily.
The exposure to bosentan at 2 mg/kg three times daily dosing of dispersible tablet is similar to that of 2 mg/kg twice daily dosing in patients with PAH aged 3 months to 12 years.
Based on these findings, exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses higher than 2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.
Hepatic Impairment
In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure to bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment.
In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and PAH associated with portal hypertension than in 3 patients with normal liver function and PAH of other etiologies.
The pharmacokinetics of TRACLEER have not been evaluated in patients with severe liver impairment (Child-Pugh Class C) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)] .
Renal Impairment
In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to subjects with normal renal function. These differences do not appear to be clinically important.
Drug Interactions
Ketoconazole
Co-administration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. No dose adjustment of TRACLEER is necessary, but increased effects of TRACLEER should be considered.
Warfarin
Co-administration of bosentan 500 mg twice daily for 6 days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of TRACLEER and warfarin in patients with PAH did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among TRACLEER- and placebo-treated patients.
Digoxin, Nimodipine, and Losartan
Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan.
Sildenafil
In normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of PAH or erectile dysfunction.
Tadalafil
Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure (AUC) by 42% and C max by 27% following multiple dose co-administration. Tadalafil did not affect the exposure (AUC and C max) of bosentan or its metabolites.
Figure 3. CYP Induction-mediated effect of bosentan on other drugs
Figure 4. Effects of other drugs on bosentan
12.1 Mechanism of Action
Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. Bosentan has a slightly higher affinity for ET A receptors than for ET B receptors. The clinical impact of dual endothelin blockage is unknown.
Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disease.
13 NONCLINICAL TOXICOLOGY
13.1 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/m 2 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/m 2 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).
14 CLINICAL STUDIES
14.1 Pulmonary Arterial Hypertension
WHO Functional Class III-IV
Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg twice daily and 250 mg twice daily) of TRACLEER with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (WHO functional Class III–IV) PAH: idiopathic or heritable PAH (72%) or PAH associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with PAH associated with other conditions such as HIV disease or recurrent pulmonary emboli.
In both studies, TRACLEER or placebo was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. TRACLEER was given at a dose of 62.5 mg twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351.
The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years.
Submaximal Exercise Ability
Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 4.
| BREATHE-1 | Study 351 | ||||
|---|---|---|---|---|---|
| TRACLEER
125 mg twice daily (n=74) | TRACLEER
250 mg twice daily (n=70) | Placebo
(n=69) | TRACLEER
125 mg twice daily (n=21) | Placebo
(n=11) |
|
| Distance in meters: mean ± standard deviation. Changes are to week 16 for BREATHE-1 and to week 12 for Study 351. | |||||
| Baseline | 326 ± 73 | 333 ± 75 | 344 ± 76 | 360 ± 86 | 355 ± 82 |
| End point | 353 ± 115 | 379 ± 101 | 336 ± 129 | 431 ± 66 | 350 ± 147 |
| Change from baseline | 27 ± 75 | 46 ± 62 | -8 ± 96 | 70 ± 56 | -6 ± 121 |
| Placebo – subtracted | 35 * | 54 † | 76 ‡ | ||
In both trials, treatment with TRACLEER resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 5). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended [see Dosage and Administration (2.1)] . There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences.
Figure 5. Mean Change in 6-min Walk Distance (BREATHE-1)
Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined TRACLEER (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean ± standard error of the mean.
Hemodynamic Changes
Invasive hemodynamic parameters were assessed in Study 351. Treatment with TRACLEER led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 5).
The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown.
| TRACLEER
125 mg twice daily | Placebo | ||
|---|---|---|---|
| Values shown are means ± SD | |||
| CI (L/min/m 2) | n=20 | n=10 | |
| Baseline | 2.35±0.73 | 2.48±1.03 | |
| Absolute Change | 0.50±0.46 | -0.52±0.48 | |
| Treatment Effect | 1.02 * | ||
| Mean PAP (mmHg) | n=20 | n=10 | |
| Baseline | 53.7±13.4 | 55.7±10.5 | |
| Absolute Change | -1.6±5.1 | 5.1±8.8 | |
| Treatment Effect | -6.7 † | ||
| PVR (dyn∙sec∙cm -5) | n=19 | n=10 | |
| Baseline | 896±425 | 942±430 | |
| Absolute Change | -223±245 | 191±235 | |
| Treatment Effect | -415 * | ||
| Mean RAP (mmHg) | n=19 | n=10 | |
| Baseline | 9.7±5.6 | 9.9±4.1 | |
| Absolute Change | -1.3±4.1 | 4.9±4.6 | |
| Treatment Effect | -6.2 * | ||
Symptoms and Functional Status
Symptoms of PAH were assessed by Borg dyspnea score, WHO functional class, and rate of "clinical worsening." Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in TRACLEER-treated patients. There was a significant reduction in the rate of clinical worsening (Table 6 and Figure 6). Figure 6 shows the log-rank test reflecting clinical worsening over 28 weeks.
| BREATHE-1 | Study 351 | |||
|---|---|---|---|---|
| TRACLEER
125/250 mg twice daily (n=144) | Placebo
(n=69) | TRACLEER
125 mg twice daily (n=21) | Placebo
(n=11) |
|
| Note: Patients may have had more than one reason for clinical worsening. | ||||
| Patients with clinical worsening
[n (%)] | 9 (6%) * | 14 (20%) | 0 (0%) † | 3 (27%) |
| Death | 1 (1%) | 2 (3%) | 0 (0%) | 0 (0%) |
| Hospitalization for PAH | 6 (4%) | 9 (13%) | 0 (0%) | 3 (27%) |
| Discontinuation due to worsening of PAH | 5 (3%) | 6 (9%) | 0 (0%) | 3 (27%) |
| Receipt of epoprostenol ‡ | 4 (3%) | 3 (4%) | 0 (0%) | 3 (27%) |
Figure 6. Time to Clinical Worsening (BREATHE-1)
Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (n=144 in the TRACLEER group and n=69 in the placebo group) participated in the first 16 weeks of the study. A subset of this population (n=35 in the TRACLEER group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks.
WHO Functional Class II
In a randomized, double-blind, multicenter, placebo-controlled trial, 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received TRACLEER 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n=93), or placebo (n=92) for 6 months. Enrolled patients were treatment-naïve (n=156) or on a stable dose of sildenafil (n=29). The coprimary endpoints were change from baseline to month 6 in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO functional class and hemodynamics were assessed as secondary endpoints.
Compared with placebo, TRACLEER treatment was associated with a reduced incidence of worsening of at least one functional class (3% TRACLEER vs. 13% placebo, p=0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO 2; p <0.05). The +19 m mean (+14 m median) increase in 6-minute walk distance with TRACLEER vs. placebo was not significant (p=0.08). There was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with TRACLEER compared with placebo (hazard ratio 0.2, p=0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline.
Long-term Treatment of PAH
Long-term follow-up of patients with Class III and IV PAH who were treated with TRACLEER in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment.
These uncontrolled observations do not allow comparison with a group not given TRACLEER and cannot be used to determine the long-term effect of TRACLEER on mortality.
Pediatric Studies
The efficacy of bosentan was evaluated in an open-label, uncontrolled study in 19 pediatric patients with PAH aged 3 to 15 years. Patients had primary pulmonary hypertension (n=10) or PAH related to congenital heart diseases (9 patients) and were WHO functional class II (n=15, 79%) or class III (n=4; 21%) at baseline. Patients were dosed with bosentan at approximately 2 mg/kg twice daily (body weight adjusted dose, corresponding to the recommended adult dose) [see Dosage and Administration (2.1)] for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the study.
Hemodynamics were measured in 17 patients (Table 7). The mean decrease in PVR was 389 dyn∙sec∙cm -5, which was similar to the effect seen in adults. Hemodynamic improvements from baseline were similar with or without co-administration of epoprostenol.
| TRACLEER
2 mg/kg twice daily |
|
|---|---|
| Values shown are means ± SD | |
| CI (L/min/m 2) | n=17 |
| Baseline | 4.0±1.5 |
| Absolute Change | 0.5±1.4 |
| Mean PAP (mmHg) | n=18 |
| Baseline | 60±18 |
| Absolute Change | -8±9 |
| PVR (dyn∙sec∙cm -5) | n=17 |
| Baseline | 1195±755 |
| Absolute Change | -389±616 |
| Mean RAP (mmHg) | n=18 |
| Baseline | 6.1±2.7 |
| Absolute Change | -0.5±2.3 |
Pulmonary Arterial Hypertension in Adults related to Congenital Heart Disease with Left-to-Right Shunts
A small study (N=54) and its open-label extension (N=37) of up to 40 weeks in adult patients with Eisenmenger physiology demonstrated effects of TRACLEER on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).
14.2 Lack of Benefit in Congestive Heart Failure
TRACLEER is not effective in the treatment of congestive heart failure with left ventricular dysfunction. In a pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction <35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or TRACLEER (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. Use of TRACLEER was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first 4 to 8 weeks after TRACLEER was initiated. In a placebo-controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4–8 weeks of treatment with TRACLEER. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
16 HOW SUPPLIED/STORAGE AND HANDLING
62.5 mg film-coated, round, biconvex, orange-white tablets, debossed with identification marking "62,5", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.
NDC 66215-101-06: Bottle containing 60 tablets.
NDC 66215-101-03: Carton of 30 tablets in 10 blister strips of 3 tablets.
125 mg film-coated, oval, biconvex, orange-white tablets, debossed with identification marking "125", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.
NDC 66215-102-06: Bottle containing 60 tablets.
NDC 66215-102-03: Carton of 30 tablets in 10 blister strips of 3 tablets.
32 mg tablets for oral suspension, pale yellow to off-white, clover-shaped, quadrisected on one side and debossed with identification marking "32" on the other side, packaged in child resistant Aluminum/Aluminum peel-push blisters.
NDC 66215-103-56: Carton of 56 tablets for oral suspension in 4 blister-strips of 14 tablets.
NDC 66215-103-14: Blister strip of 14 tablets for oral suspension.
32 mg tablets for oral suspension, pale yellow to off-white, round, bisected on one side and debossed with identification marking "32" on the other side, packaged in child resistant Aluminum/Aluminum peel-push blisters.
NDC 66215-232-56: Carton of 56 tablets for oral suspension in 4 blister-strips of 14 tablets.
NDC 66215-232-14: Blister strip of 14 tablets for oral suspension.
Store at 20ºC to 25ºC (68ºF to 77ºF). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]. These storage temperatures apply to both film-coated and dispersible tablets. Divided dispersible tablets should be stored under the same conditions and used within 7 days. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to 7 days.
Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Restricted access
Advise the patient that TRACLEER is only available through a restricted access program called the Bosentan REMS Program.
As a component of the Bosentan 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:
-
Hepatotoxicity
Discuss with the patient the requirement to measure serum aminotransferases monthly. -
Embryo-fetal toxicity
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 (8.1)] .
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 certified pharmacies that are enrolled in the Bosentan REMS Program.
Patients must sign the Bosentan REMS Program Patient Enrollment Form to confirm that they understand the risks of TRACLEER. -
Lactation
Advise women not to breastfeed during treatment with TRACLEER [see Use in Specific Populations (8.2)]. -
Infertility
Advise males of reproductive potential that TRACLEER may impair fertility [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. -
Phenylketonurics
TRACLEER dispersible tablets contain phenylalanine, a component of aspartame. Each dispersible tablet contains 1.87 mg of phenylalanine.
Manufactured for:
Actelion Pharmaceuticals US, Inc.
a Janssen Pharmaceutical Company
Titusville, NJ 08560, USA
For patent information: www.janssenpatents.com
© 2001 – 2019 Actelion Pharmaceuticals US, Inc.
JN20220715
| Medication Guide
TRACLEER ® (TRA-KLEER) (BOSENTAN) TABLETS |
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|---|---|---|---|---|---|---|---|---|
| This Medication Guide has been approved by the U.S. Food and Drug Administration. | Revised: 02/2024 | |||||||
| Read the Medication Guide that comes with TRACLEER before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. | ||||||||
|
What is the most important information I should know about TRACLEER?
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|
Acceptable birth control options |
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| Option 1 | Option 2 | Option 3 | Option 4 | |||||
| One method from this list: | or | One method from this list: | or | One method from this list: | or | One method from this list: | ||
| Standard intrauterine device (Copper T 380A IUD)
Intrauterine system (LNg 20 IUS: progesterone IUS) Tubal sterilization | Estrogen and progesterone oral contraceptives ("the pill")
Estrogen and progesterone transdermal patch Vaginal ring Progesterone injection Progesterone implant | Diaphragm with spermicide
Cervical cap with spermicide | Partner's vasectomy | |||||
| PLUS
One method from this list: | ||||||||
| PLUS
One method from this list: | Male condom
Diaphragm with spermicide Cervical cap with spermicide Estrogen and progesterone oral contraceptives ("the pill") Estrogen and progesterone transdermal patch Vaginal ring Progesterone injection Progesterone implant | |||||||
| Male condom | ||||||||
| PLUS
One method from this list: | ||||||||
| Male condom
Diaphragm with spermicide Cervical cap with spermicide | ||||||||
| TRACLEER 32 mg dispersible tablets contain Aspartame. Phenylketonurics: Contains Phenylalanine 1.87 mg per 32 mg dispersible tablet.
See " What are the possible side effects of TRACLEER?" for more information about side effects. |
||||||||
| What is TRACLEER?
TRACLEER is a prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs. TRACLEER can improve your ability to exercise and can slow the worsening of your physical condition and symptoms. TRACLEER lowers high blood pressure in your lungs and lets your heart pump blood more efficiently. TRACLEER is only: Prescribed by healthcare providers who are enrolled in the Bosentan REMS Program. Available to people who understand and agree to enroll in the Bosentan REMS Program. |
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| Who should not take TRACLEER?
Do not take TRACLEER if you:
|
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| What should I tell my healthcare provider before taking TRACLEER?
TRACLEER may not be right for you. Tell your healthcare provider about all your medical conditions, including if you:
|
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| There may be more than one brand name medicine. Ask your healthcare provider if you are not sure if your medicine is one that is listed above.
Know the medicines you take. Keep a list of them and show it to your healthcare provider or pharmacist when you get a new medicine. |
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| How should I take TRACLEER?
Your healthcare provider will give you detailed information about the Bosentan REMS Program.
|
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|
What are the possible side effects of TRACLEER?
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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How should I store TRACLEER?
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| General information about TRACLEER
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRACLEER for a condition for which it was not prescribed. Do not give TRACLEER to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about TRACLEER. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TRACLEER that is written for health professionals. For more information call 1-800-526-7736 (1-800-JANSSEN), go to www.TRACLEER.com. |
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| What are the ingredients in TRACLEER?
Active ingredient: bosentan Inactive ingredients in 62.5 mg and 125 mg film-coated tablets: corn starch, ethylcellulose, glyceryl behenate, hydroxypropylmethylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, povidone, pregelatinized starch, sodium starch glycolate, talc, titanium dioxide, and triacetin. Inactive ingredients in 32 mg dispersible tablets: acesulfame potassium, aspartame (E951), calcium hydrogen, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, phosphate anhydrous, silica colloidal anhydrous, tartaric acid, and tutti frutti flavor. Manufactured for: Actelion Pharmaceuticals US, Inc. a Janssen Pharmaceutical Company Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2001 – 2019 Actelion Pharmaceuticals US, Inc. JN20220715 |
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PRINCIPAL DISPLAY PANEL - 62.5 mg Tablet Bottle Carton
NDC 66215-101-06
Tracleer
®
(bosentan) tablets
62.5 mg
Attention: Dispense with
enclosed Medication Guide.
Rx only
60 film-coated tablets
janssen
PRINCIPAL DISPLAY PANEL - 125 mg Tablet Bottle Carton
NDC 66215-102-06
Tracleer
®
(bosentan) tablets
125 mg
Attention: Dispense with
enclosed Medication Guide.
Rx only
60 film-coated tablets
janssen
PRINCIPAL DISPLAY PANEL - 32 mg Tablet Blister Pack Carton
NDC 66215-103-56
TRACLEER
®
(Bosentan)
Tablets for Oral Suspension
32 mg
Phenylketonurics:
Contains Phenylalanine
1.87 mg per tablet for oral suspension
Rx only
Contains:56 tablets for oral suspension per carton.
Each carton contains 4 blister-strips of 14 tablets each.
Attention:Dispense with
enclosed Medication Guide.
Store this medicine out of
the reach of children.
ACTELION
PRINCIPAL DISPLAY PANEL - 32 mg Tablet Blister Pack Carton - 232
NDC 66215-232-56
Tracleer
®
(bosentan) Tablets for Oral Suspension
32 mg
Phenylketonurics:
Contains Phenylalanine
1.87 mg per tablet for oral suspension
Rx only
Contains: 56 tablets for oral suspension per carton.
Each carton contains 4 blister-strips of 14 tablets each.
Attention: Dispense with
enclosed Medication Guide.
This package is child-resistant.
Store this medicine out of
the reach of children.
janssen
