Version October 2024
Do not administer macitentan/tadalafil to a pregnant female patient because it may cause fetal harm. In female patients 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.
For all female patients, macitentan/tadalafil is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS).
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.
Special populations:
• REMS program: Females regardless of their reproductive potential must be enrolled in the REMS program; prescribers and pharmacies must also be enrolled in the program. Females of reproductive potential must be able to comply with pregnancy testing and contraception requirements of the program. Further information is available at 1-888-572-2934 or www.MacitentanREMS.com.
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): $505.41
10-40 mg (per each): $505.41
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 2016 [group 3]).
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 2016; 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.
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 enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Alpha1-Blockers (Nonselective): Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect 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 enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Alprostadil: Phosphodiesterase 5 Inhibitors may enhance the adverse/toxic effect of Alprostadil. Risk X: Avoid combination
Amiodarone: May increase the serum concentration of Macitentan. Risk C: Monitor therapy
Amyl Nitrite: Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Amyl Nitrite. Risk X: Avoid combination
Blood Pressure Lowering Agents: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bosentan: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Macitentan. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tadalafil. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Macitentan. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Macitentan. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tadalafil. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Macitentan. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
Etravirine: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fluconazole: May increase the serum concentration of Macitentan. Risk X: Avoid combination
Fosamprenavir: May increase the 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 the 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
Lenacapavir: May increase the 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
Lorcaserin (Withdrawn From US Market): May enhance the adverse/toxic effect of Phosphodiesterase 5 Inhibitors. Specifically, the risk of developing priapism may be increased. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
Nitroprusside: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Nitroprusside. Risk X: Avoid combination
Phosphodiesterase 5 Inhibitors: May enhance the adverse/toxic effect of other Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
Riociguat: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
Sapropterin: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Simeprevir: May increase the serum concentration of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Sparsentan: May enhance the adverse/toxic effect of Endothelin Receptor Antagonists. Risk X: Avoid combination
Vasodilators (Organic Nitrates): Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk X: Avoid combination
Vericiguat: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
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, monthly during treatment, and 1 month after macitentan/tadalafil is discontinued. Patients who could become pregnant must be enrolled in the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) program and use reliable contraception as described in the medication guide 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.
Refer to individual monographs for additional information.
It is not known if macitentan or tadalafil are present in breast 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; pregnancy status (test prior to therapy initiation, monthly during treatment, and 1 month after therapy is discontinued in patients who could become pregnant); Hb and Hct prior to initiation and repeat as clinically appropriate.
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.
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