Opsynvi Use In Pregnancy & Lactation

Pregnancy: Risk Summary: Based on data from animal reproduction studies, OPSYNVI is contraindicated during pregnancy. Macitentan, a component of OPSYNVI, may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female. Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as OPSYNVI 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.
Available data from a randomized controlled trial, observational studies, and case series with tadalafil use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In tadalafil animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats and mice during organogenesis at exposures 7 times the maximum recommended human dose (MRHD) of 40 mg/day (see Data as follows).
There are risks to the mother and the fetus associated with PAH in pregnancy (see Clinical Considerations as follows). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise pregnant women of the potential risk to a fetus [see Use in Pregnancy under Contraindications and Use in Pregnancy: Embryo-fetal Toxicity under Precautions].
The 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 PAH, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including heart failure, stroke, spontaneous abortion, intrauterine growth restriction, premature labor, and preterm birth.
Data: Animal Data: Macitentan: 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.
Tadalafil: Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.
Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC. In one of two perinatal/postnatal developmental studies in rats, a reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed-effect-level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately 5 times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than 8 times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance.
Lactation: Risk Summary: There are no data on the presence of tadalafil, macitentan, and/or their metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats (see Data as follows). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in breastfed infants from OPSYNVI, advise women not to breastfeed during treatment with OPSYNVI.
Data: Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma.
Females and Males of Reproductive Potential: Based on data from animal reproductive toxicity studies, OPSYNVI can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Use in Pregnancy under Contraindications, and previous text].
Pregnancy Testing: Verify that patients who can become pregnant are not pregnant prior to initiating OPSYNVI. 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 OPSYNVI should use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with OPSYNVI to prevent pregnancy [see Use in Pregnancy: Embryo-fetal Toxicity under Precautions].
Infertility: Males: Macitentan: Based on findings in animals, macitentan may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Decreased Sperm Count under Precautions, Pharmacology: Pharmacodynamics, and Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].
Tadalafil: Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men or women [see Pharmacology: Pharmacodynamics, and Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].