8 USE IN SPECIFIC POPULATIONS •Nursing mothers: Discontinue drug or breastfeeding. (8.3) •Renal impairment: Not recommended in patients with creatinine clearance <15 mL/min or on dialysis. (8.7) •Hepatic impairment: Not recommended in patients with severe (Child Pugh C) hepatic impairment. (8.8) •Smoking: May require dosages higher than 2.5 mg three times a day if tolerated. Dose decrease may be required in patients who stop smoking. (2.4, 7.2) 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity and miscarriage when administered to a pregnant woman and is contraindicated during pregnancy [see Contraindications (4.1)]. There are limited available data with ADEMPAS use in pregnant women. In animal reproduction studies, oral administration of riociguat to pregnant rats during organogenesis was teratogenic and embryotoxic at exposures approximately 8 times and 2 times, respectively, the human exposure. In reproduction studies with pregnant rabbits, oral administration of riociguat during organogenesis caused abortions and fetal toxicity at exposures approximately 4 times and 13 times, respectively, the maximum recommended human dose (MRHD). Advise pregnant women of the potential 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. Data Animal Data In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time-concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of riociguat in human milk, the effects on the breastfed infant, or the effect on milk production. Riociguat is present in rat milk. Because of the potential for serious adverse reactions from ADEMPAS, such as hypotension, in breastfed infants, advise women not to breastfeed during treatment with ADEMPAS. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with Adempas, monthly during treatment, and one month after discontinuation of treatment with Adempas. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk to the fetus [see Boxed Warning, Dosage and Administration (2.3) and Use in Specific Populations (8.1)]. Contraception Females Female patients of reproductive potential must use acceptable methods of contraception during treatment with Adempas and for 1 month after treatment with Adempas. 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]. 8.4 Pediatric Use Safety and effectiveness of Adempas in pediatric patients have not been established [see Nonclinical Toxicology (13.2)]. 8.5 Geriatric Use Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients showed a higher exposure to Adempas [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) [see Clinical Pharmacology (12.3)].