Macitentan (Monograph)

Brand name: Opsumit
Drug class: Endothelin receptor antagonists
Chemical name: N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propyl-sulfamide
Molecular formula: C₁₉H₂₀Br₂N₆O₄S
CAS number: 441798-33-0

Medically reviewed by Drugs.com on Mar 17, 2025. Written by ASHP.

Introduction

Vasodilator; an endothelin-receptor antagonist.

Uses for Macitentan

Pulmonary Arterial Hypertension

Management of pulmonary arterial hypertension (PAH; WHO group 1) 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 prior to initiating treatment with macitentan. Initiate treatment in females of reproductive potential only after a negative pregnancy test.

• Obtain liver enzyme tests prior to initiation of macitentan.

• Measure hemoglobin concentrations prior to initiation of macitentan.

Patient Monitoring

• Obtain a pregnancy test in females of reproductive potential monthly during treatment and 1 month after stopping macitentan.

• Obtain liver enzyme tests during treatment as clinically indicated.

• Monitor for signs of fluid retention.

• Measure hemoglobin concentrations during treatment as clinically indicated.

REMS

• Because of the risk of embryofetal toxicity, macitentan is available to female patients only through a restricted distribution program called the Opsumit Risk Evaluation and Mitigation Strategy (REMS). All female patients regardless of childbearing potential must enroll in the program prior to initiating macitentan; in addition, females of childbearing potential must comply with all pregnancy testing and contraception requirements of the program. Certain restrictions and conditions also apply to prepubertal females. Male patients are exempt from these restrictions and do not need to enroll in the program.

• Clinicians and pharmacies must also be registered with the Opsumit REMS and comply with all terms of the program (including patient education and safety requirements) before they can prescribe or dispense macitentan. Pharmacies must only dispense the drug to authorized patients. For additional information about the Opsumit REMS program, including certified pharmacies or wholesale distributors, clinicians may call 866-228-3546 or consult [Web].

• As a condition of the Opsumit REMS Program, macitentan therapy should be initiated in females of childbearing potential only after a negative pregnancy test is obtained; pregnancy tests must be performed monthly during therapy and at 1 month following discontinuance of therapy.

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.

Prescribing Limits

Adults

Pulmonary Arterial Hypertension

Oral

Safety and efficacy of dosages >10 mg daily not established; not recommended.

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.)

Available for females only through the Opsumit REMS Program, a restricted distribution program. 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. Perform monthly pregnancy tests in females of childbearing potential.

If macitentan is used during pregnancy or patient becomes pregnant during therapy, apprise patient of potential fetal hazard.

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. Consider increased risk of pregnancy-associated maternal and fetal morbidity and mortality in patients with PAH.

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. Monthly pregnancy tests required in females of childbearing potential. 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.

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

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; importance of advising females of childbearing potential to avoid pregnancy and to use acceptable methods of contraception during and for 1 month following discontinuance of macitentan therapy. Acceptable methods of contraception include one highly effective form of contraception (intrauterine device [IUD], contraceptive implant, or tubal sterilization) or a combination of methods (either one hormonal and one barrier method or 2 barrier methods where one form is the male condom). Acceptable hormonal methods of contraception include estrogen-progestin combination oral contraceptives or transdermal contraceptive systems, vaginal ring, and progesterone injections. Acceptable barrier methods include male condoms, diaphragms with spermicide, and cervical caps with spermicide. Even if the partner has had a vasectomy, an additional hormonal or barrier method must be used.

• Importance of advising females to inform their clinician immediately if a menstrual period is missed or pregnancy is suspected; clinicians should perform a pregnancy test if pregnancy is suspected for any reason and provide counseling on the use of emergency contraception in the event of unprotected sexual intercourse or known or suspected contraceptive failure. Apprise patient of potential risk to fetus if pregnancy occurs.

• Importance of all female patients (regardless of childbearing potential) enrolling in the Opsumit REMS program and complying with all contraceptive and pregnancy testing requirements. Importance of monitoring reproductive status of prepubertal females and immediately reporting any changes to a clinician.

• Importance of periodic monitoring of red blood cell counts during treatment.

• Potential risk of liver toxicity. Importance of patients informing 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. Importance of patients informing clinicians of signs of fluid retention.

• Potential risk of decreased sperm counts in men and potential effects on fertility.

• Importance of taking macitentan as prescribed and of not interrupting or discontinuing therapy without consulting a clinician.

• Importance of not taking a double dose to make up for a missed dose but instead taking the missed dose as soon as it is remembered, and then resuming the next dose at the regularly scheduled time.

• Importance of advising patients to not split, chew, or crush tablets.

• Importance of distributing the FDA-approved medication guide with every prescription and reviewing the information with female patients. (See REMS.) Importance of patients carefully reading the medication guide before initiating therapy and each time prescription is refilled.

• Importance of females informing their clinician if they are or plan to become pregnant or plan to breast-feed; advise women not to breastfeed during treatment with macitentan.

• 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Distribution of macitentan is restricted in female patients. (See REMS under Dosage and Administration: General.)

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