How should Adempas (riociguat) be initiated, titrated, and monitored in adults with pulmonary arterial hypertension or inoperable/persistent chronic thromboembolic pulmonary hypertension, and what are its contraindications?

Adempas (Riociguat) Initiation, Titration, and Monitoring

Start riociguat at 1 mg three times daily (or 0.5 mg three times daily in patients at risk for hypotension), then increase by 0.5 mg every 2 weeks based on systolic blood pressure >95 mmHg and absence of hypotensive symptoms, up to a maximum of 2.5 mg three times daily. 1

Indications

Riociguat is FDA-approved for:

• CTEPH (WHO Group 4): Persistent/recurrent chronic thromboembolic pulmonary hypertension after surgical treatment or inoperable CTEPH 1
• PAH (WHO Group 1): To improve exercise capacity, WHO functional class, and delay clinical worsening, either as monotherapy or combined with endothelin receptor antagonists or prostanoids 1

Initiation Protocol

Standard Starting Dose

• 1 mg three times daily for most patients 1
• 0.5 mg three times daily for patients who may not tolerate hypotensive effects 1

Special Populations Requiring Lower Starting Dose (0.5 mg TID)

• Patients receiving strong CYP and P-gp/BCRP inhibitors (ketoconazole, itraconazole, ritonavir) 1
• Patients at risk for hypotension 1
• Patients transitioning from PDE-5 inhibitors 1

Titration Schedule

The dose adjustment occurs every 2 weeks based on blood pressure tolerance:

• Check systolic blood pressure before each dose increase
• If SBP >95 mmHg AND no hypotensive symptoms: Increase by 0.5 mg TID 1
• If hypotensive symptoms occur: Decrease by 0.5 mg TID 1
• Maximum dose: 2.5 mg three times daily 1
• For smokers: Consider titrating above 2.5 mg TID if tolerated 1

The 8-week titration scheme allows individual optimization balancing tolerability and efficacy, with most patients in clinical trials achieving the maximum 2.5 mg dose while some benefited at lower doses 2.

Monitoring Requirements

Pregnancy Testing (Critical - REMS Program)

• Before treatment initiation
• Monthly during treatment
• One month after discontinuation 1

Riociguat carries a black box warning for embryo-fetal toxicity and is only available through the Adempas REMS Program for all female patients 1.

Blood Pressure Monitoring

• Monitor systolic blood pressure at each dose adjustment (every 2 weeks during titration)
• Monitor for signs/symptoms of hypotension throughout treatment 1
• Particularly important when co-administering strong CYP/P-gp/BCRP inhibitors 1

Clinical Response Assessment

Based on ESC/ERS guidelines, assess for adequate clinical response using:

• 6-minute walk distance (improvements of 33-57 meters observed in trials) 3, 4
• WHO functional class
• Hemodynamic parameters (pulmonary vascular resistance decreased by ~215-219 dyn·s·cm⁻⁵) 3, 5
• NT-proBNP levels 5

Dose Interruption Management

• If missed <3 days: Continue with next scheduled dose 1
• If interrupted ≥3 days: Re-titrate from starting dose 1

Drug Transition Protocols

From PDE-5 Inhibitors to Riociguat

• Discontinue sildenafil ≥24 hours before starting riociguat 1
• Discontinue tadalafil ≥48 hours before starting riociguat 1
• Consider 0.5 mg starting dose in patients at risk for hypotension 1

From Other PAH Therapies

• Washout period of ≥3 days for patients switching from unsatisfactory prior PAH-targeted therapy 4

Absolute Contraindications

1. Pregnancy (Category X) 1
2. Concomitant use with PDE-5 inhibitors (sildenafil, tadalafil) or other sGC stimulators 6, 1
3. Concomitant use with nitrates or nitric oxide donors 1

Critical Safety Considerations

Most Common Adverse Events

• Dyspepsia, headache, and hypotension (most frequent) 3
• Peripheral edema 7
• Syncope (6% in real-world study) 4
• Bleeding risk 8

Guideline-Based Treatment Positioning

According to ESC/ERS 2015 guidelines, riociguat is listed as a soluble cGMP stimulator option for PAH treatment 9, 6. The guidelines note that combination of riociguat and PDE-5 inhibitors is contraindicated 6.

For high-risk patients (WHO FC IV), initial combination therapy including IV prostacyclin analogues should be prioritized, with riociguat considered as part of sequential combination therapy if initial treatment fails 6.

Administration Options

• Swallow whole tablets with water, OR
• Crush and mix with water or soft foods (applesauce) immediately before administration for patients unable to swallow whole tablets 1

Real-World Outcomes

Long-term safety data shows 78.8% of patients remained on riociguat at 24 months with mean treatment duration of 20.1 months, confirming favorable tolerability in clinical practice 10. The medication demonstrated consistent benefits across treatment-naïve patients and those switched from other PAH therapies 4.