Macitentan (Monograph)

Brand name: Opsumit
Drug class: Endothelin receptor antagonists

Medically reviewed by Drugs.com on Jun 10, 2025. Written by ASHP.

Warning

Based on animal data, may cause fetal harm if used during pregnancy.

Exclude pregnancy in females of childbearing potential before initiation of therapy and prevent thereafter by using acceptable methods of contraception during and for 1 month following discontinuance of therapy.
When pregnancy is detected, discontinue macitentan as soon as possible.

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Introduction

Vasodilator; an endothelin-receptor antagonist.

Uses for Macitentan

Pulmonary Arterial Hypertension

Management of pulmonary arterial hypertension (PAH; WHO group 1) in adults to reduce the risks of disease progression and hospitalization. Efficacy established 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 over approximately 2 years.

Has been designated an orphan drug by FDA for treatment of PAH.

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications. Endothelin-receptor antagonists such as macitentan are recommended among several options for treatment of WHO/NYHA class II or III PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

Macitentan Dosage and Administration

General

Pretreatment Screening

Obtain a pregnancy test in females of reproductive potential.
Obtain liver enzyme tests.
Measure hemoglobin concentrations.

Patient Monitoring

Obtain liver enzyme tests during treatment as clinically indicated.
Monitor for signs of fluid retention.
Measure hemoglobin concentrations during treatment as clinically indicated.

Administration

Oral Administration

Administer orally without regard to meals.

Do not split, chew, or crush tablets.

If a dose is missed, take as soon as it is remembered that day, then resume next dose at regularly scheduled time; do not take 2 doses at the same time to make up for a missed dose.

Dosage

Adults

Pulmonary Arterial Hypertension

Oral

10 mg once daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Macitentan

Contraindications

Pregnancy.
History of hypersensitivity reaction to macitentan or any component.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals. (See Boxed Warning.)

Exclude pregnancy in females of childbearing potential prior to initiation; prevent pregnancy thereafter with acceptable methods of contraception during and for 1 month following cessation of therapy. If patient becomes pregnant during therapy, apprise patient of potential hazard to the fetus.

When pregnancy is detected, discontinue macitentan as soon as possible.

Other Warnings and Precautions

Hepatotoxicity

Serious hepatotoxicity (e.g., liver failure) reported with some endothelin-receptor antagonists (ERAs; e.g., bosentan, sitaxsentan [not commercially available in US]).

Elevations in AST/ALT of >3 or >8 times ULN observed in 3.4 or 2.1%, respectively, of patients receiving macitentan in principal efficacy study.

Monitor closely for adverse hepatic effects. Obtain liver function tests prior to initiation of therapy and repeat thereafter as clinically indicated.

Discontinue 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 increased bilirubin concentrations >2 times ULN. May consider reinitiation of therapy in patients who experience asymptomatic aminotransferase elevations after concentrations normalize.

Fluid Retention

Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of endothelin receptor antagonists (ERAs).

Patients with preexisting left ventricular dysfunction are at increased risk for significant fluid retention. Postmarketing cases of edema and fluid retention reported; some required intervention with a diuretic or hospitalization.

Monitor for signs of fluid retention. If clinically significant fluid retention develops, evaluate patient to determine cause (e.g., macitentan or underlying heart failure) and possible need to discontinue macitentan.

Hemoglobin Decrease

Decreases in hemoglobin and hematocrit reported early during therapy, followed by stabilization; rarely have required transfusion.

Monitor hemoglobin concentrations prior to initiation and as clinically indicated during therapy.

Do not initiate therapy in patients with severe anemia.

Pulmonary Edema with Pulmonary Veno-Occlusive Diseases

If manifestations of pulmonary edema occur, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue drug.

Decreased Sperm Counts

Reduced sperm counts observed in some men receiving other ERAs; possibility of adverse effects on spermatogenesis with macitentan cannot be excluded. Unknown whether effects on fertility are reversible. Counsel male patients about potential adverse effects on fertility.

Specific Populations

Pregnancy

May cause embryofetal toxicity, including birth defects and fetal death; contraindicated during pregnancy. Data limited on use in pregnant women. If used during pregnancy, or if patient becomes pregnant during therapy, advise patient of fetal risk.

Lactation

Distributed into milk in rats; not known whether drug is distributed into human milk. Advise women not to breastfeed during treatment.

Females and Males of Reproductive Potential

Exclude pregnancy in females of childbearing potential prior to initiation and prevent thereafter with acceptable methods of contraception during and for 1 month following cessation of therapy. If used during pregnancy or if patient becomes pregnant during therapy, apprise patient of potential hazard to fetus.

May cause adverse effects on spermatogenesis. Decreased sperm counts reported in men receiving other ERAs. Counsel male patients about potential adverse effects on fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients for treatment of PAH.

Geriatric Use

No overall differences in safety or efficacy relative to younger patients.

Hepatic Impairment

Decreased systemic exposure to macitentan in patients with hepatic impairment; however, not considered clinically important.

Renal Impairment

Increased systemic exposure to macitentan and its active metabolite in patients with severe renal impairment (Cl_cr 15–29 mL/minute); however, not considered clinically important.

Common Adverse Effects

Common adverse effects (≥3%): anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, urinary tract infection.

Drug Interactions

Metabolized principally by CYP3A4, and to a lesser extent by CYP2C19. At clinically relevant concentrations, does not inhibit or induce CYP enzymes.

Macitentan and active metabolite are not a substrate or inhibitor of P-glycoprotein (P-gp) or multi-drug resistance protein.

Macitentan and active metabolite not expected to significantly interact 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.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential increased macitentan exposure; avoid concomitant use.

Potent inducers of CYP3A4: Potential decreased macitentan exposure; avoid concomitant use.

Moderate dual or combined CYP3A4 and CYP2C9 inhibitors: Potential increased macitentan exposure; avoid concomitant use. Avoid concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with macitentan.

Drugs Affecting or Affected by Transport Systems

No identified effects on pharmacokinetics of concomitant use of a BCRP substrate drug (riociguat 1 mg and rosuvastatin 10 mg).

Specific Drugs

Drug	Interaction	Comments
Cyclosporine	No substantial alteration in systemic exposure to macitentan or its metabolites at steady state	No dosage adjustments necessary
HIV protease inhibitors (e.g., ritonavir)	Potential increased exposure to macitentan when used with HIV protease inhibitors that are potent CYP3A4 inhibitors	Avoid concomitant use; in patients who require potent CYP3A4 inhibitor drugs as part of their HIV treatment, PAH therapies other than macitentan are recommended
Hormonal contraceptives	No effect on pharmacokinetics of norethisterone 1 mg and ethinyl estradiol 35 µg	No dosage adjustments necessary
Ketoconazole	Ketoconazole, a potent CYP3A4 inhibitor, increased systemic exposure to macitentan by approximately twofold, but decreased exposure to active metabolite	Avoid concomitant use
Rifampin	Rifampin, a potent CYP3A4 inducer, substantially reduced systemic exposure to and trough plasma concentrations of macitentan	Avoid concomitant use
Sildenafil	Systemic exposure to and peak plasma concentrations of macitentan not substantially altered; exposure to sildenafil slightly increased	No dosage adjustments necessary
Warfarin	No effect on warfarin exposure or INR

Macitentan Pharmacokinetics

Absorption

Bioavailability

Exhibits dose-proportional pharmacokinetics following oral administration of doses of 1–30 mg once daily.

Peak plasma concentrations attained by about 8 hours after oral administration.

Food

Food does not affect systemic exposure.

Distribution

Plasma Protein Binding

>99%.

Elimination

Metabolism

Undergoes hepatic metabolism, principally by CYP3A4, with minor contributions by CYP2C8, CYP2C9, and CYP2C19.

Oxidative depropylation forms active metabolite that contributes about 40% of pharmacologic activity of macitentan; systemic exposure to this metabolite approximately threefold higher than that of the parent drug.

Elimination Route

Following administration of radiolabeled drug in healthy individuals, approximately 50 and 24% of total radioactivity (but not unchanged drug or active metabolite) recovered in urine and feces, respectively.

Half-life

16 hours for macitentan; 48 hours for active metabolite.

Special Populations

Systemic exposure of macitentan decreased by about 6–34% in patients with various degrees of hepatic impairment.

Systemic exposure to macitentan and its active metabolite increased by 30 and 60%, respectively, in patients with severe renal impairment (Cl_cr 15–29 mL/minute).

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Actions

Nonselective (dual receptor) endothelin-1 (ET-1) receptor antagonist that acts on both ET-1 type A and type B receptors; binds with sustained and high affinity to these receptors in pulmonary arterial smooth muscle cells.
ET-1 is a potent vasoconstrictor and mediator of a variety of deleterious effects (e.g., fibrosis, proliferation, hypertrophy, inflammation); increased concentrations detected in plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disorder.
Differs from other endothelin-receptor antagonists in ET-1 receptor selectivity; clinical importance of selective versus nonselective endothelin receptor blockade not known.
Improves hemodynamics (e.g., pulmonary vascular resistance, cardiac output) in patients with PAH; some beneficial effects on right ventricular hypertrophy also demonstrated in preclinical studies.
Does not interact with hepatic bile transport proteins (i.e., bile salt export pump [BSEP]) or organic anion-transporting polypeptides (OATP 1B1 and 1B3).

Advice to Patients

Risk of fetal harm; advise females of childbearing potential to avoid pregnancy and to use acceptable methods of contraception prior to, during, and for 1 month following discontinuance of macitentan therapy.
Advise patients to inform their clinician immediately if pregnancy is suspected; clinicians should provide counseling on the use of emergency contraception in the event of unprotected sexual intercourse or known or suspected contraceptive failure. Apprise patients of potential risk to fetus if pregnancy occurs.
Stress importance of periodic monitoring of red blood cell counts during treatment.
Potential risk of liver toxicity. Advise patients to inform clinicians of any unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.
Potential risk of peripheral edema and fluid retention. Advise patients to inform clinicians of signs of fluid retention.
Inform patients of the potential risk of decreased sperm counts and potential effects on fertility.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed; advise women not to breastfeed during treatment with macitentan.
Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., drugs for HIV) and OTC drugs or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.