WARNING: EMBRYO-FETAL TOXICITY Adempas 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) , and Use in Specific Populations (8.1) ]. Exclude pregnancy prior to the start of treatment with Adempas. Advise use of effective contraception prior to initiation of treatment, during treatment, and for one month after treatment with Adempas [see Dosage and Administration (2.3) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ]. If pregnancy is detected, discontinue Adempas as soon as possible [see Warnings and Precautions (5.1) ]. WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning Based on animal data, Adempas may cause fetal harm if used during pregnancy. ( 4.1 , 5.1 , 8.1 ) Exclude pregnancy before start of treatment Use effective contraception prior to initiation of treatment, during treatment, and for one month after treatment with Adempas. ( 2.3 , 5.1 , 8.6 ) When pregnancy is detected, discontinue Adempas as soon as possible. ( 5.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Symptomatic hypotension ( 5.2 ) • Bleeding ( 5.3 ) • Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment ( 5.4 ) 5.1 Embryo-Fetal Toxicity Based on data from animal reproduction studies, Adempas may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The available human data for riociguat do not establish the presence or absence of major birth defects related to the use of Adempas. Counsel patients who can become pregnant on the potential risk to a fetus. Exclude pregnancy prior to initiation of treatment with Adempas. Advise females of reproductive potential to use effective contraception prior to initiation of treatment, during treatment with Adempas and for at least one month after the last dose. When pregnancy is detected, discontinue Adempas as soon as possible [see Dosage and Administration (2.3) , Contraindications (4.1) and Use in Specific Populations (8.1 , 8.3) ] . 5.2 Hypotension Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . Consider a dose reduction if patient develops signs or symptoms of hypotension. 5.3 Bleeding In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage. 5.4 Pulmonary Veno-Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Adempas.
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) ] • Hypotension [see Warnings and Precautions (5.2) ] • Bleeding [see Warnings and Precautions (5.3) ] Adverse reactions occurring more frequently (≥3%) on Adempas compared to placebo are headache, dyspepsia/gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure to Adempas in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490; Placebo: n = 214) was between the age of 18 and 80 years [see Clinical Studies (14.1 , 14.2) ]. The safety profile of Adempas in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on Adempas than placebo (≥3%) are displayed in Table 1 below. Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of Adempas. The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for Adempas and 5.1% for placebo (pooled data). Table 1: Adverse Reactions Occurring More Frequently (≥3%) on Adempas than Placebo (Pooled from CHEST-1 and PATENT-1) Adverse Reactions Adempas % (n=490) Placebo % (n=214) Headache 27 18 Dyspepsia and Gastritis 21 8 Dizziness 20 13 Nausea 14 11 Diarrhea 12 8 Hypotension 10 4 Vomiting 10 7 Anemia (including laboratory parameters) 7 2 Gastroesophageal reflux disease 5 2 Constipation 5 1 Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studies the safety profile was similar to that observed in the placebo controlled phase 3 trials.