Riociguat (riociguat)

Because smoking can decrease plasma concentrations of riociguat, consider titrating doses to a dosage higher than the usual recommended maximum dosage of 2.5 mg 3 times daily, if tolerated, in patients who smoke. This recommendation is based on pharmacokinetic modeling; safety and efficacy of such dosages have not been established. Conversely, a dosage reduction may be required in patients who stop smoking.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Riociguat/Nitrates & Nitric Oxide Donors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nitrates activate guanyl cyclase, an enzyme that increases levels of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation. Riociguat stimulates the nitric oxide-soluble guanylate cyclase-cGMP pathway and also increases cGMP. Concurrent use of nitrates with riociguat results in potentiation of the effect of both agents.(1)

CLINICAL EFFECTS: The concurrent use riociguat and nitrates potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The administration of riociguat to patients receiving nitrates, or nitric oxide donors, in any form is contraindicated.(1)

DISCUSSION: Riociguat (2.5 mg) potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) when taken 4 hour and 8 hours after riociguat. Syncope was reported in some patients.(1)

Riociguat/Pde Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Riociguat stimulates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also increases cGMP.(1) Aminophylline, avanafil, dipyridamole, sildenafil, tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE), which is responsible for the breakdown of cGMP.(1)

CLINICAL EFFECTS: The concurrent use of PDE inhibitors and riociguat potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1)

PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitors may be higher in the following patients: those older than 65, with hepatic impairment, with severe renal impairment, or using concomitant CYP3A4 inhibitors. This may increase the severity of the interaction.

PATIENT MANAGEMENT: The administration of riociguat to patients receiving PDE inhibitors, including specific PDE-5 inhibitors (avanafil (5), sildenafil (2), tadalafil (3,6), or vardenafil (4)) and nonspecific PDE inhibitors (aminophylline, dipyridamole, theophylline) is contraindicated.(1) If transitioning from sildenafil to riociguat, discontinue sildenafil at least 24 hours prior to administering riociguat.(1) If transitioning from tadalafil to riociguat, discontinue tadalafil at least 48 hours prior to administering riociguat. Consider starting riociguat at 0.5 mg in patients at risk for hypotension.(1) If transitioning from riociguat to a PDE inhibitor, discontinue riociguat at least 24 hours prior to administering a PDE inhibitor.(1)

DISCUSSION: In a study of 7 PAH patients maintained on sildenafil (20 mg TID), single doses of riociguat (0.5 mg and 1 mg, sequentially) showed additive hemodynamic effects.(1) In clinical trials, there was a high rate of discontinuation for hypotension among patients receiving sildenafil (20 mg TID) and riociguat (1 mg to 2.5 mg TID) and one death.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Riociguat/Abacavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Riociguat is primarily metabolized by CYP1A1 and to a lesser extent by CYP3A4/3A5 and CYP2J2.(1,2) Abacavir has been shown to inhibit CYP1A1 in vitro and may decrease the metabolism of riociguat.(2,3)

CLINICAL EFFECTS: Concurrent use of abacavir with riociguat may result in elevated systemic levels and toxicity (e.g. hypotension) from riociguat.(2,3)

PREDISPOSING FACTORS: The risk for riociguat-associated hypotension is higher in patients with a systolic blood pressure (SBP) < or = 110 prior to treatment initiation or dose increase. Patient specific factors such as renal or hepatic impairment, or age > 65 years are associated with higher systemic exposure to riociguat and may increase interaction risk or severity.(1,4)

PATIENT MANAGEMENT: The US manufacturer of abacavir states that the dose of riociguat may need to be reduced when used concurrently.(3) Although the manufacturer of riociguat does not make any recommendations for dose adjustment when used with a CYP1A1 inhibitor, it has been suggested that the initial dose of riociguat be reduced to 0.5 mg 3 times daily. This is the same dose modification recommended during concurrent therapy with strong CYP and P-gp/BCRP inhibitors, based on a similar magnitude of interaction between riociguat and ketoconazole.(2) Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of abacavir.

DISCUSSION: In an interaction study of 8 HIV-positive patients without pulmonary hypertension, abacavir (given as a fixed-dose combination of abacavir 600 mg-dolutegravir 50 mg-lamivudine 300 mg once daily) increased the area-under-curve (AUC) of single-dose riociguat 0.5 mg by about 3-fold, compared to historical healthy volunteers administered single-dose riociguat 0.5 mg alone.(2) The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure (AUC) relative to dose is 90%. The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.

Riociguat/Dual Strong Cyp3a4 Inhibitor & P-Gp Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Riociguat is primarily metabolized by CYP1A1 and to a lesser extent by CYP3A4/3A5, CYP2C8, and CYP2J2.(1) P-glycoprotein (P-gp) and BCRP (breast cancer resistance protein) transport proteins participate in the biliary/fecal elimination of riociguat.(2) Dual inhibitors of CYP3A4 and P-gp may inhibit metabolic and transporter-based elimination of riociguat.(2)

CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity (e.g. hypotension) from riociguat.(1)

PREDISPOSING FACTORS: The risk for riociguat-associated hypotension is higher in patients with a systolic blood pressure (SBP) < or = 110 prior to treatment initiation or dose increase. Patient specific factors such as renal or hepatic impairment, or age > 65 years are associated with higher systemic exposure(1) to riociguat and may increase interaction risk or severity.

PATIENT MANAGEMENT: The manufacturer recommends a lower riociguat starting dose of 0.5 mg three times daily in patients receiving concomitant treatment with dual strong CYP and P-gp inhibitors.(1) The US manufacturer of itraconazole states that concurrent use with riociguat is not recommended during and two weeks after itraconazole treatment.(3) Patients stabilized on riociguat when a dual strong CYP and P-gp inhibitor is initiated may need to have their riociguat dose lowered for the duration of concurrent therapy. Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of the dual strong CYP and P-gp inhibitors.

DISCUSSION: In an interaction study, ketoconazole (an inhibitor of CYP1A1, CYP3A4, and P-gp) given 400 mg once daily increased the mean maximum concentration (Cmax) and area-under-curve (AUC) of riociguat by 46% and 150%, respectively.(2) The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure(AUC)relative to dose is 90%. The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Riociguat/Antacids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of interaction is not clear. Increased gastric pH is thought to decrease riociguat solubility and absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of riociguat with an antacid may result in decreased levels and effectiveness of riociguat.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration of antacids and riociguat by at least 1 hour.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Administration of 10 mL of an aluminum hydroxide-magnesium hydroxide containing antacid decreased the area-under-curve (AUC)and maximum concentration (Cmax)of riociguat by 34% and 56% respectively.(1)

*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.

• Pregnancy
• Pulmonary veno-occlusive disease

• Hypovolemia
• Increased risk of bleeding
• Left ventricular outflow obstruction
• Tobacco smoker

• Hypotension

Adverse reactions occurring more frequently (>=3%) with riociguat compared to placebo in clinical studies include headache, dyspepsia/gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.

Less Frequent

• Anemia
• Hemorrhage
• Hypotension

Rare or Very Rare

• Hemoptysis
• Pulmonary hemorrhage

More Frequent

• Diarrhea
• Dizziness
• Dyspepsia
• Headache disorder
• Nausea
• Vomiting

Less Frequent

• Acute abdominal pain
• Constipation
• Gastritis
• Gastroesophageal reflux disease

Rare or Very Rare

• Abdominal distension
• Dysphagia
• Epistaxis
• Nasal congestion
• Palpitations
• Peripheral edema

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Safety and efficacy of riociguat have not been established in pediatric patients.

Based on data from animal reproduction studies, riociguat may cause embryo-fetal toxicity and miscarriage when administered to a pregnant woman and is contraindicated during pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.) If riociguat is used during pregnancy or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. (See Females and Males of Reproductive Potential under Cautions.)

Riociguat and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because of the potential for serious adverse reactions to riociguat in nursing infants, advise women not to breastfeed during treatment with riociguat.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In clinical studies of riociguat, approximately 23% of the patients were 65 years of age or older and 6% were 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric and younger patients in these studies, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

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