Adempas

Drug overview for ADEMPAS (riociguat):

Generic name: RIOCIGUAT (RYE-oh-SIG-ue-at)
Drug class: Pulmonary Antihypertensive Agents, cGMP pathway
Therapeutic class: Cardiovascular Therapy Agents

Riociguat, a soluble guanylate cyclase (sGC) stimulator, is a vasodilator.

No enhanced Uses information available for this drug.

DRUG IMAGES

ADEMPAS 1 MG TABLET
ADEMPAS 0.5 MG TABLET

The following indications for ADEMPAS (riociguat) have been approved by the FDA:

Indications:
Chronic thromboembolic pulmonary hypertension
Pulmonary arterial hypertension

Professional Synonyms:
Hypertensive pulmonary arterial disease
Pulmonary hypertensive arterial disease

Dosing information for ADEMPAS
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
ADEMPAS 0.5 MG TABLET	Maintenance	Adults take 1 tablet (0.5 mg) by oral route 3 times per day doses about 6 to 8 hours apart
ADEMPAS 1 MG TABLET	Maintenance	Adults take 1 tablet (1 mg) by oral route 3 times per day doses about 6 to 8 hours apart
ADEMPAS 1.5 MG TABLET	Maintenance	Adults take 1 tablet (1.5 mg) by oral route 3 times per day doses about 6 to 8 hours apart
ADEMPAS 2 MG TABLET	Maintenance	Adults take 1 tablet (2 mg) by oral route 3 times per day doses about 6 to 8 hours apart
ADEMPAS 2.5 MG TABLET	Maintenance	Adults take 1 tablet (2.5 mg) by oral route 3 times per day doses about 6 to 8 hours apart

The following drug interaction information is available for ADEMPAS (riociguat):

Contraindicated
Severe
Moderate

There are 2 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Riociguat/Nitrates & Nitric Oxide Donors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Nitrates activate guanyl cyclase, an enzyme that increases levels of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation. Riociguat stimulates the nitric oxide-soluble guanylate cyclase-cGMP pathway and also increases cGMP. Concurrent use of nitrates with riociguat results in potentiation of the effect of both agents.(1) CLINICAL EFFECTS: The concurrent use riociguat and nitrates potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The administration of riociguat to patients receiving nitrates, or nitric oxide donors, in any form is contraindicated.(1) DISCUSSION: Riociguat (2.5 mg) potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) when taken 4 hour and 8 hours after riociguat. Syncope was reported in some patients.(1)	AMYL NITRITE, BIDIL, GONITRO, ISORDIL, ISORDIL TITRADOSE, ISOSORBIDE, ISOSORBIDE DINIT-HYDRALAZINE, ISOSORBIDE DINITRATE, ISOSORBIDE MONONITRATE, ISOSORBIDE MONONITRATE ER, NIPRIDE RTU, NITHIODOTE, NITRO-BID, NITRO-DUR, NITRO-TIME, NITROGLYCERIN, NITROGLYCERIN IN D5W, NITROGLYCERIN PATCH, NITROLINGUAL, NITROMIST, NITROSTAT, RECTIV, SODIUM NITRITE, SODIUM NITROPRUSSIDE, SODIUM NITROPRUSSIDE-0.9% NACL
Riociguat/PDE Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Riociguat stimulates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway and also increases cGMP.(1) Aminophylline, avanafil, dipyridamole, sildenafil, tadalafil, theophylline, and vardenafil inhibit phosphodiesterase (PDE), which is responsible for the breakdown of cGMP.(1) CLINICAL EFFECTS: The concurrent use of PDE inhibitors and riociguat potentiates the hypotensive effects of both agents, which may result in dizziness, syncope, heart attack, or stroke.(1) PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitors may be higher in the following patients: those older than 65, with hepatic impairment, with severe renal impairment, or using concomitant CYP3A4 inhibitors. This may increase the severity of the interaction. PATIENT MANAGEMENT: The administration of riociguat to patients receiving PDE inhibitors, including specific PDE-5 inhibitors (avanafil (5), sildenafil (2), tadalafil (3,6), or vardenafil (4)) and nonspecific PDE inhibitors (aminophylline, dipyridamole, theophylline) is contraindicated.(1) If transitioning from sildenafil to riociguat, discontinue sildenafil at least 24 hours prior to administering riociguat.(1) If transitioning from tadalafil to riociguat, discontinue tadalafil at least 48 hours prior to administering riociguat. Consider starting riociguat at 0.5 mg in patients at risk for hypotension.(1) If transitioning from riociguat to a PDE inhibitor, discontinue riociguat at least 24 hours prior to administering a PDE inhibitor.(1) DISCUSSION: In a study of 7 PAH patients maintained on sildenafil (20 mg TID), single doses of riociguat (0.5 mg and 1 mg, sequentially) showed additive hemodynamic effects.(1) In clinical trials, there was a high rate of discontinuation for hypotension among patients receiving sildenafil (20 mg TID) and riociguat (1 mg to 2.5 mg TID) and one death.(1)	ADCIRCA, ALYQ, AMINOPHYLLINE, ASPIRIN-DIPYRIDAMOLE ER, AVANAFIL, CIALIS, DIPYRIDAMOLE, ELIXOPHYLLIN, ENTADFI, OPSYNVI, REVATIO, SILDENAFIL CITRATE, STENDRA, TADALAFIL, TADLIQ, THEO-24, THEOPHYLLINE, THEOPHYLLINE ANHYDROUS, THEOPHYLLINE ER, THEOPHYLLINE ETHYLENEDIAMINE, VARDENAFIL HCL, VIAGRA

Drug Interaction

Drug Names

Riociguat/Nitrates & Nitric Oxide Donors

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

AMYL NITRITE, BIDIL, GONITRO, ISORDIL, ISORDIL TITRADOSE, ISOSORBIDE, ISOSORBIDE DINIT-HYDRALAZINE, ISOSORBIDE DINITRATE, ISOSORBIDE MONONITRATE, ISOSORBIDE MONONITRATE ER, NIPRIDE RTU, NITHIODOTE, NITRO-BID, NITRO-DUR, NITRO-TIME, NITROGLYCERIN, NITROGLYCERIN IN D5W, NITROGLYCERIN PATCH, NITROLINGUAL, NITROMIST, NITROSTAT, RECTIV, SODIUM NITRITE, SODIUM NITROPRUSSIDE, SODIUM NITROPRUSSIDE-0.9% NACL

Riociguat/PDE Inhibitors

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

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

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

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

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

Consider starting riociguat at 0.5 mg in patients at risk for hypotension.(1) If transitioning from riociguat to a PDE inhibitor, discontinue riociguat at least 24 hours prior to administering a PDE inhibitor.(1)

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

ADCIRCA, ALYQ, AMINOPHYLLINE, ASPIRIN-DIPYRIDAMOLE ER, AVANAFIL, CIALIS, DIPYRIDAMOLE, ELIXOPHYLLIN, ENTADFI, OPSYNVI, REVATIO, SILDENAFIL CITRATE, STENDRA, TADALAFIL, TADLIQ, THEO-24, THEOPHYLLINE, THEOPHYLLINE ANHYDROUS, THEOPHYLLINE ER, THEOPHYLLINE ETHYLENEDIAMINE, VARDENAFIL HCL, VIAGRA

There are 2 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Riociguat/Dual Strong CYP3A4 Inhibitor & P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Riociguat is primarily metabolized by CYP1A1 and to a lesser extent by CYP3A4/3A5, CYP2C8, and CYP2J2.(1) P-glycoprotein (P-gp) and BCRP (breast cancer resistance protein) transport proteins participate in the biliary/fecal elimination of riociguat.(2) Dual inhibitors of CYP3A4 and P-gp may inhibit metabolic and transporter-based elimination of riociguat.(2) CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity (e.g. hypotension) from riociguat.(1) PREDISPOSING FACTORS: The risk for riociguat-associated hypotension is higher in patients with a systolic blood pressure (SBP) < or = 110 prior to treatment initiation or dose increase. Patient specific factors such as renal or hepatic impairment, or age > 65 years are associated with higher systemic exposure(1) to riociguat and may increase interaction risk or severity. PATIENT MANAGEMENT: The manufacturer recommends a lower riociguat starting dose of 0.5 mg three times daily in patients receiving concomitant treatment with dual strong CYP and P-gp inhibitors.(1) The US manufacturer of itraconazole states that concurrent use with riociguat is not recommended during and two weeks after itraconazole treatment.(3) Patients stabilized on riociguat when a dual strong CYP and P-gp inhibitor is initiated may need to have their riociguat dose lowered for the duration of concurrent therapy. Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of the dual strong CYP and P-gp inhibitors. DISCUSSION: In an interaction study, ketoconazole (an inhibitor of CYP1A1, CYP3A4, and P-gp) given 400 mg once daily increased the mean maximum concentration (Cmax) and area-under-curve (AUC) of riociguat by 46% and 150%, respectively.(2) The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure(AUC)relative to dose is 90%. The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.	APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VOQUEZNA TRIPLE PAK, ZOKINVY
Riociguat/Abacavir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Riociguat is primarily metabolized by CYP1A1 and to a lesser extent by CYP3A4/3A5 and CYP2J2.(1,2) Abacavir has been shown to inhibit CYP1A1 in vitro and may decrease the metabolism of riociguat.(2,3) CLINICAL EFFECTS: Concurrent use of abacavir with riociguat may result in elevated systemic levels and toxicity (e.g. hypotension) from riociguat.(2,3) PREDISPOSING FACTORS: The risk for riociguat-associated hypotension is higher in patients with a systolic blood pressure (SBP) < or = 110 prior to treatment initiation or dose increase. Patient specific factors such as renal or hepatic impairment, or age > 65 years are associated with higher systemic exposure to riociguat and may increase interaction risk or severity.(1,4) PATIENT MANAGEMENT: The US manufacturer of abacavir states that the dose of riociguat may need to be reduced when used concurrently.(3) Although the manufacturer of riociguat does not make any recommendations for dose adjustment when used with a CYP1A1 inhibitor, it has been suggested that the initial dose of riociguat be reduced to 0.5 mg 3 times daily. This is the same dose modification recommended during concurrent therapy with strong CYP and P-gp/BCRP inhibitors, based on a similar magnitude of interaction between riociguat and ketoconazole.(2) Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of abacavir. DISCUSSION: In an interaction study of 8 HIV-positive patients without pulmonary hypertension, abacavir (given as a fixed-dose combination of abacavir 600 mg-dolutegravir 50 mg-lamivudine 300 mg once daily) increased the area-under-curve (AUC) of single-dose riociguat 0.5 mg by about 3-fold, compared to historical healthy volunteers administered single-dose riociguat 0.5 mg alone.(2) The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure (AUC) relative to dose is 90%. The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.	ABACAVIR, ABACAVIR-LAMIVUDINE, TRIUMEQ, TRIUMEQ PD, ZIAGEN

Drug Interaction

Drug Names

Riociguat/Dual Strong CYP3A4 Inhibitor & P-gp Inhibitors

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

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

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

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

PATIENT MANAGEMENT: The manufacturer recommends a lower riociguat starting dose of 0.5 mg three times daily in patients receiving concomitant treatment with dual strong CYP and P-gp inhibitors.(1) The US manufacturer of itraconazole states that concurrent use with riociguat is not recommended during and two weeks after itraconazole treatment.(3)

Patients stabilized on riociguat when a dual strong CYP and P-gp inhibitor is initiated may need to have their riociguat dose lowered for the duration of concurrent therapy. Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of the dual strong CYP and P-gp inhibitors.

DISCUSSION: In an interaction study, ketoconazole (an inhibitor of CYP1A1, CYP3A4, and P-gp) given 400 mg once daily increased the mean maximum concentration (Cmax) and area-under-curve (AUC) of riociguat by 46% and 150%, respectively.(2) The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure(AUC)relative to dose is 90%.

The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.

APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VOQUEZNA TRIPLE PAK, ZOKINVY

Riociguat/Abacavir

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

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

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

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

PATIENT MANAGEMENT: The US manufacturer of abacavir states that the dose of riociguat may need to be reduced when used concurrently.(3) Although the manufacturer of riociguat does not make any recommendations for dose adjustment when used with a CYP1A1 inhibitor, it has been suggested that the initial dose of riociguat be reduced to 0.5 mg 3 times daily.

This is the same dose modification recommended during concurrent therapy with strong CYP and P-gp/BCRP inhibitors, based on a similar magnitude of interaction between riociguat and ketoconazole.(2) Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of abacavir.

DISCUSSION: In an interaction study of 8 HIV-positive patients without pulmonary hypertension, abacavir (given as a fixed-dose combination of abacavir 600 mg-dolutegravir 50 mg-lamivudine 300 mg once daily) increased the area-under-curve (AUC) of single-dose riociguat 0.5 mg by about 3-fold, compared to historical healthy volunteers administered single-dose riociguat 0.5 mg alone.(2)

The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure (AUC) relative to dose is 90%. The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.

ABACAVIR, ABACAVIR-LAMIVUDINE, TRIUMEQ, TRIUMEQ PD, ZIAGEN

There are 1 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Riociguat/Antacids SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The mechanism of interaction is not clear. Increased gastric pH is thought to decrease riociguat solubility and absorption.(1) CLINICAL EFFECTS: Simultaneous administration of riociguat with an antacid may result in decreased levels and effectiveness of riociguat.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Separate the administration of antacids and riociguat by at least 1 hour.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well. DISCUSSION: Administration of 10 mL of an aluminum hydroxide-magnesium hydroxide containing antacid decreased the area-under-curve (AUC)and maximum concentration (Cmax)of riociguat by 34% and 56% respectively.(1)	CALCIUM ACETATE, CALCIUM CHLORIDE, CALCIUM GLUCONATE, CALCIUM GLUCONATE MONOHYDRATE, GAVILYTE-C, GAVILYTE-G, GAVILYTE-N, GOLYTELY, KONVOMEP, OMEPRAZOLE-SODIUM BICARBONATE, PEG 3350-ELECTROLYTE, PEG-3350 AND ELECTROLYTES, SODIUM BICARBONATE, VAXCHORA BUFFER COMPONENT

Drug Interaction

Drug Names

Riociguat/Antacids

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

CALCIUM ACETATE, CALCIUM CHLORIDE, CALCIUM GLUCONATE, CALCIUM GLUCONATE MONOHYDRATE, GAVILYTE-C, GAVILYTE-G, GAVILYTE-N, GOLYTELY, KONVOMEP, OMEPRAZOLE-SODIUM BICARBONATE, PEG 3350-ELECTROLYTE, PEG-3350 AND ELECTROLYTES, SODIUM BICARBONATE, VAXCHORA BUFFER COMPONENT

The following contraindication information is available for ADEMPAS (riociguat):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Pregnancy. *Concomitant therapy with nitrates or nitric oxide donors in any form (e.g., amyl nitrite, nitroglycerin). *Concomitant therapy with PDE inhibitors, including specific PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) and nonspecific PDE inhibitors (e.g., dipyridamole, theophylline).

*Concomitant therapy with other soluble guanylate cyclase stimulators. *Pulmonary hypertension associated with idiopathic interstitial pneumonias.

There are 2 contraindications. Absolute contraindication.

Contraindication List
Pregnancy
Pulmonary veno-occlusive disease

There are 4 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Hypovolemia
Increased risk of bleeding
Left ventricular outflow obstruction
Tobacco smoker

There are 1 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Hypotension

The following adverse reaction information is available for ADEMPAS (riociguat):

Overview
Severe
Less Severe

Adverse reaction overview.

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

There are 5 severe adverse reactions.

More Frequent	Less Frequent
None.	Anemia Hemorrhage Hypotension

Rare/Very Rare
Hemoptysis Pulmonary hemorrhage

There are 16 less severe adverse reactions.

More Frequent	Less Frequent
Diarrhea Dizziness Dyspepsia Headache disorder Nausea Vomiting	Acute abdominal pain Constipation Gastritis Gastroesophageal reflux disease

Rare/Very Rare
Abdominal distension Dysphagia Epistaxis Nasal congestion Palpitations Peripheral edema

The following precautions are available for ADEMPAS (riociguat):

Pediatric
Pregnant
Lactation
Geriatric

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

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

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

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

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

Chronic thromboembolic pulmonary hypertension
I27.24	Chronic thromboembolic pulmonary hypertension
Pulmonary arterial hypertension
I27.0	Primary pulmonary hypertension
I27.21	Secondary pulmonary arterial hypertension