Drug information of riociguat

riociguat

Drug group:

Riociguat is used to treat adults with chronic thromboembolic pulmonary hypertension (CTEPH) that can be treated with surgery, or that cannot be treated with surgery

Mechanism of effect

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP).  Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway.

Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO.

Pharmacodynamic

Not Available

Pharmacokinetics

Absorption

The pharmacokinetics of riociguant are dose proportional from 0.5 mg to 2.5 mg. The absolute bioavailability is approximately 94%. After oral administration, peak plasma concentrations were achieved within 1.5 hours. Food does not affect the bioavailability of riociguat.

Volume of distribution

Volume of distribution at steady state = 30 L

Protein binding

95% with serum albumin and alpha-1–acidic glycoprotein being the main binding components.

Metabolism

The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.

Route of elimination

Riociguat is eliminated in the urine (40%) and feces (53%).

Half life

About 12 hours in patients and 7 hours in healthy subjects.

Clearance

Not Available

Drug indications

Riociguat is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. Riociguat is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening. Efficacy was shown in patients on Riociguat monotherapy or in combination with endothelin receptor antagonists or prostanoids

Dosage

Initial dose: 1 mg PO TID; consider 0.5 mg PO TID if patient may not tolerate hypotensive effect

If systolic blood pressure >95 mmHg and no symptoms of hypotension, up-titrate dose by 0.5 mg PO TID with dose increases no sooner than 2 weeks apart to highest tolerated dose (not to exceed 2.5 mg PO TID)

Drug contraindications

Pregnancy (see Black Box Warnings)

Coadministration with nitrates or nitric oxide donors (eg, amyl nitrite), PDE inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil), or nonspecific PDE inhibitors (eg, dipyridamole, theophylline) because of additive hypotension

Administration within 24 hr of sildenafil

Tatalafil 24 hr before or within 48 hr after riociguat

 

Prevent pregnancy during treatment and for 1 month after stopping treatment

 

Side effects

Headache (27%)

Dyspepsia and gastritis (21%)

Dizziness (20%)

Nausea (14%)

Diarrhea (12%)

1-10%

Hypotension (10%)

Vomiting (10%)

Anemia (7%)

GERD (5%)

Constipation (5%)

Serious bleeding (2.4%)

 

  • amyl nitrite
  • avanafil
  • dipyridamole
  • isosorbide dinitrate
  • isosorbide mononitrate
  • nitroglycerin IV
  • nitroglycerin PO
  • nitroglycerin sublingual
  • nitroglycerin transdermal
  • nitroglycerin translingual
  • sildenafil
  • tadalafil
  • theophylline
  • vardenafil

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Alerts

Contraindicated in pregnant females because it may cause fetal harm

In females of reproductive potential, exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment

Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception (ie, 1 highly effective form of contraception [IUD, contraceptive implants, or tubal sterilization] or a combination of methods (hormone method with a barrier method or 2 barrier methods)

Available to females only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program

Pregnancy level

Based on data from animal reproduction studies, therapy may cause embryo-fetal toxicity and miscarriage when administered to a pregnant woman and is contraindicated during pregnancy; in reproduction studies with pregnant rabbits, oral administration during organogenesis caused abortions and fetal toxicity at exposures approximately 4 times and 13 times, respectively, the maximum recommended human (MRHD); advise pregnant women of the potential risk to a fetus

Females of reproductive potential must have a negative pregnancy test before initiation, monthly during, and 1 month after discontinuation of treatment; contraception must also be used during and for 1 month after treatment (see Boxed Warning)

If pregnancy suspected, contact healthcare provider immediately

Breast feeding warning

There are no data on presence of riociguat in human milk, effects on breastfed infant, or on milk production; drug is present in rat milk; because of potential for serious adverse reactions, such as hypotension, in breastfed infants, advise women not to breastfeed during therapy

Drug forms

Adempas

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