New Drug Update: Riociguat (Adempass®) Kanika Kapoor, PharmD Candidate, Ohio Northern University and John Lindsley, PharmD, BCPS (AQ Cardiology) Riociguat was approved in the United States by the FDA in October of 2013 as the first soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. Riociguat currently has two FDA-‐ approved indications. The first is to improve symptoms in patients with chronic thromboembolic PH (CTEPH, WHO group 4) who are symptomatic despite surgery or cannot undergo surgery.1 The second indication is to improve symptoms and delay disease progression in pulmonary arterial hypertension (PAH, WHO group 1) Riociguat sensitizes soluble guanylate cyclase to endogenous nitric oxide and ultimately releases cyclic guanosine monophosphate. This leads to vasodilation and a decrease in proliferation, fibrosis and inflammation.1,3 The FDA recommended dosing for riociguat is listed in the table below. Table Riociguat Dosing Recommendations (Oral administration) Patient Population All individuals
Initial Dose* 1 mg TID
Maximum Dose 2.5 mg TID
Drug interaction with strong CYP or P-‐gp/BCRP inhibitors
0.5 mg TID
2.5 mg TID
1 mg TID
>2.5 mg TID
Smokers
*In patients with hypotension prior to initiation, consider an initial dose reduction to 0.5 mg TID Abbreviations: CYP, cytochrome P450; P-‐gp, P-‐glycoprotein; BCRP, breast cancer resistance protein; TID, three times a day
The efficacy of riociguat was studied in two phase 3, placebo-‐controlled, double-‐blind, multinational, multicenter studies, CHEST-‐1 and PATENT-‐1. 2-‐3 The CHEST-‐1 study evaluated CTEPH patients and PATENT-‐1 randomized PAH patients. Efficacy of riociguat was demonstrated using the 6-‐minute walking distance at the end of 12 weeks for the PATENT-‐1 trial and 16 weeks for the CHEST-‐1 trial. In both studies, the riociguat group had an increased mean distance, as compared to a mean decrease in the placebo group (p<0.001). The riociguat group also showed a significant reduction in pulmonary vascular resistance and N-‐terminal pro-‐brain natriuretic peptide levels (p<0.001). The most common adverse events reported were headache, dyspepsia, dizziness and peripheral edema. Riociguat is a REMS medication due to its high risk of fetal harm. Women of child-‐bearing age are required to complete a pregnancy test prior to therapy initiation, on a monthly basis, and 1 month post-‐ discontinuation. Additional contraindications include the use of nitrates or nitrate donors such as amyl nitrate, and phosphodiesterase inhibitors. When used concomitantly with antacids, separate administration by one hour. Major adverse effects include symptomatic hypotension and bleeding. Pulmonary edema can also occur in patients with pulmonary veno-‐occlusive disease. Use should be avoided in patients with creatinine clearance <15mL/min, on dialysis, or those with severe hepatic dysfunction.1 References
1. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Drug Approval Package. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204819s000lbl.pdf (accessed April 18, 2014). 2. Ghofrani H, Grimminger F, Hoeper M, et al. Riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension: a randomized, double-‐blind, placebo-‐controlled study (CHEST-‐1). Chest 2012; 142: 1023A 3. Ghofrani, H. A., Galie, N, et al. Riociguat for the treatment of pulmonary arterial hypertension. N. Engl. J. Med. 2013; 369: 330–34