Version July 2025
Macitentan/tadalafil is contraindicated for use during pregnancy because it may cause fetal harm based on animal data. Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with macitentan/tadalafil. Advise use of effective contraception before the initiation of treatment, during treatment, and for one month after stopping treatment with macitentan/tadalafil. When pregnancy is detected, discontinue macitentan/tadalafil as soon as possible.
Dosage guidance :
Safety: Do not administer in patients taking nitrates (regularly or intermittently) due to risk for severe hypotension. If a patient taking macitentan/tadalafil develops chest pain, delay nitrate administration for ≥48 hours after the last macitentan/tadalafil dose.
Pulmonary arterial hypertension:
Note: Consult a pulmonary arterial hypertension specialist for all management decisions; choice of therapy is dependent on etiology, risk stratification, and cardiopulmonary comorbidities (Ref).
Treatment naive or transitioning from endothelin receptor antagonist (ERA) monotherapy:
Oral: Initial: Macitentan 10 mg/tadalafil 20 mg once daily for 1 week; if tolerated may increase to macitentan 10 mg/tadalafil 40 mg once daily.
Transitioning from phosphodiesterase type 5 (PDE-5) inhibitor monotherapy or PDE-5 inhibitor/ERA combination therapy:
Oral: Macitentan 10 mg/tadalafil 40 mg once daily.
Missed doses: Administer as soon as possible then administer the next dose at the regularly scheduled time; do not take 2 doses at the same time if a dose has been missed.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: Avoid use.
Hemodialysis: Use not recommended.
Liver impairment prior to treatment initiation:
Initial or dose titration in patients with preexisting liver cirrhosis:
Mild to moderate impairment (Child-Turcotte-Pugh class A or B): No dosage adjustment necessary.
Severe impairment (Child-Turcotte-Pugh class C) or ALT or AST >3 times ULN: Avoid use.
Acute hepatoxicity during treatment:
Elevated liver transaminases (clinically relevant) or elevated transaminases either in combination with symptoms of hepatic injury or bilirubin >2 times ULN: Discontinue therapy; may consider reinitiation if liver transaminases have normalized and there are no clinical signs of hepatotoxicity.
Refer to adult dosing; use with caution.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults. Also see individual agents.
>10%:
Cardiovascular: Edema (≤21%; including peripheral edema)
Endocrine & metabolic: Fluid retention (≤21%)
Hematologic & oncologic: Anemia (19%)
Nervous system: Headache (18%; including migraine)
1% to 10%:
Cardiovascular: Flushing (4%), hypotension (7%), palpitations (4%)
Gastrointestinal: Abdominal pain (7%), nausea (6%), vomiting (4%)
Genitourinary: Abnormal uterine bleeding (5%)
Hepatic: Increased serum transaminases (1%)
Neuromuscular & skeletal: Back pain (5%), limb pain (3%), myalgia (6%)
Respiratory: Epistaxis (3%), nasopharyngitis (6%)
Postmarketing: Cardiovascular: Heart failure
Hypersensitivity to macitentan, tadalafil, or any component of the formulation; pregnancy; use of organic nitrate (administered regularly and/or intermittently) concurrently or within 48 hours; concurrent use of guanylate cyclase stimulators (eg, riociguat).
Canadian labeling: Additional contraindications (not in US labeling): Patients who may become pregnant; breastfeeding; previous episode of nonarteritic anterior ischemic optic neuropathy.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Anginal chest pain: Patients experiencing anginal chest pain after tadalafil administration should seek immediate medical attention.
• Color discrimination: May cause dose-related impairment of color discrimination.
• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization) associated with other endothelin antagonists. Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with severe chronic heart failure.
• Hearing loss: Sudden decrease or loss of hearing has been reported; hearing changes may be accompanied by tinnitus and dizziness. A direct relationship between therapy and hearing loss has not been determined.
• Hematologic effects: Decreases in Hb and Hct have been observed and may occur early in therapy with subsequent stabilization. Decreases in Hb rarely required transfusion. Use is not recommended in patients with severe anemia.
• Hepatic effects: Increases in serum liver aminotransferases, hepatotoxicity, and liver failure have been reported with macitentan.
• Hypotension: Decreases in BP may occur due to vasodilator effects; use with caution in patients with preexisting hypotension, autonomic dysfunction, and/or left ventricular outflow obstruction (eg, aortic stenosis or hypertrophic obstructive cardiomyopathy); may be more sensitive to hypotensive actions.
• Priapism: Painful erection >6 hours in duration has been reported. Instruct patients to seek immediate medical attention if erection persists >4 hours. Use with caution in patients who have conditions that may predispose them to priapism (eg, sickle cell anemia, multiple myeloma, leukemia).
• Vision loss: Sudden vision loss in one or both eyes may be a sign of nonarteritic anterior ischemic optic neuropathy (NAION); a direct relationship to PDE-5 inhibitors has not been established. Risk factors for NAION include low cup-to-disc ratio ("crowded disc"), coronary artery disease, diabetes, hypertension, hyperlipidemia, smoking, and age >50 years. Safety has not been evaluated in patients with known hereditary degenerative retinal disorders (eg, retinitis pigmentosa); use is not recommended.
Disease-related concerns:
• Anatomical penis deformation: Use tadalafil with caution in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie disease).
• Cardiovascular disease: Safety and efficacy in pulmonary arterial hypertension have not been evaluated in patients with clinically significant aortic and/or mitral valve disease, life-threatening arrhythmias, hypotension (<90/50 mm Hg), uncontrolled hypertension, significant left ventricular dysfunction, pericardial constriction, restrictive or congestive cardiomyopathy, or symptomatic coronary artery disease. Use caution in patients with left ventricular outflow obstruction (eg, aortic stenosis, hypertrophic obstructive cardiomyopathy); may be more sensitive to vasodilator effects.
• Hepatic impairment: Avoid use in patients with severe hepatic impairment or cirrhosis.
• Pulmonary veno-occlusive disease: Pulmonary vasodilators may exacerbate the cardiovascular status in patients with pulmonary veno-occlusive disease (PVOD). Use is not recommended; no clinical data exists in patients with PVOD. In patients with unrecognized PVOD, signs of pulmonary edema should prompt investigation into this diagnosis.
• Renal impairment: Avoid use in patients with severe impairment; use is not recommended in patients receiving dialysis.
Concurrent drug therapy issues:
• Nitrates: Concomitant use (regularly/intermittently) with all forms of nitrates is contraindicated. Nitrate-mediated vasodilation is markedly exaggerated and prolonged in the presence of PDE-5 inhibitors. When nitrate administration is medically necessary following the use of tadalafil, at least 48 hours should elapse after the tadalafil dose and before nitrate administration; close medical supervision is recommended.
Dosage form specific issues:
• Lactose: May contain lactose; do not use with galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption syndromes.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Opsynvi: Macitentan 10 mg and tadalafil 20 mg, Macitentan 10 mg and tadalafil 40 mg
No
Tablets (Opsynvi Oral)
10-20 mg (per each): $518.20
10-40 mg (per each): $518.20
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Opsynvi: Macitentan 10 mg and tadalafil 40 mg
Oral: Swallow tablet whole. Do not split, crush, or chew tablets. May be administered with or without food.
Macitentan is a hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218490s000lbl.pdf#page=32, must be dispensed with this medication.
Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (World Health Organization [WHO] Group 1 and WHO functional class [FC] II or III) to reduce the risk of clinical worsening events and hospitalization and improve exercise ability.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy) that have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May increase hypotensive effects of Phosphodiesterase 5 Inhibitors. Risk C: Monitor
Alpha1-Blockers (Nonselective): Phosphodiesterase 5 Inhibitors may increase hypotensive effects of Alpha1-Blockers (Nonselective). Management: Ensure patient is stable on one agent prior to initiating the other, and always initiate combination using the lowest possible dose of the drug being added. When tadalafil is used for treatment of BPH, concurrent alpha 1-blockers are not recommended. Risk D: Consider Therapy Modification
Alpha1-Blockers (Uroselective): May increase hypotensive effects of Phosphodiesterase 5 Inhibitors. Risk C: Monitor
Alprostadil: Phosphodiesterase 5 Inhibitors may increase adverse/toxic effects of Alprostadil. Risk X: Avoid
Amiodarone: May increase serum concentration of Macitentan. Risk C: Monitor
Amyl Nitrite: Phosphodiesterase 5 Inhibitors may increase vasodilatory effects of Amyl Nitrite. Risk X: Avoid
Blood Pressure Lowering Agents: Phosphodiesterase 5 Inhibitors may increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Bosentan: May decrease serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase serum concentration of Bosentan. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease serum concentration of Macitentan. Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease serum concentration of Tadalafil. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Macitentan. Risk X: Avoid
CYP3A4 Inhibitors (Moderate): May increase serum concentration of Macitentan. Risk C: Monitor
CYP3A4 Inhibitors (Moderate): May increase serum concentration of Tadalafil. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of Macitentan. Risk X: Avoid
Dapoxetine: May increase orthostatic hypotensive effects of Phosphodiesterase 5 Inhibitors. Risk X: Avoid
Etravirine: May decrease serum concentration of Phosphodiesterase 5 Inhibitors. Risk C: Monitor
Fluconazole: May increase serum concentration of Macitentan. Risk X: Avoid
Fosamprenavir: May increase serum concentration of Tadalafil. Management: Initiate tadalafil for pulmonary arterial hypertension at 20 mg after at least 1 week of fosamprenavir therapy. Increase to tadalafil 40 mg as tolerated. For erectile dysfunction, limit the tadalafil dose to 10 mg every 72 hours. Risk D: Consider Therapy Modification
Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Grapefruit Juice: May increase serum concentration of Macitentan. Risk C: Monitor
Grapefruit Juice: May increase serum concentration of Tadalafil. Risk C: Monitor
Lenacapavir: May increase serum concentration of Tadalafil. Management: Avoid this combination in patients taking tadalafil for pulmonary arterial hypertension. In patients taking tadalafil for ED or BPH monitor for increased tadalafil effects and toxicities. Risk D: Consider Therapy Modification
Molsidomine: May increase hypotensive effects of Phosphodiesterase 5 Inhibitors. Risk X: Avoid
Nitroprusside: Phosphodiesterase 5 Inhibitors may increase hypotensive effects of Nitroprusside. Risk X: Avoid
Phosphodiesterase 5 Inhibitors: May increase adverse/toxic effects of Phosphodiesterase 5 Inhibitors. Risk X: Avoid
Riociguat: Phosphodiesterase 5 Inhibitors may increase hypotensive effects of Riociguat. Risk X: Avoid
Sapropterin: May increase hypotensive effects of Phosphodiesterase 5 Inhibitors. Risk C: Monitor
Simeprevir: May increase serum concentration of Phosphodiesterase 5 Inhibitors. Risk C: Monitor
Sparsentan: May increase adverse/toxic effects of Endothelin Receptor Antagonists. Risk X: Avoid
Vasodilators (Organic Nitrates): Phosphodiesterase 5 Inhibitors may increase vasodilatory effects of Vasodilators (Organic Nitrates). Risk X: Avoid
Vericiguat: May increase hypotensive effects of Phosphodiesterase 5 Inhibitors. Risk X: Avoid
Grapefruit juice may increase serum levels/toxicity of tadalafil. Management: Monitor for increased effects/toxicity with concomitant use.
Exclude pregnancy prior to initiation. Pregnancy tests should be conducted prior to therapy in patients who could become pregnant. Conduct additional pregnancy testing if the onset of menses is delayed or if pregnancy is suspected during treatment.
Patients who could become pregnant should use effective contraception prior to starting treatment, during therapy, and for 1 month after the last dose of macitentan/tadalafil.
Sperm morphology, motility, or concentrations may be decreased with use; fertility may be impaired.
Refer to individual monographs for additional information.
Use is contraindicated in pregnant patients. Discontinue as soon as possible if pregnancy is detected.
Refer to individual monographs for additional information.
It is not known if macitentan or tadalafil are present in human milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
Refer to individual monographs for additional information.
Liver enzymes (baseline then as clinically indicated); Hb (baseline then as clinically indicated); signs and symptoms of liver injury (eg, abdominal pain, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, vomiting); peripheral edema; BP; Hb and Hct prior to initiation and repeat as clinically appropriate; exclude pregnancy prior to initiating therapy in patients who could become pregnant.
Macitentan: Blocks endothelin (ET)-1 from binding to endothelin receptor subtypes ETA and ETB on vascular endothelium and smooth muscle. Stimulation of these receptors is associated with vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation.
Tadalafil: Inhibits phosphodiesterase type 5 (PDE-5) in smooth muscle of pulmonary vasculature where PDE-5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation; vasodilation in the pulmonary bed and the systemic circulation (to a lesser degree) may occur.
See individual agents.
