pulmonary hypertension agents
soluble guanylate cyclase stimulators (sGS)
- Treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH, WHO Group 4) after surgery or in non-surgical candidates.
- Treatment of pulmonary arterial hypertension (PAH, WHO Group 1)
Stimulates soluble guanyl cyclase (sGC) 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.
Absorption: Well absorbed following oral administration (94%)
Protein Binding: 95%
Metabolism and Excretion: Extensively metabolized (by CYP P1A1, CYP3A, CYP2C8, and CYP2J2); M1 metabolite is pharmacologically active; metabolites are excreted in urine and feces (great individual variation)
Half-life: 12 hr
TIME/ACTION PROFILE (improvement in 6–min walk distance)
|PO||within 2 wk||8–16 wk||unknown|
- 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: May cause fetal harm, pregnancy should be avoided (negative pregnancy tests required before and monthly during treatment);
- Lactation:Discontinue breastfeeding.
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);
- Rep: Patients with reproductive potential;
- Geri: Elderly may have ↑ blood levels and be more sensitive to drug effects;
- Pedi: Safety and effectiveness not established.
Adverse Reactions/Side Effects
CNS: dizziness, headache
CV: pulmonary edema (↑ in veno-occlusive disease), hypotension
GI: dyspepsia, gastritis, nausea, vomiting, constipation, diarrhea, gastroesopheal reflux, ↑ liver enzymes
Hemat: BLEEDING, anemia
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- ↑ 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 sildenafil ≥24 hr prior to starting riociguat; discontinue tadalafil ≥48 hr prior to starting riociguat; discontinue riociguat ≥24 hr before starting PDE-5 inhibitor.
- Strong CYP and P-gp/BRCP 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 re-adjustment required after smoking cessation.
St. John's wort ↓ blood levels and may ↓ effectiveness.
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 (re-adjust 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.
Tablets: 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg
- Monitor hemodynamic parameters and exercise tolerance prior to and every 2 wks 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 x 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.
- Activity intolerance (Indications)
- 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 wks. 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.
- 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: 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.
Increased exercise tolerance.
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