Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.
Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.
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.
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.
CrCl ≥15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.
CrCl <15 mL/minute: Use is not recommended (has not been studied)
Dialysis: Nondialyzable. Use is not recommended (has not been studied)
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): Use is not recommended (has not been studied).
Refer to adult dosing. Use with caution; riociguat exposure is increased.
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.
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
No
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
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/204819s015lbl.pdf#page=24 must be dispensed with this medication.
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.
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
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.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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
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); concomitant administration with other soluble guanylate cyclase stimulators.
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to riociguat or any component of the formulation; breastfeeding.
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.
Substrate of BCRP/ABCG2, CYP2C8 (minor), CYP3A4 (minor), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abacavir: May increase the serum concentration of Riociguat. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Amyl Nitrite: May enhance the hypotensive effect of Riociguat. Risk X: 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. Risk C: 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. Monitor clinical response to riociguat more closely in patients using this combination. Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: 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. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: 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. Risk C: 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. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Riociguat. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Riociguat. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dipyridamole: May enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
Doxofylline: May enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: 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. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Ibudilast: May enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase the serum concentration of Riociguat. Risk C: Monitor therapy
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. Risk D: 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. Risk D: Consider therapy modification
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease the serum concentration of Riociguat. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk C: Monitor therapy
Molsidomine: Riociguat may enhance the hypotensive effect of Molsidomine. Risk X: Avoid combination
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Riociguat may enhance the hypotensive effect of Nitroprusside. Risk X: 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. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Roflumilast-Containing Products: May enhance the hypotensive effect of Riociguat. Risk C: Monitor therapy
Soluble Guanylate Cyclase Stimulators: Riociguat may enhance the adverse/toxic effect of Soluble Guanylate Cyclase Stimulators. Risk X: Avoid combination
Theophylline Derivatives: May enhance the hypotensive effect of Riociguat. Risk X: 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. Risk D: Consider therapy modification
Vasodilators (Organic Nitrates): May enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
Vericiguat: Soluble Guanylate Cyclase Stimulators may enhance the adverse/toxic effect of Vericiguat. Risk X: Avoid combination
[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.
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.
It is not known if riociguat is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
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.
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
Protein binding: Plasma: ~95%
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.
Bioavailability: ~94%
Half-life elimination: Patients: 12 hours; Healthy subjects: 7 hours
Time to peak, plasma: 1.5 hours
Excretion: Feces (~53%); urine (~40%)
Older adult: Higher exposure to riociguat
Cigarette smoking: Plasma concentrations are reduced by 50% to 60% in smokers.
Tablets (Adempas Oral)
0.5 mg (per each): $164.16
1 mg (per each): $164.16
1.5 mg (per each): $164.16
2 mg (per each): $164.16
2.5 mg (per each): $164.16
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