Opsynvi

Drug overview for OPSYNVI (macitentan/tadalafil):

Generic name: macitentan/tadalafil (MA-si-TEN-tan/ta-DA-la-fil)
Drug class: Pulmonary Antihypertensive Agents, cGMP pathway
Therapeutic class: Cardiovascular Therapy Agents

Macitentan and tadalafil (macitentan/tadalafil) is a fixed combination of macitentan (an endothelin receptor antagonist (ERA)) and tadalafil (a phosphodiesterase type 5 (PDE5)) inhibitor.

No enhanced Uses information available for this drug.

DRUG IMAGES

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The following indications for OPSYNVI (macitentan/tadalafil) have been approved by the FDA:

Indications:
Pulmonary arterial hypertension

Professional Synonyms:
Hypertensive pulmonary arterial disease
Pulmonary hypertensive arterial disease

Dosing information for OPSYNVI
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
OPSYNVI 10-20 MG TABLET	Maintenance	Adults take 1 tablet by oral route once daily
OPSYNVI 10-40 MG TABLET	Maintenance	Adults take 1 tablet by oral route once daily

The following drug interaction information is available for OPSYNVI (macitentan/tadalafil):

Contraindicated
Severe
Moderate

There are 3 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
CGMP Specific PDE Type-5 Inhibitors/Nitrates 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). cGMP produces smooth muscle relaxation. Avanafil,(1) sildenafil,(2) tadalafil,(3,4) and vardenafil (5-7) inhibit phosphodiesterase type 5 (PDE5), which is responsible for the breakdown of cGMP. Concurrent use of nitrates with avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in potentiation of the effect of nitrates. CLINICAL EFFECTS: The concurrent use of CGMP specific PDE type-5 inhibitors and nitrates potentiates the hypotensive effects of nitrates(1-7) which may result in dizziness, syncope, heart attack, or stroke.(4) The concurrent use of sildenafil and sodium nitroprusside may potentiate the antiaggregatory effect of sodium nitroprusside in addition to increased hypotensive effects.(2) PREDISPOSING FACTORS: Plasma levels of the PDE type-5 inhibitor 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 avanafil to patients receiving organic nitrates, either regularly and/or intermittently, is contraindicated. In a patient who has taken avanafil, at least 12 hours should elapse after the last dose of avanafil before nitrate administration is considered and it should only be administered under close medical supervision with appropriate hemodynamic monitoring.(1) The administration of sildenafil to patients receiving organic nitrates, either regularly and/or intermittently, in any form is contraindicated.(2) The administration of tadalafil to patients receiving any form of organic nitrate, either regularly and/or intermittently, is contraindicated.(3,4) Patients should be instructed to seek immediate medical attention if they experience anginal chest pain following tadalafil. In such cases where nitrate administration is considered medically necessary, at least 48 hours should elapse after tadalafil administration before nitrate administration is considered. In such cases, nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.(4) The administration of vardenafil to patients receiving nitrates or nitric oxide donors is contraindicated.(5-7) In patients prescribed vardenafil in whom nitrate administration is deemed medically necessary in a life-threatening situation, the Canadian manufacturer of vardenafil states that at least 24 hours should have elapsed after the last dose of vardenafil before the nitrate administration is considered. Nitrates should only be administered under close medical supervision with appropriate hemodynamic monitoring.(7) The concomitant use of nicorandil(8) or subinguinal nitroglycerin(9) and PDE type-5 inhibitors is contraindicated. Treat hypotension resulting from concurrent use as a nitrate overdose, with elevation of the extremities and central volume expansion.(10) DISCUSSION: Nitrates activate guanylate cyclase, an enzyme that increases levels of cGMP. cGMP produces smooth muscle relaxation. Avanafil,(1) sildenafil,(2) tadalafil,(3,4) and vardenafil (5-7) inhibit PDE5, which is responsible for the breakdown of cGMP. Concurrent use of nitrates with avanafil,(1) sildenafil,(2) tadalafil,(3,4) or vardenafil(5-7) results in potentiation of the effect of nitrates. It is unknown when nitrates, if necessary, can be safely administered to patients who have taken CGMP specific PDE type-5 inhibitors. Following a single 100 mg oral dose of sildenafil, peak plasma levels are approximately 440 ng/mL and levels 24 hours post dose are approximately 2 ng/ml. Sildenafil plasma levels at 24 hours post dose are three to eight times higher in the following patients: those age greater than 65, those with hepatic impairment, those with severe renal impairment (creatinine clearance less than 30 ml/min), and those with concomitant use of potent CYP P-450-3A4 inhibitors (erythromycin). Although plasma levels of sildenafil are lower at 24 hours post dose, the manufacturer of sildenafil states that it is still unknown whether nitrates can safely be coadministered at that time.(2) In vitro studies with human platelets have shown that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside.(2) In a study of 150 subjects who received tadalafil (20 mg) daily for 7 days, sublingual nitroglycerin was administered at 2, 4, 8, 24, 48, 72, and 96 hours after tadalafil. A significant interaction between tadalafil and nitroglycerin was observed up to and including 24 hours post-tadalafil. At 48 hours, the interaction was not observed by most hemodynamic measures. After 48 hours, the interaction was not detectable.(4) In a population-based cohort study of 61,487 men who received nitrates, 5,710 (9%) concurrently received PDE Type-5 inhibitors (PDE5i). Crude hazard ratios found a significant and inverse association between combination use of nitrates and PDE5i and all cause, cardiovascular, and non-cardiovascular mortality. All-cause mortality incidence rates were 2.69 cases per 100 person-years for the nitrate and PDE5i group vs 3.83 cases per 100 person-years in the nitrate-only group. Concurrent use of nitrates and PDE5i found a multivariate adjusted HR for all-cause mortality of 1.39 (95% CI: 1.28-1.51). Concurrent use of nitrates and PDE5i found an adjusted HR for cardiovascular death, non-cardiovascular death, myocardial infarction, heart failure, revascularization, and major adverse cardiovascular event (MACE) in patients treated with both nitrates and PDE5i was 1.34 (95% CI: 1.11-1.62), 1.40 (95% CI: 1.27-1.54), 1.72 (95% CI: 1.55-1.90), 1.67 (95% CI: 1.48-1.90), 1.95 (95% CI: 1.78-2.13), and 1.70 (95% CI: 1.58-1.83), respectively, compared with patients with nitrates only.(11)	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)	ADEMPAS
Sparsentan/Angiotensin II Receptor Blockers; Endothelin Receptor Antagonists; Aliskiren 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: Sparsentan is an antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor which are thought to contribute to the pathogenesis of IgA nephropathy.(1) Coadministration with angiotensin II receptor blockers (ARBs), endothelin receptor antagonists (ERAs), or aliskiren may result in additive inhibition of angiotensin. CLINICAL EFFECTS: Concurrent use of sparsentan with ARBs, ERAs, or aliskiren may result in hypotension, syncope, hyperkalemia, and changes in renal function (including renal failure).(1) PREDISPOSING FACTORS: Patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion may be at risk of developing acute kidney injury on sparsentan.(1) Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia.(1) PATIENT MANAGEMENT: Do not coadminister sparsentan with ARBs, ERAs, or aliskiren. Prior to initiating treatment with sparsentan, discontinue use of ARBs, ERAs, and aliskiren.(1) DISCUSSION: The US manufacturer of sparsentan states that concomitant use of sparsentan with ARBs, ERAs, or aliskiren is contraindicated.(1)	FILSPARI

There are 8 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
Macitentan/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of macitentan.(1) CYP3A4 is the primary metabolism pathway of macitentan to its less active metabolite.(1,2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease systemic levels and effectiveness of macitentan.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of macitentan recommends avoiding concurrent use of macitentan and strong CYP3A4 inducers.(2) If concurrent therapy is warranted, monitor closely for loss of efficacy and adjust macitentan dose or dosing interval if needed. Note the onset of induction is gradual; maximal induction may not occur for 2 or more weeks. When concurrent treatment with rifampin is stopped, induction will gradually wane and systemic concentrations of macitentan will gradually increase over 2 or more weeks. Monitor for toxicity and adjust dose as required. DISCUSSION: An interaction study in 10 healthy male subjects evaluated the effect of rifampin on macitentan and active metabolite pharmacokinetics. Although less potent, the active metabolite was evaluated as its longer half-life leads to a 3-fold higher systemic exposure than macitentan. About 40% of macitentan pharmacologic activity is thought due to this metabolite.(2) Subjects received a 30 mg macitentan loading dose followed by 10 mg daily for four more days. Beginning on day 6, rifampin 600 mg and macitentan 10 mg were co-administered daily for 7 days. Macitentan area-under-curve (AUC) and concentration minimum (Cmin) were measured on days 5 and 12. Co-administration decreased macitentan AUC 79% and trough concentration 93%. The AUC and Cmin of the macitentan active metabolite was unchanged and decreased 17% respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(3)	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO, XTANDI
Macitentan/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of macitentan.(1) CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of macitentan.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of macitentan states that use of strong inhibitors of CYP3A4 should be avoided. When strong CYP3A4 inhibitors are required (e.g. protease inhibitors in the treatment of HIV), use other treatment options for pulmonary arterial hypertension.(1) The Journal of American College of Cardiology (JACC) states concurrent use of macitentan and nirmatrelvir-ritonavir is not advised. JACC recommends discontinuing macitentan for at least 36 hours before initiation of nirmatrelvir-ritonavir.(2) DISCUSSION: Pretreatment with ketoconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of macitentan approximately 2.3 and 1.3-fold respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)	APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA
Sildenafil(PAH);Tadalafil(BPH,PAH)/Slt Strong 3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of sildenafil(1) and tadalafil.(2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels, clinical effects, and side effects of sildenafil(1) and tadalafil.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sildenafil states that the concurrent use of strong CYP3A4 inhibitors with sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) is not recommended.(5) The US manufacturer of tadalafil states that the concurrent use of strong CYP3A4 inhibitors with tadalafil when used for the treatment of pulmonary arterial hypertension (PAH) is not recommended.(6) The US manufacturer of itraconazole states that the concurrent use of sildenafil or tadalafil is not recommended when sildenafil or tadalafil is used for the treatment of PAH.(7) The US manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil for erectile dysfunction in patients receiving concomitant therapy with strong CYP3A4 inhibitors.(1) The US manufacturer of tadalafil states that the maximum recommended dose of as needed tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 10 mg every 72 hours.(2) The maximum recommended dose of daily tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 2.5 mg.(3) DISCUSSION: Concurrent administration of a single 100 mg dose of sildenafil with erythromycin (500 mg twice daily for five days) resulted in an increase of sildenafil area-under-curve (AUC) by 182%. Therefore, the manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil in patients receiving concomitant therapy with other strong CYP3A4 inhibitors such as itraconazole or ketoconazole.(1) Concurrent administration of a single 20 mg dose of tadalafil with ketoconazole (400 mg daily) increased tadalafil AUC and maximum concentration (Cmax) by 312% and 22%, respectively. Concurrent administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(2) Strong CYP3A4 inhibitors include adagrasib, ceritinib, clarithromycin, grapefruit, idelalisib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, nefazodone, posaconazole, ribociclib, telithromycin, and voriconazole.(1-4)	CLARITHROMYCIN, CLARITHROMYCIN ER, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, KISQALI, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, POSACONAZOLE, RECORLEV, SPORANOX, TOLSURA, VFEND, VFEND IV, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA
Vericiguat/PDE Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Vericiguat 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.(1-6) CLINICAL EFFECTS: The concurrent use of PDE inhibitors and vericiguat 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, or with severe renal impairment. This may increase the severity of the interaction. PATIENT MANAGEMENT: The manufacturer of vericiguat states that administration of vericiguat to patients receiving PDE inhibitors, including specific PDE-5 inhibitors (avanafil,(2) sildenafil,(3) tadalafil,(4,5) or vardenafil(6)) and nonspecific PDE inhibitors (aminophylline, dipyridamole, theophylline) is not recommended.(1) The manufacturers of the PDE-5 inhibitors state that concurrent use of guanylate cyclase stimulators is contraindicated.(2-6) DISCUSSION: Concomitant use of vericiguat 10 mg with single doses of sildenafil (25, 50, or 100 mg) was associated with additional seated BP reduction of up to 5.4 mm Hg (systolic/diastolic BP, MAP), compared to administration of vericiguat alone.(1)	VERQUVO
Macitentan/Dual Moderate CYP2C9 & CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Dual moderate inhibitors of CYP2C9 and CYP3A4 may inhibit the metabolism of macitentan.(1) CLINICAL EFFECTS: Concurrent use of a dual moderate inhibitor of CYP2C9 and CYP3A4 may result in elevated levels and increased effects of macitentan.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of macitentan states that use of dual moderate inhibitors of CYP2C9 and CYP3A4 should be avoided. Concomitant use of both a moderate CYP3A4 inhibitor and a moderate CYP2C9 inhibit should also be avoided.(1) DISCUSSION: Based on pharmacokinetic (PBPK) modeling, dual moderate inhibitors of CYP2C9 and CYP3A4 such as fluconazole are predicted to increase macitentan exposure by 4-fold.(1) Dual moderate inhibitors of CYP2C9 and CYP3A4 include: amiodarone and fluconazole.(2)	AMIODARONE HCL, AMIODARONE HCL-D5W, DIFLUCAN, FLUCONAZOLE, FLUCONAZOLE-NACL, NEXTERONE, PACERONE
Tadalafil (BPH, PAH)/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may accelerate the metabolism of tadalafil.(1-3) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of tadalafil.(1-3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inducers with tadalafil is not recommended. If concurrent use is necessary, closely monitor for treatment response.(1-3) DISCUSSION: Rifampin (600 mg daily), a strong CYP3A4 inducer, reduced tadalafil 10 mg single-dose exposure AUC by 88% and Cmax by 46%, respectively, compared to tadalafil alone.(1-3) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(4,5)	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO, XTANDI
Tadalafil (PAH)/Nirmatrelvir-Ritonavir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The nirmatrelvir-ritonavir may inhibit the metabolism of tadalafil by CYP3A4.(1-2) CLINICAL EFFECTS: The concurrent administration of nirmatrelvir-ritonavir may result in elevated levels of tadalafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of nirmatrelvir-ritonavir states the concurrent use of tadalafil for pulmonary arterial hypertension (PAH) should be avoided.(2) The US manufacturers of the protease inhibitors state that in patients who have received a protease inhibitor for at least one week, the initial dosage of tadalafil for the treatment of primary pulmonary hypertension should be 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(3-11) The US manufacturers of the protease inhibitors state that in patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be discontinued for 24 hours before beginning protease inhibitor therapy other than nelfinavir without concurrent ritonavir. After one week, tadalafil may be resumed at a dosage of 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(3-11) In patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily prior to beginning therapy with nelfinavir without concurrent ritonavir. The dosage may be increased to 40 mg daily based upon tolerability.(5) The US manufacturer of tadalafil states that the recommended dose of as needed tadalafil for the treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in patients receiving concurrent strong CYP3A4 inhibitors.(1) The US manufacturer of tadalafil states that the recommended dose of daily tadalafil for the treatment of erectile dysfunction in patients taking strong CYP3A4 inhibitors is 2.5 mg.(1) Patients should be counseled that they are at an increased risk of tadalafil adverse effects, including hypotension, syncope, visual changes, and priapism. Patients experiencing these effects should report them promptly to their physician. DISCUSSION: Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (500 mg or 600 mg twice daily) increased tadalafil area-under-curve (AUC) by 32% and decreased tadalafil concentration maximum (Cmax) by 30%. Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily for 17 doses) had no significant effects on the AUC of a single dose of tadalafil (10 mg). Tadalafil Cmax decreased 30%. Tipranavir Cmax, AUC, and concentration minimum (Cmin) decreased by 10%, 15%, and 19%, respectively. Administration of a single dose of tipranavir/ritonavir (500/200 mg) increased the AUC of a single dose of tadalafil (10 mg) by 2.33-fold. Tadalafil Cmax decreased 22%. Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.	PAXLOVID
Tadalafil (PAH)/Lenacapavir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lenacapavir may inhibit the metabolism of tadalafil by CYP3A4.(1-4) CLINICAL EFFECTS: The concurrent administration of lenacapavir may result in elevated levels of tadalafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of lenacapavir states the concurrent use of tadalafil for pulmonary arterial hypertension (PAH) is not recommended.(2-4) The US manufacturer of tadalafil and the UK and Canadian manufacturers of lenacapavir state that the recommended dose of as needed tadalafil for the treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in patients receiving concomitant therapy.(1,3-4) The US manufacturer of tadalafil and the UK and Canadian manufacturers of lenacapavir state that the recommended dose of daily tadalafil is 2.5 mg for the treatment of erectile dysfunction in patients receiving concomitant therapy.(1,3-4) Patients should be counseled that they are at an increased risk of tadalafil adverse effects, including hypotension, syncope, visual changes, and priapism. Patients experiencing these effects should report them promptly to their physician. DISCUSSION: Concurrent administration of lenacapavir 600 mg with a single 2.5 mg dose of midazolam (a CYP3A4 substrate) increased midazolam maximum concentration (Cmax) and area-under-curve (AUC) by 1.94-fold and 3.59-fold, respectively.(2-4) Concurrent administration of a single 20 mg dose of tadalafil with ketoconazole (400 mg daily) increased tadalafil AUC and maximum concentration (Cmax) by 312% and 22%, respectively. Concurrent administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(1)	SUNLENCA

There are 5 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
CGMP Specific PDE Type-5 Inhibitors/Alpha-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of avanafil,(1) sildenafil,(2-5) tadalafil,(6-9) or vardenafil(10-14) and an alpha-blocker may result in additive or synergistic effects on blood pressure. CLINICAL EFFECTS: Concurrent use of avanafil,(1) sildenafil,(2-5) tadalafil,(6-9) or vardenafil(10-14)) and an alpha-blocker may result in symptomatic hypotension. PREDISPOSING FACTORS: Patients who have a history of hemodynamic instability on alpha-blocker therapy prior to initiating avanafil, sildenafil, tadalafil, or vardenafil may be at an increased risk of symptomatic hypotension during concurrent therapy. PATIENT MANAGEMENT: The US manufacturer of avanafil states that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning avanafil therapy. Avanafil should be initiated at the 50 mg dosage. In patients stabilized on avanafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(1) The US, Australian, Canadian, and UK manufacturers of sildenafil state that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning sildenafil therapy. Sildenafil should be initiated at the lowest possible dosage. In patients stabilized on sildenafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(2-5) The US manufacturer of tadalafil states that patients taking tadalafil for erectile dysfunction (ED) and alpha-blockers should be stabilized on their alpha-blocker prior to beginning tadalafil therapy. Tadalafil should be initiated at the lowest possible dosage. In patients stabilized on tadalafil therapy, alpha-blocker therapy should be initiated at the lowest possible dose. The combination of tadalafil and an alpha-blocker for treatment of benign prostatic hyperplasia (BPH) is not recommended. Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting tadalafil for once daily use for the treatment of BPH.(6) The Australian manufacturer of tadalafil states that tadalafil should be used with caution in patients taking alpha-blockers.(7) The Canadian manufacturer of tadalafil states that it may be used with tamsulosin and should be used with caution with other alpha-blockers.(8) The UK manufacturer of tadalafil states that concurrent use with alpha-blockers is not recommended.(9) The US, Canadian, and UK manufacturers of vardenafil state that patients taking alpha-blockers should be stabilized on their alpha-blocker prior to beginning vardenafil therapy. Vardenafil should be initiated at the lowest possible dosage. In patients stabilized on vardenafil therapy, alpha-blocker therapy should be initiated at the lowest possible dosage.(10-12) The UK manufacturer of vardenafil states that vardenafil may be give at any time in relation to tamsulosin; however, a dose separation period of 6 hour should be considered for other alpha-blockers.(12) The Australian manufacturer of vardenafil states that concurrent use with alpha-blockers is not recommended.(13) The US manufacturers of doxazosin,(14) prazosin(15) and terazosin(16) state that PDE-5 inhibitor therapy should be initiated at the lowest dose. DISCUSSION: In a study in 24 subjects, concurrent use of avanafil (200 mg) with doxazosin (1 mg on Day 1, titrated to 8 mg for Days 8-18) resulted in 7 subjects experiencing potentially clinically significant changes in blood pressure.(1) In a study in 24 subjects, concurrent use of avanafil (200 mg) with tamsulosin (0.4 mg Days 1-11) resulted in 5 subjects experiencing potentially clinically significant changes in blood pressure.(1) Simultaneous administration of sildenafil (25 mg) and doxazosin (4 mg) resulted in mean additional reductions of supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic. When doxazosin (4 mg) was simultaneously administered with higher doses of sildenafil, there were reports of symptomatic postural hypotension within one to four hours.(2) In a study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving alfuzosin (10 mg daily) resulted in mean maximum decreases in standing and supine systolic blood pressure by 2.2 mmHg and 4.4 mmHg, respectively. There were no subjects with a decrease from baseline standing systolic blood pressure greater than 30 mmHg.(6) In a study, concurrent administration of a single dose of tadalafil (20 mg) to 18 healthy subjects receiving doxazosin (8 mg daily) resulted in significant augmentation of the blood-pressure lowering effects of doxazosin (by 9.8 mmHg). The number of subjects with a standing blood pressure of less than 85 mmHg was greater after concurrent doxazosin and tadalafil than when compared to doxazosin with placebo (28% versus 6%). One subject reported vertigo and another reported dizziness. No syncope was reported.(5,14) In a second study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving doxazosin (4-8 mg daily) also resulted in augmentation of the blood-pressure lowering affects of doxazosin. One subject reported symptomatic hypotension and another reported dizziness with concurrent therapy.(6) In a study, concurrent administration of a single dose of tadalafil (20 mg) to healthy subjects receiving tamsulosin (0.4 mg daily) resulted in no significant decreases in blood pressure.(6,17) Hypotension has been reported with concurrent use of terazosin and phosphodiesterase-5 inhibitors.(16) With simultaneous administration of vardenafil (10 mg) and terazosin (10 mg), 6 of 8 healthy subjects experienced a standing systolic blood pressure of less than 85 mmHg. With simultaneous vardenafil (20 mg) and terazosin (10 mg), 2 of 9 subjects experienced a standing systolic blood pressure of less than 85 mmHg. When vardenafil (20 mg) was administered 6 hours apart from terazosin (10 mg), 7 of 28 subjects experienced a standing systolic blood pressure of less than 85 mmHg.(10) With simultaneous administration of vardenafil (10 mg) and tamsulosin (0.4 mg), two of 16 subjects experienced a standing systolic blood pressure of less than 85 mmHg. When vardenafil (20 mg) was administered six hours apart from tamsulosin (0.4 mg), one of 24 subjects experienced a standing systolic blood pressure of less than 85 mmHg.(10) In a study in subjects with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy, simultaneous vardenafil (5 mg) and tamsulosin resulted in no effects on blood pressure. Simultaneous vardenafil (5 mg) with terazosin resulted in hypotension in some subjects. This effect did not occur when vardenafil and terazosin were separated by 6 hours.(12) In a placebo controlled, crossover study in 22 subjects with benign prostatic hyperplasia receiving tamsulosin, subjects received single doses of vardenafil (10 mg and 20 mg). No patients exhibited symptomatic hypotension. Three patients receiving 20 mg of vardenafil reported dizziness, but none had a systolic blood pressure of less than 95 mmHg.(18) In a placebo-controlled study in 24 health male subjects, administration of sildenafil (100 mg) or tadalafil (20 mg) with silodosin resulted in an increase in positive orthostatic tests in the 12 hours after concurrent administration when compared with the administration of silodosin alone. There were no reports of symptomatic orthostasis or dizziness.(19)	ALFUZOSIN HCL ER, CARDURA, CARDURA XL, DAPIPRAZOLE HCL, DIBENZYLINE, DOXAZOSIN MESYLATE, DUTASTERIDE-TAMSULOSIN, FLOMAX, JALYN, MOXISYLYTE HCL, PHENOXYBENZAMINE HCL, PHENTOLAMINE MESYLATE, PRAZOSIN HCL, RAPAFLO, SILODOSIN, TAMSULOSIN HCL, TERAZOSIN HCL, TEZRULY, TOLAZOLINE HCL, UROXATRAL
Tizanidine/Selected Antihypertensives SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)	TIZANIDINE HCL, ZANAFLEX
Apomorphine/Selected Antihypertensives and Vasodilators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1) PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1) PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)	APOKYN, APOMORPHINE HCL, ONAPGO
Tadalafil (PAH)/Select Protease Inhibitors; Cobicistat SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The protease inhibitors may inhibit the metabolism of tadalafil.(1-10) CLINICAL EFFECTS: The concurrent administration of a protease inhibitor may result in elevated levels of tadalafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1-10) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturers of the protease inhibitors state that in patients who have received a protease inhibitor for at least one week, the initial dosage of tadalafil for the treatment of primary pulmonary hypertension should be 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(2-10) The US manufacturers of the protease inhibitors state that in patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be discontinued for 24 hours before beginning protease inhibitor therapy other than nelfinavir without concurrent ritonavir. After one week, tadalafil may be resumed at a dosage of 20 mg daily. The dosage may be increased to 40 mg daily based upon tolerability.(2-10) In patients who have been receiving tadalafil for the treatment of primary pulmonary hypertension, tadalafil should be adjusted to 20 mg daily prior to beginning therapy with nelfinavir without concurrent ritonavir. The dosage may be increased to 40 mg daily based upon tolerability.(7) The US manufacturers of tadalafil(1) and the protease inhibitors(2-10) state that the recommended dose of as needed tadalafil for the treatment of erectile dysfunction is 10 mg of tadalafil every 72 hours in patients receiving concurrent therapy. The US manufacturer of tadalafil states that the recommended dose of daily tadalafil for the treatment of erectile dysfunction in patients taking potent inhibitors of CYP3A4 is 2.5 mg.(1) Patients should be counseled that they are at an increased risk of tadalafil adverse effects, including hypotension, syncope, visual changes, and priapism. Patients experiencing these effects should report them promptly to their physician. DISCUSSION: Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (500 mg or 600 mg twice daily) increased tadalafil area-under-curve (AUC) by 32% and decreased tadalafil concentration maximum (Cmax) by 30%. Concurrent administration of tipranavir/ritonavir (500/200 mg twice daily for 17 doses) had no significant effects on the AUC of a single dose of tadalafil (10 mg). Tadalafil Cmax decreased 30%. Tipranavir Cmax, AUC, and concentration minimum (Cmin) decreased by 10%, 15%, and 19%, respectively. Administration of a single dose of tipranavir/ritonavir (500/200 mg) increased the AUC of a single dose of tadalafil (10 mg) by 2.33-fold. Tadalafil Cmax decreased 22%. Concurrent administration of a single dose of tadalafil (20 mg) with ritonavir (200 mg twice daily) increased tadalafil AUC by 124%.	APTIVUS, ATAZANAVIR SULFATE, DARUNAVIR, EVOTAZ, FOSAMPRENAVIR CALCIUM, GENVOYA, KALETRA, LOPINAVIR-RITONAVIR, PREZCOBIX, PREZISTA, REYATAZ, STRIBILD, SYMTUZA, TYBOST, VIRACEPT
Macitentan/Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Macitentan is primarily metabolized by CYP3A4, with minor contributions from CYP2C8, CYP2C9, and CYP2C19. Moderate inhibitors of CYP3A4 may inhibit the metabolism of macitentan.(1) CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of macitentan, including hepatotoxicity and fluid retention.(1) PREDISPOSING FACTORS: Concomitant use of a moderate CYP2C9 inhibitor increases the magnitude of this interaction and the risk of adverse events. PATIENT MANAGEMENT: The manufacturer of macitentan states that concurrent use of both a moderate CYP2C9 inhibitor and a moderate CYP3A4 inhibitor should be avoided.(1) While the manufacturer does not provide recommendations for concurrent use of a moderate CYP3A4 inhibitor alone, it would be prudent to use caution and monitor for adverse effects. DISCUSSION: Based on pharmacokinetic (PBPK) modeling, dual moderate inhibitors of CYP2C9 and CYP3A4 such as fluconazole are predicted to increase macitentan exposure by 4-fold.(1) Pretreatment with ketoconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of macitentan by approximately 2.3 and 1.3-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, schisandra, tofisopam, treosulfan, verapamil, and voxelotor.(2)	AKYNZEO, APONVIE, APREPITANT, ATAZANAVIR SULFATE, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CINVANTI, CLOFAZIMINE, CONIVAPTAN-D5W, COPIKTRA, CRESEMBA, DANZITEN, DARUNAVIR, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, E.E.S. 200, E.E.S. 400, EMEND, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, EVOTAZ, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, FOSAMPRENAVIR CALCIUM, GLEEVEC, GRAFAPEX, IMATINIB MESYLATE, IMKELDI, INREBIC, MATZIM LA, MULTAQ, NILOTINIB HCL, ORLADEYO, PREVYMIS, PREZCOBIX, PREZISTA, REYATAZ, SUNLENCA, SYMTUZA, TASIGNA, TAVNEOS, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, VAPRISOL-5% DEXTROSE, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR, XALKORI, XENLETA

The following contraindication information is available for OPSYNVI (macitentan/tadalafil):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Pregnancy. *Hypersensitivity. *Concomitant use of organic nitrates. *Concomitant use of guanylate cyclase (GC) stimulators.

There are 5 contraindications. Absolute contraindication.

Contraindication List
Child-pugh class C hepatic impairment
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Chronic kidney disease stage 5 (failure) GFr<15 ml/min
Lactation
Pregnancy

There are 21 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Alcohol intoxication
Anemia
Anterior ischemic optic neuropathy
Aortic valve stenosis
Child-pugh class A hepatic impairment
Child-pugh class B hepatic impairment
Chronic heart failure
Chronic kidney disease stage 2 (mild) GFR 60-89 ml/min
Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
Fibrosis of corpus cavernosum
Hypertrophic cardiomyopathy
Hypotension
Life-threatening cardiac arrhythmias
Penile angulation
Peptic ulcer
Peyronie's disease
Pigmentary retinopathy
Pulmonary veno-occlusive disease
Restrictive cardiomyopathy
Unstable angina pectoris

There are 10 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Cerebrovascular accident
Hearing loss
Increased risk of bleeding
Increased risk of bleeding due to coagulation disorder
Kidney disease with likely reduction in glomerular filtration rate (GFr)
Leukemia
Multiple myeloma
Seizure disorder
Severe uncontrolled hypertension
Sickle cell disease

The following adverse reaction information is available for OPSYNVI (macitentan/tadalafil):

Overview
Severe
Less Severe

Adverse reaction overview.

The most common adverse reactions (>=10%) observed with macitentan/tadalafil in clinical studies were edema/fluid retention, anemia, and headache/migraine.

There are 35 severe adverse reactions.

More Frequent	Less Frequent
Anemia	Abnormal hepatic function tests

Rare/Very Rare
Abnormal hepatic function tests Acute myocardial infarction Angina Angioedema Anterior ischemic optic neuropathy Blurred vision Cerebrovascular accident Chest pain Conjunctivitis Drug-induced hepatitis Dysphagia Dyspnea Esophagitis Exfoliative dermatitis Facial edema Hearing loss Heart failure Hepatic failure Hyperbilirubinemia Hypertension Hypotension Kidney disease with reduction in glomerular filtration rate (GFr) Orthostatic hypotension Palpitations Priapism Rectal bleeding Retinal vascular occlusion Seizure disorder Stevens-johnson syndrome Syncope Tachycardia Vision impairment Visual field defect

Rare/Very Rare

Abnormal hepatic function tests
Acute myocardial infarction
Angina
Angioedema
Anterior ischemic optic neuropathy
Blurred vision
Cerebrovascular accident
Chest pain
Conjunctivitis
Drug-induced hepatitis
Dysphagia
Dyspnea
Esophagitis
Exfoliative dermatitis
Facial edema
Hearing loss
Heart failure
Hepatic failure
Hyperbilirubinemia
Hypertension
Hypotension
Kidney disease with reduction in glomerular filtration rate (GFr)
Orthostatic hypotension
Palpitations
Priapism
Rectal bleeding
Retinal vascular occlusion
Seizure disorder
Stevens-johnson syndrome
Syncope
Tachycardia
Vision impairment
Visual field defect

There are 56 less severe adverse reactions.

More Frequent	Less Frequent
Bronchitis Headache disorder Influenza Pharyngitis Urinary tract infection	Acute abdominal pain Anemia Back pain Cough Diarrhea Dyspepsia Flushing Gastroesophageal reflux disease Myalgia Nasal congestion Nausea Pain in extremities Palpitations Pharyngitis Upper respiratory infection

Rare/Very Rare
Acquired chromatopsia Arthralgia Body fluid retention Conjunctival hyperemia Dizziness Drowsy Edema Epistaxis Eye tearing Eyelid edema Fatigue Flushing Frequent erections Gastritis General weakness Hyperhidrosis Hypoesthesia Insomnia Loose stools Migraine Nasal congestion Neck pain Ocular pain Oligospermia Pain Paresthesia Peripheral edema Pruritus of skin Skin rash Tinnitus Transient global amnesia Urticaria Vertigo Visual changes Vomiting Xerostomia

Rare/Very Rare

Acquired chromatopsia
Arthralgia
Body fluid retention
Conjunctival hyperemia
Dizziness
Drowsy
Edema
Epistaxis
Eye tearing
Eyelid edema
Fatigue
Flushing
Frequent erections
Gastritis
General weakness
Hyperhidrosis
Hypoesthesia
Insomnia
Loose stools
Migraine
Nasal congestion
Neck pain
Ocular pain
Oligospermia
Pain
Paresthesia
Peripheral edema
Pruritus of skin
Skin rash
Tinnitus
Transient global amnesia
Urticaria
Vertigo
Visual changes
Vomiting
Xerostomia

The following precautions are available for OPSYNVI (macitentan/tadalafil):

Pediatric
Pregnant
Lactation
Geriatric

The safety and efficacy of macitentan/tadalafil in pediatric patients have not been established.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Based on data from animal reproduction studies, macitentan/tadalafil is contraindicated during pregnancy. Macitentan may cause embryofetal toxicity, including birth defects and fetal death, when administered to pregnant patients. Macitentan was teratogenic in rabbits and rats at all doses tested.

Available data from a randomized controlled trial, observational studies, and case series of tadalafil use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In tadalafil animal reproduction studies, no adverse developmental effects were observed with oral administration of the drug to pregnant rats and mice during organogenesis at exposures 7 times the maximum recommended human dose (MRHD) of 40 mg/day. There are risks to the mother and the fetus associated with PAH in pregnancy.

If macitentan/tadalafil is used during pregnancy, or if the patient becomes pregnant while taking the combination drug, advise pregnant women of the potential risk to a fetus. In patients with PAH, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including heart failure, stroke, spontaneous abortion, intrauterine growth restriction, premature labor, and preterm birth.

There are no data on the presence of tadalafil, macitentan, and/or their metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in breastfed infants from macitentan/tadalafil, advise women not to breastfeed during treatment with the fixed-combination preparation.

Of the total number of patients in the clinical study of macitentan/tadalafil for PAH, 20% were 65 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger adults.

Pulmonary arterial hypertension
I27.0	Primary pulmonary hypertension
I27.21	Secondary pulmonary arterial hypertension