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Riociguat

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 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

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

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) or nonspecific PDE inhibitors (eg, dipyridamole, theophylline)

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to riociguat or any component of the formulation; breast-feeding

Dosing: Adult

Chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension: Oral: Initial: 1 mg 3 times daily; may initiate dose at 0.5 mg 3 times daily in patients who may not tolerate the hypotensive effects. If tolerated, may increase the dose by 0.5 mg 3 times daily if systolic blood pressure remains >95 mm Hg and the patient has no signs or symptoms of hypotension; increase dose at intervals of ≥2 weeks. Maximum dose: 2.5 mg 3 times daily.

Missed doses: If a dose is missed, continue with the next regularly scheduled dose. If therapy is interrupted for ≥3 days, retitration is required.

Dosage adjustment for concurrent use in patients receiving strong multi-pathway CYP and P-gp/BCRP inhibitors (eg, azole antifungals or protease inhibitors): Consider a starting dose of 0.5 mg 3 times daily.

Dosage adjustment for patients who smoke: Dose may be titrated to >2.5 mg 3 times daily, if tolerated. A decreased dose may be necessary in patients who stop smoking during therapy.

Dosing: Geriatric

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

Dosing: Renal Impairment

CrCl ≥15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling.

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer’s labeling.

Severe hepatic impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

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.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Storage

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

Drug Interactions

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

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

Antihepaciviral Combination Products: May increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times daily. Patients receiving such a combination should also be monitored closely for signs or symptoms of hypotension. 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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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

Cobicistat: May increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day. Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 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. 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. 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

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

Itraconazole: May increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day. Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

Ketoconazole (Systemic): May increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day. Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. 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. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

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

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

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). 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

Protease Inhibitors: May increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day (for adults). Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

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

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. 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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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. Prevent pregnancy during treatment and for 1 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 (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.

• 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.

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. Females of reproductive potential must be able to comply with pregnancy testing and contraception requirements of the program. Call 855-4-ADEMPAS or visit www.adempasREMS.com for more information.

• Pregnancy: [US Boxed Warning]: May cause fetal harm if given to pregnant women. 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. Females of childbearing potential should not become pregnant during therapy or for 1 month following discontinuation of riociguat. Women 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.

• 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

Monitor blood pressure and signs and symptoms of hypotension. Monitor for significant peripheral edema and improvements in pulmonary function and exercise tolerance. Women 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.

Pregnancy Risk Factor

X

Pregnancy Considerations

Use is contraindicated in pregnant women.

Reproduction studies in animals have shown evidence of fetal abnormalities and use is contraindicated in women who are or may become pregnant. [U.S. Boxed Warnings]: Riociguat may cause fetal harm if given to pregnant women. Riociguat is available to females only through the restricted Adempas Risk Evaluation and Mitigation Strategy (REMS) Program. 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. Females of childbearing potential should not become pregnant during therapy or for 1 month following discontinuation riociguat. 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. Women 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. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (Badesch, 2007; McLaughlin, 2009).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, vomiting, heartburn, diarrhea, or constipation. Have patient report immediately to prescriber signs of bleeding (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 bleeding that is very bad or that will not stop), severe dizziness, passing out, arrhythmia, dysphagia, abdominal edema, swelling of arms or legs, angina, pale skin, or loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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