Manufacturing Establishments6
FDA-registered manufacturing facilities and establishments involved in the production, packaging, or distribution of this drug product.
Actelion Pharmaceuticals US, Inc.
481296960
Actelion Pharmaceuticals US, Inc.
240769596
Haupt Pharma Wuelfing GmbH
Actelion Pharmaceuticals US, Inc.
333274975
Actelion Pharmaceuticals US, Inc.
676446492
Actelion Pharmaceuticals US, Inc.
484572565
Actelion Pharmaceuticals US, Inc.
481885861
Products4
Detailed information about drug products covered under this FDA approval, including NDC codes, dosage forms, ingredients, and administration routes.
Tracleer
Product Details
Tracleer
Product Details
Tracleer
Product Details
Tracleer
Product Details
Drug Labeling Information
Complete FDA-approved labeling information including indications, dosage, warnings, contraindications, and other essential prescribing details.
RECENT MAJOR CHANGES SECTION
DESCRIPTION SECTION
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.
INDICATIONS & USAGE SECTION
Highlight: TRACLEER is an endothelin receptor antagonist 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%) ( 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 ( 1).
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.
DOSAGE & ADMINISTRATION SECTION
Highlight: * Patients older than 12 years of age: initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after 4 weeks ( 2.2).
- Patients 12 years of age and younger: dosage is based on weight, see Table 1 ( 2.2).
- Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3×Upper Limit of Normal (ULN) ( 2.1).
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.
Table 1: Dosing Recommendations|
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 |
|
32 mg twice daily |
32 mg twice daily |
|
48 mg twice daily |
48 mg twice daily |
|
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.
Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3×ULN|
ALT/AST levels |
Treatment and monitoring recommendations |
|---|---|
|
Confirm by another aminotransferase test; if confirmed,
|
|
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,
|
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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)] .
DOSAGE FORMS & STRENGTHS SECTION
Highlight: * Film-coated tablet: 62.5 mg and 125 mg ( 3)
- Tablet for oral suspension: 32 mg ( 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.
BOXED WARNING SECTION
WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY
See full prescribing information for complete boxed warning.
TRACLEER is available only through a restricted distribution program called the Bosentan REMS Program because of these risks (5.3):
Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with TRACLEER (5.1).
*Measure liver aminotransferases prior to initiation of treatment and then monthly (2.1,5.1). *Discontinue TRACLEER if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2×ULN (2.4,5.1).
Based on animal data, TRACLEER is likely to cause major birth defects if used during pregnancy (4.1,5.2,8.1).
*Must exclude pregnancy before and during treatment (2.1,4.1,8.1). *To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER (4.1,5.2,8.1).
WARNINGS AND PRECAUTIONS SECTION
Highlight: * Fluid retention: May require intervention ( 5.4).
- Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing TRACLEER ( 5.5).
- Decreased sperm counts ( 5.6).
- Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter ( 5.7).
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)] .
OVERDOSAGE SECTION
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.
SPL MEDGUIDE SECTION
|
Medication Guide | ||||||||
|---|---|---|---|---|---|---|---|---|
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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?
Serious birth defects. TRACLEER can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking TRACLEER or during TRACLEER treatment. Serious birth defects from TRACLEER can happen early in pregnancy. Females who are able to get pregnant must have a negative pregnancy test before starting treatment with TRACLEER, each month during treatment with TRACLEER, and 1 month after stopping treatment with TRACLEER. * Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do a pregnancy test and will order a pregnancy test for you depending on your menstrual cycle. * Females whoare ableto get pregnant are females who: * have entered puberty, even if they have not started their menstrual period,and * have a uterus,and * have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. * Females whoare not ableto get pregnant are females who: * have not yet entered puberty,or * do not have a uterus,or * have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removedor * are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant must use two acceptable forms of birth control during treatment with TRACLEER, and for one month after stopping TRACLEER because the medicine may still be in the body. * If you have had a tubal sterilization or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed. * Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with TRACLEER. * If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control. **Seethe chart below**** for Acceptable Birth Control Options during treatment with TRACLEER. If you are the parent or caregiver of a female child who started taking TRACLEER before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty.Your child may reach puberty before having her first menstrual period. | ||||||||
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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) |
Estrogen and progesterone oral contraceptives ("the pill") |
Diaphragm with spermicide |
Partner's vasectomy | |||||
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PLUS | ||||||||
|
PLUS |
Male condom | |||||||
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Male condom | ||||||||
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PLUS | ||||||||
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Male condom | ||||||||
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TRACLEER 32 mg dispersible tablets contain Aspartame. Phenylketonurics:
Contains Phenylalanine 1.87 mg per 32 mg dispersible tablet. | ||||||||
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What is TRACLEER? | ||||||||
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Who should not take TRACLEER? are pregnant, plan to become pregnant, or become pregnant during TRACLEER treatment. TRACLEER can cause serious birth defects.All females should read thebirth defectssection of*"What is the most important information I should know about TRACLEER?"**
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What should I tell my healthcare provider before taking TRACLEER? *have liver problems. *are breast-feeding or plan to breast feed. TRACLEER passes into your breast milk. It is not known if TRACLEER in breast milk can harm your baby. You and your healthcare provider should decide if you will take TRACLEER or breastfeed. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRACLEER and other medicines may affect how each other works and cause side effects. Especially tell your healthcare provider if you take: | ||||||||
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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. | ||||||||
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How should I take TRACLEER?
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What are the possible side effects of TRACLEER? *See "What is the most important information I should know about TRACLEER?" *Fluid retention and swelling of your ankles and legs. TRACLEER can cause your body to hold too much water, and you may get swelling of your ankles and legs. Tell your healthcare provider if you have swelling of your ankles and legs that happens either with or without weight gain, or if you have more trouble with your breathing than normal. Your healthcare provider will look for the cause of this. *Lower Sperm Count. Some men who take TRACLEER may have lower sperm counts. This may affect your ability to father a child. Tell your healthcare provider if fertility is a concern for you. *Low red blood cell levels (anemia). Your healthcare provider will do blood tests to check your red blood cells during treatment with TRACLEER. The most common side effects of TRACLEER include:
Tell your doctor if you have any side effect that bothers you or that does not
go away. These are not all the possible side effects of TRACLEER. For more
information, ask your doctor or pharmacist. | ||||||||
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How should I store TRACLEER?
Keep TRACLEER and all medicines out of the reach of children. | ||||||||
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General information about TRACLEER | ||||||||
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What are the ingredients in TRACLEER? |
SPL UNCLASSIFIED SECTION
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