RIOCIGUAT

Clinical safety rating: caution

Comprehensive clinical and safety monograph for RIOCIGUAT (RIOCIGUAT).

How it works

Riociguat stimulates soluble guanylate cyclase (sGC), an enzyme in the nitric oxide (NO) signaling pathway, by sensitizing sGC to endogenous NO and directly stimulating sGC independently of NO. This increases intracellular cyclic guanosine monophosphate (cGMP) levels, leading to vasodilation and inhibition of platelet aggregation.

What the body does with it

Metabolism	Primarily metabolized by CYP1A1, CYP3A4, and CYP3A5; also metabolized by CYP2C8 and CYP2J2. Undergoes N-demethylation and N-glucuronidation.
Excretion	Primarily hepatic metabolism, with minimal renal excretion. Approximately 50-60% of the dose is excreted in feces as metabolites, and about 40-50% in urine as metabolites (4-9% unchanged in urine). Biliary excretion of parent drug is negligible.
Half-life	Terminal elimination half-life is approximately 7 hours (range 5-12 hours) in patients with pulmonary arterial hypertension. In healthy subjects, half-life is about 5-7 hours. Steady state is achieved within 3-5 days of twice-daily dosing.
Protein binding	Approximately 95-98% bound to plasma proteins, primarily to serum albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Volume of distribution is approximately 30-50 L (0.4-0.7 L/kg for a 70 kg individual), indicating extensive extravascular distribution.
Bioavailability	Absolute oral bioavailability is approximately 60-70%. Food does not significantly affect absorption; may be taken with or without food.
Onset of Action	Oral administration: Hemodynamic effects (reduction in pulmonary vascular resistance) are observed within 1-2 hours. Symptomatic improvement may take several weeks.
Duration of Action	Hemodynamic effects persist for >12 hours after a single oral dose, supporting twice-daily dosing. Chronic therapy maintains clinical benefits (improved exercise capacity, WHO functional class) over months to years.

Classification & Brands

Dosing & administration

1 mg orally three times daily for 2 weeks, then increase by 0.5 mg every 2 weeks to target maintenance dose of 2.5 mg three times daily, as tolerated.

Dosage form	TABLET
Renal impairment	eGFR 30-49 mL/min: start at 0.5 mg three times daily for 2 weeks, then titrate. eGFR 15-29 mL/min: contraindicated (no data). eGFR <15 mL/min or dialysis: contraindicated.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: contraindicated (no data). Child-Pugh C: contraindicated.
Pediatric use	Not approved for use in pediatric patients (safety and efficacy not established).
Geriatric use	No specific dose adjustment required; use standard adult dosing, but monitor for hypotension and renal function due to age-related decline.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for RIOCIGUAT (RIOCIGUAT).

Breastfeeding	Unknown if distributed into human milk. Risk to infant cannot be ruled out. M/P ratio not available. Discontinue breastfeeding or drug, considering importance to mother.
Teratogenic Risk	Riociguat is contraindicated in pregnancy due to animal studies showing embryotoxicity, including increased rates of abortion and malformations. Human data are lacking; avoid use in pregnant women.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Do not use riociguat in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP). Riociguat may increase the risk of serious cardiovascular events or death in these patients.

Side Effect Profile

Serious Effects

Absolute Contraindications

Concomitant use with nitrates or nitric oxide donors; concomitant use with phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil, tadalafil); pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP); severe hepatic impairment (Child-Pugh C).

Clinical Precautions

Precautions

Hypotension; bleeding risk (especially in patients with severe hemoptysis, pulmonary hemorrhage, or on anticoagulation); pulmonary veno-occlusive disease (PVOD); concurrent use with nitrates or PDE-5 inhibitors; smoking cessation (may require dose adjustment).

Clinical Tips & Counseling

Drug interactions

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RIOCIGUAT

Clinical safety rating: caution

Comprehensive clinical and safety monograph for RIOCIGUAT (RIOCIGUAT).

How it works

What the body does with it

Metabolism	Primarily metabolized by CYP1A1, CYP3A4, and CYP3A5; also metabolized by CYP2C8 and CYP2J2. Undergoes N-demethylation and N-glucuronidation.
Excretion	Primarily hepatic metabolism, with minimal renal excretion. Approximately 50-60% of the dose is excreted in feces as metabolites, and about 40-50% in urine as metabolites (4-9% unchanged in urine). Biliary excretion of parent drug is negligible.
Half-life	Terminal elimination half-life is approximately 7 hours (range 5-12 hours) in patients with pulmonary arterial hypertension. In healthy subjects, half-life is about 5-7 hours. Steady state is achieved within 3-5 days of twice-daily dosing.
Protein binding	Approximately 95-98% bound to plasma proteins, primarily to serum albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Volume of distribution is approximately 30-50 L (0.4-0.7 L/kg for a 70 kg individual), indicating extensive extravascular distribution.
Bioavailability	Absolute oral bioavailability is approximately 60-70%. Food does not significantly affect absorption; may be taken with or without food.
Onset of Action	Oral administration: Hemodynamic effects (reduction in pulmonary vascular resistance) are observed within 1-2 hours. Symptomatic improvement may take several weeks.
Duration of Action	Hemodynamic effects persist for >12 hours after a single oral dose, supporting twice-daily dosing. Chronic therapy maintains clinical benefits (improved exercise capacity, WHO functional class) over months to years.

Classification & Brands

Dosing & administration

1 mg orally three times daily for 2 weeks, then increase by 0.5 mg every 2 weeks to target maintenance dose of 2.5 mg three times daily, as tolerated.

Dosage form	TABLET
Renal impairment	eGFR 30-49 mL/min: start at 0.5 mg three times daily for 2 weeks, then titrate. eGFR 15-29 mL/min: contraindicated (no data). eGFR <15 mL/min or dialysis: contraindicated.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: contraindicated (no data). Child-Pugh C: contraindicated.
Pediatric use	Not approved for use in pediatric patients (safety and efficacy not established).
Geriatric use	No specific dose adjustment required; use standard adult dosing, but monitor for hypotension and renal function due to age-related decline.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for RIOCIGUAT (RIOCIGUAT).

Breastfeeding	Unknown if distributed into human milk. Risk to infant cannot be ruled out. M/P ratio not available. Discontinue breastfeeding or drug, considering importance to mother.
Teratogenic Risk	Riociguat is contraindicated in pregnancy due to animal studies showing embryotoxicity, including increased rates of abortion and malformations. Human data are lacking; avoid use in pregnant women.
Fetal Monitoring