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Class: Vasodilating Agents
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
Brands: Opsumit

Medically reviewed on July 31, 2017


  • May cause fetal harm; contraindicated in females who are pregnant.1

    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.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

  • Distribution of macitentan is restricted in all female patients.1 (See Restricted Distribution Program under Dosage and Administration.)

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for macitentan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of macitentan and consists of the following: medication guide, elements to assure safe use, and implementation system. See See also Restricted Distribution Program under Dosage and Administration: General.


Vasodilator; an endothelin-receptor antagonist.1 7 8 9 10 11

Uses for Macitentan

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1) to delay disease progression (i.e., death, initiation of IV or sub-Q prostanoids, clinical worsening).1 3 Efficacy established principally in patients with NYHA/WHO functional class II or III PAH (idiopathic, heritable, associated with connective tissue diseases, or caused by congenital heart disease) who were receiving macitentan as monotherapy or in combination with a phosphodiesterase (PDE) type 5 inhibitor or inhaled prostanoid over approximately 2 years.1 3

Endothelin-receptor antagonists (e.g., ambrisentan, bosentan, macitentan) recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.27 38 40

Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.7 27 38 40

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid, PDE type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially).6 40 Such combination therapy may provide additive and/or synergistic benefits.6 24 25 27 29 38 40

Has been designated an orphan drug by FDA for treatment of PAH.2

Macitentan Dosage and Administration


    Restricted Distribution Program
  • Distribution of macitentan to female patients is restricted; available only through the Opsumit REMS.1 (See Boxed Warning and also see REMS.)

  • All female patients (regardless of childbearing potential), clinicians, and pharmacies must enroll in the program in order to receive, prescribe, and dispense the drug, respectively; in addition, females of childbearing potential must comply with pregnancy testing and contraception requirements.1 41 Male patients do not need to enroll.1 41 Additional information available at 866-228-3546 or [Web].1

  • Dispense no more than a 30-day supply of macitentan at one time to prepubertal females and females of childbearing potential; confirm with patients of childbearing potential that required pregnancy testing was completed prior to dispensing.5

  • Advise prepubertal patients and/or their parent/guardian to immediately report changes in reproductive status of the patient (e.g., breast development, pubic hair)41 to clinician.1 5 41

  • Distribute medication guide each time macitentan is dispensed.1 5


Oral Administration

Administer orally without regard to meals.1

Do not split, chew, or crush tablets.1 41

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.41




10 mg once daily.1

Prescribing Limits



Safety and efficacy of dosages >10 mg daily not established; not recommended.1

Special Populations

Hepatic Impairment

Dosage adjustment not required.4 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not required.4 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Macitentan


  • Pregnancy.1


Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.1 (See Boxed Warning.)

If macitentan is used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.1 (See Advice to Patients.)

Hepatic Effects

Serious hepatotoxicity (e.g., liver failure) reported with some endothelin-receptor antagonists (e.g., bosentan, sitaxsentan [not commercially available in US]).1 4 7 10 18

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.1 3

Monitor closely for adverse hepatic effects.1 4 (See Advice to Patients.) Obtain liver function tests prior to initiation of therapy and repeat thereafter as clinically indicated.1

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 of >2 times ULN.1 May consider reinitiation of therapy in patients who experience asymptomatic aminotransferase elevations after concentrations normalize.1

Hematologic Effects

Decreases in hemoglobin and hematocrit reported early during therapy, followed by stabilization; rarely have required transfusion.1 3 4

Monitor hemoglobin concentrations prior to initiation and as clinically indicated during therapy.1

Do not initiate therapy in patients with severe anemia.1

Pulmonary Effects

If manifestations of pulmonary edema occur, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue drug.1

Fertility in Males

Reduced sperm counts observed in some men receiving other endothelin-receptor antagonists; possibility of adverse effects on spermatogenesis with macitentan cannot be excluded.1

Specific Populations


Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications, under Cautions.)


Distributed into milk in rats; not known whether drug is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety or efficacy relative to younger patients.1

Hepatic Impairment

Decreased systemic exposure to macitentan in patients with hepatic impairment; however, not considered clinically important.1 17

Renal Impairment

Increased systemic exposure to macitentan and its active metabolite in patients with severe renal impairment (Clcr 15–29 mL/minute); however, not considered clinically important.1 17

Common Adverse Effects

Anemia,1 3 nasopharyngitis/pharyngitis,1 3 bronchitis,1 3 headache,1 3 influenza,1 urinary tract infection.1

Interactions for Macitentan

Metabolized principally by CYP3A4, and to a lesser extent by CYP2C19.1 13 14 At clinically relevant concentrations, does not inhibit or induce CYP enzymes.1 13

Not a substrate or inhibitor of P-glycoprotein (P-gp) or the organic anion transport proteins (OATP) 1B1 and 1B3.1 14 15

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential increased macitentan exposure; avoid concomitant use.1

Potent inducers of CYP3A4: Potential decreased macitentan exposure; avoid concomitant use.1

Specific Drugs





No substantial alteration in systemic exposure to macitentan or its metabolites at steady state1 15

No dosage adjustments necessary1

HIV protease inhibitors (e.g., ritonavir)

Potential increased exposure to macitentan when used with HIV protease inhibitors that are potent CYP3A4 inhibitors1

Avoid concomitant use; in patients who require potent CYP3A4 inhibitor drugs as part of their HIV treatment, PAH therapies other than macitentan are recommended1


Increased systemic exposure to macitentan by approximately twofold, but decreased exposure to active metabolite1 14

Manufacturer states to avoid concomitant use1


Substantially reduced systemic exposure to and trough plasma concentrations of macitentan1 15

Avoid concomitant use1


Systemic exposure to and peak plasma concentrations of macitentan not substantially altered; exposure to sildenafil slightly increased1

No dosage adjustments necessary1


No effect on warfarin exposure or INR1

Macitentan Pharmacokinetics



Exhibits dose-proportional pharmacokinetics following oral administration of doses of 1–30 mg once daily.1 18

Peak plasma concentrations attained by about 8 hours after oral administration.1 9 18


Food does not affect systemic exposure.1


Plasma Protein Binding




Undergoes hepatic metabolism, principally by CYP3A4, with minor contribution by CYP2C19.1 9 12

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.1 9 10 12

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.1 12


16 hours for macitentan; 48 hours for active metabolite.1 18

Special Populations

Systemic exposure of macitentan decreased by about 6–34% in patients with various degrees of hepatic impairment.1 17

Systemic exposure to macitentan and its active metabolite increased by 30 and 60%, respectively, in patients with severe renal impairment (Clcr 15–29 mL/minute).1 17





20–25°C (may be exposed to 15–30°C).1


  • 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.1 6 10 19 20

  • 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.1 4 8 20 23 40

  • Differs from other endothelin-receptor antagonists in ET-1 receptor selectivity; clinical importance of selective versus nonselective endothelin receptor blockade not known.6 9 10 22 40

  • 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.1 6 20

  • Does not interact with hepatic bile transport proteins (i.e., bile salt export pump [BSEP]) or organic anion-transporting polypeptides (OATP 1B1 and 1B3).1 6 9 10 15 18

Advice to Patients

  • Risk of fetal harm; importance of advising women of childbearing potential to avoid pregnancy and to use acceptable methods of contraception during and for 1 month following discontinuance of macitentan therapy.1 41 Acceptable methods of contraception include one highly effective form of contraception (intrauterine device [IUD], progesterone 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).1 41 Acceptable hormonal methods of contraception include estrogen-progestin combination oral contraceptives or transdermal contraceptive systems, vaginal ring, and progesterone injections.41 Acceptable barrier methods include male condoms, diaphragms with spermicide, and cervical caps with spermicide.41 Even if the partner has had a vasectomy, an additional hormonal or barrier method must be used.1 41

  • Importance of advising women 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.1 41 Apprise patient of potential risk to fetus if pregnancy occurs.1

  • Importance of female patients enrolling in the Opsumit REMS program and complying with all contraceptive and pregnancy testing requirements.1 41 Importance of monitoring reproductive status of prepubertal females and immediately reporting changes to clinician.1 41

  • Importance of periodic monitoring of RBC counts during treatment.1 41

  • Potential risk of liver toxicity.1 41 Importance of patients informing clinicians of any unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.1 41

  • Importance of taking macitentan as prescribed and of not interrupting or discontinuing therapy without consulting a clinician.41

  • 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 next dose at regularly scheduled time.41

  • Importance of advising patients to not split, chew, or crush tablets.1 41

  • Importance of distributing the FDA-approved medication guide with every prescription and reviewing the information with female patients.1 5 41 (See REMS.) Importance of patients carefully reading the medication guide before initiating therapy and each time prescription is refilled.41

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 41

  • 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.1 41

  • Importance of informing patients of other important precautionary information.1 41 (See Cautions.)


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.1 (See Restricted Distribution Program under Dosage and Administration.)



Dosage Forms


Brand Names



Tablets, film-coated

10 mg



AHFS DI Essentials. © Copyright 2018, Selected Revisions July 31, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.


1. Actelion. Opsumit (macitentan) tablets prescribing information. South San Francisco, CA; 2013 Oct.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [January 7, 2014]. From FDA web site.

3. Pulido T, Adzerikho I, Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369:809-18.

4. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 204410Orig1s000: Summary Review. From FDA website.

5. Opsumit (macitentan) risk evaluation and mitigation strategy (REMS). Available from FDA web site. Accessed 2014 Jan 24.

6. Actelion Pharmaceuticals US. South San Francisco, CA; Personal communication.

7. Hong IS, Coe HV, Catanzaro LM. Macitentan for the Treatment of Pulmonary Arterial Hypertension. Ann Pharmacother 2014; 48:538-47.

8. Patel T, McKeage K. Macitentan: first global approval. Drugs. 2014; 74:127-33.

9. Sidharta PN, van Giersbergen PL, Halabi A et al. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011; 67:977-84.

10. Dingemanse J, Sidharta PN, Maddrey WC et al. Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf 2013; 13:391-405.

11. Bolli MH, Boss C, Binkert C et al. The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012; 55:7849-61.

12. Bruderer S, Hopfgartner G, Seiberling M et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012; 42:901-10.

13. Weiss J, Theile D, Rüppell MA et al. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013; 701:168-75.

14. Atsmon J, Dingemanse J, Shaikevich D et al. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet. 2013; 52:685-92.

15. Bruderer S, Aänismaa P, Homery MC et al. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012; 14:68-78.

17. Sidharta PN, Lindegger N, Ulc I et al. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. 2013; :.

18. Sidharta PN, van Giersbergen PL, Dingemanse J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol. 2013; 53:1131-8.

19. Gatfield J, Mueller Grandjean C, Sasse T et al. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012; 7:e47662.

20. Iglarz M, Binkert C, Morrison K et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008; 327:736-45.

22. Opitz CF, Ewert R, Kirch W et al. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter?. Eur Heart J. 2008; 29:1936-48.

23. Giaid A, Yanagisawa M, Langleben D et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993; 328:1732-39.

24. Channick RN. Combination therapy in pulmonary arterial hypertension. Am J Cardiol. 2013; 111(8 Suppl):16C-20C.

25. Zhu B, Wang L, Sun L et al. Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis. J Cardiovasc Pharmacol. 2012; 60:342-6.

27. Barst RJ, Gibbs JS, Ghofrani HA et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S78-84.

29. Gokhman R, Smithburger PL, Kane-Gill SL et al. Pharmacologic and Pharmacokinetic Rationale for Combination Therapy in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol 2010; 56:686-95.

38. McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009; 53:1573-619.

40. Galiè N, Corris PA, Frost A et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D60-72.

41. Actelion. Opsumit (macitentan) tablets medication guide. South San Francisco, CA; 2013 Oct.