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Riociguat

Medically reviewed by Drugs.com. Last updated on Jul 28, 2020.

Pronunciation

(rye oh SIG ue at)

Index Terms

  • Adempas
  • BAY 63-2521

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

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

Brand Names: U.S.

  • Adempas

Pharmacologic Category

  • Soluble Guanylate Cyclase (sGC) Stimulator

Pharmacology

Riociguat has a dual mode of action. It sensitizes soluble guanylate cyclase (sGC) to endogenous nitric oxide (NO) by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC independent of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.

Distribution

~30 L

Metabolism

Mainly cleared by metabolism by CYP1A1, CYP3A, CYP2C8 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke. M1 is only 1/3 to 1/10 as potent as the parent drug and is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with pulmonary arterial hypertension are about half those for riociguat.

Excretion

Feces (~53%); urine (~40%)

Time to Peak

Plasma: 1.5 hours

Half-Life Elimination

Patients: 12 hours; Healthy subjects: 7 hours

Protein Binding

Plasma: ~95%

Special Populations: Elderly

Higher exposure to riociguat

Special Populations Note

Cigarette smoking: Plasma concentrations are reduced by 50% to 60% in smokers.

Use: Labeled Indications

Chronic thromboembolic pulmonary hypertension: Treatment of persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class in adults.

Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (PAH) (WHO group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening in adults.

Contraindications

Pregnancy; coadministration with nitrates or nitric oxide donors (eg, amyl nitrite) in any form; concomitant administration with phosphodiesterase (PDE) inhibitors, including specific PDE-5 inhibitors (eg, sildenafil, tadalafil, vardenafil; do not use within 24 hours of sildenafil or 24 hours before or within 48 hours after tadalafil) or nonspecific PDE inhibitors (eg, dipyridamole, theophylline); pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to riociguat or any component of the formulation; breastfeeding.

Dosing: Adult

Chronic thromboembolic pulmonary hypertension or Pulmonary arterial hypertension:

Note: A clinician with expertise in pulmonary arterial hypertension should be consulted for all management decisions. Riociguat is contraindicated in patients taking a PDE-5 inhibitor due to potentially severe hypotension (ACCP [Klinger 2019]).

Oral: Initial: 1 mg 3 times daily; may initiate 0.5 mg 3 times daily in patients at higher risk of hypotension. If systolic BP remains >95 mm Hg and the patient has no signs or symptoms of hypotension, increase the dose by 0.5 mg 3 times daily at intervals of ≥2 weeks to a maximum dose of 2.5 mg 3 times daily.

Missed doses: If therapy is interrupted for ≥3 days, re-titration is required.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Transitioning from a PDE-5 inhibitor to riociguat:

Transitioning from sildenafil to riociguat: Discontinue sildenafil ≥24 hours prior to administering riociguat.

Transitioning from tadalafil to riociguat: Discontinue tadalafil ≥48 hours prior to administering riociguat.

Transitioning from riociguat to a PDE-5 inhibitor: Discontinue riociguat ≥24 hours prior to administering sildenafil or tadalafil.

Dosing: Geriatric

Refer to adult dosing. Use with caution; riociguat exposure is increased.

Dosing: Adjustment for Toxicity

Hypotension: Decrease dose by 0.5 mg 3 times daily if hypotensive effects are not tolerated.

Pulmonary edema: Consider the possibility of pulmonary veno-occlusive disease (PVOD); if confirmed discontinue treatment with riociguat.

Administration

Oral: Administer with or without food. For patients unable to swallow whole tablets, may crush and mix with water or soft foods (eg, applesauce) immediately prior to administration.

Storage

Store at 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abacavir: May increase the serum concentration of Riociguat. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Amyl Nitrite: May enhance the hypotensive effect of Riociguat. Avoid combination

Anagrelide: May enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Antacids: May decrease the serum concentration of Riociguat. Management: Separate the administration of antacids and riociguat by at least 1 hour in order to minimize any potential interaction. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Apremilast: May enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Avoid combination

Cilostazol: May enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Crisaborole: May enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Riociguat. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyridamole: May enhance the hypotensive effect of Riociguat. Avoid combination

Doxofylline: May enhance the hypotensive effect of Riociguat. Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Enoximone: May enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Ibudilast: May enhance the hypotensive effect of Riociguat. Avoid combination

Inhibitors of CYP3A4 (Strong) and BCRP: May increase the serum concentration of Riociguat. Management: Consider a riociguat starting dose of 0.5 mg 3 times a day when initiating riociguat in patients receiving strong CYP3A4 and BCRP inhibitors. Monitor for hypotension when these agents are combined and reduce the riociguat dose as needed. Consider therapy modification

Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum concentration of Riociguat. Management: Consider a riociguat starting dose of 0.5 mg 3 times a day when initiating riociguat in patients receiving strong CYP3A4 and P-gp inhibitors. Monitor for hypotension when these agents are combined and reduce the riociguat dose as needed. Exceptions: Clarithromycin. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Milrinone: May enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Molsidomine: Riociguat may enhance the hypotensive effect of Molsidomine. Avoid combination

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Riociguat may enhance the hypotensive effect of Nitroprusside. Avoid combination

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Riociguat. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Proton Pump Inhibitors: May decrease the serum concentration of Riociguat. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Roflumilast: May enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Theophylline Derivatives: May enhance the hypotensive effect of Riociguat. Avoid combination

Tobacco (Smoked): May decrease the serum concentration of Riociguat. Management: In patients who smoke, consider titrating to riociguat doses greater than 2.5 mg three times daily if tolerable. A decrease in riociguat dose should be considered in patients who stop smoking. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Vasodilators (Organic Nitrates): May enhance the hypotensive effect of Riociguat. Avoid combination

Adverse Reactions

Frequency not always defined.

Cardiovascular: Hypotension (3% to 10%; Ghofrani 2013), palpitations, peripheral edema

Central nervous system: Headache (27%), dizziness (20%)

Gastrointestinal: Dyspepsia (13% to 19%; Ghofrani 2013), nausea (14%), diarrhea (12%), vomiting (10%), gastritis (2% to 6%; Ghofrani 2013), constipation (5%), gastroesophageal reflux disease (5%), abdominal distention, dysphagia

Hematologic & oncologic: Anemia (7%), major hemorrhage (2%; including vaginal hemorrhage, catheter site hemorrhage, subdural hematoma, hematemesis, and intra-abdominal hemorrhage)

Respiratory: Hemoptysis (1%), epistaxis, nasal congestion

ALERT: U.S. Boxed Warning

Embryo-fetal toxicity:

Do not administer riociguat to a pregnant patient because it may cause fetal harm.

Female patients of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and for 1 month after stopping treatment. To prevent pregnancy, females of reproductive potential must use effective forms of contraception during treatment and for 1 month after stopping treatment.

For all female patients, riociguat is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) program.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Serious bleeding has been observed; consider periodic monitoring for bleeding.

• CNS effects: Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypotension: Reduces blood pressure. Use with caution in patients at increased risk for symptomatic hypotension or ischemia (eg, patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction) or concurrent use of antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider initiating at a lower dose for patients at risk of hypotension and/or dose reduction if hypotension develops.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment. Not recommended in patients with severe hepatic impairment (Child-Pugh class C).

• Pulmonary veno-occlusive disease: Use is not recommended in patients with pulmonary veno-occlusive disease (PVOD). Discontinue in any patient with pulmonary edema suggestive of PVOD.

• Renal impairment: Use with caution in patients with renal impairment. Not recommended in patients with creatinine clearance <15 mL/minute or on dialysis.

Special populations:

• Females: [US Boxed Warning]: Riociguat is available to females only through the restricted Adempas Risk Evaluation and Mitigation Strategy (REMS) program. All females, regardless of their reproductive potential, must be enrolled in the REMS program; prescribers and pharmacies must also be enrolled in the program. Call 855-4-ADEMPAS or visit www.adempasREMS.com for more information.

• Pregnancy: [US Boxed Warning]: Do not administer riociguat to a pregnant patient because it may cause fetal harm. All females of reproductive potential should have a negative pregnancy test prior to beginning therapy and testing should continue monthly during treatment and one month after discontinuing therapy. Effective contraception should be used during therapy and for 1 month following discontinuing riociguat.

• Smokers: Riociguat concentrations are 50% to 60% lower in patients who smoke compared to nonsmokers; consider titrating dose to >2.5 mg 3 times daily, if tolerated. A decreased dose may be necessary in patients who stop smoking during therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Blood pressure and signs and symptoms of hypotension; significant peripheral edema and improvements in pulmonary function and exercise tolerance. Females of childbearing potential must have a negative pregnancy test prior to the initiation of therapy, monthly during treatment, and 1 month after discontinuation of therapy.

Reproductive Considerations

[US Boxed Warning]: Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and for 1 month after stopping treatment. To prevent pregnancy, females of reproductive potential must use effective forms of contraception during treatment and for 1 month after stopping treatment.

[US Boxed Warning]: Riociguat is available to females only through the restricted Adempas Risk Evaluation and Mitigation Strategy (REMS) program. All females, regardless of their reproductive potential, must be enrolled in the REMS program; prescribers and pharmacies must also be enrolled in the program. Females of reproductive potential must be able to comply with pregnancy testing and contraception requirements of the program. Patients may use one highly effective form of contraception (intrauterine device, contraceptive implant, or tubal sterilization) or a combination of methods (hormonal contraceptive with a barrier method or two barrier methods). A hormonal contraceptive or barrier method must be used in addition to a partner's vasectomy, if that method is chosen. Females should be counseled on pregnancy prevention and planning and instructed to notify their prescriber immediately if a pregnancy should occur.

Pregnancy Considerations

Use is contraindicated during pregnancy.

[US Boxed Warning]: Do not administer riociguat to a pregnant female because it may cause fetal harm.

Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).

All females regardless of their reproductive potential must be enrolled in the REMS program; prescribers and pharmacies must also be enrolled in the program.

Patient Education

What is this drug used for?

• It is used to treat high blood pressure in the lungs.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Nausea

• Vomiting

• Heartburn

• Diarrhea

• Constipation

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.

• Dizziness

• Passing out

• Abnormal heartbeat

• Trouble swallowing

• Abdominal swelling

• Swelling of arms or legs

• Chest pain

• Pale skin

• Severe loss of strength and energy

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.