Macitentan, an endothelin-receptor antagonist, is a vasodilator.1, 7, 8, 9, 11
Pulmonary Arterial Hypertension
Macitentan is used in the management of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group 1 pulmonary hypertension) in adults to reduce the risks of disease progression and hospitalization.1, 3 Clinical studies establishing efficacy of the drug for this use were conducted principally in patients with WHO functional class II or III PAH (idiopathic, heritable, associated with connective tissue diseases, or caused by congenital heart disease) who were receiving macitentan for an average of 2 years.1, 3, 42 Macitentan has been designated an orphan drug by FDA for use in the treatment of PAH.2
Efficacy of macitentan for the management of PAH has been established in a long-term (average treatment duration approximately 2 years), randomized, double-blind, placebo-controlled study (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome [SERAPHIN]) in 742 patients with WHO group 1 PAH (57% idiopathic or heritable, 31% associated with connective tissue disorders, and 12% caused by other etiologies [congenital heart disease, drugs/toxins, HIV]).1, 3, 7 Most patients had NYHA/WHO functional class II (52%) or III (46%) symptoms at study entry and 64% were receiving concomitant therapy with a phosphodiesterase type 5 inhibitor and/or an oral/inhaled prostanoid.1, 3 Macitentan (10 mg once daily) was substantially more effective than placebo in reducing the progression of PAH; the primary composite end point of time to first occurrence of death, atrial septostomy, lung transplantation, initiation of IV/subcutaneous prostanoid therapy, or worsening of PAH (defined as a sustained decrease in 6-minute walking distance of at least 15% from baseline in addition to worsening of WHO functional class and need for additional PAH treatments) was reduced by 45% with macitentan therapy.1, 3 The median duration of treatment with macitentan or placebo was 118 or 101 weeks, respectively.1 The beneficial effect of macitentan was driven largely by a reduction in clinical worsening events (deterioration in 6-minute walking distance, worsening of PAH symptoms, and need for additional PAH treatments).1, 3 Macitentan therapy also improved several secondary measures of efficacy, including PAH-related death or hospitalization (50% risk reduction) and 6-minute walking distance (placebo-corrected mean increase of 22 meters at 6 months); there was no difference in all-cause mortality between the treatment groups.1, 3 A single arm, noncomparative open-label extension study of the SERAPHIN trial (SERAPHIN OL) evaluated long-term outcomes in 242 patients who received macitentan in SERAPHIN over a median exposure period of 4.6 years.1, 42 Kaplan-Meier estimates for survival at 1, 2, 5, and 7 years were 95, 89, 73, and 63%, respectively.1
Current expert consensus guidelines recommend that all adult patients with symptomatic (World Health Organization [WHO] or New York Heart Association [NYHA] functional classification [FC] II-IV) pulmonary arterial hypertension (PAH) be treated with established PAH-specific medications (e.g., prostacyclin derivative [e.g., epoprostenol, treprostinil], PDE type 5 inhibitor [i.e. sildenafil, tadalafil], endothelin receptor antagonist [e.g., ambrisentan, bosentan, macitentan], or a soluble guanylate cyclase stimulator [e.g., riociguat]) to reduce symptoms, improve functional capacity, and to delay progression of PAH, hospitalization, and death.700 Selection of drug therapy should be based on disease severity (WHO/NYHA class), risk of further short-term deterioration, comorbid illnesses, concomitant medications, expected tolerance of known side effects, route of administration (i.e., oral, parenteral, inhaled), costs of therapy, and patient preferences.700 In addition, patients with PAH should receive supportive care (e.g., oxygen, diuretics, anticoagulants).700
For treatment-naïve PAH patients with WHO/NYHA FC II or III symptoms who are not candidates for, or who have failed calcium-channel blocking agent therapy, experts recommend initial combination therapy with ambrisentan and tadalafil, but give this a weak recommendation based on moderate quality evidence.700 Monotherapy with an endothelin-receptor antagonist (e.g., ambrisentan, bosentan, macitentan), phosphodiesterase type 5 inhibitor (e.g., sildenafil, tadalafil), or soluble guanylate cyclase stimulator (e.g., riociguat) can be initiated for patients who are intolerant to or unwilling to take combination treatment.700 Initial treatment with continuous IV epoprostenol, IV treprostinil, or subcutaneous treprostinil is recommended in patients with WHO/NYHA FC III who have evidence of rapid disease progression or poor prognosis; inhaled or oral prostanoids are recommended in patients who are unwilling and not able to manage parenteral prostanoids.700 In patients with WHO FC III PAH who have evidence of disease progression and/or poor clinical prognosis despite treatment with one or two classes of oral agents, consideration should be given to the addition of a parenteral or inhaled prostanoid (e.g., IV epoprostenol, IV treprostinil, inhaled treprostinil, inhaled iloprost).700
Macitentan is administered orally without regard to meals.1 Macitentan tablets should not be split, chewed, or crushed.1
If a dose of macitentan is missed, the dose should be taken as soon as it is remembered that day, and the next dose should be resumed at the regularly scheduled time; 2 doses should not be taken at the same time to make up for a missed dose.1
Store macitentan tablets at 20-25ºC (excursions permitted between 15-30°C).1
Pulmonary Arterial Hypertension
The recommended dosage of macitentan for the treatment of pulmonary arterial hypertension (PAH) in adults is 10 mg once daily.1 The manufacturer states that dosages exceeding 10 mg daily have not been evaluated in patients with PAH and are therefore not recommended.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Fetal/Neonatal Morbidity and Mortality
A boxed warning about the risk of embryofetal toxicity is included in the prescribing information for macitentan.1 Macitentan may cause fetal harm if used during pregnancy; teratogenic (e.g., cardiovascular abnormalities, mandibular arch fusion abnormalities) and embryotoxic (e.g., reduced survival) effects have been demonstrated in animals.1 Available human data for endothelin receptor antagonists (ERAs) do not establish the presence or absence of major birth defects related to macitentan therapy.1
Pregnancy must be excluded in females of childbearing potential prior to initiation of macitentan therapy and prevented thereafter by the use of acceptable methods of contraception during and for 1 month following cessation of therapy.1 If the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus.1 When pregnancy is detected, the clinician should discontinue macitentan as soon as possible.1
Other Warnings and Precautions
Serious hepatotoxicity and liver failure have been reported in patients receiving other ERAs (e.g., bosentan, sitaxsentan [not commercially available in the US]).1, 4, 7, 18 Elevations in serum aminotransferase (AST/ALT) concentrations to more than 3 times the upper limit of normal (ULN) were reported in 3.4% of patients receiving macitentan and 4.5% of those receiving placebo in the principal clinical study of the drug; AST/ALT elevations to more than 8 times the ULN occurred in 2.1 and 0.4% of patients in these respective treatment groups.1, 3
Although findings to date do not suggest a high potential for macitentan to cause hepatotoxicity,4, 40 such a risk cannot be ruled out and patients should be monitored closely for adverse hepatic effects.1, 4
Obtain liver function tests prior to initiation of macitentan therapy and repeat thereafter as clinically indicated.1 Discontinue the drug if clinically important elevations of aminotransferase concentrations occur or if aminotransferase elevations are accompanied by manifestations of hepatic disease (e.g., nausea, vomiting, fever, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, itching) or an increase in bilirubin concentrations to more than 2 times the ULN.1 Consider reinitiation of macitentan therapy in patients who experience asymptomatic aminotransferase elevations after such elevations normalize.1
Peripheral edema and fluid retention are known clinical consequences of pulmonary arterial hypertension (PAH) and known effects of ERAs.1 In the placebo-controlled study of macitentan in PAH, edema occurred in 21.9% of patients treated with macitentan 10 mg and in 20.5% of those treated with placebo.1
Patients with preexisting left ventricular dysfunction may be at increased risk for developing significant fluid retention after initiation of ERA treatment.1 In a small study in patients with pulmonary hypertension due to left ventricular dysfunction, more patients treated with macitentan developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized to placebo.1 Postmarketing cases of edema and fluid retention occurring within weeks of starting macitentan have been reported; some of these have required intervention with a diuretic or hospitalization for decompensated heart failure.1
Monitor for signs of fluid retention after macitentan initiation.1 If clinically significant fluid retention develops, evaluate the patient to determine the cause (e.g., macitentan or underlying heart failure) and the possible need to discontinue macitentan.1
As with other ERAs, reductions in hemoglobin concentration and hematocrit have been reported with macitentan; these decreases generally occur early during therapy and stabilize thereafter.1, 3, 4 In the principal efficacy study of macitentan in patients with PAH, a mean decrease in hemoglobin concentration of about 1 g/dL was reported in patients receiving the drug after 18 months; hemoglobin concentrations decreased to less than 10 g/dL in 8.7% of patients receiving macitentan compared with 3.4% of those receiving placebo.1 Such decreases rarely have required transfusion.1
Measure hemoglobin concentrations prior to initiation of macitentan therapy and monitor as clinically indicated thereafter.1 Do not initiate the drug in patients with severe anemia.1
Pulmonary Edema with Pulmonary Veno-Occlusive Disease
If manifestations of pulmonary edema occur during macitentan therapy, the possibility of pulmonary veno-occlusive disease should be considered; if confirmed, the drug should be discontinued.1
Macitentan, like other ERAs, may cause adverse effects on spermatogenesis.1 Decreased sperm counts have been reported in some men who were receiving other ERAs.1 It is unknown whether effects on fertility would be reversible.1 Counsel male patients about the potential adverse effects of macitentan on fertility.1
Based on data from animal reproduction studies, macitentan may cause embryofetal toxicity, including birth defects and fetal death, when administered to pregnant females and is contraindicated during pregnancy.1 Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as macitentan have not identified an increased risk of major birth defects; however, these data are limited.1 If macitentan is used during pregnancy, or if the patient becomes pregnant while taking macitentan, clinicians should advise the patient of the fetal risk.1
It is not known whether macitentan is distributed into human milk or has effects on the breastfed infant or on milk production.1 Because of the potential for serious adverse reactions to macitentan in nursing infants, advise women not to breastfeed during treatment with macitentan.1
Females and Males of Reproductive Potential
Exclude pregnancy in females of childbearing potential prior to initiation of macitentan therapy and prevent thereafter by the use of acceptable methods of contraception during and for 1 month following cessation of therapy.1 If macitentan is used during pregnancy or if the patient becomes pregnant during therapy, apprise the patient of the potential hazard to the fetus.1
Macitentan, like other ERAs, may cause adverse effects on spermatogenesis.1 Decreased sperm counts have been reported in some men who were receiving other ERAs.1 Counsel male patients about the potential adverse effects of macitentan on fertility.1
Safety and efficacy of macitentan have not been established in pediatric patients for the treatment of PAH.1
In an open-label, randomized trial with an extension period, 148 pediatric patients 2 to 17 years of age with PAH were evaluated.1 Results revealed that macitentan did not demonstrate a clinical benefit compared with standard of care PAH treatment.1 Adverse reactions in the trial were similar in nature to those seen in clinical trials in adults.1
In the principal clinical study of macitentan in patients with PAH, 14% of the patients were 65 years of age or older.1 No overall differences in safety or efficacy were observed between these geriatric patients and younger individuals.1
Systemic exposure of macitentan is decreased by about 6-34% in patients with hepatic impairment, but this change is not considered to be clinically important.1, 17
Systemic exposure to macitentan and its active metabolite is increased by 30 and 60%, respectively, in patients with severe renal impairment (creatinine clearance of 15-29 mL/minute); these changes are not considered to be clinically important.1, 17
The most common adverse effects reported with macitentan in clinical trials and occurring at least 3% more frequently with the drug than with placebo include anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection.1
Macitentan is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4, and to a lesser extent by CYP2C19.1, 13, 14 At clinically relevant concentrations, macitentan does not appear to inhibit or induce CYP enzymes.1, 13 The drug and its active metabolite are not substrates or inhibitors of the P-glycoprotein (P-gp) efflux transporter or multi-drug resistance protein.1 Macitentan and its active metabolite are not expected to have significant interaction with the organic anion transport proteins (OATP) 1B1 and 1B3, multidrug and toxin extrusion protein (MATE-1, MATE-2K), bile salt export pump (BSEP), sodium-taurocholate co-transporting polypeptide (NTCP), organic cation transporter (OCT-1, OCT-3), organic anion transporter (OAT-1, OAT-3), or breast-cancer resistance protein (BCRP) at clinically relevant plasma concentrations.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of macitentan with potent inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir) may increase exposure to macitentan and should be avoided.1
Concomitant use of macitentan with potent inducers of CYP3A4 (e.g., rifampin) may decrease exposure to macitentan and should be avoided.1
Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors
Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic modeling.1 Avoid concomitant use of macitentan with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone).1
Concomitant use of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with macitentan should also be avoided.1
Drugs Affecting or Affected by Transport Systems
Macitentan 10 mg once daily did not affect the pharmacokinetics of concomitant use of a BCRP substrate drug (riociguat 1 mg and rosuvastatin 10 mg).1
In healthy individuals, concomitant administration of macitentan and cyclosporine (a CYP3A4 inhibitor) did not substantially alter systemic exposure to macitentan or its metabolites at steady state.1, 15 No dosage adjustment is necessary when these drugs are administered concomitantly.1
HIV protease inhibitors such as ritonavir are potent inhibitors of CYP3A4 and can therefore increase systemic exposure to macitentan if used concomitantly.1 Although the effects of ritonavir coadministration on macitentan pharmacokinetics have not been established, ritonavir is expected to increase macitentan exposure to a similar extent as that observed with ketoconazole.1
Concomitant use of macitentan and HIV protease inhibitors that are potent inhibitors of CYP3A4 is not recommended.1 In patients who require the use of a potent CYP3A4 inhibitor drug as part of their HIV treatment regimen, PAH therapies other than macitentan are recommended.1
Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl estradiol 35 µg).1
In healthy individuals, concomitant administration of macitentan and ketoconazole (a potent CYP3A4 inhibitor) increased systemic exposure to macitentan by approximately twofold and reduced exposure to the active metabolite by about 26%.1, 14 While some experts suggest that these changes are not clinically important,7, 14 the manufacturer recommends that concomitant use of macitentan and ketoconazole be avoided.1
In healthy individuals, concomitant administration of macitentan and rifampin (a potent CYP3A4 inducer) substantially reduced systemic exposure and trough plasma concentrations of macitentan.1, 15 Concomitant use of these drugs should be avoided.1
In healthy individuals, concomitant administration of macitentan and sildenafil did not substantially alter systemic exposure or peak plasma concentrations of macitentan; exposure to sildenafil was increased by 15%, but this degree of change is not considered clinically important.1 No dosage adjustment is necessary when these drugs are administered concomitantly.1
Concomitant administration of warfarin and macitentan did not alter exposure to warfarin and had no effect on the international normalized ratio (INR).1
Macitentan, a nonselective (dual receptor) endothelin-1 (ET-1) receptor antagonist, is a vasodilator.1, 7, 8, 9, 11 ET-1 is a potent vasoconstrictor and mediator of a variety of deleterious effects (e.g., fibrosis, proliferation, hypertrophy, inflammation); increased concentrations of ET-1 have been detected in the plasma and lung tissue of patients with pulmonary arterial hypertension (PAH), suggesting a pathogenic role for ET-1 in this disorder.1, 4, 8, 20, 23, 40 Macitentan binds with sustained and high affinity to both ET-1 type A and type B receptors in pulmonary arterial smooth muscle cells.1, 19, 20 Selectivity for these ET-1 receptors differs among the various endothelin-receptor antagonists; although dual blockade is thought to be advantageous in fully inhibiting the effects of ET-1-induced endothelial dysfunction, the clinical importance of selective versus nonselective endothelin receptor blockade is not known.9, 22, 40 Macitentan improves hemodynamics (e.g., pulmonary vascular resistance, cardiac output) in patients with PAH and also has shown some beneficial effects on right ventricular hypertrophy in preclinical studies.1, 20
Macitentan exhibits dose-proportional pharmacokinetics following oral doses ranging from 1-30 mg.1, 18 Peak concentrations of the drug are attained by about 8 hours after a dose.1, 9, 12, 18 Macitentan is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4, with minor contributions by CYP2C8, CYP2C9, and CYP2C19.1, 9, 12 An oxidative depropyl metabolite has been identified as the main active metabolite, which represents about 40% of the pharmacologic activity of macitentan and has a systemic exposure approximately threefold higher than that of the parent drug.1, 9, 12 Following administration of radiolabeled macitentan in healthy individuals, approximately 50 and 24% of total radioactivity is recovered in urine and feces, respectively.1, 12 Elimination half-lives of the drug and its active metabolite are approximately 16 and 48 hours, respectively.1, 18 Neither macitentan nor its active metabolite interacts with proteins involved in hepatic bile transport (i.e., bile salt export pump [BSEP]) or with the organic anion-transporting polypeptides (i.e., OATP 1B1 and 1B3); such effects have been demonstrated with other endothelin-receptor antagonists and may be a contributing factor to the apparent differences observed in hepatotoxic potential between the agents.1, 9, 15, 18
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions June 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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