RIOCIGUAT Drug Interactions: What You Need to Know

INTERACTIONS

• Strong CYP and P-gp/BCRP inhibitors: For patients receiving strong CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg three times a day. Monitor for hypotension. (7.2 )
• Antacids: Separate administration by at least 1 hour. ( 7.2 )

7.1 Pharmacodynamic Interactions with Adempas Other Soluble Guanylate Cyclase Stimulators: Co-administration of Adempas is contraindicated in patients with use of other soluble guanylate cyclase (sGC) stimulators <span class="opacity-50 text-xs">[see Contraindications ( 4.4 )]</span>. Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension <span class="opacity-50 text-xs">[see Contraindications ( 4.2 ) and Clinical Pharmacology ( 12.2 )]</span> .

Pde

Inhibitors: Co-administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil [see Dosage and Administration (2.6)]. Clinical experience with co-administration of Adempas and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited.

7.2 Pharmacokinetic Interactions with Adempas Smoking: Plasma concentrations in smokers are reduced by 50% to 60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]</span>. Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV 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 Adempas 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )]</span> . Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered. <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

4 CONTRAINDICATIONS

• Pregnancy ( 4.1 )
• Use with nitrates or nitric oxide donors in any form ( 4.2 , 7.1 )
• Use with PDE inhibitors ( 2.6 , 4.3 , 7.1 )
• Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators. ( 4.4 , 7.1 )
• Pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) ( 4.4 )

4.1 Pregnancy Based on data from animal reproduction studies, Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> .

4.2 Nitrates and Nitric Oxide Donors Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated <span class="opacity-50 text-xs">[see Drug Interactions (7.1) and Clinical Pharmacology ( 12.2 )]</span> .

4.3 Phosphodiesterase Inhibitors Concomitant administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE 5 inhibitors (such as dipyridamole or theophylline) is contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.6), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )]</span>. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.

4.4 Soluble Guanylate Stimulators Adempas is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

4.5 Pulmonary Hypertension Associated with Idiopathic Interstitial Pneumonias (PH-IIP) Adempas is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

AND PRECAUTIONS

• Symptomatic hypotension ( 5.3 )
• Bleeding ( 5.4 )
• Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment ( 5.5 )

5.1 Embryo-Fetal Toxicity Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment, monthly during treatment, and for one month after stopping treatment. Advise females of reproductive potential to use effective contraception during treatment with ADEMPAS and for at least one month after the last dose <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.1 , 8.3 )]</span> . For females, Adempas is only available through a restricted program under the Adempas REMS Program <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

5.2 Adempas REMS Program Females can only receive Adempas through the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program, a restricted distribution program <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. Important requirements of the Adempas REMS Program include the following:

• Prescribers must be certified with the program by enrolling and completing training.
• All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.
• Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations ( 8.3 )].
• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas. Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4 ADEMPAS.

5.3 Hypotension Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]</span> . Consider a dose reduction if patient develops signs or symptoms of hypotension.

5.4 Bleeding In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.

5.5 Pulmonary Veno-Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Adempas.