July 27, 2016
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Included as part of the PRECAUTIONS section.


Embryo-fetal Toxicity

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 and Use in Specific Populations].

OPSUMIT is available for females through the OPSUMIT REMS Program, a restricted distribution program [see OPSUMIT REMS Program].


For all females, OPSUMIT is available only through a restricted program called the OPSUMIT REMS Program, because of the risk of embryo-fetal toxicity [see CONTRAINDICATIONS, Embryo-fetal Toxicity, and Use In Specific Populations].

Notable requirements of the OPSUMIT REMS Program include the following:

  • Prescribers must be certified with the program by enrolling and completing training.
  • All females, regardless of reproductive potential, must enroll in the OPSUMIT REMS Program 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].
  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT.

Further information is available at www.OPSUMITREMS.com or 1-866-228-3546. Information on OPSUMIT certified pharmacies or wholesale distributors is available through Actelion Pathways at 1-866-228-3546.


Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the study of OPSUMIT in PAH is shown in Table 1.

Table 1 : Incidence of Elevated Aminotransferases in the SERAPHIN Study

  OPSUMIT 10 mg
> 3 x ULN 3.4% 4.5%
> 8 x ULN 2.1% 0.4%

In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were 3.3% in the OPSUMIT 10 mg group vs. 1.6% for placebo. Obtain liver enzyme tests prior to initiation of OPSUMIT and repeat during treatment as clinically indicated.

Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin > 2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT. Consider reinitiation of OPSUMIT when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

Hemoglobin Decrease

Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSUMIT. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT 10 mg group and in 3.4% of the placebo group. Decreases in hemoglobin seldom require transfusion. Initiation of OPSUMIT is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated [see ADVERSE REACTIONS].

Pulmonary Edema With Pulmonary Veno-occlusive Disease (PVOD)

Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT.

Decreased Sperm Counts

Other ERAs have caused adverse effects on spermatogenesis. Counsel men about potential effects on fertility [see Use in Specific Populations and Nonclinical Toxicology].

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity

Instruct patients on the risk of fetal harm when OPSUMIT is used in pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Instruct females of reproductive potential to use effective contraception and to contact her physician if they suspect they may be pregnant. Female patients must enroll in the OPSUMIT REMS program.


For female patients, OPSUMIT is available only through a restricted program called the OPSUMIT REMS Program [see WARNINGS AND PRECAUTIONS]. Male patients are not enrolled in the OPSUMIT REMS.

Inform female patients (and their guardians, if applicable) of the following notable requirements.

  • Female patients must sign an enrollment form.
  • Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations].

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.

Review the Medication Guide and REMS educational materials with female patients.

Decrease In Hemoglobin

Advise patients on the importance of hemoglobin testing.


Some members of this pharmacological class are hepatotoxic. Educate patients on signs of hepatotoxicity. Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.


Patients should be advised not to split, crush, or chew tablets.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility


Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3-and 42-fold in male and female rats, respectively.


Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats.

Impairment Of Fertility

Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected.

Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19-to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.

Use In Specific Populations


Pregnancy Category X.

Risk Summary

OPSUMIT may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect dose was not established in either species. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see CONTRAINDICATIONS].

Animal Data

In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.

Nursing Mothers

It is not known whether OPSUMIT is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue OPSUMIT.

Pediatric Use

The safety and efficacy of OPSUMIT in children have not been established.

Geriatric Use

Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Females And Males Of Reproductive Potential


Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with OPSUMIT and monthly pregnancy tests during treatment with OPSUMIT. Advise patients to contact their health care provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients on the potential risk to the fetus [see BOXED WARNING and DOSAGE AND ADMINISTRATION].

Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with OPSUMIT and for 1 month after treatment with OPSUMIT. 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). 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].


Testicular effects: Like other endothelin receptor antagonists, OPSUMIT may have an adverse effect on spermatogenesis [see WARNINGS AND PRECAUTIONS and Nonclinical Toxicology].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 7/1/2016


Report Problems to the Food and Drug Administration


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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