Included as part of the "PRECAUTIONS" Section
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].
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.
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
|>8 x ULN
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 [see ADVERSE REACTIONS].
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 re-initiation of OPSUMIT when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
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 [see ADVERSE REACTIONS].
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.
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
OPSUMIT, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility [see Use In Specific Populations and Nonclinical Toxicology ].
Patient Counseling Information
Advise patient to read FDA-approved patient labeling (Medication Guide).
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 [see Use In Specific Populations].
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.
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.
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
Review the Medication Guide and REMS educational materials with female patients.
Advise women not to breastfeed during treatment with OPSUMIT [see Use In Specific Populations ].
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
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.
Patients should be advised not to split, crush, or chew tablets.
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
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 (see Clinical Considerations). There are limited data on OPSUMIT use in pregnant women. 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].
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.
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.
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.
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.
Females And Males Of Reproductive Potential
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 [see WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].
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 WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS,ADVERSE REACTIONS and Nonclinical Toxicology ].
The safety and efficacy of OPSUMIT in children have not been established.
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.