What is Adempas (riociguat)?

Adempas (Riociguat): A Soluble Guanylate Cyclase Stimulator for Pulmonary Hypertension

Adempas (riociguat) is a first-in-class soluble guanylate cyclase (sGC) stimulator specifically approved for the treatment of adults with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) to improve exercise capacity and WHO functional class. 1

Mechanism of Action

Riociguat works through a novel mechanism:

• Stimulates soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system
• Enhances the synthesis of cyclic guanosine monophosphate (cGMP), a mediator of vasodilation
• Sensitizes sGC to endogenous nitric oxide (NO) and can also directly stimulate sGC independent of NO
• Results in vasodilation of the pulmonary arterial bed and reduction in pulmonary vascular resistance

FDA-Approved Indications

Riociguat is approved for:

1. CTEPH (WHO Group 4):

   • For patients with inoperable CTEPH
   • For persistent/recurrent CTEPH after surgical treatment (pulmonary endarterectomy)
   • Class I recommendation (highest level) according to ESC/ERS guidelines 1

2. PAH (WHO Group 1):

   • For treatment of PAH to improve exercise capacity and WHO functional class
   • Can be used as monotherapy or in combination with endothelin receptor antagonists or prostanoids

Clinical Efficacy

In CTEPH:

• In a pivotal 16-week trial of 261 patients with inoperable CTEPH or persistent/recurrent CTEPH after surgery:
  • Increased 6-minute walking distance by 39 meters compared to placebo (p<0.001)
  • Reduced pulmonary vascular resistance by 246 dyn·cm·s⁻⁵ (p<0.001)
  • Improved WHO functional class in 33% of patients (vs 15% with placebo) 1, 2

In PAH:

• In a 12-week trial of 443 patients with PAH:
  • Increased 6-minute walking distance by 30 meters compared to placebo
  • Reduced pulmonary vascular resistance by 223 dyn·s/cm⁵
  • Improved hemodynamic parameters including mean pulmonary arterial pressure and cardiac output
  • Reduced N-terminal pro-BNP levels
  • Improved WHO functional class 1, 2

Dosing and Administration

• Starting dose: 1 mg three times daily
• Dose is titrated by 0.5 mg increments at 2-week intervals
• Maximum dose: 2.5 mg three times daily
• Dose adjustments are based on systolic blood pressure (should be ≥95 mmHg) and signs/symptoms of hypotension
• Special populations requiring cautious titration:
  • Elderly patients
  • Patients with hepatic or renal impairment
  • Smokers (may require higher doses due to increased metabolism) 3

Important Safety Considerations

1. Contraindications:

   • Co-administration with PDE-5 inhibitors (sildenafil, tadalafil) due to risk of severe hypotension
   • Pregnancy (teratogenic potential)
   • Nitrates or nitric oxide donors

2. Common adverse effects (related to vasodilatory properties):

   • Headache
   • Dizziness
   • Dyspepsia
   • Peripheral edema
   • Hypotension

3. Serious adverse effects:

   • Bleeding risk, including pulmonary hemorrhage
   • Syncope (1% of patients)
   • Potential for serious drug interactions 4, 2

4. Risk Evaluation and Mitigation Strategy (REMS) program required due to teratogenic potential

Clinical Pearls and Caveats

• Riociguat is the only medication approved specifically for CTEPH, making it a critical option for these patients
• Pulmonary endarterectomy remains the first-line treatment for CTEPH when feasible, as it is potentially curative 4
• Riociguat should only be initiated and monitored at specialized pulmonary hypertension centers by physicians experienced in treating PAH/CTEPH 1, 3
• Blood pressure monitoring is essential during dose titration
• Smoking status should be assessed, as smoking increases riociguat metabolism, potentially requiring higher doses
• The benefit appears more pronounced in patients with WHO functional class III (marked limitation of activity) than class II (slight limitation) 2

Drug Interactions

• Absolute contraindication: PDE-5 inhibitors (sildenafil, tadalafil) due to risk of life-threatening hypotension
• Use with caution: Antihypertensives, nitrates, strong CYP1A1 inhibitors, CYP3A4 inhibitors/inducers, P-glycoprotein substrates
• Smoking induces CYP1A1, potentially reducing riociguat levels 5

Riociguat represents an important advancement in the management of both CTEPH and PAH, offering a therapeutic option for patients with limited alternatives, particularly those with inoperable or persistent/recurrent CTEPH after surgery.