Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

TRACLEER (NDA-209279)

(BOSENTAN)

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

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11/05/2025 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Bosentan REMS

Subsection title revised

Additions and/or revisions underlined:

Because of the risks of hepatotoxicity, TRACLEER is available only through a restricted program called the Bosentan REMS. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions (5.1)].

Required components of the Bosentan REMS are:

Healthcare professionals who prescribe TRACLEER must review the prescriber educational materials, enroll in the Bosentan REMS 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.
To receive TRACLEER, all patients must understand the risks and benefits, and complete a patient enrollment form with their prescriber.
Pharmacies that dispense TRACLEER must enroll in the program and agree to comply with the Bosentan REMS requirements.

Further information about TRACLEER and the Bosentan REMS is available at www.BosentanREMSProgram.com or 1-866-359-2612.

5.3 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

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. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of TRACLEER. Advise females of reproductive potential about the potential risk to a fetus. Exclude pregnancy prior to TRACLEER treatment. Advise females of reproductive potential to use effective contraception prior to initiation of treatment with TRACLEER, during treatment, and for at least one month after the last dose. When pregnancy is detected, discontinue TRACLEER as soon as possible [see Dosage and Administration (2.1), Contraindications (4.1), Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions 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 [see Contraindications (4.1)]. Available data from postmarketing reports and published literature over decades of use with endothelin receptor antagonists (ERA) in the same class as TRACLEER have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. 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 [see Animal Data]. Advise pregnant women of the potential risk to a fetus.

…

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Based on data from animal reproductive toxicity studies, TRACLEER may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1), Use in Specific Populations (8.1)].

Pregnancy Testing

Verify that females of reproductive potential are not pregnant prior to initiating 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 [see Dosage and Administration (2.1), Contraindications (4.1), Warnings and Precautions (5.3)].

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 should use effective methods of contraception prior to initiation of treatment, during treatment, and for 1 month after treatment with TRACLEER [see Warnings and Precautions (5.3)]. 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.

…

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

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

…

Because of the risk for liver damage, TRACLEER is only available through a restricted program called the Bosentan REMS. Before you begin taking TRACLEER, you must read and agree to all of the requirements of the Bosentan REMS.

Serious birth defects.

TRACLEER can cause serious birth defects if taken during pregnancy. You should not be pregnant when you start taking TRACLEER or during TRACLEER treatment. Serious birth defects from TRACLEER may happen early in pregnancy. Females who are able to get pregnant should have a negative pregnancy test before starting treatment with TRACLEER.

…

Females who are able to get pregnant should use effective birth control prior to starting treatment with TRACLEER, during treatment with TRACLEER, and for one month after stopping TRACLEER because the medicine may still be in the body.
- Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for effective birth control that you may use to prevent pregnancy during treatment with TRACLEER.

…

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:

have liver problems.

are pregnant or plan to become pregnant. See “What is the most important information I should know about TRACLEER?”

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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 and that TRACLEER is available only from certified pharmacies enrolled in the Bosentan REMS.

As a component of the Bosentan REMS, prescribers must review the contents of the TRACLEER Medication Guide with the patient before initiating TRACLEER and patients must sign the Patient Enrollment Form to confirm that they understand the risks of TRACLEER.

Instruct patients that the risks associated with TRACLEER include hepatotoxicity. Discuss with the patient the requirement to measure serum aminotransferases monthly [see Dosage and Administration (2.1, 2.4), Warnings and Precautions (5.1, 5.2)].

Embryo-Fetal toxicity

Counsel female patients of reproductive potential about the need to use effective contraception prior to treatment, during treatment with TRACLEER and for one month after treatment discontinuation. Females of reproductive potential should have a negative pregnancy test prior to treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.3), Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)].

…

02/08/2024 (SUPPL-10)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

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.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

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:

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.

05/16/2019 (SUPPL-5)

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-4)

Approved Drug Label (PDF)

Boxed Warning

WARNING: RISKS OF HEPATOXICITY and EMBRYO-FETAL TOXICITY

(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)

17 PATIENT COUNSELING INFORMATION

(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.

Medication Guide

(Newly added Medication Guide; please refer to labeling)