riociguat

Stimulates soluble guanylate cyclase, a cardiopulmonary enzyme and receptor for nitric oxide, which when stimulated produces cyclic guanine monophosphate, an important regulator of vascular tone, proliferation, fibrosis, and inflammation. This pathway is dysregulated in pulmonary hypertension.

Therapeutic effects:

Improved symptoms/exercise tolerance and delayed worsening.

Pharmacokinetics ⬆ ⬇

Absorption: Well absorbed following oral administration (94%)

Distribution: Unknown.

Protein Binding: 95%

Metabolism/Excretion: Extensively metabolized by the liver via the CYP1A1, CYP3A, CYP2C8, and CYP2J2 isoenzymes; M1 metabolite is pharmacologically active; metabolites are excreted in urine and feces.

Half-Life: 12 hr

Time/Action Profile ⬆ ⬇

(improvement in 6-min walk distance)

ROUTE	ONSET	PEAK	DURATION
PO	within 2 wk	8–16 wk	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Severe hepatic impairment;
Severe renal impairment (CCr <15 mL/min or on dialysis);
Known pulmonary veno-occlusive disease;
Pulmonary hypertension associated with idiopathic interstitial pneumonia;
Concurrent use of nitrates, nitric oxide donors, specific phosphodiesterase-5 (PDE) inhibitors (sildenafil, vardenafil, or tadalafil), nonspecific PDE inhibitors (dipyridamole or theophylline), or other soluble guanylate cyclase stimulators;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Resting hypotension, hypovolemia, severe left-ventricular outflow obstruction, or autonomic dysfunction (↑ risk of hypotension, consider dose reduction);
Cigarette smokers (require ↑ doses, with subsequent adjustment if smoking is stopped);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children;
Geri: Older adults may have levels and be more sensitive to drug effects.

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypotension

GI: dyspepsia, gastritis, nausea, vomiting, constipation, diarrhea, gastroesophageal reflux, ↑liver enzymes

Hemat: anemia, BLEEDING

Neuro: dizziness, headache

Resp: pulmonary edema (↑ in veno-occlusive disease)

Interactions ⬆ ⬇

Drug-drug:

↑risk of hypotension with concurrent use of nitrates, nitric oxide donors (including amyl nitrate), specific PDE-5 inhibitors (including sildenafil, tadalafil, or vardenafil), and nonspecific PDE-5 inhibitors (including dipyridamole or theophylline); concurrent use contraindicated; do not administer within 24 hr of sildenafil; do not administer 24 hr before or within 48 hr after tadalafil.
Concurrent use with soluble guanylate cyclase stimulators (including vericiguat) is contraindicated.
Strong CYP and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors, including azole antifungals (ketoconazole and itraconazole) and protease inhibitors (ritonavir), ↑ levels and the risk of adverse reactions including hypotension; consider ↓ initial dose.
Strong CYP3A inducers, including carbamazepine, phenobarbital, phenytoin, and rifampin, ↓ levels and may ↓ effectiveness.
Concurrent use of antihypertensives, including diuretics, may ↑ risk of hypotension.
Antacids↓ absorption; separate doses by ≥1 hr.
Cigarette smoking ↓levels and effectiveness; ↑ dose may be necessary and dose readjustment required after smoking cessation.

Drug-Natural Products:

St. John's wort ↓levels and may ↓ effectiveness.

Route/Dosage ⬆ ⬇

PO (Adults ): 1 mg 3 times daily initially; if hypotension a risk factor, initiate treatment with 0.5 mg 3 times daily; ↑ dose by 0.5 mg at 2 wk (or more) intervals up to maintenance dose of 2.5 mg 3 times daily; Smokers: Consider titrating to doses >2.5 mg 3 times daily if tolerated (readjust following smoking cessation); Concurrent CYP and P-gp/BRCP inhibitors: Consider initiating treatment at 0.5 mg 3 times daily, with careful monitoring for hypotension.

Availability ⬆ ⬇

(Generic available)

Tablets: 0.5 mg; 1 mg; 1.5 mg; 2 mg; 2.5 mg

Assessment ⬆ ⬇

Monitor hemodynamic parameters and exercise tolerance prior to and every 2 wk during therapy.
Assess for signs and symptoms of pulmonary edema (shortness of breath). If confirmed, discontinue therapy.
Monitor patient for bleeding (hemoptysis, vagina, catheter site, hematemesis, intra-abdominal, cerebral) during therapy.

Lab Test Considerations:

Obtain a negative pregnancy test prior to beginning, monthly during therapy, and 1 mo following treatment.
- Monitor hepatic function periodically during therapy. May cause ↑ AST, ALT, and bilirubin. If clinically relevant ↑ of AST or ALT occur, or if ↑ are accompanied by ↑ bilirubin >2 times upper limit of normal or by clinical symptoms of hepatotoxicity, discontinue therapy. May reinitiate therapy when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
- Monitor CBC before starting and periodically during therapy. May cause anemia. Avoid therapy in patients with severe anemia.

Implementation ⬆ ⬇

Only available through a restricted program, Adempas Risk Evaluation and Mitigation Strategy (REMS). Prescribers and pharmacies must be enrolled and certified. All female patients must enroll and comply with pregnancy testing and contraception requirements. Male patients do not need to enroll.
PO: Administer 3 times daily. If patient at risk for hypotension, begin with 0.5 mg dose. If systolic BP >95 and patient is asymptomatic, may increase by 0.5 mg three times/day up to 2.5 mg three times daily. Do not increase sooner than every 2 wk. If symptoms of hypotension occur, decrease dose by 0.5 mg three times/day. If dose is missed more than 3 days, begin titration again.
- Titrate patients who smoke to doses >2.5 mg three times/day, if tolerated. May need to decrease dose if patient stops smoking.
- May be administered without regard to food. Tablets may be crushed and mixed with water or soft foods (applesauce) immediately before administration for patients unable to swallow.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take riociguat as directed. If dose is missed, omit and continue with next scheduled dose.
Advise patient to avoid taking antacids within 1 hr of riociguat.
Advise patient to notify health care professional if they smoke.
May cause dizziness. Caution patient to avoid driving and other activities requiring alertness until response to medication is known.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
Rep: May cause fetal harm. Instruct females to use effective contraception (intrauterine device IUD, contraceptive implants, tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods) during and for at least one month following discontinuation of therapy. If a partner’s vasectomy is method of contraception, a hormone or barrier method must be used along with this method. Counsel patient on emergency contraception. May decrease sperm count in male patients. Advise females of reproductive potential to notify health care professional immediately if pregnancy is suspected and avoid breastfeeding during therapy.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇