ADEMPAS

Adempas (riociguat) is a soluble guanylate cyclase stimulator tablet for oral administration.

Riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate with the following structural formula: C 20 H 19 FN 8 O 2 Riociguat is a white to yellowish, crystalline, non-hygroscopic substance with a molecular weight of 422.42 g/mol.

In solid form it is stable to temperature, light, and humidity.

The solubility at 25°C in water: 4 mg/L, in ethanol: 800 mg/L, in 0.1 HCl (pH 1): 250 mg/L and in buffer (phosphate) pH 7: 3 mg/L. In the pH range of to 4 the solubility showed strong pH-dependency.

Solubility increases at lower pH values.

Each round film-coated tablet contains 0.5 mg (1.0, 1.5, 2.0, 2.5 mg) riociguat.

The inactive ingredients are cellulose microcrystalline, crospovidone, hypromellose 5cP, lactose monohydrate, magnesium stearate, sodium laurylsulfate, hydroxypropylcellulose, hypromellose 3cP, propylene glycol, and titanium dioxide.

Adempas 1, 1.5, 2 and 2.5 mg tablets contain, in addition, ferric oxide yellow.

Adempas and 2.5 mg tablets contain, in addition, ferric oxide red.

• Persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class.

• Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening. 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. 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%) .

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO).

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. 12.2 Pharmacodynamics 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.

Hemodynamic parameters were assessed in CTEPH patients in CHEST-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 dynscm -5 ) was shown in the Adempas 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 Adempas Placebo Pulmonary Capillary Wedge Pressure (mmHg) 0.59 0.18 0.58 –0.36 to 1.53 Right Atrial Pressure (mmHg) –1.04 –0.55 –0.55 –1.72 to 0.62 Pulmonary 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 6.25 Cardiac Output (L/min) 0.81 –0.03 0.86 0.59 to 1.12 Cardiac Index (L/min/m 2 ) 0.45 –0.01 0.47 0.33 to 0.62 Pulmonary Vascular Resistance (dynscm -5 ) –226 23.1 –246 –303 to –190 Pulmonary Vascular Resistance Index (dynscm -5 m 2 ) –397 48.3 –449 –554 to –344 Systemic Vascular Resistance (dynscm -5 ) –445 16.6 –478 –602 to –354 Systemic Vascular Resistance Index (dynscm -5 m 2 ) –799 53.7 –914 –1141 to –687 Hemodynamic parameters were assessed in PAH patients in PATENT-1.

Right heart catheterization was performed at the beginning and the end of the study period in 339 patients.

PVR (-226 dynseccm -5 ) was shown in the Adempas 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 Adempas Placebo Pulmonary Capillary Wedge Pressure (mmHg) 1.08 0.46 0.41 –0.36 to 1.18 Right Atrial Pressure (mmHg) –0.20 0.97 –1.01 –2.15 to 0.13 Pulmonary 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 6.84 Cardiac Output (L/min) 0.93 –0.01 0.93 0.7 to 1.15 Cardiac Index (L/min/m 2 ) 0.54 –0.02 0.56 0.44 to 0.69 Pulmonary Vascular Resistance (dynscm -5 ) –223 –8.9 –226 –281 to –170 Pulmonary Vascular Resistance Index (dynscm -5 m 2 ) –374 –22.4 –377 –469 to –285 Systemic Vascular Resistance (dynscm -5 ) –448 –67.5 –395 –473 to –316 Systemic Vascular Resistance Index (dynscm -5 m 2 ) –753 –130 –675 –801 to –550 Biomarkers In the CHEST-1 study, Adempas 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 Adempas 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 lowering effect of sublingual nitroglycerin (0.4 mg) taken and 8 hours after riociguat.

Syncope was reported in some patients.

Phosphodiesterase-5 inhibitors: In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg three times a day), single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive hemodynamic effects.

Among patients with

PAH on stable sildenafil treatment (20 mg, three times a day) and riociguat (1 to 2.5 mg, three times a day) there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.

Concomitant administration of riociguat and warfarin did not alter prothrombin time.

Concomitant use of riociguat and aspirin did not affect bleeding time or platelet aggregation. 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 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.

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.

CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are co-administered.

Effects of Riociguat on other Drugs

Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil.

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.

• Bleeding 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.

To report SUSPECTED ADVERSE

REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc.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 and 80 years.

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 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.

In cases of overdose, blood pressure should be closely monitored and supported as appropriate.

Based on extensive plasma protein binding, riociguat is not expected to be dialyzable.

• Use with nitrates or nitric oxide donors in any form.

• Use with PDE inhibitors.

• Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators.

• Pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) 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. 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. 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.

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. 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).

• Initiate treatment at 1 mg taken three times a day.

• For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg, three times a day.

• 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.

• Tablets may be crushed and mixed with water or soft foods for patients who have difficulty swallowing. 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. 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 Obtain pregnancy tests prior to start of treatment and monthly during treatment. 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. 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. 2.6 Transitioning to and from Adempas.

• Discontinue sildenafil at least 24 hours prior to administering Adempas.

• Discontinue tadalafil at least 48 hours prior to administering Adempas.

Consider initiating

Adempas at a starting dose of 0.5 mg in patients at risk of hypotension.

Monitor for signs and symptoms of hypotension on initiation.

• Discontinue Adempas at least 24 hours prior to administering a PDE5-inhibitor.

Adempas (riociguat) tablets are film-coated, round, and debossed with the “Bayer cross” on one side.

Side 2 NDC 50419-xxx-xx Bottle of 9 Bottle of 90 Blister of 42 0.5 mg White 0.5 R 250-91 250-01 250-03 1 mg Pale yellow 1 R 251-91 251-01 251-03 1.5 mg Yellow-orange 1.5 R 252-91 252-01 252-03 2 mg Pale orange 2 R 253-91 253-01 253-03 2.5 mg Red-orange 2.5 R 254-91 254-01 254-03 16.2 Storage and Handling Store at 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) .

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.

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.

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 mg/kg/day) is approximately 2 times that in humans at the MRHD.

In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD.

Safety and effectiveness of

Adempas in pediatric patients have not been established.

Of the total number of subjects in clinical studies of Adempas, 23% were and over, and 6% were and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients showed a higher exposure to Adempas.