Riociguat

Usage

Riociguat is prescribed for the treatment of certain types of pulmonary hypertension (high blood pressure in the arteries of the lungs). Specifically, it is indicated for:

• Chronic thromboembolic pulmonary hypertension (CTEPH) (WHO Group 4): This is for persistent/recurrent CTEPH after surgical treatment or for inoperable CTEPH. Riociguat helps improve exercise capacity and WHO functional class.
• Pulmonary arterial hypertension (PAH) (WHO Group 1): It is used to improve exercise capacity, WHO functional class, and delay clinical worsening in adult patients.

Pharmacological Classification: Riociguat is a soluble guanylate cyclase (sGC) stimulator.

Mechanism of Action: Riociguat directly stimulates sGC, enhancing the production of cyclic guanosine monophosphate (cGMP). This leads to vasodilation (widening of blood vessels) in the pulmonary arteries, reducing pulmonary vascular resistance and ultimately improving cardiac output. Riociguat also has a sensitizing effect, making sGC more responsive to endogenous nitric oxide, further promoting vasodilation.

Alternate Names

Riociguat is the generic name.

Brand Name: Adempas®

How It Works

Pharmacodynamics: Riociguat’s primary effect is the reduction of pulmonary vascular resistance and blood pressure in the pulmonary arteries through vasodilation. This reduces the workload on the right side of the heart, improving exercise capacity and overall cardiovascular function in patients with PAH and CTEPH.

Pharmacokinetics:

• Absorption: Riociguat is rapidly absorbed after oral administration, reaching peak plasma concentrations within 1-2 hours. Food does not significantly affect absorption.
• Metabolism: Riociguat is primarily metabolized by CYP1A1 and to a lesser extent by CYP3A4 and CYP2C8. The major circulating metabolite is M1, which also has pharmacologic activity.
• Elimination: Riociguat and its metabolites are primarily eliminated via hepatic metabolism and biliary/fecal excretion, with a small portion excreted renally. The elimination half-life is approximately 7-12 hours.

Mode of Action: Riociguat acts by directly stimulating sGC, independent of nitric oxide, and also by sensitizing sGC to endogenous nitric oxide. This dual mechanism of action leads to increased cGMP levels, causing smooth muscle relaxation and vasodilation in the pulmonary vasculature.

Receptor binding, enzyme inhibition or neurotransmitter modulation: Riociguat directly binds to and stimulates sGC, leading to increased cGMP levels. It does not primarily act through receptor binding, enzyme inhibition, or neurotransmitter modulation other than its interaction with sGC.

Elimination pathways: Primarily hepatic metabolism and biliary/fecal excretion. Minor renal excretion.

Dosage

Standard Dosage

Adults:

• Initial dose: 1 mg orally three times daily (TID), approximately 6-8 hours apart.
• Maintenance dose: Titrate the dose by 0.5 mg TID at intervals no sooner than every 2 weeks, as tolerated, up to a maximum of 2.5 mg TID. Monitor blood pressure during titration.
• Patients at risk of hypotension: Consider an initial dose of 0.5 mg TID.

Children:

• Children (6-17 years with PAH and body weight ≥20 kg): Dosage is based on body weight and is calculated to provide similar riociguat exposure to adults. Safety and efficacy have not been established in children younger than 6 years of age.

Special Cases:

• Elderly Patients: Higher risk of hypotension. Careful dose titration is essential.
• Patients with Renal Impairment: Not recommended for patients with creatinine clearance <15 mL/min or on dialysis.
• Patients with Hepatic Dysfunction: Not recommended for patients with severe hepatic impairment (Child-Pugh C). Caution is advised in patients with mild to moderate hepatic impairment.
• Patients with Comorbid Conditions: Consider dose adjustments based on the individual patient’s clinical status and concomitant medications.

Clinical Use Cases

Riociguat’s dosage recommendations are specific to PAH and CTEPH. It’s not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations outside of its PAH/CTEPH indications.

Dosage Adjustments

Dose adjustments may be necessary based on patient-specific factors including:

• Hypotension: Decrease the dose by 0.5 mg TID.
• Strong CYP3A4 and P-gp/BCRP Inhibitors: Consider a lower initial dose of 0.5 mg TID.
• Smoking: Patients who smoke may require higher doses (up to 2.5 mg TID, as tolerated), and a dose decrease may be required if the patient quits smoking during treatment.

Side Effects

Common Side Effects:

Headache, dizziness, dyspepsia (indigestion), nausea, diarrhea, vomiting, anemia, peripheral edema (swelling in the extremities), hypotension.

Rare but Serious Side Effects:

Severe hypotension, bleeding (including hemoptysis, epistaxis, and gastrointestinal bleeding), hepatic dysfunction.

Long-Term Effects:

The long-term safety profile of riociguat is still being studied.

Adverse Drug Reactions (ADR):

Severe hypotension requiring intervention, significant bleeding events, and evidence of hepatic injury are serious ADRs that warrant immediate attention.

Contraindications

• Pregnancy
• Concurrent use of PDE-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil), nitrates, or nitric oxide donors
• Concomitant use of other sGC stimulators
• Pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP)
• Severe hepatic impairment (Child-Pugh C)

Drug Interactions

• PDE-5 inhibitors, nitrates, and nitric oxide donors: Concomitant use can cause severe hypotension.
• Strong CYP3A4 and P-gp/BCRP Inhibitors (e.g., azole antifungals, HIV protease inhibitors): Increased riociguat exposure and risk of hypotension.
• Strong CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine): Decreased riociguat exposure.
• Antacids: Reduced riociguat absorption. Administer riociguat at least 2 hours before or 1 hour after antacids.

Pregnancy and Breastfeeding

• Pregnancy: Riociguat is contraindicated in pregnancy due to the risk of fetal harm and teratogenicity. Monthly pregnancy tests are required for females of reproductive potential. Effective contraception must be used during treatment and for one month after discontinuation.
• Breastfeeding: Riociguat is excreted in animal milk and is not recommended during breastfeeding.

Drug Profile Summary

• Mechanism of Action: sGC stimulator, leading to vasodilation.
• Side Effects: Headache, dizziness, dyspepsia, nausea, diarrhea, hypotension, bleeding.
• Contraindications: Pregnancy, PDE-5 inhibitors, nitrates, PH-IIP.
• Drug Interactions: PDE-5 inhibitors, nitrates, CYP3A4 inhibitors/inducers, antacids.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy, not recommended while breastfeeding.
• Dosage: 1-2.5 mg TID.
• Monitoring Parameters: Blood pressure, signs of bleeding, liver function tests.

Popular Combinations

Riociguat may be used in combination with endothelin receptor antagonists (ERAs) or prostanoids in patients with PAH. The combination may offer additional hemodynamic benefits.

Precautions

• Monitor blood pressure closely, especially during dose titration.
• Assess for signs and symptoms of hypotension and bleeding.
• Females of reproductive potential must use effective contraception.
• Avoid use in patients with severe renal or hepatic impairment.
• Caution in elderly patients.
• Advise patients to stop smoking.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Riociguat?

A: The initial dose is 1 mg TID. Titrate by 0.5 mg TID every 2 weeks up to a maximum of 2.5 mg TID, as tolerated, while monitoring blood pressure. For patients at risk of hypotension, start with 0.5 mg TID.

Q2: What are the most common side effects of Riociguat?

A: Headache, dizziness, nausea, diarrhea, and hypotension are the most common side effects.

Q3: Is Riociguat safe to use during pregnancy?

A: No, Riociguat is contraindicated in pregnancy due to teratogenic effects. Females of reproductive potential should have negative pregnancy tests before starting treatment and monthly during treatment. Effective contraception is mandatory.

Q4: How should Riociguat be administered?

A: Riociguat tablets should be taken orally three times daily, approximately 6-8 hours apart, with or without food. Tablets can be crushed and mixed with water or soft food, if necessary.

Q5: What are the contraindications to using Riociguat?

A: Contraindications include pregnancy, concurrent use of PDE-5 inhibitors, nitrates/nitric oxide donors, other sGC stimulators, and PH-IIP. Severe hepatic impairment is also a contraindication.

Q6: What drug interactions should I be aware of with Riociguat?

A: Riociguat interacts with PDE-5 inhibitors, nitrates, strong CYP3A4 inhibitors/inducers, and antacids. Co-administration of these drugs should be avoided or carefully managed.

Q7: What monitoring parameters are important when prescribing Riociguat?

A: Blood pressure should be monitored regularly, especially during dose titration. Monitor for signs or symptoms of bleeding and assess liver function periodically.

Q8: Can Riociguat be used in patients with renal impairment?

A: Riociguat is not recommended in patients with severe renal impairment (creatinine clearance <15 mL/min) or those on dialysis.

Q9: How does smoking affect Riociguat therapy?

A: Smoking reduces riociguat exposure. Patients should be advised to quit smoking. Dose adjustments may be necessary for smokers and for patients who quit smoking during treatment.

Q10: What should I do if a patient on Riociguat develops hypotension?

A: If hypotension occurs, reduce the riociguat dose by 0.5 mg TID. Monitor the patient closely and provide supportive care as needed.