Adempas

Guanylate Cyclase Stimulants
Guanylate Cyclase Stimulants for PAH

Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

Oral Administration

Riociguat may be taken with or without food.
For patients unable to swallow whole tablets, riociguat may be crushed and mixed with water or soft food (e.g., applesauce) immediately prior to administration.
If a dose is missed, instruct patients to continue with the next regularly scheduled dose; however, if therapy is interrupted for >= 3 days, riociguat must be retitrated.

Severe

hematemesis / Delayed / 0-1.0
pulmonary edema / Early / Incidence not known
spontaneous fetal abortion / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

gastritis / Delayed / 21.0-21.0
hypotension / Rapid / 10.0-10.0
anemia / Delayed / 7.0-7.0
constipation / Delayed / 5.0-5.0
bleeding / Early / 2.4-2.4
subdural hematoma / Early / 0-1.0
hemoptysis / Delayed / 1.0-1.0
vaginal bleeding / Delayed / 0-1.0
palpitations / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known

Mild

headache / Early / 27.0-27.0
dyspepsia / Early / 21.0-21.0
dizziness / Early / 20.0-20.0
nausea / Early / 14.0-14.0
diarrhea / Early / 12.0-12.0
vomiting / Early / 10.0-10.0
gastroesophageal reflux / Delayed / 5.0-5.0
epistaxis / Delayed / Incidence not known
nasal congestion / Early / Incidence not known

Pregnancy

Riociguat is contraindicated for use in pregnancy. Exclude pregnancy prior to initiation of therapy. Riociguat may cause fetal harm if administered to a pregnant woman. When administered to rats at doses equivalent to approximately 2- and 8-times the human exposure, riociguat caused teratogenic and embryotoxic effects including an increased rate of cardiac ventricular-septal defect and post-implantation loss. When administered to rabbits, abortions were observed at doses 4-times the human exposure and fetal toxicity was seen with doses equivalent to 13-times the human exposure. If riociguat is used during pregnancy or if the patient becomes pregnant while taking this drug, counsel the patient of the potential hazard to a fetus.

Contraception requirements, pregnancy testing, reproductive risk

Discuss the reproductive risk of riociguat and contraception requirements, including the need for pregnancy testing before and during therapy with the female patient of childbearing potential. For females of childbearing potential, exclude pregnancy prior to initiation of therapy. Follow-up pregnancy tests should occur monthly during treatment for and 1 month after stopping treatment. Advise female patients of childbearing potential to contact their physician immediately if they become pregnant or suspect they may be pregnant. If a pregnancy test is positive, counsel the patient on the potential risks to the fetus and discuss options. To prevent pregnancy, females of reproductive potential must use acceptable contraception methods during treatment and for 1 month after discontinuation of riociguat therapy. The patient may choose a single highly effective contraceptive form, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of a hormonal contraceptive with a barrier method or 2 barrier methods. If a male partner’s vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception.

Adempas

Rx

Oral soluble guanylate cyclase stimulator; contraindicated for use with certain medications (review drug interactions)
Approved for the treatment of adults with pulmonary arterial hypertension (PAH) and chronic-thromboembolic pulmonary hypertension (CTEPH)
Contraindicated for use during pregnancy; females must be enrolled in the AdempasREMS program

For the treatment of pulmonary hypertension, including pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertension. For the treatment of pulmonary hypertension to improve exercise ability and WHO functional class and delay clinical worsening in persons with WHO Group 1 pulmonary hypertension. Oral dosage Adults

1 mg PO 3 times daily, initially.  Consider 0.5 mg PO 3 times daily initially in persons who may not tolerate the hypotensive effect. Increase dose by 0.5 mg 3 times daily every 2 weeks or more if systolic blood pressure remains more than 95 mmHg with no signs or symptoms of hypotension. Max: 2.5 mg PO 3 times daily.  Decrease dose by 0.5 mg 3 times daily for symptoms of hypotension. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Studies establishing effectiveness included predominately patients with WHO functional class II or III and etiologies of idiopathic or heritable pulmonary hypertension (61%) or pulmonary hypertension associated with connective tissue diseases (25%).

For the treatment of chronic-thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise ability and WHO functional class. Oral dosage Adults

1 mg PO 3 times daily, initially; consider 0.5 mg PO 3 times daily initially in persons who may not tolerate the hypotensive effect. Increase dose by 0.5 mg 3 times daily every 2 weeks or more if systolic blood pressure remains more than 95 mmHg with no signs or symptoms of hypotension. Max: 2.5 mg PO 3 times daily. Decrease dose by 0.5 mg 3 times daily for symptoms of hypotension. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Hepatic Impairment

Safety and efficacy have not been established in patients with severe hepatic impairment (Child Pugh C), therefore use is not recommended. No dosage adjustments are recommended in patients with mild to moderate hepatic impairment.

Renal Impairment

CrCl 15 mL/minute or more: No dosage adjustments are needed.
CrCl less than 15 mL/minute: Safety and efficacy have not been established, therefore use is not recommended.
 
Intermittent hemodialysis
Safety and efficacy have not been established; therefore, use is not recommended.

Abacavir: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Abacavir; Lamivudine, 3TC: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Guaifenesin; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acetaminophen; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Acrivastine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Aluminum Hydroxide: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Aluminum Hydroxide; Magnesium Carbonate: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Aluminum Hydroxide; Magnesium Trisilicate: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Amphetamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Amphetamine; Dextroamphetamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Antacids: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Apalutamide: (Moderate) Dosage recommendations for riociguat are not available if coadministration with apalutamide is necessary. Riociguat is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers may significantly reduce riociguat exposure, but data are not available.
Aprepitant, Fosaprepitant: (Moderate) Use caution if riociguat and aprepitant, fosaprepitant are used concurrently and monitor for an increase in riociguat-related adverse effects for several days after administration of a multi-day aprepitant regimen. Riociguat is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of riociguat. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Articaine; Epinephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Aspirin, ASA; Dipyridamole: (Contraindicated) Coadministration of riociguat and phosphodiesterase inhibitors, including nonspecific phosphodiesterase inhibitors like dipyridamole ,is contraindicated due to the risk of hypotension. A high rate of discontinuation for hypotension has been reported when riociguat was combined with specific phosphodiesterase-5 inhibitors, for example.
Avanafil: (Contraindicated) Use of riociguat and avanafil is contraindicated due to the risk of hypotension. Discontinue riociguat at least 24 hours prior to avanafil administration. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including avanafil, may potentiate the hypotensive effects of riociguat.
Benzphetamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Brompheniramine; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Brompheniramine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Bupivacaine; Epinephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Calcium Carbonate: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Calcium Carbonate; Magnesium Hydroxide: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Calcium Carbonate; Simethicone: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Calcium; Vitamin D: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Carbamazepine: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Cetirizine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Chlorpheniramine; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Chlorpheniramine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Cilostazol: (Moderate) Coadministration of riociguat and phosphodiesterase inhibitors, including specific phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) and nonspecific phosphodiesterase inhibitors (dipyridamole or theophylline, aminophylline) is contraindicated due to the risk of hypotension. Clinical experience with other phosphodidesterase inhibitors (e.g., milrinone, cilostazol, and roflumilast) is limited. The addition of riociguat to a stable sildenafil regimen (20 mg three times a day) resulted in additive hemodynamic effects in an exploratory interaction study in 7 patients with pulmonary arterial hypertension (PAH). Among patients with PAH on stable sildenafil treatment and riociguat there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Codeine; Phenylephrine; Promethazine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Daclatasvir: (Minor) Systemic exposure of riociguat, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of riociguat; monitor patients for potential adverse effects.
Delavirdine: (Moderate) Concomitant use of riociguat with strong cytochrome CYP3A inhibitors may result in hypotension. Delavirdine is a potent inhibitor of CYP3A4. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Desloratadine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dexbrompheniramine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dexmethylphenidate: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dextroamphetamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Diethylpropion: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Diphenhydramine; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dipyridamole: (Contraindicated) Coadministration of riociguat and phosphodiesterase inhibitors, including nonspecific phosphodiesterase inhibitors like dipyridamole ,is contraindicated due to the risk of hypotension. A high rate of discontinuation for hypotension has been reported when riociguat was combined with specific phosphodiesterase-5 inhibitors, for example.
Dobutamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Dopamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Doxapram: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Elbasvir; Grazoprevir: (Moderate) Administering riociguat with elbasvir; grazoprevir may result in elevated riociguat plasma concentrations. Riociguat is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Enzalutamide: (Major) Dosage recommendations for riociguat are not available if coadministration with enzalutamide is necessary. Riociguat is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Strong CYP3A4 inducers may significantly reduce riociguat exposure, but data are not available.
Ephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Ephedrine; Guaifenesin: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Epinephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Fexofenadine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Finasteride; Tadalafil: (Contraindicated) Use of riociguat and tadalafil is contraindicated due to the risk of hypotension. Do not administer riociguat 24 hours before or within 48 hours after tadalafil. When transitioning therapy, consider initiating riociguat at a starting dose of 0.5 mg PO 3 times daily in patients at risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including tadalafil, may potentiate the hypotensive effects of riociguat.
Fosamprenavir: (Major) Concomitant use of riociguat and fosamprenavir may result in altered riociguat plasma concentrations. Riociguat is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a potent inhibitor and moderate inducer of CYP3A4.
Fosphenytoin: (Moderate) Coadministration of riociguat with phenytoin or fosphenytoin may significantly reduce riociguat exposure; however, riociguat dosage adjustment recommendations are not available. Riociguat is a CYP3A4 substrate and phenytoin and fosphenytoin are strong CYP3A4 inducers.
Gemfibrozil: (Moderate) Coadministration may result in a significant increase in riociguat exposure. A dose reduction of riociguat may be required if used concomitantly with gemfibrozil. Use riociguat and gemfibrozil together with caution. Riociguat is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor.
Guaifenesin; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Guaifenesin; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Hydrocodone; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Ibuprofen; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Indinavir: (Moderate) Concomitant use of riociguat with strong cytochrome CYP3A inhibitors may result in hypotension. Indinavir is a potent inhibitor of CYP3A4. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with riociguat may result in increased serum concentrations of riociguat. Riociguat is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring for adverse effects, such as hypotension, are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Isoniazid, INH; Rifampin: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Isoproterenol: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Itraconazole: (Major) Avoid riociguat use during and for up to 2 weeks after discontinuation of itraconazole treatment unless benefits of treatment outweigh the potentially increased risk of side effects. Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as itraconazole, increases riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg three times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Ketoconazole: (Major) Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (e.g., ketoconazole, itraconazole) or anti-retroviral protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Levoketoconazole: (Major) Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (e.g., ketoconazole, itraconazole) or anti-retroviral protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Lidocaine; Epinephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Lisdexamfetamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Lonafarnib: (Major) Consider a starting dose of 0.5 mg PO three times daily when initiating riociguat in patients receiving lonafarnib; concurrent use may increase riociguat exposure. Monitor for signs and symptoms of hypotension on initiation and during treatment with lonafarnib. Consider a dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Riociguat is a substrate of CYP3A4, P-gp, and BCRP; lonafarnib is a strong CYP3A4 and P-gp inhibitor.
Lopinavir; Ritonavir: (Major) Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors, such as ritonavir, increases riociguat exposure and may result in hypotension. Consider a starting adult dose of 0.5 mg PO three times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Loratadine; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Lumacaftor; Ivacaftor: (Moderate) Concomitant use of riociguat and lumacaftor; ivacaftor may alter riociguat exposure. Riociguat is a substrate of CYP3A4, CYP2C8, and the drug transporter P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and P-gp. Caution and close monitoring are advised if these drugs are used together.
Lumacaftor; Ivacaftor: (Moderate) Concomitant use of riociguat and lumacaftor; ivacaftor may alter riociguat exposure. Riociguat is a substrate of CYP3A4, CYP2C8, and the drug transporter P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and P-gp. Caution and close monitoring are advised if these drugs are used together.
Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Magnesium Hydroxide: (Major) Separate administration of riociguat from antacids by at least 1 hour. Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption.
Methamphetamine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat

. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Methylphenidate: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Midodrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Milrinone: (Moderate) Coadministration of riociguat and phosphodiesterase inhibitors, including specific phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) and nonspecific phosphodiesterase inhibitors (dipyridamole or theophylline, aminophylline) is contraindicated due to the risk of hypotension. Clinical experience with other phosphodidesterase inhibitors (e.g., milrinone, cilostazol, and roflumilast) is limited. The addition of riociguat to a stable sildenafil regimen (20 mg three times a day) resulted in additive hemodynamic effects in an exploratory interaction study in 7 patients with pulmonary arterial hypertension (PAH). Among patients with PAH on stable sildenafil treatment and riociguat there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.
Mitotane: (Major) Use caution if mitotane and riociguat are used concomitantly, and monitor for decreased efficacy of riociguat and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and riociguat is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of riociguat.
Naproxen; Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Nefazodone: (Moderate) Concomitant use of riociguat with strong cytochrome CYP3A inhibitors may result in hypotension. Nefazodone is a potent inhibitor of CYP3A4. In addition, nefazodone may cause orthostatic hypotension in some patients; this effect may be additive with riociguat. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Nirmatrelvir; Ritonavir: (Major) Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors, such as ritonavir, increases riociguat exposure and may result in hypotension. Consider a starting adult dose of 0.5 mg PO three times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Nitrates: (Contraindicated) Coadministration of riociguat and nitrates or nitric oxide donors (e.g., amyl nitrite) is contraindicated due to the risk of hypotension. The blood pressure lowering effect of sublingual nitroglycerin was potentiated when administered 4 and 8 hours after riociguat. Syncope was reported in some patients.
Nitroprusside: (Contraindicated) Concomitant use of nitroprusside and riociguat is contraindicated due to the risk of additive hypotension.
Norepinephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Phendimetrazine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Phenobarbital: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Phentermine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Phentermine; Topiramate: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Phenytoin: (Moderate) Coadministration of riociguat with phenytoin or fosphenytoin may significantly reduce riociguat exposure; however, riociguat dosage adjustment recommendations are not available. Riociguat is a CYP3A4 substrate and phenytoin and fosphenytoin are strong CYP3A4 inducers.
Prilocaine; Epinephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Promethazine; Phenylephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Pseudoephedrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Pseudoephedrine; Triprolidine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Racepinephrine: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Rifampin: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Rifapentine: (Moderate) Coadministration of riociguat with rifapentine may significantly reduce riociguat exposure; however, riociguat dosage adjustment recommendations are not available. Riociguat is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Ritonavir: (Major) Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors, such as ritonavir, increases riociguat exposure and may result in hypotension. Consider a starting adult dose of 0.5 mg PO three times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Roflumilast: (Moderate) Coadministration of riociguat and phosphodiesterase inhibitors, including specific phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) and nonspecific phosphodiesterase inhibitors (dipyridamole or theophylline, aminophylline) is contraindicated due to the risk of hypotension. Clinical experience with other phosphodidesterase inhibitors (e.g., milrinone, cilostazol, and roflumilast) is limited. The addition of riociguat to a stable sildenafil regimen (20 mg three times a day) resulted in additive hemodynamic effects in an exploratory interaction study in 7 patients with pulmonary arterial hypertension (PAH). Among patients with PAH on stable sildenafil treatment and riociguat there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.
Serdexmethylphenidate; Dexmethylphenidate: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Sildenafil: (Contraindicated) Use of riociguat and sildenafil is contraindicated due to the risk of hypotension. Discontinue riociguat at least 24 hours prior to sildenafil administration and do not administer within 24 hours of sildenafil. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of riociguat, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
St. John's Wort, Hypericum perforatum: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Sympathomimetics: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Tadalafil: (Contraindicated) Use of riociguat and tadalafil is contraindicated due to the risk of hypotension. Do not administer riociguat 24 hours before or within 48 hours after tadalafil. When transitioning therapy, consider initiating riociguat at a starting dose of 0.5 mg PO 3 times daily in patients at risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including tadalafil, may potentiate the hypotensive effects of riociguat.
Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with riociguat is necessary, and monitor for an increase in riociguat-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and riociguat is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to riociguat is likely to increase.
Theophylline, Aminophylline: (Contraindicated) Coadministration of riociguat and phosphodiesterase inhibitors, including nonspecific phosphodiesterase inhibitors (e.g., theophylline, aminophylline) is contraindicated due to the risk of hypotension.
Tipranavir: (Moderate) Concomitant use of riociguat with strong cytochrome CYP3A inhibitors may result in hypotension. Tipranavir is a potent inhibitor of CYP3A4. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking riociguat. Riociguat doses higher than 2.5 mg three times a day may be considered to match exposure seen in nonsmoking patients. In patients who smoke tobacco, plasma concentrations of riociguat are reduced by 50% to 60% compared to nonsmokers.
Tucatinib: (Major) Consider a starting dose of 0.5 mg PO 3 times daily when initiating riociguat in patients receiving tucatinib; concurrent use may increase riociguat exposure. Monitor for signs and symptoms of hypotension on initiation and during treatment with tucatinib. Consider a dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Riociguat is a substrate of CYP3A4 and P-glycoprotein (P-gp); tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Vardenafil: (Contraindicated) Use of riociguat and vardenafil is contraindicated due to the risk of hypotension. Discontinue riociguat at least 24 hours prior to vardenafil administration. Monitor for signs and symptoms of hypotension during transition of therapy. PDE5 inhibitors, including vardenafil, may potentiate the hypotensive effects of riociguat.
Vericiguat: (Contraindicated) Coadministration of vericiguat with other soluble guanylate cyclase (sGC) stimulators, such as riociguat, is contraindicated.
Zafirlukast: (Minor) It is possible that an increase in the exposure of riociguat may occur when coadministered with drugs that inhibit CYP2C8 such as zafirlukast. Although in vivo data has not substantiated clinically relavent interactions with CYP2C8 substrates, patients should be monitored for hypotension if zafirlukast is coadministered with riociguat.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and riociguat is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

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

Adults

2.5 mg PO 3 times daily.

Geriatric

2.5 mg PO 3 times daily.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Riociguat is a soluble guanylate cyclase stimulator. Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, cyclic guanosine monophosphate (cGMP) is synthesized. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat sensitizes sGC to endogenous NO by stabilizing NO-sGC binding and directly stimulates sGC via a different binding site, independently of NO. When riociguat stimulates the NO-sGC-cGMP pathway, generation of cGMP with subsequent vasodilation is increased.

Riociguat is administered orally. Pharmacokinetic parameters are dose proportional. Riociguat plasma concentrations directly correlate to hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance, and cardiac output. Riociguat is highly bound to plasma proteins (95%) and is metabolized by CYP1A1, CYP3A, CYP2C8 and CYP2J2. The major active metabolite, M1, is catalyzed via CYP1A1, and is 1/3 to 1/30 as potent as riociguat. M1 is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with pulmonary arterial hypertension (PAH) are about half those for riociguat. Excretion occurs via both renal and fecal/biliary routes. The terminal elimination half-life is prolonged in patients with PAH (12 hours) compared with healthy subjects (7 hours).
 
Affected cytochrome P450 isoenzymes:
Riociguat is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In addition, riociguat is metabolized by CYP1A1, CYP3A, CYP2C8 and CYP2J2 and the major active metabolite is formed via CYP1A1. Therefore, pharmacokinetic interactions are possible when riociguat is coadministered with inhibitors or inducers or these enzymes and/or transporter proteins.

Oral Route

Following oral administration, riociguat is rapidly absorbed with maximum plasma concentrations occurring within 1.5 hours. The absolute bioavailability is about 94%; food has no effect on bioavailability. Average systemic clearance of riociguat was about 1.8 L/h in patients with PAH and about 3.4 L/h in healthy subjects.

Pregnancy

Riociguat is contraindicated for use in pregnancy. Exclude pregnancy prior to initiation of therapy. Riociguat may cause fetal harm if administered to a pregnant woman. When administered to rats at doses equivalent to approximately 2- and 8-times the human exposure, riociguat caused teratogenic and embryotoxic effects including an increased rate of cardiac ventricular-septal defect and post-implantation loss. When administered to rabbits, abortions were observed at doses 4-times the human exposure and fetal toxicity was seen with doses equivalent to 13-times the human exposure. If riociguat is used during pregnancy or if the patient becomes pregnant while taking this drug, counsel the patient of the potential hazard to a fetus.

Discuss the reproductive risk of riociguat and contraception requirements, including the need for pregnancy testing before and during therapy with the female patient of childbearing potential. For females of childbearing potential, exclude pregnancy prior to initiation of therapy. Follow-up pregnancy tests should occur monthly during treatment for and 1 month after stopping treatment. Advise female patients of childbearing potential to contact their physician immediately if they become pregnant or suspect they may be pregnant. If a pregnancy test is positive, counsel the patient on the potential risks to the fetus and discuss options. To prevent pregnancy, females of reproductive potential must use acceptable contraception methods during treatment and for 1 month after discontinuation of riociguat therapy. The patient may choose a single highly effective contraceptive form, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of a hormonal contraceptive with a barrier method or 2 barrier methods. If a male partner’s vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception.