Riociguat (Monograph)

Brand name: Adempas
Drug class: Vasodilating Agents, Miscellaneous
Chemical name: N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbamic acid, methyl ester
Molecular formula: C₂₀H₁₉FN₈O₂
CAS number: 625115-55-1

Medically reviewed by Drugs.com on Mar 27, 2023. Written by ASHP.

Introduction

Vasodilator; a soluble guanylate cyclase (sGC) stimulator.

Uses for Riociguat

Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Management of CTEPH (WHO group 4 pulmonary hypertension) to improve exercise capacity and WHO functional class in patients with inoperable disease or persistent/recurrent pulmonary hypertension after surgery (i.e., pulmonary endarterectomy).

Standard treatment for CTEPH is pulmonary endarterectomy; some experts recommend riociguat for symptomatic patients with persistent or recurrent pulmonary hypertension following surgical management or for those who are not candidates for surgical treatment.

Has been designated an orphan drug by FDA for treatment of CTEPH.

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and NYHA/WHO functional class and to delay clinical worsening.

Efficacy established principally in patients with NYHA/WHO functional class II or III PAH (idiopathic, heritable, or associated with connective tissue diseases) receiving the drug as monotherapy or in combination with an endothelin-receptor antagonist or a prostanoid.

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications. Riociguat is recommended among several options for treatment of WHO/NYHA class II or III PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

Has been designated an orphan drug by FDA for treatment of PAH.

Riociguat Dosage and Administration

General

Pretreatment Screening

• Obtain a pregnancy test in females of reproductive potential prior to start of treatment with riociguat.

Patient Monitoring

• Obtain pregnancy tests monthly during treatment in females of reproductive potential.

• Monitor for signs and symptoms of hypotension.

REMS

• Because of the risk of embryofetal toxicity, riociguat is available to female patients only through a restricted distribution program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program. All female patients regardless of childbearing potential must enroll in the program prior to initiating riociguat therapy; in addition, females of childbearing potential must comply with all pregnancy testing and contraception requirements of the program. Certain restrictions and conditions also apply to prepubertal females. Male patients are exempt from these restrictions and do not need to enroll in the program.

• Clinicians and pharmacies (including both inpatient and outpatient) must be certified with the Adempas REMS Program in order to prescribe and dispense the drug. Pharmacies must only dispense to authorized patients. Dispensing to females of childbearing potential should occur only after obtaining confirmation from the patient that the required pregnancy tests were completed. Pregnancy tests should be performed monthly during therapy and at 1 month following discontinuance of therapy.

• For additional information about the Adempas REMS Program, clinicians may call 855-423-3672 or consult [Web].

Administration

Oral Administration

Administer orally without regard to meals.

If a dose is missed, take next dose at the regularly scheduled time; if treatment is interrupted for ≥3 days, retitrate dosage.

For patients unable to swallow whole tablets, may be crushed and mixed with water or soft foods (such as applesauce) immediately before administration.

Dosage

Adults

CTEPH

Oral

Initially, 1 mg 3 times daily (doses approximately 6–8 hours apart).

Consider reduced initial dosage of 0.5 mg 3 times daily in patients who may not tolerate the hypotensive effects of the drug.

Adjust dosage based on response and tolerance. In patients without manifestations of hypotension and in whom systolic BP >95 mm Hg, may titrate dosage up to maximum of 2.5 mg 3 times daily. Adjust dosage in increments of 0.5 mg 3 times daily at intervals of at least 2 weeks. If symptoms of hypotension occur at any time, reduce dosage by 0.5 mg 3 times daily.

In patients receiving concomitant therapy with potent inhibitors of CYP and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP), consider reduced initial dosage of 0.5 mg 3 times daily. Monitor for hypotension upon initiation of and during such concomitant therapy.

PAH

Oral

Initially, 1 mg 3 times daily (doses approximately 6–8 hours apart).

Consider reduced initial dosage of 0.5 mg 3 times daily in patients who may not tolerate the hypotensive effects of the drug.

Adjust dosage based on response and tolerance. In patients without manifestations of hypotension and in whom systolic BP >95 mm Hg, may titrate dosage up to maximum of 2.5 mg 3 times daily. Adjust dosage in increments of 0.5 mg 3 times daily at intervals of at least 2 weeks. If symptoms of hypotension occur at any time, reduce dosage by 0.5 mg 3 times daily.

In patients receiving concomitant therapy with potent inhibitors of CYP and P-gp/BCRP, consider reduced initial dosage of 0.5 mg 3 times daily. Monitor for hypotension upon initiation of and during such concomitant therapy.

Transitioning to and from Riociguat

Transitioning to riociguat from sildenafil: discontinue sildenafil at least 24 hours prior to administering riociguat.

Transitioning to riociguat from tadalafil: discontinue tadalafil at least 48 hours prior to administering riociguat. Consider initiating riociguat at a starting dose of 0.5 mg in patients at risk of hypotension. Monitor for signs and symptoms of hypotension on initiation.

Transitioning to a PDE type 5 inhibitor from riociguat: Discontinue riociguat at least 24 hours prior to administering a PDE type 5 inhibitor. Monitor for signs and symptoms of hypotension on initiation.

Dosage Modifications in Smokers

Consider titrating to a dosage higher than the usual recommended maximum dosage of 2.5 mg 3 times daily, if tolerated, in patients who smoke. Such dosage recommendations based on pharmacokinetic modeling; safety and efficacy not established in smokers. Dosage reduction may be required in patients who stop smoking.

Dosage Modification for Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes and Transport Systems

In patients receiving concomitant therapy with potent inhibitors of CYP and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP), consider reduced initial dosage of riociguat 0.5 mg 3 times daily. Monitor for hypotension upon initiation of and during such concomitant therapy.

Prescribing Limits

Adults

CTEPH

Oral

Maximum recommended dosage 2.5 mg 3 times daily; consider higher dosage in patients who smoke.

PAH

Oral

Maximum recommended dosage 2.5 mg 3 times daily; consider higher dosage in patients who smoke.

Special Populations

Hepatic Impairment

Not recommended in patients with severe (Child Pugh class C) hepatic impairment.

Renal Impairment

Not recommended in patients with Cl_cr <15 mL/minute or on dialysis.

Geriatric Patients

Dosage adjustments based solely on age not necessary.

Cautions for Riociguat

Contraindications

• Pregnancy.

• Concomitant therapy with nitrates or nitric oxide donors in any form (e.g., amyl nitrite, nitroglycerin).

• Concomitant therapy with PDE inhibitors, including specific PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) and nonspecific PDE inhibitors (e.g., dipyridamole, theophylline).

• Concomitant therapy with other soluble guanylate cyclase stimulators.

• Pulmonary hypertension associated with idiopathic interstitial pneumonias.

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals. (See Boxed Warning.)

Exclude pregnancy prior to initiation of therapy; perform monthly pregnancy tests during therapy and at 1 month following discontinuance of therapy.

If riociguat is used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.

Hypotension

Risk of hypotension. Consider potential for symptomatic hypotension or ischemia in patients with predisposing risk factors (e.g., hypovolemia, severe left-ventricular outflow obstruction, resting hypotension, autonomic dysfunction, concomitant use of antihypertensive agents or drugs that can increase exposure to riociguat).

Concomitant use of nitrates, nitric oxide donors, or phosphodiesterase inhibitors can potentiate hypotensive effects of riociguat.

If manifestations of hypotension occur at any time, reduce dosage.

Bleeding

Bleeding (e.g., hemoptysis, vaginal bleeding, catheter site bleeding, subdural hematoma, hematemesis, intra-abdominal bleeding) reported, including at least 1 death.

Pulmonary Veno-occlusive Disease

If acute pulmonary edema occurs, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue riociguat.

Specific Populations

Pregnancy

Based on data from animal studies, may cause embryo-fetal toxicity and miscarriage; contraindicated during pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If riociguat is used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard. (See Females and Males of Reproductive Potential under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Advise women not to breastfeed during treatment with riociguat.

Females and Males of Reproductive Potential

Females of reproductive potential must have a negative pregnancy test prior to starting treatment, monthly during treatment, and 1 month after discontinuation. Advise patients to contact healthcare provider if they become pregnant or suspect they may be pregnant. Counsel patients on risk to fetus.

Exclude pregnancy in females of childbearing potential prior to initiation; prevent thereafter with acceptable methods of contraception during and for 1 month following cessation of therapy.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in safety or efficacy relative to younger patients.

Hepatic Impairment

Safety and efficacy not established in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Safety and efficacy not established in patients with severe renal impairment (Cl_cr<15 mL/minute) or in those undergoing dialysis.

Common Adverse Effects

Common adverse reactions (≥3%): headache, dyspepsia/gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, constipation.

Drug Interactions

Metabolized by CYP1A1, 3A4, 3A5, and 2J2.

Substrate of P-gp and BCRP.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A inhibitors or inducers: Potential pharmacokinetic interaction (increased or decreased riociguat concentrations, respectively); caution is advised and dosage adjustments may be necessary.

CYP1A1 inducers (e.g., cigarette smoke): Potential pharmacokinetic interaction (decreased riociguat concentrations); caution is advised and dosage adjustments may be necessary.

Drugs Affecting Hepatic Microsomal Enzymes and Efflux Transport Systems

Concomitant use of potent inhibitors of both CYP and P-gp/BRCP is expected to substantially increase exposure to riociguat and, thus, risk of hypotension. Dosage adjustments may be required.

Specific Drugs

Riociguat Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations attained in approximately 0.5–1.5 hours. Plasma concentrations of the active M-1 metabolite are about 50% of those of the parent drug.

Food

Food does not affect absorption.

Distribution

Plasma Protein Binding

Approximately 95%.

Elimination

Metabolism

Principally undergoes hepatic metabolism by CYP1A1, 3A4, 3A5, and 2J2. Converted to major active M-1 metabolite by CYP1A1, then further metabolized to inactive N-glucuronide conjugate.

Elimination Route

Following oral administration of radiolabeled dose, approximately 40 and 53% of total radioactivity recovered in urine and feces, respectively.

Half-life

Elimination half-life about 7 hours in healthy individuals and 12 hours in patients with pulmonary hypertension.

Special Populations

In geriatric patients, systemic exposure to riociguat may be increased.

In patients with renal impairment, systemic exposure to riociguat may be increased.

Stability

Storage

Oral

Tablets

25°C (excursions permitted between 15–30°C).

Actions

• Promotes vasodilation via effects on the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) pathway. Impairment of this nitric oxide signaling pathway, including decreased synthesis of nitric oxide and insufficient stimulation of sGC, demonstrated in patients with pulmonary hypertension.

• Dual mechanism of action; increases sensitivity of sGC to endogenous nitric oxide and also directly stimulates sGC independent of nitric oxide, resulting in increased levels of cGMP and subsequent vasodilation.

• In patients with pulmonary hypertension, improves hemodynamics (e.g., pulmonary vascular resistance, pulmonary artery pressure, cardiac output) and concentrations of N-terminal prohormone of brain (pro-brain) natriuretic peptide, a biomarker of heart function.

• Some antiproliferative and antifibrotic effects also observed.

Advice to Patients

• Risk of fetal harm; importance of advising females of childbearing potential to avoid pregnancy and to use acceptable methods of contraception during and for 1 month following discontinuance of riociguat therapy. Acceptable methods of contraception include one highly effective form of contraception (intrauterine device [IUD], progesterone implant, or tubal sterilization) or a combination of methods (either one hormonal and one barrier method or 2 barrier methods where one form is the male condom). Acceptable hormonal methods of contraception include estrogen-progestin combination oral contraceptives or transdermal contraceptive systems, vaginal ring, and progesterone injections. Acceptable barrier methods include male condoms, diaphragms with spermicide, and cervical caps with spermicide. Even if the partner has had a vasectomy, an additional hormonal or barrier method must be used.

• Advise females to inform their clinician immediately if a menstrual period is missed or pregnancy is suspected; clinicians should provide counseling on the use of emergency contraception in the event of unprotected sexual intercourse or contraceptive failure. Apprise patient of potential risk to fetus if pregnancy occurs.

• Importance of monthly pregnancy testing.

• Importance of all female patients (regardless of childbearing potential) enrolling in the Adempas REMS program and complying with contraceptive and pregnancy testing requirements. Importance of monitoring reproductive status of prepubertal females and immediately reporting changes to clinician.

• Risk of hemoptysis; importance of advising patients to report any potential manifestations of hemoptysis to their clinician.

• Importance of advising patients that smoking during riociguat therapy may decrease concentrations of the drug and reduce efficacy; importance of informing clinician if smoking is started or stopped during riociguat therapy as riociguat dosage adjustment may be needed.

• Importance of advising patients to not take antacids within 1 hour of riociguat administration and to avoid use of nitrates, nitric oxide donors, and PDE inhibitors while undergoing riociguat therapy.

• Risk of dizziness; importance of advising patients to avoid driving or operating machinery until effects of the drug on the individual are known and to consult their clinician, if necessary.

• Importance of taking riociguat as prescribed and of not discontinuing therapy or altering dosage without consulting a clinician.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription (e.g., azole antifungal agents, HIV protease inhibitors) and OTC drugs, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed; advise women not to breastfeed during treatment with riociguat.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of riociguat is restricted in female patients. (See REMS under Dosage and Administration.)

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