riociguat

riociguat

(rye-oh-sig-ue-at ) ,

Adempas

(trade name)

Classification

Therapeutic: pulmonary hypertension agents
Pharmacologic: soluble guanylate cyclase stimulators sgs
Pregnancy Category: X

Indications

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)

Action

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.

Therapeutic effects

Improved symptoms/exercise tolerance and delayed worsening.

Pharmacokinetics

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

ROUTEONSETPEAKDURATION
POwithin 2 wk8–16 wkunknown

Contraindications/Precautions

Contraindicated in: Severe hepatic impairment (Child Pugh C)Severe renal impairment (CCr <15 mL/min or on dialysis)Known pulmonary veno-occlusive disease; Concurrent use of nitrates, nitric oxide donors or phosphodiesterase (PDE) inhibitors; Obstetric: May cause fetal harm, pregnancy should be avoided (negative pregnancy tests required before and monthly during treatment) Lactation: Discontinue breast feeding
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)Patients with reproductive potential (effective contraception is required) Geriatric: Elderly may have ↑ blood levels and be more sensitive to drug effects; Pediatric: Safe and effective use in children has not been established.

Adverse Reactions/Side Effects

Central nervous system

  • dizziness (most frequent)
  • headache (most frequent)

Cardiovascular

  • pulmonary edema (↑ in veno-occlusive disease)
  • hypotension (most frequent)

Gastrointestinal

  • dyspepsia (most frequent)
  • gastritis (most frequent)
  • nausea (most frequent)
  • vomiting (most frequent)
  • constipation
  • diarrhea
  • gastroesopheal reflux
  • ↑ liver enzymes

Hematologic

  • bleeding (life-threatening)
  • anemia

Interactions

Drug-Drug interaction

↑ risk of hypotension with concurrent use of nitrates, nitric oxide donors (including amyl nitrate ) or phosphodiesterase (PDE) inhibitors including specific PDE-5 inhibitors such as sildenafil, tadalafil or vardenafil and non-specific PDE inhibitors such as dipyridamole or theophylline, concurrent use is contraindicated 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.

Route/Dosage

Oral (Adults) 1 mg three times daily initially; if hypotension a risk factor, initiate treatment with 0.5 mg three times daily. Increase dose by 0.5 mg at 2 wk (or more) intervals up to maintenance dose of 2.5 mg three times daily; smokers— consider titrating to doses >2.5 mg three times daily if tolerated (re-adjust following smoking cessation); concurrent CYP and P-gp/BRCP inhibitors— consider initiating treatment at 0.5 mg three times daily, with careful monitoring for hypotension.

Availability

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

Nursing implications

Nursing assessment

  • 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.

Potential Nursing Diagnoses

Activity intolerance (Indications)

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.
  • Oral: 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.

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.
  • 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.

Evaluation/Desired Outcomes

  • Increased exercise tolerance.
References in periodicals archive ?
Clinical review report: riociguat (Adempas) for the treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1), as monotherapy or in combination with endothelin receptor antagonists in adult patients ([greater than or equal to]18 years of age) with functional class II or III pulmonary hypertension [Internet].
CHICAGO -- Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).
The first developed sGC stimulator is called "riociguat." It has been developed for the treatment of pulmonary hypertension and is a potent compound known for its powerful effects on pulmonary hemodynamics.
His previous roles included leading global brand strategy at Bayer HealthCare Pharmaceuticals (ETR: BAYN) for the launch of a first-in-class, rare-disease agent, Adempas (riociguat).
Felix et al., "Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: A phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study," Circulation, vol.
Throughout the past 20 years, numerous specific pharmacological agents have been approved for the treatment of PAH, including prostacyclin pathway agonists (intravenous prostacyclin, synthetic analogs of prostacyclin, and nonprostanoid prostacyclin receptor agonists), endothelin receptor antagonists (ERAs), phosphodiesterase type5 inhibitors (PDE-5Is), and the first soluble guanylate cyclase (sGC) stimulator (riociguat) [7].
In addition to the basic treatment, two patients also received targeted drug therapy (riociguat in the first case, sildenafil and bosentan in the second case).
Recent treatment guidelines recommend treatment of PAH with macitentan (endothelin-1 receptor blocker), sildenafil (PDE5-inhibitor), iloprost (prostacyclin analog), or newly introduced riociguat (sGC stimulator) [43].
The use of other currently available pulmonary vasodilators, such as the endothelin receptor antagonists (ERA) and the recently approved soluble guanylate cyclase stimulator, riociguat, should probably be avoided in acute RVF due to concerns about unreliable oral absorption.
modulators, including Bayer's Adempas (riociguat), which is