FDA Approves Adempas (riociguat) for Chronic Thromboembolic and Pulmonary Arterial Hypertension

Adempas is a soluble guanylate cyclase (sGC) stimulator. It sensitizes sGC to endogenous nitric oxide (NO) by stabilizing the NO-sGC binding, and also directly stimulates sGC independently of NO, leading to increased intracellular cGMP levels, resulting in vasodilation.

Adempas is indicated for 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 delay clinical worsening. Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies included predominantly patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).

Initiate treatment at 1 mg taken three times a day. For patients who may not tolerate the hypotensive effect, 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. Tablets may be crushed and mixed with water or soft foods. If a dose is missed, continue with the next scheduled dose. If treatment is interrupted for 3 days or more, re-titrate. In patients who smoke, consider titrating to dosages higher than 2.5 mg three times a day; a dose decrease may be required if smoking stops. When initiating in patients receiving strong CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg three times a day. When transitioning from PDE5 inhibitors: discontinue sildenafil at least 24 hours prior, tadalafil at least 48 hours prior; consider starting at 0.5 mg. When transitioning to a PDE5 inhibitor, discontinue Adempas at least 24 hours prior.

CTEPH: A double-blind, multinational study (CHEST-1) in 261 patients with CTEPH (inoperable or persistent/recurrent after surgery). Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients started at 1 mg three times a day. Patients with systolic BP <95 mmHg were excluded. The dose was titrated every 2 weeks based on systolic BP and signs/symptoms of hypotension. Stable oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed; NO donors, endothelin receptor antagonists, prostacyclin analogues, and PDE5 inhibitors were not. The trial demonstrated improvement in exercise capacity and WHO functional class. PAH: Trial data not available in label.

Contraindications: Concomitant use with nitrates or nitric oxide donors (e.g., amyl nitrite) in any form; concomitant use with specific PDE-5 inhibitors (e.g., sildenafil, tadalafil) or other sGC stimulators; pregnancy. Warnings: Hypotension: Monitor blood pressure; consider dose reduction if symptoms occur. Use with strong CYP and P-gp/BCRP inhibitors may increase riociguat exposure; monitor for hypotension. In patients who smoke, riociguat exposure is reduced; dose adjustment may be needed.

Adempas is an oral sGC stimulator approved for two forms of pulmonary hypertension: CTEPH (persistent/recurrent after surgery or inoperable) and PAH (WHO Group 1). In CTEPH, it is the first medical therapy approved for this indication. In PAH, it provides an additional oral option, with efficacy shown as monotherapy or in combination with endothelin receptor antagonists or prostanoids. It is contraindicated with nitrates and PDE5 inhibitors, requiring careful management when transitioning.