Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

OPSUMIT (NDA-204410)

(MACITENTAN)

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

Download Data

Expand all

04/02/2025 (SUPPL-31)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: EMBRYO-FETAL TOXICITY

OPSUMIT is contraindicated for use during pregnancy because it may cause fetal harm based on animal data [see Contraindications (4.1), Warnings and Precautions (5.1), Use in Specific Populations (8.1)].

Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with OPSUMIT. Advise use of effective contraception before the initiation of treatment, during treatment, and for one month after stopping treatment with OPSUMIT [see Dosage and Administration (2.2), Use in Specific Populations (8.3)]. When pregnancy is detected, discontinue OPSUMIT as soon as possible [see Warnings and Precautions (5.1)].

5 Warnings and Precautions

5.1 Embryo-fetal Toxicity

Additions and/or revisions underlined:

Based on data from animal reproduction studies, OPSUMIT may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The available human data for ERAs do not establish the presence or absence of major birth defects related to the use of OPSUMIT. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of therapy with OPSUMIT. Advise patients who can become pregnant to use effective contraceptive methods prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with OPSUMIT. When pregnancy is detected, discontinue use as soon as possible [see Dosage and Administration (2.2), Contraindications (4.1), and Use in Specific Populations (8.1, 8.3)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as OPSUMIT 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. Macitentan was teratogenic in rabbits and rats at all doses tested. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus [see Contraindications (4.1)].

…

8.3 Females and Males of Reproductive Potential

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

Pregnancy Testing

Verify that patients who can become pregnant are not pregnant prior to initiating OPSUMIT. The patient should contact their 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 should discuss the risks to the pregnancy, and the fetus.

Contraception

Patients who can become pregnant who are using OPSUMIT should use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with OPSUMIT to prevent pregnancy [see Warnings and Precautions (5.1)].

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Embryo-Fetal Toxicity

Counsel female patients of reproductive potential about the need to use effective methods of contraception prior to initiation of treatment with OPSUMIT, during treatment and for one month after treatment discontinuation. Females of reproductive potential should have a negative pregnancy test prior to treatment with OPSUMIT [see Contraindications (4.1), and Use in Specific Populations (8.1, 8.3)].

…

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.

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

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

• Serious birth defects.

  …

  Females who are able to get pregnant should use effective birth control before starting treatment with OPSUMIT, during treatment, and for one month after stopping OPSUMIT because the medicine may still be in the body.

  …

02/28/2025 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Embryo-fetal Toxicity

Additions and/or revisions underlined:

OPSUMIT may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests [see Dosage and Administration (2.2) and Use in Specific Populations (8.1, 8.3)].

OPSUMIT is available for females through the Macitentan-Containing Products REMS, a restricted distribution program [see Warnings and Precautions (5.2)].

5.2 Macitentan-Containing Products REMS

Subsection title revised

Additions and/or revisions underlined:

For all females, OPSUMIT is available only through a restricted program called the Macitentan- Containing Products REMS, because of the risk of embryo-fetal toxicity [see Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].

Notable requirements of the Macitentan-Containing Products REMS include the following:

• Prescribers must be certified with the Macitentan-Containing Products REMS by enrolling and completing training.

• All females, regardless of reproductive potential, must enroll in the Macitentan-Containing Products REMS prior to initiating OPSUMIT. Male patients are not enrolled in the REMS.

• Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)].

• Pharmacies must be certified with the Macitentan-Containing Products REMS and must only dispense to patients who are authorized to receive OPSUMIT.

Further information is available at www.MacitentanREMS.com or 1-888-572-2934. Information on Macitentan-Containing Products REMS certified pharmacies or wholesale distributors is available at 1-888-572-2934.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of OPSUMIT in pediatric patients have not been established for the treatment of PAH.

OPSUMIT was evaluated in 148 pediatric patients 2 to 17 years of age with PAH in a single open- label, randomized trial with an extension period in which all patients received treatment. The trial did not demonstrate a clinical benefit of OPSUMIT compared with standard of care in the treatment of PAH. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population. Adverse reactions observed in the trial were similar in nature to those reported in clinical trials in adults.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Females can only receive OPSUMIT through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS). If you are a female who can get pregnant, you must talk to your healthcare provider, understand the benefits and risks of OPSUMIT, and agree to all of the instructions in the Macitentan-Containing Products REMS.

Males can receive OPSUMIT without taking part in the Macitentan-Containing Products REMS.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Macitentan-Containing Products REMS

For female patients, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products REMS [see Warnings and Precautions (5.2)]. Male patients are not enrolled in the Macitentan-Containing Products REMS.

…

05/26/2023 (SUPPL-24)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of OPSUMIT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: hypersensitivity reactions (angioedema, pruritus and rash)

Vascular disorders: flushing

10/25/2021 (SUPPL-22)

Approved Drug Label (PDF)

4 Contraindications

4.2 Hypersensitivity

(Newly added subsection)

OPSUMIT is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product [see Adverse Reactions (6.2)].

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

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Who should not take OPSUMIT?

Do not take OPSUMIT if you are pregnant, plan to become pregnant, or become pregnant during treatment with OPSUMIT. OPSUMIT can cause serious birth defects (see the Medication Guide section above called “What is the most important information I should know about OPSUMIT?”).

Do not take OPSUMIT if you are allergic to macitentan or any of the ingredients in OPSUMIT. See the end of this Medication Guide for a complete list of ingredients in OPSUMIT.

Tell your healthcare provider about all your medical conditions and all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

OPSUMIT and other medicines may affect each other causing side effects. Do not start any new medicine until you check with your healthcare provider.

Especially tell your healthcare provider if you take an HIV medicine.

…

05/26/2021 (SUPPL-21)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors

(Newly Added Subsection)

Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic (PBPK) modelling. Avoid concomitant use of OPSUMIT with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology (12.3)].

Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT should also be avoided [see Clinical Pharmacology (12.3)]

10/16/2018 (SUPPL-10)

Approved Drug Label (PDF)

4 Contraindications

4.1 Pregnancy

(Additions and/or revisions are underlined)

OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is contraindicated in females who are pregnant. OPSUMIT was consistently shown to have teratogenic effects when administered to animals. If OPSUMIT is used during pregnancy, advise the patient of the potential risk to a fetus.

5 Warnings and Precautions

5.7 Decreased Sperm Counts

(Additions and/or revisions are underlined)

OPSUMIT, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility.

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, OPSUMIT may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy. There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy. There are limited data on OPSUMIT use in pregnant women. Macitentan was teratogenic in rabbits and rats at all dosestested. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the 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.

Clinical Considerations

Disease-associated maternal or embryo/fetal risk

In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor.

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 macitentan in human milk, the effects on the breastfed infant, or the effect on milk production.  Because of the potential for serious adverse reactions in breastfed infants from OPSUMIT advise women not to breastfeed during treatment with OPSUMIT.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Females

Pregnancy Testing:

Verify the pregnancy status of females of reproductive potential prior to initiating OPSUMIT, monthly during treatment and one month after stopping treatment with OPSUMIT. 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.

Males

Infertility

Based on findings in animals, OPSUMIT may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise patient to read FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity

Counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with OPSUMIT and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use reliable methods of contraception while taking OPSUMIT and for one month after discontinuing OPSUMIT.

OPSUMIT REMS Program

Patients may choose one highly effective form of contraception (intrauterine devices (IUD), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods).

Patients should be instructed to contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.

Advise women not to breastfeed during treatment with OPSUMIT.

03/21/2017 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Fluid Retention

(Newly added subsection)

Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs. In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema was 21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group.

Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. In a small study of OPSUMIT in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the OPSUMIT group developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized to placebo. Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported.

Monitor for signs of fluid retention after OPSUMIT initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as OPSUMIT or underlying heart failure, and the possible need to discontinue OPSUMIT.

6 Adverse Reactions

(Additions and/or revisions are underlined)

Clinically significant adverse reactions that appear in other sections of the labeling include:

• Embryo-fetal Toxicity

• Hepatotoxicity

• Fluid Retention

• Decrease in Hemoglobin

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Gastrointestinal disorders: Elevations of liver aminotransferases (ALT, AST) and liver injury have been reported with Opsumit use; in most cases alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis). Endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Fluid Retention

Educate patients on signs of fluid retention. Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs.

Medication Guide

(Additions and/or revisions are underlined)

What are the possible side effects of Opsumit? Opsumit can cause serious side effects, including:

• Fluid retention can happen within weeks after starting Opsumit. Tell your healthcare provider right away if you have any unusual weight gain or swelling of your ankles or legs. Your healthcare provider will look for the cause of any fluid retention.

10/21/2016 (SUPPL-9)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following:

Gastrointestinal disorders: Elevations of liver aminotransferases (ALT, AST) and liver injury have been reported with Opsumit use; in most cases alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis). Endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure.

06/15/2016 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

• Cardiac disorders: symptomatic hypotension (addition)

02/17/2016 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing

General disorders and administration site conditions: edema/fluid retention

• Cases of edema and fluid retention occurred within weeks of starting Opsumit, some requiring intervention with a diuretic, fluid management or hospitalization for decompensated heart failure.