Macitentan is an endothelin receptor antagonist that is used in the therapy of pulmonary arterial hypertension (PAH). Macitentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.


Macitentan (ma" si ten' tan) is a nonselective inhibitor of the endothelin-1 receptors, both type A and B. Inhibition of endothelin receptors disrupts the intracellular pathways that lead to vasoconstriction, thus causing vasodilation. Because macitentan has high affinity for pulmonary endothelin receptors, it preferentially causes vasodilation in the pulmonary vasculature, thereby decreasing pulmonary vascular pressure. In prospective, randomized controlled trials, macitentan was effective in alleviating symptoms, improving exercise capacity and prolonging the time to clinical worsening in patients with idiopathic PAH. Macitentan was the third endothelin receptor antagonist to be approved in the United States (2013). The current indications are for symptomatic pulmonary arterial hypertension, classified as WHO group 1 (idiopathic). Use of macitentan in forms of PAH due to heart failure, thromboembolic disease or connective tissue disease should be considered experimental as its efficacy in these forms of PAH has not been adequately shown. Macitentan is available in tablets of 10 mg under the brand name Opsumit and the recommended dose is 10 mg once daily. Because of the potential for teratogenicity, macitentan is available for treating women only as a part of a risk evaluation and mitigation strategy (REMS) program in which documentation of adequate methods for birth control are required. Common side effects include headaches, dizziness, anemia, edema, flushing, rhinitis and dyspepsia that are frequent with most vasodilator therapies. Uncommon, but potentially severe adverse reactions include embryo-fetal toxicity, decrease in sperm counts, anemia and hypersensitivity reactions.


Macitentan is associated with a low rate of serum aminotransferase elevations (0% to 4%) that, in clinical trials, was similar to the rate among placebo recipients. These elevations were usually mild, transient and not associated with symptoms, but were above 8 times the ULN in 2% of subjects (vs 0.4% of controls) in at least one long term study. For these reasons, the product label recommends that patients have serum enzymes tested before starting therapy and be alerted to the possibility and symptoms of liver injury during therapy. While there have been no published reports of clinically apparent liver injury with jaundice associated with macitentan, it has had limited general use. Other endothelin receptor antagonists (bosentan, sitaxentan) have been linked to several instances of acute liver injury, some of which have been severe. The onset of illness was usually within 1 to 6 months of starting bosentan and the enzyme pattern was typically hepatocellular or mixed. Immunoallergic features were not present and autoantibodies absent or present in low titer. Macitentan and ambrisentan have not been linked to similar cases.

Likelihood score: E* (unlikely but suspected cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which macitentan might cause liver injury is not known. Macitentan is metabolized by the cytochrome P450 system (CYP 2C9 and 3A4), which may lead to production of a toxic intermediate and can also cause drug-drug interactions, particularly with strong inducers or inhibitors of CYP 3A4. One possible reason for why macitentan is associated with a relatively low rate of ALT elevations and hepatotoxicity is its higher potency and lower daily dose (10 mg) in comparison to bosentan (125 to 250 mg).

Outcome and Management

The serum enzyme elevations associated with macitentan use have been mild-to-moderate and self-limited in course, often resolving despite drug continuation. There is no information on cross sensitivity to hepatic injury among the various endothelin receptor antagonists.

Drug Class: Pulmonary Arterial Hypertension Agents

Other Drugs in the Class: Endothelin Receptor Antagonists: Ambrisentan, Bosentan



Macitentan – Opsumit®


Pulmonary Arterial Hypertension Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 30 September 2017

Abbreviations used: PAH, pulmonary arterial hypertension

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    (Textbook of hepatotoxicity published in 1999, before the availability of endothelin receptor antagonists).
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    (Textbook on drug induced liver injury; clinical features of liver injury due to the endothelin receptor antagonists are not specifically discussed).
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    (Among 64 patients with PAH treated with 1 of 4 doses of ambrisentan for 12 weeks, 3.1% developed ALT elevations above 3 times ULN and 2 patients discontinued therapy because of ALT values, but none had symptoms or jaundice).
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  • Galié N, Rubin Lj, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi E, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008; 371: 2093-100. [PubMed: 18572079]
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    (Among 178 patients with pulmonary fibrosis treated with macitentan or placebo for one year, there were no differences in changes in lung function or time to worsening or death between the two groups, and serum ALT elevations above 3 times ULN occurred in 3.4% on macitentan vs 5% on placebo).
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    (Among 742 patients with PAH treated with two doses of macitentan [3 or 10 mg daily] or placebo for one year, exercise tolerance was improved and time to clinical worsening delayed by macitentan, while side effects included headache, rhinitis and anemia; ALT elevations above 3 times ULN occurred in 3.4-3.6% of macitentan vs 4.5% of placebo recipients and were accompanied by bilirubin elevations in 1.7-2.1% vs 1.7%).
  • Macitentan (Opsumit) for pulmonary arterial hypertension. Med Lett Drugs Ther 2014; 56 (1436): 15-6. [PubMed: 24663031]
    (Concise review of the mechanism of action, clinical efficacy, safety and costs of macitentan shortly after its approval for use in the US; mentions that rates of ALT elevations during macitentan therapy are no higher than with placebo, but elevations above 8 times ULN occurred in 2.1% with macitentan vs 0.4% with placebo).
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    (Systematic review of the literature, including 21 trials in 3644 patients, found relative risk of ALT or AST elevations above 3 times ULN to be 2.98 for endothelin receptor antagonists compared to placebo controls).
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    (Review of recently approved drugs for PAH including macitentan, riociguat and oral treprostinil; mentions that macitentan was not associated with a higher rate of serum enzyme elevations in comparison to placebo therapy, but that testing of serum enzymes before treatment is recommended and intermittent monitoring is prudent).
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    (Among 30 Japanese patients with PAH treated with macitentan for at least 6 months, exercise tolerance and pulmonary function improved, and ALT elevations occurred in only one patient [3%] compared to 16% of bosentan treated subjects monitored in Japanese postmarketing studies).
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    (Systematic review of 24 randomized trials of endothelin receptor antagonists indicated higher rates of "abnormal liver function" in patients receiving bosentan and macitentan, but not ambrisentan).
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    (Among 24 patients with PAH switched from bosentan to macitentan for unstated reasons, mean serum ALT and AST did not change although one patient had to stop macitentan because of ALT elevations).