Review of Selected NMEs 2014

Jack DeRuiter, PhD; Pamela L. Holston, RPh, BS, BA; Taylor Joseph DeRuiter, PharmD Candidate


US Pharmacist. 2014;39:HS-2-HS-15. 

In This Article

Riociguat (Adempas, Bayer Healthcare Pharmaceuticals)

Indication and Clinical Profile1,2

Riociguat was approved to treat persistent and recurrent chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Pulmonary hypertension is caused by abnormally high blood pressure in the arteries of the lungs that makes the right side of the heart work harder than normal. In its various forms, pulmonary hypertension is a chronic, progressive, debilitating disease, often leading to death or the need for lung transplantation.

Approval of riociguat was based on two multicenter, double-blind, randomized, placebo-controlled trials: the CHEST-1 trial for CTEPH and the PATENT-1 trial for PAH. Both trials used as a primary endpoint the change in 6-minute walking distance (6MWD) from baseline. CHEST-1 was conducted over 16 weeks in 261 patients with inoperable CTEPH, and PATENT-1 was conducted over 12 weeks in 445 patients with PAH that was either untreated or treated with a prostacyclin analogue or an endothelin receptor blocker. CHEST-1 and PATENT-1 demonstrated significant improvements in 6MWD of 46 min and 36 min, respectively, in patients treated with riociguat versus placebo. In CHEST-1, riociguat therapy also resulted in statistically significant improvements in pulmonary vascular resistance, N-terminal prohormone brain natriuretic peptide, and World Health Organization functional class.

Pharmacology and Pharmacokinetics1,2

Riociguat (Figure 1) is a diaminopyrimidine that acts on soluble guanylate cyclase (sGC), a protein that, upon binding with nitric oxide (NO), catalyzes the formation of guanosine monophosphate (cGMP). cGMP then acts as a second messenger, resulting in subsequent vasodilation in vascular smooth muscle in the cardiopulmonary system. Riociguat stabilizes NO binding to sGC and also acts as a direct stimulator of sGC independently of NO.

Figure 1.


The absolute bioavailability of riociguat is 94% when the drug is taken with or without food. It reaches a peak plasma concentration in about 1.5 hours and has a half-life of 12 hours. Riociguat undergoes metabolism by several cytochrome isozymes, with the formation of the major metabolite being catalyzed by CYP1A1 followed by N-glucuronidation. It does not appear to significantly induce or inhibit metabolism by any major cytochrome isozyme. Riociguat is eliminated primarily both renally (40%) and fecally (53%).

Adverse Reactions and Drug Interactions1,2

The most common adverse reactions (≥5%) reported in clinical trials were gastrointestinal abnormalities (dyspepsia/gastritis, nausea, diarrhea, vomiting, constipation, gastroesophageal reflux), headache, dizziness, edema, anemia, and hypotension. Serious bleeding events also occurred in 2.4% of patients taking riociguat. The drug's label has a boxed warning stating that riociguat should not be given to women who are pregnant or may become pregnant, owing to its potential for embryo-fetal toxicity (Pregnancy Category X). Female patients can receive the drug only through enrollment in the Adempas Risk Evaluation and Mitigation Strategies (REMS) program. Females with reproductive potential also must comply with the program's requirements for pregnancy testing and contraception (see manufacturer's program guidelines). Physicians and pharmacies must enroll in the REMS restricted-distribution program in order to be certified to prescribe and dispense riociguat.

Riociguat should not be used concomitantly with nitrates, NO donors, or phosphodiesterase inhibitors, owing to the increased risk of hypotensive events. Coadministration with strong CYP inhibitors and P-glycoprotein (Pgp)/breast cancer resistance protein (BCRP) inhibitors should be avoided, as these will increase riociguat exposure and may also increase the risk of hypotensive events. As smoking has been shown to reduce riociguat concentrations by 50% to 60%, patients who smoke may require a dosage >2.5 mg per day to equal the drug exposure in nonsmokers.

Dosage and Administration1,2

Riociguat is supplied as 0.5-mg, 1-mg, 1.5-mg, 2-mg, and 2.5-mg tablets. The recommended starting dosage is 1 mg three times daily, and if the patient has no signs or symptoms of hypotension (systolic blood pressure >95 mmHg), the dosage may be up-titrated by 0.5 mg three times daily to a maximum of 2.5 mg three times daily. Dosage increases should be made no sooner than 2 weeks apart. The dosage should be decreased by 0.5 mg taken three times daily if the patient shows symptoms of hypotension. In patients who smoke, dosages higher than 2.5 mg three times daily may be considered; however, a reduction may be required upon smoking cessation. A starting dosage of 0.5 mg three times daily should be considered in patients who are also taking strong CYP or Pgp/BCRP inhibitors. No dosage adjustment is recommended for elderly patients or those with renal impairment or mild-to-moderate hepatic impairment. Riociguat is not recommended in patients with creatinine clearance <15 mL/min or in those on dialysis. The safety and efficacy of riociguat have not been established in pediatric patients or in patients with severe hepatic impairment.