by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Data not available for dose adjustmentritonavirSerious - Use Alternative (3)ritonavir will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. ritonavir will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if needed ritonavir will increase the level or effect of riociguat by Other (see comment). Avoid or Use Alternate Drug. Coadministration of riociguat (an ABCG2 [BCRP] substrate) with strong ABCG2 inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededroflumilastMonitor Closely (1)riociguat, roflumilast. Either increases toxicity of the other by additive vasodilation. Modify Therapy/Monitor Closely. Riociguat is contraindicated with specific PDE-5 inhibitors (eg sildenafil, tadalafil, vardenafil) and nonspecific PDE-5 inhibitors (eg theophylline, dipyridamole) due to risk of hypotension; data are limited with other PDE inhibitors (eg, milrinone, cilostazol, roflumilast).rucaparibMonitor Closely (1)rucaparib will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.safinamideMonitor Closely (1)safinamide will increase the level or effect of riociguat by Other (see comment). Use Caution/Monitor. Safinamide and its major metabolite may inhibit intestinal BCRP. Monitor BCRP substrates for increased pharmacologic or adverse effects.saquinavirSerious - Use Alternative (3)saquinavir will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. saquinavir will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if needed saquinavir will increase the level or effect of riociguat by Other (see comment). Avoid or Use Alternate Drug. Coadministration of riociguat (an ABCG2 [BCRP] substrate) with strong ABCG2 inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededsarecyclineMonitor Closely (1)sarecycline will increase the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.sildenafilContraindicated (1)sildenafil, riociguat. Either increases effects of the other by additive vasodilation. Contraindicated. Coadministration of PDE-5 inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil) and guanylate cyclase stimulators (eg, riociguat) is contraindicated due to risk of additive hypotension; do not administer within 24 hr of each other.simvastatinSerious - Use Alternative (1)simvastatin will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededsmokingMonitor Closely (1)smoking will decrease the level or effect of riociguat by increasing metabolism. Modify Therapy/Monitor Closely. Consider titrating riociguat to dosage >2.5 mg PO TID if tolerated; may need to decrease dose if quit smokingsodium bicarbonateMonitor Closely (1)sodium bicarbonate decreases levels of riociguat by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. Separate administration by at least 1 hour.sofosbuvir/velpatasvirMonitor Closely (1)sofosbuvir/velpatasvir will increase the level or effect of riociguat by Other (see comment). Use Caution/Monitor. Velpatasvir is an inhibitor of the drug transporter BCRP. Coadministration may increase systemic exposure of drugs that are BCRP substrates.sotorasibSerious - Use Alternative (1)sotorasib will decrease the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.St John's WortMonitor Closely (1)St John's Wort will decrease the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Data not available for dose adjustmentstiripentolMonitor Closely (3)stiripentol, riociguat. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment. stiripentol will increase the level or effect of riociguat by Other (see comment). Modify Therapy/Monitor Closely. Stiripentol is a BCRP transport inhibitor. Consider dosage reduction for BCRP substrates if adverse effects are experienced when coadministered. stiripentol will increase the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.sunitinibSerious - Use Alternative (2)sunitinib will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if needed sunitinib will increase the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Coadministration of riociguat (P-gp substrate) with strong P-gp inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededtacrolimusSerious - Use Alternative (1)tacrolimus will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededtadalafilContraindicated (1)tadalafil, riociguat. Either increases effects of the other by additive vasodilation. Contraindicated. Coadministration of PDE-5 inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil) and guanylate cyclase stimulators (eg, riociguat) is contraindicated due to risk of additive hypotension; do not administer 24 hr before or within 48hr of each other.tafamidisMonitor Closely (1)tafamidis will increase the level or effect of riociguat by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.tafamidis meglumineMonitor Closely (1)tafamidis meglumine will increase the level or effect of riociguat by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.tamoxifenSerious - Use Alternative (1)tamoxifen will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededtazemetostatMonitor Closely (1)tazemetostat will decrease the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tecovirimatMonitor Closely (2)tecovirimat will increase the level or effect of riociguat by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19. Monitor for adverse effects if coadministered with sensitive substrates of these enzymes. tecovirimat will decrease the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.tepotinibSerious - Use Alternative (1)tepotinib will increase the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.theophyllineContraindicated (1)theophylline, riociguat. Either increases effects of the other by additive vasodilation. Contraindicated. Coadministration of nonspecific PDE-5 inhibitors (eg, dipyridamole, theophylline) and guanylate cyclase stimulators (eg, riociguat) is contraindicated due to risk of additive hypotension.tipranavirMonitor Closely (1)tipranavir will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)tipranavir will increase the level or effect of riociguat by Other (see comment). Avoid or Use Alternate Drug. Coadministration of riociguat (an ABCG2 [BCRP] substrate) with strong ABCG2 inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededtucatinibMonitor Closely (1)tucatinib will increase the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.Serious - Use Alternative (1)tucatinib will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.ulipristalSerious - Use Alternative (1)ulipristal will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededvandetanibSerious - Use Alternative (2)vandetanib will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if needed vandetanib will increase the level or effect of riociguat by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Coadministration of riociguat (P-gp substrate) with strong P-gp inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededvardenafilContraindicated (1)vardenafil, riociguat. Either increases effects of the other by additive vasodilation. Contraindicated. Coadministration of PDE-5 inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil) and guanylate cyclase stimulators (eg, riociguat) is contraindicated due to risk of additive hypotension.vemurafenibSerious - Use Alternative (1)vemurafenib will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededverapamilSerious - Use Alternative (1)verapamil will increase the level or effect of riociguat by decreasing metabolism. Avoid or Use Alternate Drug. Coadministration of riociguat (substrate of CYP isoenzymes 1A1, 2C8, 3A, 2J2) with strong CYP inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededvericiguatContraindicated (1)riociguat, vericiguat. Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Vericiguat is contraindicated with use of other soluble guanylate cyclase (sGC) stimulators.voriconazoleSerious - Use Alternative (1)voriconazole will increase the level or effect of riociguat by Other (see comment). Avoid or Use Alternate Drug. Coadministration of riociguat (an ABCG2 [BCRP] substrate) with strong ABCG2 inhibitors may require a decreased initial dose of 0.5 mg PO TID; monitor for signs of hypotension and reduce dose if neededvoxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid. >10% Headache (27%) Dyspepsia and gastritis (21%) Dizziness (20%) Nausea (14%) Diarrhea (12%) 1-10% Hypotension (10%) Vomiting (10%) Anemia (7%) GERD (5%) Constipation (5%) Serious bleeding (2.4%) Hemoptysis (1%) Black Box Warnings Contraindicated in pregnant females because it may cause fetal harm In females of reproductive potential, exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception (ie, 1 highly effective form of contraception [IUD, contraceptive implants, or tubal sterilization] or a combination of methods (hormone method with a barrier method or 2 barrier methods) Available to females only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) ProgramContraindications Pregnancy (see Black Box Warnings) Coadministration with nitrates or nitric oxide donors (eg, amyl nitrite), PDE inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil),