ADEMPAS

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 administ...

14.1 Chronic-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 Adempas titrated up to 2.5 mg th...

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 ADVERS...

• 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 Based on data from animal reproduction studies, Adempas ma...

• 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 embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. The available human data for sGCs do not establish the presence or absence of major birth defects related to the use of Adempas. ...

7 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 contrain...