WARNING: EMBRYO-FETAL TOXICITY Do not administer riociguat to a pregnant female because it may cause fetal harm [See Contraindications (4.1) , Warningsand 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 1month after stopping treatment.To prevent pregnancy,females of reproductive potential must use effective formsof contraception during treatment and for one month after stopping treatment [See Dosage and Administration (2.3) , Warnings and Precautions (5.1 , 5.2), and Use in Specific Populations (8.3)]. For all female patients, riociguat tablet is available only through a restricted program called the riociguat Risk Evaluationand Mitigation Strategy (REM-S) Program [See Warnings and Precautions (5.1 , 5.2)]. WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning Do not administer riociguat to a pregnant femalebecause it may cause fetal harm. ( 4.1 , 5.1 , 8.1 ) Females of reproductive potential: Excludepregnancy before start of treatment, monthlyduring treatment, and 1 month after treatmentdiscontinuation. Prevent pregnancy duringtreatment and for one month after treatmentdiscontinuation by use of effective forms ofcontraception. ( 2.3 , 5.1 , 5.2 , 8.6 ) For females, riociguat is available only througha restricted program called the riociguat REMSProgram. ( 5.1 , 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Symptomatic hypotension (5.3) Bleeding (5.4) Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment (5.5) 5.1 Embryo-Fetal Toxicity Based on data from animal reproduction studies, riociguat may cause embryo-fetal toxicity when administered to a pregnant femaleand is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain apregnancy test before the start of treatement, monthly during treatment, and for one month after stopping treatment. Advise femalesof reproductive potential to use effective contraception during treatment with riociguat and for at least one month after the last dose [see Dosage and Administration (2.3) and Use in Specific Populations (8.1 , 8.3) ]. For females, riociguat is only available through a restricted program under the riociguat REMS Program [see Warnings andPrecautions (5.2)]. 5.2 Riociguat REMS Program Females can only receive riociguat through the riociguat Risk Evaluation and Mitigation Strategy (REM-S) Program, a restricteddistribution program [see Warnings and Precautions (5.1) ]. Important requirements of the riociguat REMS Program include the following: Prescribers must be certified with the program by enrolling and completing training. All females, regardless of reproductive potential, must enroll in the riociguat REMS Program prior to initiating riociguat. Malepatients are not enrolled in the riociguat REMS Program. Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Usein Specific Populations (8.3)]. Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive riociguat. Further information, including a list of certified pharmacies, is available at www.Riociguat REMS.com or 1-855-4 Riociguat. 5.3 Hypotension Riociguat 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. 5.4 Bleeding In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking riociguat compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking riociguat 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. 5.5 Pulmonary Veno-Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of riociguat 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 riociguat.
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 (5.3) ] Bleeding [see Warnings and Precautions (5.4) ] Adverse reactions occurring more frequently (≥3%) on riociguat 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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or 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 riociguat 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 (riociguat: 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 riociguat 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 riociguat 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 riociguat. The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for riociguat and 5.1% for placebo (pooled data). Table 1: Adverse Reactions Occurring More Frequently (≥3%) on Riociguat than Placebo (Pooled from CHEST-1 and PATENT-1) Adverse Reactions Riociguat % (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 riociguat 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.