ADEMPAS ® ( riociguat )

•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.

C20H19FN8O2

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..

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.

•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.

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.

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.
•Antacids: Separate administration by at least 1 hour.

USE IN SPECIFIC POPULATIONS
•Nursing mothers: Discontinue drug or breastfeeding.
•Renal impairment: Not recommended in patients with creatinine clearance <15 mL/min or on dialysis.
•Hepatic impairment: Not recommended in patients with severe (Child Pugh C) hepatic impairment.
•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.

•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.

Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
Issued October 2013

©2013 Bayer HealthCare Pharmaceuticals Inc.
Revised: 10/2013. Accessed 01/2014

-----------Drug Updates----------
Drug:  ADEMPAS (riociguat) tablets, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2013