Company: Bayer HealthCare
Pharmacologic class: Soluble guanylate cyclase (sGC) stimulator
Active ingredient: Riociguat 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg; tabs.
Indication: Treatment of 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 WHO functional class, and delay clinical worsening.
Pharmacology: Riociguat has a dual mode of action: it sensitizes sGC to endogenous nitric oxide (NO) by stabilizing the NO-sGC binding. Also, riociguat directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cyclic guanosine monophosphate (cGMP) pathway and leads to increased cGMP generation with subsequent vasodilation.
Clinical trials: CHEST-1, a double-blind, multicenter study, was conducted in 261 patients with CTEPH. Patients were randomized to Adempas titrated up to 2.5 mg three times daily (n=173) or placebo (n=88).
The primary end point was change from baseline in six-minute walking distance after 16 weeks based on imputed values. Improvements in walking distance were apparent from week 2 onward. At week 16, the placebo adjusted mean increase in six-minute walking distance within the Adempas group was 46 m (95% CI: 25 m-67 m; P <0.0001). The median difference in six-minute walking distance was 39 m (95% CI: 25 m-54 m). Patients treated with Adempas (83%) experienced an improvement in six-minute walking distance vs. placebo (57%).
An open-label extension study, CHEST-2, included 237 patients who had completed CHEST-1. The mean treatment duration for the total population was 582 days (+/− 317 days). The probabilities of survival at one and two years were 97% and 94%, respectively.
For more clinical trial data, see full labeling.
Adults: Initially 1 mg three times daily; if intolerant, consider starting at 0.5 mg three times daily. Increase dose by 0.5 mg (three times daily) at intervals of two or more weeks as tolerated (systolic BP >95 mm Hg and no hypotension); maximum 2.5 mg three times daily.
If intolerant at any time, decrease dose by 0.5 mg three times daily. Smokers: consider titrating to doses >2.5 mg three times daily; may require dose reduction after smoking cessation. Concomitant strong CYP450 and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors: initiate at 0.5 mg three times daily.
Children: Not established.
Contraindications: Pregnancy (Category X). Concomitant nitrates or nitric oxide donors in any form, specific or nonspecific phosphodiesterase inhibitors (e.g., sildenafil [Revatio, Viagra], tadalafil [Adcirca, Cialis], vardenafil [Levitra, Staxyn], dipyridamole [Persantine], theophylline).
Warnings/Precautions: In females of reproductive potential, exclude pregnancy prior to starting, monthly during, and for one month after treatment discontinuation; must use acceptable methods of contraception. Risk of hypotension or ischemia in hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction; consider dose reduction if signs/symptoms occur. Bleeding risk. Pulmonary veno-occlusive disease: not recommended; discontinue if confirmed. Severe hepatic (Child Pugh C) or renal impairment (creatinine clearance <15 mL/min), or on dialysis: not recommended. Nursing mothers: not recommended.
Interactions: See Contraindications. Potentiated by strong CYP450 and P-gp/BCRP inhibitors (e.g., ketoconazole [Nizoral], itraconazole [Onmel, Sporanox], ritonavir [Norvir]); monitor for hypotension. Antagonized by smoking. May be antagonized by strong CYP3A inducers (e.g., rifampin [Rifadin], phenytoin [Dilantin, Phenytek], carbamazepine, phenobarbital, St. John’s Wort). Separate dosing of antacids by one hour or more of riociguat.
Adverse reactions: Headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, vomiting, anemia, gastroesophageal reflux, constipation.
Note: For all female patients: available only through the Adempas REMS program. To enroll call 855.4ADEMPAS or www.AdempasREMS.com.
How supplied: Tabs—42, 90
For more information, call 855.4ADEMPAS or visit www.Adempas-us.com.