Version May 2024
Pulmonary arterial hypertension: Oral: Macitentan 10 mg/tadalafil 40 mg once daily. Note: Initiate therapy with combination product only after stabilization of individual doses of macitentan 10 mg and tadalafil 40 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild to moderate impairment: Dosage adjustment not necessary. Patients with moderate impairment may have a higher risk of experiencing hypotension and anemia.
Severe impairment: Use not recommended.
Dialysis: Use not recommended (has not been studied).
Baseline ALT or AST >3 × ULN: Initiation of therapy is not recommended.
Mild impairment: Dosage adjustment not necessary.
Moderate to severe impairment: Use not recommended.
Refer to adult dosing; use with caution.
See individual agents.
Hypersensitivity to macitentan, tadalafil, or any component of the formulation; pregnancy or patients who may become pregnant; breastfeeding; previous episode of nonarteritic anterior ischemic optic neuropathy; concurrent use of organic nitrate (regularly and/or intermittently) or guanylate cyclase stimulators (eg, riociguat).
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. Use caution in patients with retinitis pigmentosa; a minority have genetic disorders of retinal phosphodiesterases (no safety information available).
• 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 rarely; hearing changes may be accompanied by tinnitus and dizziness. Instruct patients to seek medical assistance for sudden decrease in hearing or loss of hearing. A direct relationship between therapy and hearing loss has not been determined.
• Hematologic effects: A reduction in hematocrit/hemoglobin has been observed and may occur early in therapy with subsequent stabilization. Decreases in hemoglobin 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. Discontinue treatment in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (eg, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, right upper quadrant pain, vomiting) or elevated bilirubin (>2 times ULN). Upon normalization of hepatic enzymes, may consider reinitiation of therapy in patients not experiencing clinical signs of hepatotoxicity.
• Hypotension: Decreases in blood pressure may occur due to vasodilator effects; use with caution in patients with left ventricular outflow obstruction (aortic stenosis or hypertrophic obstructive cardiomyopathy); may be more sensitive to hypotensive actions. Concurrent use with alpha-adrenergic antagonist therapy may cause symptomatic hypotension; patients should be hemodynamically stable prior to initiating therapy at the lowest possible dose. Patients should avoid or limit concurrent substantial ethanol consumption as this may increase the risk of symptomatic hypotension.
• Vision loss: Vision loss (rare) may be a sign of nonarteritic anterior ischemic optic neuropathy (NAION); causal relationship to PDE5 inhibitors not established. Instruct patients to discontinue therapy and seek medical assistance for sudden loss of vision in one or both eyes. Patients who have already experienced NAION are at an increased risk of recurrence. Other risk factors for NAION include low cup-to-disc ratio ("crowded disc"), coronary artery disease, diabetes, hypertension, hyperlipidemia, smoking, and age >50 years . Use with caution in these patients and only when the benefits outweigh the risks. 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: Use with caution in patients with mild hepatic impairment. Use is not recommended in patients with moderate to severe hepatic impairment or cirrhosis.
• Pulmonary veno-occlusive disease (PVOD): Pulmonary vasodilators may exacerbate the cardiovascular status in patients with 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: Use with caution in patients with moderate to severe impairment; increased risk of hypotension and anemia.
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.
Not available in the United States.
No
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.
Note: Not approved in the United States.
Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to reduce morbidity in adult patients of WHO functional class (FC) II or III whose PAH is idiopathic, heritable, or associated with connective tissue disease or congenital heart disease.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
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 Lexicomp 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). Risk X: Avoid combination
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
Rate and extent of absorption are not affected by food. 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 and monthly during treatment. Patients who could become pregnant should use reliable contraception during therapy and for 1 month after the last dose of macitentan/tadalafil. Use is contraindicated in patients who could become pregnant.
Sperm morphology, motility, or concentrations may be decreased with use.
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.
Use is contraindicated in breastfeeding patients. Refer to individual monographs for additional information.
Liver enzymes (baseline and then monthly during the first year); monitor for clinical signs and symptoms of liver injury (eg, abdominal pain, anorexia, dark urine, fatigue, fever, itching, jaundice, nausea, vomiting); hemoglobin (baseline, after one month, and then periodically); BP. Monitor for significant peripheral edema and evaluate etiology if it occurs. Exclude pregnancy prior to initiation. Pregnancy tests should be conducted prior to therapy and monthly during treatment.
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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