Riociguat 2.5 mg Tablet, Film Coated, 90-count — NDC 70710-2160-9 (Billing 70710-2160-09)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation.

Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding.

Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation. The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.

12.2Pharmacodynamics There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output [ see Clinical Studies (14) ] . Hemodynamic parameters were assessed in CTEPH patients in CHEST-1 [ see Clinical Studies (14.1) ] . Right heart catheterization was performed at the beginning and the end of the study period in 233 patients.

A statistically significant reduction of PVR (-246 dyn*s*cm -5 ) was shown in the riociguat group vs. placebo. Improvements in other hemodynamic parameters (not pre-specified as endpoints) are displayed in Table 2 below. Table 2: CHEST-1, Change In Hemodynamic Parameters from Baseline to Last Visit (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus placebo) Parameter (unit) Mean change LS mean difference 95% CI Riociguat Placebo Pulmonary Capillary Wedge Pressure (mmHg) 0.59 0.18 0.58 –0.36 to

1.53Right Atrial Pressure (mmHg) –1.04 –0.55 –0.55 –1.72 to

0.62Pulmonary Arterial Pressure Systolic (mmHg) –6.84 0.95 –7.52 –10.88 to –4.16 Pulmonary Arterial Pressure Diastolic (mmHg) –3.05 0.67 –3.62 –5.30 to –1.95 Pulmonary Arterial Pressure Mean (mmHg) –4.31 0.76 –4.96 –6.75 to –3.16 Mean Arterial Pressure (mmHg) –9.27 –0.29 –9.15 –11.83 to –6.46 Mixed Venous Oxygen Saturation (%) 2.95 –0.44 3.85 1.46 to

6.25Cardiac Output (L/min) 0.81 –0.03 0.86 0.59 to

1.12Cardiac Index (L/min/m 2 ) 0.45 –0.01 0.47 0.33 to

0.62Pulmonary Vascular Resistance (dyn*s*cm -5 ) –226 23.1 –246 –303 to –190 Pulmonary Vascular Resistance Index (dyn*s*cm -5 *m 2 ) –397 48.3 –449 –554 to –344 Systemic Vascular Resistance (dyn*s*cm -5 ) –445 16.6 –478 –602 to –354 Systemic Vascular Resistance Index (dyn*s*cm -5 *m 2 ) –799 53.7 –914 –1141 to –687 Hemodynamic parameters were assessed in PAH patients in PATENT-1 [ see Clinical Studies (14.2) ] . Right heart catheterization was performed at the beginning and the end of the study period in 339 patients.

A statistically significant reduction of PVR (-226 dyn*sec*cm -5 ) was shown in the riociguat individual titration group (to maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3. Table 3: PATENT-1, Change in Hemodynamic Parameters from Baseline to Last Visit (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus Placebo) Parameter (unit) Mean change LS mean difference 95% CI Riociguat Placebo Pulmonary Capillary Wedge Pressure (mmHg) 1.08 0.46 0.41 –0.36 to

1.18Right Atrial Pressure (mmHg) –0.20 0.97 –1.01 –2.15 to

0.13Pulmonary Arterial Pressure Systolic (mmHg) –5.39 0.78 –6.73 –9.43 to –4.04 Pulmonary Arterial Pressure Diastolic (mmHg) –3.19 –1.12 –2.41 –4.15 to –0.68 Pulmonary Arterial Pressure mean (mmHg) –3.93 –0.5 –3.83 –5.61 to –2.06 Mean Arterial Press… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation.

Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding.

Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation. The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.

12.3Pharmacokinetics 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

3.4L/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 (5.3) 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. figure-01 figure-02

12.2Pharmacodynamics There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output [ see Clinical Studies (14) ] . Hemodynamic parameters were assessed in CTEPH patients in CHEST-1 [ see Clinical Studies (14.1) ] . Right heart catheterization was performed at the beginning and the end of the study period in 233 patients.

A statistically significant reduction of PVR (-246 dyn*s*cm -5 ) was shown in the riociguat group vs. placebo. Improvements in other hemodynamic parameters (not pre-specified as endpoints) are displayed in Table 2 below. Table 2: CHEST-1, Change In Hemodynamic Parameters from Baseline to Last Visit (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus placebo) Parameter (unit) Mean change LS mean difference 95% CI Riociguat Placebo Pulmonary Capillary Wedge Pressure (mmHg) 0.59 0.18 0.58 –0.36 to

1.53Right Atrial Pressure (mmHg) –1.04 –0.55 –0.55 –1.72 to

0.62Pulmonary Arterial Pressure Systolic (mmHg) –6.84 0.95 –7.52 –10.88 to –4.16 Pulmonary Arterial Pressure Diastolic (mmHg) –3.05 0.67 –3.62 –5.30 to –1.95 Pulmonary Arterial Pressure Mean (mmHg) –4.31 0.76 –4.96 –6.75 to –3.16 Mean Arterial Pressure (mmHg) –9.27 –0.29 –9.15 –11.83 to –6.46 Mixed Venous Oxygen Saturation (%) 2.95 –0.44 3.85 1.46 to

6.25Cardiac Output (L/min) 0.81 –0.03 0.86 0.59 to

1.12Cardiac Index (L/min/m 2 ) 0.45 –0.01 0.47 0.33 to

0.62Pulmonary Vascular Resistance (dyn*s*cm -5 ) –226 23.1 –246 –303 to –190 Pulmonary Vascular Resistance Index (dyn*s*cm -5 *m 2 ) –397 48.3 –449 –554 to –344 Systemic Vascular Resistance (dyn*s*cm -5 ) –445 16.6 –478 –602 to –354 Systemic Vascular Resistance Index (dyn*s*cm -5 *m 2 ) –799 53.7 –914 –1141 to –687 Hemodynamic parameters were assessed in PAH patients in PATENT-1 [ see Clinical Studies (14.2) ] . Right heart catheterization was performed at the beginning and the end of the study period in 339 patients.

A statistically significant reduction of PVR (-226 dyn*sec*cm -5 ) was shown in the riociguat individual titration group (to maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3. Table 3: PATENT-1, Change in Hemodynamic Parameters from Baseline to Last Visit (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus Placebo) Parameter (unit) Mean change LS mean difference 95% CI Riociguat Placebo Pulmonary Capillary Wedge Pressure (mmHg) 1.08 0.46 0.41 –0.36 to

1.18Right Atrial Pressure (mmHg) –0.20 0.97 –1.01 –2.15 to

0.13Pulmonary Arterial Pressure Systolic (mmHg) –5.39 0.78 –6.73 –9.43 to –4.04 Pulmonary Arterial Pressure Diastolic (mmHg) –3.19 –1.12 –2.41 –4.15 to –0.68 Pulmonary Arterial Pressure mean (mmHg) –3.93 –0.5 –3.83 –5.61 to –2.06 Mean Arterial Pressure (mmHg) –8.54 –1.4 –7.25 –9.6 to –4.90 Mixed Venous Oxygen Saturation (%) 3.15 –2.33 5.02 3.2 to

6.84Cardiac Output (L/min) 0.93 –0.01 0.93 0.7 to

1.15Cardiac Index (L/min/m 2 ) 0.54 –0.02 0.56 0.44 to

0.69Pulmonary Vascular Resistance (dyn*s*cm -5 ) –223 –8.9 –226 –281 to –170 Pulmonary Vascular Resistance Index (dyn*s*cm -5 *m 2 ) –374 –22.4 –377 –469 to –285 Systemic Vascular Resistance (dyn*s*cm -5 ) –448 –67.5 –395 –473 to –316 Systemic Vascular Resistance Index (dyn*s*cm -5 *m 2 ) –753 –130 –675 –801 to –550 Biomarkers In the CHEST-1 study, riociguat significantly reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP), placebo-corrected mean change from baseline -444 ng/L, 95% CI -843 to -45.

In the PATENT-1 study riociguat demonstrated a statistically significant reduction of NT-proBNP, placebo-corrected mean change from baseline: -432 ng/L, 95% CI -782 to -82. Pharmacodynamic interactions Nitrates : Riociguat 2.5 mg tablets potentiated the blood pressure lo… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Chronic-Thromboembolic Pulmonary Hypertension A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they: were technically inoperable for pulmonary endarterectomy, with PVR >300 dyn*sec*cm -5 and mean pulmonary artery pressure >25 mmHg measured at least 90 days after the start of full anticoagulation, or had recurrent or persisting pulmonary hypertension defined as PVR > 300 dyn*sec*cm -5 measured at least 180 days following pulmonary endarterectomy.

Patients were randomized to riociguat titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study.

The dose of riociguat was titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline). The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks.

The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline.

The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively. Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3.

Figure 3: CHEST-1 Mean Change from Baseline in the 6-Minute Walk Distance The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used.

Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the riociguat group was 46 m (95% confidence interval [CI]: 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m).

Figure 4 illustrates the results of the riociguat and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with riociguat benefit compared to those treated with placebo.

As demonstrated in Figure 4, 143 patients receiving riociguat (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo. Figure 4: CHEST-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance Placebo-adjusted changes in 6MWD at 16 weeks were evaluated in subgroups (see Figure 5) Figure 5: Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance (meters) by Prespecified Subgroups fig-05 WHO Functional Class improvements in the CHEST-1 trial are shown in Table 4.

Table 4: Effects of Riociguat on the Change in WHO Functional Class in CHEST-1 from Baseline to Week 16 Change in WHO Functional Class Riociguat (n=173) Placebo (n=87) Improved 57 (33%) 13 (15%) Stable 107 (62%) 68 (78%) Deteriorated 9 (… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis , Impairment of Fertility Carcinogenesis : Carcinogenicity studies of riociguat were conducted in mice and rats. In mice, oral administration of riociguat (up to 25 mg/kg/day in males and 32 mg/kg/day in females) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 6 times the human’s exposure.

In rats, oral administration of riociguat (up to 20 mg/kg/day) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 7 times the human exposure. Mutagenesis : Riociguat and M1 did not show genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster V79 cells, or the in vivo micronucleus assay in the mouse.

Impairment of fertility : In rats, no effects on male or female fertility were observed. In male rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and throughout the mating period had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area.

In female rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and during mating and continuing to gestation Day 7 had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area.

13.2Animal Toxicology In growing rats, effects on bone formation were observed, including thickening of the growth plates, disorganized trabecular bone, and diffuse hyperostosis [ see Use in Specific Populations (8.4)].