• Chronic thromboembolic pulmonary hypertension (CTEPH, WHO Group 4) after surgery or in non-surgical candidates.
• Pulmonary arterial hypertension (PAH, WHO Group 1)

Contraindicated in:

• Severe hepatic impairment (Child Pugh C)
• Severe renal impairment (CCr <15 mL/min or on dialysis)
• Known pulmonary veno-occlusive disease
• Pulmonary hypertension associated with idiopathic interstitial pneumonias
• Concurrent use of nitrates, nitric oxide donors, specific phosphodiesterase-5 (PDE) inhibitors (sildenafil, vardenafil, or tadalafil) or nonspecific PDE inhibitors (dipyridamole or theophylline)
• OB: Pregnancy (may cause fetal harm);
• Lactation: Lactation.

Use Cautiously in:

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

CV: pulmonary edema (↑ in veno-occlusive disease), hypotension.

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

Hemat: BLEEDING, anemia.

Neuro: dizziness, headache.

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 non-specific PDE-5 inhibitors such as dipyridamole or theophylline; concurrent use contraindicated; discontinue sildenafil24 hr prior to starting riociguat; discontinue tadalafil48 hr prior to starting riociguat; discontinue riociguat 24 hr before starting PDE-5 inhibitor.
• Strong CYP and P-gp/BCRP inhibitors including azole antifungals (ketoconazole and itraconazole) and protease inhibitors (ritonavir) ↑ blood levels and the risk of adverse reactions including hypotension (consider ↓ initial dose).
• Strong CYP3A inducers including carbamazepine, phenobarbital, phenytoin and rifampin↓ blood levels and may ↓ effectiveness.
• Concurrent use of antihypertensives including diuretics may ↑ risk of hypotension.
• Antacids↓ absorption (separate doses by at least 1 hr)
• Cigarette smoking ↓blood levels and effectiveness, ↑ dose may be necessary and dose readjustment required after smoking cessation.

Drug-Natural Products:

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

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

• 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.

Adempas

• Stimulates soluble guanyl 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.

• Improved symptoms/exercise tolerance and delayed worsening.

Therapeutic Classification:pulmonary hypertension agents

Pharmacologic Classification: soluble guanylate cyclase stimulators (sGS)

Absorption: Well absorbed following oral administration (94%).

Distribution: Unknown.

Protein Binding: 95%.

Metabolism/Excretion: Extensively metabolized (by CYP1A1, CYP3A, CYP2C8, and CYP2J2); M1 metabolite is pharmacologically active; metabolites are excreted in urine and feces (great individual variation).

Half-life: 12 hr.

(improvement in 6–min walk distance)

• 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.
• Caution female patients that riociguat may harm fetus. 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 a mo 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 female patient to notify health care professional immediately if pregnancy is suspected and avoid breastfeeding during therapy.

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