Drug Safety-related Labeling Changes (SrLC)

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TRACLEER (NDA-021290)

(BOSENTAN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/16/2019 (SUPPL-39)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

How should I take Tracleer?

‘Certified pharmacies’ replace specialty pharmacies as related to the Bosentan REMS program.

PATIENT COUNSELING INFORMATION

‘Certified pharmacies’ replace specialty pharmacies as related to the Bosentan REMS program.

04/26/2019 (SUPPL-32)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

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.

5 Warnings and Precautions

5.3 Prescribing and Distribution Program for Bosentan

(Revised Subsection Title; Additions and/or revisions are underlined)

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.

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, 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Newly added section; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Bosentan replaces Tracleer throughout this subsection.

Patients must sign the Bosentan REMS Program Patient Enrollment Form …

(Additions and/or revisions are underlined)

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.

  • Embryo-fetal toxicity

Advise the patient that Tracleer is available only from specialty 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.

Other

REMS revisions.

09/05/2017 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hepatotoxicity

(Additions and/or revisions are underlined)

In a pooled analysis of four pediatric studies conducted in PAH (n =100), elevations in liver aminotransferases greater than or equal to 3 × ULN were observed in 2% of patients

Avoid initiation of Tracleer in patients with elevated aminotransferases (> 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult.

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

(Newly added subsection)

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.

Tracleer is only available for females through a restricted program under REMS.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following important adverse reactions are described elsewhere in the labeling:

  • Hepatotoxicity
  • Embryo-fetal Toxicity
  • Fluid Retention
6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

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…

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)…

Table 3. (The footnote below has been added to this table)         

** Respiratory Tract Infection combines the terms "Nasopharyngitis", "Upper Respiratory Tract Infection" and "Respiratory Tract Infection".

 

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.

 

Decreases in Hemoglobin and Hematocrit

The overall mean decrease in hemoglobin concentration for adult Tracleer-treated patients was 0.9 g/dL (change to end of treatment)…

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.

7 Drug Interactions

7.1 Cytochrome P450 Drug Interactions

(Additions and/or revisions are underlined)

Figure 1. CYP3A induction-mediated effect of bosentan on other drugs

(Figure has been added; please refer to label)

 

Figure 2. Effect of other drugs on bosentan

(Figure has been added; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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. 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/m2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels. 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.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from Tracleer, advise women not to breastfeed during treatment with Tracleer.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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…

Contraception

…Females of reproductive potential using Tracleer must use two acceptable methods of contraception during treatment and for 1 month after treatment with Tracleer

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.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

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. Safety in pediatric patients is supported by data from 100 pediatric patients treated with Tracleer for a median of 17 months.

 

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17. PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

  • Lactation

Advise women not to breastfeed during treatment with TRACLEER

  • Infertility

Advise males of reproductive potential that TRACLEER may impair fertility

  • Phenylketonurics

Tracleer dispersable tablets contain phenylalanine, a component of aspartame. Each dispersible tablet contains 1.87 mg of phenylalanine.

Medication Guide

(Additions and/or revisions are underlined)

What is the most important information I should know about Tracleer?

Tracleer 32 mg dispersible tablets contain Aspartame. Phenylketonurics: Contains Phenylalanine 1.87 mg per 32 mg dispersible tablet.

How should I take Tracleer?

  • If necessary, the 32 mg dispersible tablet can be divided into halves by breaking along the lines cut into the surface. Hold the tablet between the thumb and index finger on either side of one of the lines, with the line facing upwards, and break the tablet along the line (see figure below). The dispersible tablet should not be broken into quarters.

(Figure has been added; please refer to label)

  • Each 32 mg dispersible tablet, or tablet part, can be dispersed in a minimal amount of water to make a liquid medicine immediately before administration. When the tablet has fully dispersed, the liquid should be administered to the patient.

How should I store Tracleer?

  • Dispersible tablets that have been broken to adjust the dose of medicine can be stored at room temperature, between 68oF to 77oF (20oC to 25oC), and should be used within 7 days of having been broken. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to 7 days.


What are the ingredients in Tracleer?

Inactive ingredients in 62.5 mg and 125 mg film-coated tablets: corn starch, pregelatinized starch, ….

Inactive ingredients in 32 mg dispersible tablets: cellulose microcrystalline, calcium hydrogen, phosphate anhydrous, croscarmellose sodium, silica colloidal anhydrous, tartaric acid, tutti frutti flavor, aspartame (E951), acesulfame potassium, and magnesium stearate.

10/20/2016 (SUPPL-33)

Approved Drug Label (PDF)

4 Contraindications

4.4 Hypersensitivity (addition underlined)

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.

6 Adverse Reactions

6.2 Postmarketing Experience (addition underlined)

The following additional adverse reactions have been reported during the postapproval use of Tracleer…

            …Hypersensitivity, DRESS, and anaphylaxis

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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