| WARNING: EMBRYO-FETAL TOXICITY
See full prescribing information for complete boxed warning.
•Do not administer Adempas to a pregnant female because it may cause fetal harm.
•Females of reproductive potential: Exclude pregnancy before start of treatment, monthly during treatment, and 1 month after treatment discontinuation. Prevent pregnancy during treatment and for one month after treatment discontinuation by use of acceptable methods of contraception.
•For females, Adempas is available only through a restricted program called the Adempas REMS Program.
| Adempas (riociguat) is a 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:
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, titanium dioxide. Adempas 1 mg, 1.5 mg, 2 mg and 2.5 mg tablets contain, in addition, ferric oxide yellow. Adempas 2 mg and 2.5 mg tablets contain, in addition, ferric oxide red..
| 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.
| 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.
•Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening.
•Use with nitrates or nitric oxide donors in any form
•Use with phosphodiesterase (PDE) inhibitors
| •Symptomatic hypotension
•Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment
| ADVERSE REACTIONS
Adverse reactions occurring more frequently (≥3%) on Adempas compared to placebo are headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.
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.
USE IN SPECIFIC POPULATIONS
| DOSAGE AND ADMINISTRATION
•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.
|Package insert data:
©2013 Bayer HealthCare Pharmaceuticals Inc.
Initial U.S. Approval: 2013
National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
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