Riociguat

Uses

Riociguat is a stimulator of soluble guanylate cyclase indicated for the management of persistent or recurrent chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension.

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. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).

Riociguat is also used to associated treatment for these conditions: Chronic Thromboembolic Pulmonary Hypertension, Symptomatic pulmonary arterial hypertension (PAH)

How Riociguat works

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. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.

Toxicity

EMBRYO-FETAL TOXICITY Do not administer Riociguat to a pregnant female because it may cause fetal harm. 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 one month after stopping treatment by using acceptable methods of contraception. For all female patients, Riociguat is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy.

Food Interaction

• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of riociguat and may reduce its serum concentration.
• Take separate from antacids. Take at least 1 hour before or after antacids. Aluminum or magnesium hydroxide antacids may reduce riociguat absorption.
• Take with or without food.

[Moderate] ADJUST DOSE: Smoking may decrease the plasma concentrations of riociguat.

The proposed mechanism is induction of the CYP450 1A1-mediated metabolism of riociguat by polycyclic aromatic hydrocarbons present in cigarette smoke.

CYP450 1A1 is responsible for the formation of the major active metabolite, M1, which has just 1<3 to 1<10 the pharmacologic activity of riociguat.

According to the product labeling, plasma concentrations of riociguat are reduced by 50% to 60% in smokers compared to nonsmokers.

MANAGEMENT: Riociguat dosages higher than 2.5 mg three times a day may be considered in cigarette smokers, if tolerated, so as to match the exposure seen in nonsmoking patients.

However, safety and effectiveness of higher dosages have not been established.

A dosage reduction should be considered in patients who stop smoking during treatment with riociguat.

Riociguat Hypertension interaction

[Moderate] Riociguat reduces blood pressure.

There is a potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensive agents.

Caution is advised when using riociguat in these patients.

Riociguat Drug Interaction

Moderate: spironolactone, rifampin, sotalol, treprostinilUnknown: charcoal, fluticasone / salmeterol, anagrelide, glimepiride, umeclidinium / vilanterol, heparin, atorvastatin, acetaminophen, vitamin a topical, bioflavonoids, liraglutide, linagliptin, dulaglutide, liraglutide, cholecalciferol, rivaroxaban

Riociguat Disease Interaction

Moderate: hypotension, liver impairment, renal impairment

Volume of Distribution

Volume of distribution at steady state = 30 L

Elimination Route

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.

Half Life

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

Elimination Route

Riociguat is eliminated in the urine (40%) and feces (53%), largely as metabolites.

Innovators Monograph

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