Dosage & Administration
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Opsumit Prescribing Information
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)].
Pulmonary Arterial Hypertension
OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults to reduce the risks of disease progression and hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II–III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%) [see Clinical Studies (14.1)] .
Recommended Dosage
The recommended dosage of OPSUMIT is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.
Pregnancy Testing in Females of Reproductive Potential
Exclude pregnancy before initiating treatment with OPSUMIT in females of reproductive potential [see Boxed Warning, Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.3)] .
Tablets: 10 mg, bi-convex film-coated, round, white, and debossed with "10" on both sides.
Pregnancy
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 [see Clinical Considerations] . 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)] .
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 and/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.
Data
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.
Lactation
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.
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)] .
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 [see Warnings and Precautions (5.6), Adverse Reactions (6.1), and Nonclinical Toxicology (13.1)] .
Pediatric Use
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.
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.
Pregnancy
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 [see Warnings and Precautions (5.1)and Use in Specific Populations (8.1)] .
Hypersensitivity
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)] .