What is the recommended dosing and monitoring for Riociguat (Riociguat) in a patient with a history of pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH)?

Riociguat Dosing and Monitoring in PAH and CTEPH

Riociguat should be initiated at 1 mg three times daily and titrated upward by 0.5 mg increments every 2 weeks to a maximum of 2.5 mg three times daily, with dose adjustments based on systolic blood pressure (increase only if trough systolic BP >95 mmHg) and absence of hypotensive symptoms. 1

Indications for Riociguat

PAH (Pulmonary Arterial Hypertension)

• Riociguat is recommended for treatment-naive PAH patients with WHO functional class II or III symptoms who are not candidates for or have failed calcium channel blocker therapy 1, 2
• Improves 6-minute walk distance by approximately 30-40 meters, WHO functional class, and delays time to clinical worsening 1, 3
• Reduces pulmonary vascular resistance by 223 dyn/s/cm⁵ compared to placebo 1

CTEPH (Chronic Thromboembolic Pulmonary Hypertension)

• Riociguat is the only approved targeted therapy for patients with inoperable CTEPH or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA) 1, 4
• All CTEPH patients must be evaluated by a multidisciplinary team including at least one experienced PEA surgeon before initiating riociguat, as surgical PEA remains first-line treatment for operable disease 1, 4
• Increases 6-minute walk distance by 39 meters and reduces pulmonary vascular resistance by 246 dyn/s/cm⁻⁵ 4, 3

Dosing Protocol

Initial Dosing

• Start at 1 mg three times daily 1, 5
• Administer doses approximately 6-8 hours apart 6

Titration Schedule

• Increase by 0.5 mg increments every 2 weeks during the first 8 weeks 1, 5
• Only increase dose if trough systolic blood pressure is >95 mmHg AND patient has no signs or symptoms of hypotension 1
• Maximum dose: 2.5 mg three times daily 1, 6
• If patient develops hypotension or symptomatic hypotension at any dose, reduce by 0.5 mg 6

Dose Adjustments

• Patients with underlying risk factors for systemic hypotension require more cautious titration 5
• Most patients in clinical trials tolerated maximal doses (2.5 mg three times daily) 6

Monitoring Requirements

Blood Pressure Monitoring

• Monitor systolic blood pressure at trough (before next dose) during the 8-week titration period 1
• Assess for signs and symptoms of hypotension at each dose adjustment 1, 5
• Hypotension is the dose-limiting adverse effect 6

Functional Assessment

• Assess WHO functional class at baseline and during follow-up 1, 2
• Perform 6-minute walk distance testing to evaluate treatment response 1, 3

Hemodynamic Monitoring

• Obtain at least one hemodynamic assessment via right heart catheterization 6-12 months after treatment initiation 4, 2
• Monitor for improvements in pulmonary vascular resistance, mean pulmonary arterial pressure, cardiac index, and NT-proBNP 1, 3

Laboratory Monitoring

• Monitor hemoglobin levels periodically (riociguat can decrease hemoglobin) 5
• Assess for signs of bleeding, as bleeding is a serious potential adverse effect 7

Critical Contraindications and Drug Interactions

Absolute Contraindications

• Pregnancy (Category X drug) - requires enrollment in Risk Evaluation and Mitigation Strategy (REMS) program 6, 7
• Concomitant use with PDE5 inhibitors (sildenafil, tadalafil, vardenafil) - causes severe systemic hypotension 1, 2
• Male patients on riociguat must be cautioned not to use PDE5 inhibitors for erectile dysfunction 1, 2

Drug Interactions

• Strong CYP3A4 inhibitors and inducers - can significantly alter riociguat levels 5, 6
• CYP1A1 inhibitors - may increase riociguat exposure 6
• P-glycoprotein interactions - monitor for altered drug levels 6

Common Adverse Effects

Most Frequent

• Nasopharyngitis (57% in long-term studies) 8
• Peripheral edema (37%) 8
• Headache, dizziness, and gastrointestinal symptoms 1, 5

Serious Adverse Events

• Syncope (1% vs 4% placebo in PAH trials) 1
• Hemoptysis (4% in long-term extension studies, though not considered drug-related) 8
• Hypotension - most common dose-limiting effect 6, 7
• Worsening pulmonary hypertension (<1% vs 2% placebo) 1

Follow-Up Care

Specialized Center Requirements

• Patients should be followed at specialized pulmonary hypertension centers with expertise in PAH/CTEPH management 4, 2
• Centers should have access to right heart catheterization, echocardiography, CT scanning, and exercise testing 1

Long-Term Outcomes

• Three-year survival on riociguat is 91% with clinical worsening-free survival of 49% 8
• Improvements in exercise capacity and functional class are maintained at 4 years in patients remaining on treatment 8
• Median treatment duration in long-term studies was 77 months with no new safety signals 8

Important Clinical Caveats

• Riociguat should NOT be used in patients who are candidates for pulmonary endarterectomy, as surgery remains the treatment of choice for operable CTEPH 4, 7
• Lifelong anticoagulation is required for all CTEPH patients, including those on riociguat 1, 4
• Riociguat is not indicated for pulmonary hypertension due to left heart disease or lung disease (WHO Groups 2 and 3), as it only improves some hemodynamic parameters without clear clinical benefit in these populations 9, 3
• The three-times-daily dosing regimen requires careful patient counseling regarding adherence 5, 7