Adempas
Riociguat · Tablet, Film Coated · Oral
Uses
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) ] .
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 Exclude pregnancy before initiating Adempas. [see Contraindications (4.1) , Warning and Precautions (5.1) , 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.
Dosage forms and strengths
Tablets: film-coated, round, bi-convex:
• 0.5 mg, white, with "BAYER" cross on one side and "0.5" and "R" on the other side
• 1 mg, pale-yellow, with "BAYER" cross on one side and "1" and "R" on the other side
• 1.5 mg, yellow-orange, with "BAYER" cross on one side and "1.5" and "R" on the other side
• 2 mg, pale orange, with "BAYER" cross on one side and "2" and "R" on the other side
• 2.5 mg, red-orange, with "BAYER" cross on one side and "2.5" and "R" on the other side Tablets: 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg ( 3 )
Contraindications
• Pregnancy ( 4.1 )
• Use with nitrates or nitric oxide donors in any form ( 4.2 , 7.1 )
• Use with PDE inhibitors ( 2.6 , 4.3 , 7.1 )
• Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators. ( 4.4 , 7.1 )
• Pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) ( 4.5 ) 4.1 Pregnancy Use of Adempas is contraindicated in patients who are pregnant [see Warnings and Precautions (5.1) , Use in Specific Populations ( 8.1 )] . 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.2) ] . 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 [see Dosage and Administration (2.6), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )]. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil. 4.4 Soluble Guanylate Cyclase Stimulators Adempas is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators [see Drug Interactions ( 7.1 )]. 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).
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.
Side effects
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.
Drug interactions
• Strong CYP and P-gp/BCRP inhibitors: For patients receiving strong CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg three times a day. Monitor for hypotension. (7.2 )
• Antacids: Separate administration by at least 1 hour. ( 7.2 ) 7.1 Pharmacodynamic Interactions with Adempas Other Soluble Guanylate Cyclase Stimulators: Co-administration of Adempas is contraindicated in patients with use of other soluble guanylate cyclase (sGC) stimulators [see Contraindications (4.4) ] . Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension [see Contraindications (4.2) and Clinical Pharmacology (12.2) ] . PDE Inhibitors: Co-administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil [see Dosage and Administration (2.6) ]. Clinical experience with co-administration of Adempas and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited. 7.2 Pharmacokinetic Interactions with Adempas Smoking: Plasma concentrations in smokers are reduced by 50% to 60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat [see Dosage and Administration (2.5) , Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered [see Clinical Pharmacology (12.3) ]. Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas [see Clinical Pharmacology (12.3) ].
Use in specific populations
• Lactation: Advise not to breastfeed. ( 8.2 )
• Renal impairment: Not recommended in patients with creatinine clearance <15 mL/min or on dialysis. ( 8.6 )
• Hepatic impairment: Not recommended in patients with severe (Child Pugh C) hepatic impairment. ( 8.7 )
• Smoking: May require dosages higher than 2.5 mg three times a day if tolerated. Dose decrease may be required in patients who stop smoking. ( 2.4 , 7.2 ) 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, Adempas may cause fetal harm, including birth defects and fetal death, and miscarriage when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1) ] . Available data from published literature and post-marketing surveillance over a decade of use with riociguat have not identified an increased risk of major birth defects. However, these data are limited and do not establish the presence or absence of a drug-associated risk of major birth defects or miscarriage. Methodological limitations of these postmarketing reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal riociguat use. 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 patients of the potential risk to a fetus [see Contraindications (4.1) ] . 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. Data Animal Data 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. 8.2 Lactation Risk Summary There are no data on the presence of riociguat in human milk, the effects on the breastfed infant, or the effect on milk production. Riociguat is present in rat milk. Because of the potential for serious adverse reactions from Adempas, such as hypotension, in breastfed infants, advise women not to breastfeed during treatment with Adempas. 8.3 Females and Males of Reproductive Potential Based on data from animal reproductive toxicity studies, Adempas may cause fetal harm, including birth defects and fetal death, and miscarriage when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1) , Use in Specific Populations (8.1) ] . Pregnancy Testing Exclude pregnancy prior to starting treatment with Adempas in females of reproductive potential. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk to the fetus [see Boxed Warning, Dosage and Administration (2.3) and Use in Specific Populations (8.1) ]. Contraception Females Female patients of reproductive potential should use effective contraception prior to initiation of treatment, during treatment with Adempas and for 1 month after treatment with Adempas to prevent pregnancy [see Boxed Warning ]. 8.4 Pediatric Use Safety and effectiveness of Adempas in pediatric patients have not been established [see Nonclinical Toxicology (13.2) ] . 8.5 Geriatric Use Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over [see Clinical Studies (14) ]. 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 [see Clinical Pharmacology (12.3) ]. 8.6 Renal Impairment Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis [see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) [see Clinical Pharmacology (12.3) ].
Pregnancy
8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, Adempas may cause fetal harm, including birth defects and fetal death, and miscarriage when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1) ] . Available data from published literature and post-marketing surveillance over a decade of use with riociguat have not identified an increased risk of major birth defects. However, these data are limited and do not establish the presence or absence of a drug-associated risk of major birth defects or miscarriage. Methodological limitations of these postmarketing reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal riociguat use. 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 patients of the potential risk to a fetus [see Contraindications (4.1) ] . 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. Data Animal Data 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.
Pediatric use
8.4 Pediatric Use Safety and effectiveness of Adempas in pediatric patients have not been established [see Nonclinical Toxicology (13.2) ] .
Geriatric use
8.5 Geriatric Use Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over [see Clinical Studies (14) ]. 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 [see Clinical Pharmacology (12.3) ].
Overdosage
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.
Description
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 2 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 2 and 2.5 mg tablets contain, in addition, ferric oxide red. Chemical Structure
Mechanism of action
12.1 Mechanism 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.
How supplied
16.1 How Supplied Adempas (riociguat) tablets are film-coated, round, and debossed with the "Bayer cross" on one side. Color Debossing 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) [see USP Controlled Room Temperature].
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity Instruct patients on the risk of fetal harm when Adempas is used during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . Educate and counsel females of reproductive potential to use effective contraception prior to initiation of treatment with Adempas, during treatment, and for one month after stopping treatment. Instruct patients to contact their healthcare provider immediately if they suspect they may be pregnant. Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. Advise pre-pubertal females to report any changes in their reproductive status immediately to their prescriber. Lactation Advise women not to breastfeed during treatment with Adempas [see Use in Specific Populations (8.2) ] . Other Risks Associated with Adempas
• Inform patients of the contraindication of Adempas with nitrates or nitric oxide donors or PDE-5 inhibitors.
• Advise patients about the potential risks/signs of hemoptysis and to report any potential signs of hemoptysis to their physicians.
• Instruct patients on the dosing, titration, and maintenance of Adempas.
• Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Instruct patients to report all current medications and new medications to their physician.
• Advise patients that antacids should not be taken within 1 hour of taking Adempas.
• Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines [see Adverse Reactions (6.1) ] . Advise patients to be aware of how they react to Adempas before driving or operating machinery, and if needed, consult their physician. Patients should consult their physicians if dizziness gets worse with Adempas.
Label text from the FDA structured product label by Bayer HealthCare Pharmaceuticals Inc. (revised Aug 13, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Riociguat in 5 products
Adempas NDC products (5)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 50419-250 | Riociguat .5 mg/1 Tablet, Film Coated | Bayer HealthCare Pharmaceuticals Inc. | NDA |
| 50419-251 | Riociguat 1 mg/1 Tablet, Film Coated | Bayer HealthCare Pharmaceuticals Inc. | NDA |
| 50419-252 | Riociguat 1.5 mg/1 Tablet, Film Coated | Bayer HealthCare Pharmaceuticals Inc. | NDA |
| 50419-253 | Riociguat 2 mg/1 Tablet, Film Coated | Bayer HealthCare Pharmaceuticals Inc. | NDA |
| 50419-254 | Riociguat 2.5 mg/1 Tablet, Film Coated | Bayer HealthCare Pharmaceuticals Inc. | NDA |
Frequently asked questions
What is Adempas used for?
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…
What are the side effects of Adempas?
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,… See the full label for the complete list.
Who makes Adempas?
Adempas is listed by 1 labeler in the FDA NDC directory, including Bayer HealthCare Pharmaceuticals Inc..