Riociguat

⛔ FDA Black Box Warning

WARNING: EMBRYO-FETAL TOXICITY Do not administer Adempas to a pregnant female because it may cause fetal harm [see Contraindications ( 4.1 ), Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )]. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. To prevent pregnancy, females of reproductive potential must use effective forms of contraception during treatment and for one month after [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 , 5.2 ),and Use in Specific Populations ( 8.3 )]. For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program [see Warnings and Precautions ( 5.1 , 5.2 )]. WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. • Do not administer Adempas to a pregnant female because it may cause fetal harm. ( 4.1 , 5.1 , 8.1 ) • Females of reproductive potential: Exclude pregnancy before start of treatment, monthly during treatment, and 1 month after treatment discontinuation. Prevent pregnancy during treatment and for one month after treatment discontinuation by use of effective forms of contraception. ( 2.3 , 5.1, 5.2 , 8.6 ) • For females, Adempas is available only through a restricted program called the Adempas REMS Program. ( 5.1, 5.2 )

Contraindications

4 CONTRAINDICATIONS • Pregnancy ( 4.1 ) • Use with nitrates or nitric oxide donors in any form ( 4.2 , 7.1 ) • Use with PDE inhibitors ( 2.6 , 4.3 , 7.1 ) • Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators. ( 4.4 , 7.1 ) • • Pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) ( 4.4 ) 4.1 Pregnancy Based on data from animal reproduction studies, Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )] . 4.2 Nitrates and Nitric Oxide Donors Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated [see Drug Interactions (7.1) and Clinical Pharmacology ( 12.2 )] . 4.3 Phosphodiesterase Inhibitors Concomitant administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE 5 inhibitors (such as dipyridamole or theophylline) is contraindicated [see Dosage and Administration (2.6), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )]. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil. 4.4 Soluble Guanylate Stimulators Adempas is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators [see Drug Interactions ( 7.1 )]. 4.5 Pulmonary Hypertension Associated with Idiopathic Interstitial Pneumonias (PH-IIP) Adempas is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

Pregnancy & Breastfeeding

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 m