Riociguat

1 INDICATIONS AND USAGE Adempas is a soluble guanylate cyclase (sGC) stimulator indicated for the treatment of adults with: • Persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class. ( 1.1 ) • Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening. ( 1.2 ) 1.1 Chronic-Thromboembolic Pulmonary Hypertension Adempas is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class [see Clinical Studies ( 14.1 )]. 1.2 Pulmonary Arterial Hypertension Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening. Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%) [see Clinical Studies ( 14.2 )] .

2 DOSAGE AND ADMINISTRATION • Initiate treatment at 1 mg taken three times a day. ( 2.1 ) • For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg, three times a day. ( 2.1 ) • Increase dosage by 0.5 mg at intervals of no sooner than 2-weeks as tolerated to a maximum of 2.5 mg three times a day. ( 2.1 ) • Tablets may be crushed and mixed with water or soft foods for patients who have difficulty swallowing. ( 2.1 ) 2.1 Recommended Dosage in Adult Patients The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day. Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day. Crushed Tablets For patients who are unable to swallow whole tablets, Adempas may be crushed and mixed with water or soft foods (such as applesauce) immediately before administration [see Clinical Pharmacology ( 12.3 )] . 2.2 Dosage Interruption If a dose is missed, advise patients to continue with the next regularly scheduled dose. In case Adempas is interrupted for 3 days or more, re-titrate Adempas. 2.3 Pregnancy Testing in Females of Reproductive Potential Confirm negative pregnancy status prior to start of treatment. [see Use in Specific Populations ( 8.3 )]. 2.4 Use in Patients who Smoke Consider titrating to dosages higher than 2.5 mg three times a day, if tolerated, in patients who smoke. A dose decrease may be required in patients who stop smoking [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]. 2.5 Strong CYP and P-gp/BCRP Inhibitors Consider a starting dose of 0.5 mg, three times a day when initiating Adempas in patients receiving strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance protein (P-gp/BCRP) inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (for example, ritonavir). Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]. 2.6 Transitioning to and from Adempas • Discontinue sildenafil at least 24 hours prior to administering Adempas [see Contraindications ( 4.3 ) and Drug Interactions ( 7 )]. • Discontinue tadalafil at least 48 hours prior to administering Adempas [see Contraindications ( 4.3 ) and Drug Interactions ( 7 )] . Consider initiating Adempas at a starting dose of 0.5 mg in patients at risk of hypotension [see Dosage and Administration ( 2.1 )] . Monitor for signs and symptoms of hypotension on initiation. • Discontinue Adempas at least 24 hours prior to administering a PDE5-inhibitor [see Dosage and Administration ( 2.1 ), Contraindications ( 4.3 ), and Drug Interactions ( 7 )]. Monitor for signs and symptoms of hypotension on initiation.

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.

12.3 Pharmacokinetics Riociguat pharmacokinetics are dose proportional from 0.5 to 2.5 mg. Inter-individual variability of riociguat exposure (AUC) across all doses is approximately 60%, and within-subject variability is approximately 30%. Absorption and distribution The absolute bioavailability of riociguat is about 94%. Peak plasma riociguat concentrations were observed within 1.5 hours after tablet intake. Food does not affect the bioavailability of riociguat. Bioavailability (AUC and C max ) of riociguat administered orally as a crushed tablet suspended in applesauce or in water is similar to that of a whole tablet. The volume of distribution at steady state is approximately 30 L. Plasma protein binding in humans is approximately 95%, with serum albumin and α1–acidic glycoprotein being the main binding components. Riociguat is a substrate of P-gp and BCRP. Metabolism and excretion Riociguat is mainly cleared through metabolism by CYP1A1, CYP3A4, CYP3A5 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke. M1 is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with PAH are about half those for riociguat. Following oral administration of radiolabeled riociguat in healthy individuals, about 40 and 53% of the total radioactivity was recovered in urine and feces, respectively. There appears to be considerable variability in the proportion of metabolites and unchanged riociguat excreted, but metabolites were the major components of the dose excreted in most individuals. Average systemic clearance of riociguat was about 1.8 L/h in patients with PAH and about 3.4 L/h in healthy subjects. The terminal elimination half-life is about 12 hours in patients and 7 hours in healthy subjects. Specific Populations: The effect of intrinsic factors on riociguat and M1 are shown below in Figure 1. There are no clinically relevant effects of age, sex, weight, or race/ethnicity on the pharmacokinetics of riociguat or M1. No dose adjustment is warranted. Figure 1: Effect of Intrinsic Factors on Riociguat and M1 Pharmacokinetics Drug interactions: The effect of extrinsic factors on riociguat and M1 were studied in healthy subjects and are shown in Figure 2. Figure 2: Effect of Extrinsic Factors on Riociguat and M1 Pharmacokinetics *HIV protease inhibitors are strong CYP3A inhibitors and may increase riociguat plasma concentrations to levels similar to those seen with ketoconazole. ** AUC only, estimated using population pharmacokinetics methods *** AUC only for metabolite, estimated using population pharmacokinetics methods. **** Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors [see Dosage and Administration ( 2.4 , 2.5 ), Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )] . Strong CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are co-administered [see Drug Interactions ( 7.2 )]. Effects of Riociguat on other Drugs: Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil [see Contraindications ( 4.3 ) and Clinical Pharmacology ( 12.2 )]. Riociguat (2.5 mg three times per day) did not affect the systemic exposure of combined oral contraceptives containing levonorgestrel and ethinyl estradiol when concomitantly administered to healthy female subjects. Effect of Intrinsic Factors on Riociguat and M1 Pharmacokinetics Figure 2: Effect of Extrinsic Factors on Riociguat and M1 Pharmacokinetics