Macitentan Accord: Uses, Dosage & Side Effects
A dual endothelin receptor antagonist (ERA) for the long-term treatment of pulmonary arterial hypertension (PAH) in adults
Macitentan Accord is a generic formulation of macitentan, a dual endothelin receptor antagonist (ERA) approved for the long-term treatment of pulmonary arterial hypertension (PAH) in adults. PAH is a progressive and life-threatening condition characterized by abnormally high blood pressure in the pulmonary arteries, leading to right heart failure if untreated. Macitentan works by blocking both endothelin A and B receptors, reducing the harmful effects of endothelin-1 on the pulmonary vasculature. The landmark SERAPHIN trial demonstrated that macitentan 10 mg significantly reduces morbidity and mortality in PAH patients. Macitentan Accord contains the same active substance as the originator product Opsumit and is taken as one 10 mg tablet daily, with or without food.
Quick Facts: Macitentan Accord
Key Takeaways
- Macitentan Accord is a dual endothelin receptor antagonist (ERA) that blocks both ETA and ETB receptors, reducing pulmonary vascular resistance and slowing disease progression in pulmonary arterial hypertension (PAH).
- The recommended dose is 10 mg once daily, taken orally with or without food. The SERAPHIN trial demonstrated a 45% reduction in the composite endpoint of morbidity and mortality at this dose compared to placebo.
- Macitentan is strictly contraindicated in pregnancy due to teratogenicity. Women of childbearing potential must use reliable contraception and undergo monthly pregnancy testing during treatment.
- Anemia (decreased hemoglobin) is one of the most clinically significant side effects. Regular blood monitoring is essential, particularly in the first months of treatment.
- Macitentan can be used as monotherapy or in combination with other PAH-targeted therapies, including PDE5 inhibitors and prostacyclin pathway agents, in line with current ESC/ERS guidelines recommending combination therapy.
What Is Macitentan Accord and What Is It Used For?
Macitentan Accord contains the active substance macitentan, which belongs to a class of medications called endothelin receptor antagonists (ERAs). This class of drugs targets the endothelin system, which plays a central role in the development and progression of pulmonary arterial hypertension. Macitentan Accord is a generic version of the originator product and contains the same active substance in the same strength, having demonstrated bioequivalence through rigorous regulatory assessment.
Pulmonary arterial hypertension is a serious, progressive cardiovascular condition in which the small arteries in the lungs become narrowed, thickened, and stiffened. This narrowing increases the resistance to blood flow through the lungs, forcing the right ventricle of the heart to work harder to pump blood through the pulmonary circulation. Over time, the increased workload causes the right ventricle to enlarge and weaken, ultimately leading to right heart failure. PAH is classified as WHO Functional Class I through IV, with Class IV representing the most severe limitation of physical activity. Without treatment, PAH carries a poor prognosis, and even with modern therapies the condition remains life-limiting.
The endothelin system is critically involved in the pathogenesis of PAH. Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and also acts as a mitogen, promoting the abnormal proliferation of smooth muscle cells and fibroblasts in the pulmonary vascular wall. In patients with PAH, circulating levels of ET-1 are significantly elevated, and ET-1 overexpression in the pulmonary vasculature contributes to vasoconstriction, vascular remodeling, inflammation, and fibrosis. There are two main endothelin receptor subtypes: ETA and ETB. ETA receptors, predominantly located on vascular smooth muscle cells, mediate vasoconstriction and cell proliferation. ETB receptors are found both on endothelial cells (where they promote vasodilation via nitric oxide and prostacyclin release) and on smooth muscle cells (where they mediate vasoconstriction). In PAH, the balance is shifted toward pathological vasoconstriction and remodeling.
Macitentan is a dual endothelin receptor antagonist, meaning it blocks both ETA and ETB receptors. It was specifically designed through structure-activity optimization to have enhanced tissue-targeting properties compared to earlier ERAs. Macitentan is highly lipophilic, which allows it to penetrate effectively into the pulmonary vascular tissue where it exerts sustained receptor blockade. By blocking ET-1 signaling through both receptor subtypes, macitentan reduces vasoconstriction, inhibits pathological vascular remodeling, and lowers pulmonary vascular resistance. This leads to improved blood flow through the lungs, reduced workload on the right ventricle, and improved exercise capacity and functional status.
The clinical efficacy of macitentan was established in the landmark SERAPHIN trial (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), a randomized, double-blind, placebo-controlled event-driven trial involving 742 patients with symptomatic PAH across 151 centers in 39 countries. SERAPHIN was the first large-scale outcomes trial in PAH to use a morbidity-mortality composite primary endpoint. Treatment with macitentan 10 mg resulted in a 45% relative risk reduction in the composite endpoint of disease worsening (defined as death, atrial septostomy, lung transplantation, initiation of intravenous or subcutaneous prostanoids, or sustained worsening of PAH) compared to placebo (hazard ratio 0.55; 97.5% CI 0.39–0.76; p < 0.001). This benefit was observed regardless of whether patients were receiving background PAH therapy (such as PDE5 inhibitors or oral/inhaled prostanoids) at baseline, supporting the use of macitentan both as monotherapy and as part of combination treatment strategies.
Macitentan Accord is indicated for the long-term treatment of PAH in adult patients classified as WHO Functional Class II to III. The treatment goal is to slow disease progression, reduce the frequency of clinical worsening events, and improve or maintain exercise capacity and functional status. PAH may be idiopathic, heritable, associated with connective tissue disease, associated with congenital heart disease (repaired simple lesions), HIV infection, or drug/toxin exposure. Macitentan has been studied across these etiological subtypes in clinical trials.
Current international guidelines from the ESC/ERS (2022) recommend initial combination therapy with an ERA and a PDE5 inhibitor for most newly diagnosed PAH patients who are at low or intermediate risk. For patients at high risk, triple combination therapy including a prostacyclin pathway agent is recommended. Macitentan is one of the preferred ERAs for these combination regimens, based on the SERAPHIN outcomes data.
What Should You Know Before Taking Macitentan Accord?
Contraindications
There are specific situations in which Macitentan Accord must not be used. Understanding these absolute contraindications is essential for patient safety.
- Pregnancy: Macitentan is a known teratogen based on animal studies. It is absolutely contraindicated during pregnancy. Treatment must not be initiated in women who are or may become pregnant. All endothelin receptor antagonists carry a class-wide teratogenic risk.
- Women of childbearing potential not using reliable contraception: Female patients of reproductive age must use at least one highly effective method of contraception (or two complementary forms) during treatment and for one month after discontinuation. A negative pregnancy test is required before starting treatment.
- Breastfeeding: It is not known whether macitentan is excreted in human milk. Because of the potential for serious adverse effects in nursing infants, breastfeeding must be discontinued before starting treatment.
- Severe hepatic impairment: Macitentan is contraindicated in patients with severe liver disease (Child-Pugh Class C), as the drug is extensively metabolized by the liver and safety has not been established in this population.
- Baseline elevated liver aminotransferases: Macitentan should not be initiated in patients with aminotransferase levels greater than 3 times the upper limit of normal (3x ULN) at baseline.
- Hypersensitivity: Do not take Macitentan Accord if you are allergic to macitentan or any of the excipients in the formulation.
Due to the teratogenic risk, a strict pregnancy prevention program is mandatory. Female patients of childbearing potential must have a negative pregnancy test before starting treatment, and monthly pregnancy testing is recommended throughout treatment. Reliable contraception must be used during treatment and for one month after stopping macitentan. If pregnancy is suspected at any time, treatment must be stopped immediately and a pregnancy test performed.
Warnings and Precautions
Before and during treatment with Macitentan Accord, discuss the following with your doctor:
- Hepatotoxicity: While macitentan has a more favorable hepatic safety profile than some older ERAs, elevated liver enzymes have been reported. Liver function should be assessed before initiating treatment. If you develop symptoms of liver injury such as unexplained nausea, vomiting, right upper abdominal pain, fatigue, anorexia, jaundice, or dark urine, contact your doctor immediately. Treatment should be discontinued if aminotransferases rise above 3x ULN or if signs or symptoms of liver injury occur alongside elevated aminotransferases.
- Anemia and decreased hemoglobin: Macitentan causes a dose-dependent decrease in hemoglobin concentration. In the SERAPHIN trial, hemoglobin decreased to below 10 g/dL in 8.7% of patients receiving macitentan 10 mg compared to 3.4% with placebo. Hemoglobin and hematocrit levels should be checked before treatment initiation, at regular intervals during treatment (the EMA recommends after 1 month and then every 3 months), and as clinically indicated. Initiating treatment is not recommended in patients with severe anemia. If a clinically significant decrease in hemoglobin occurs, further investigation should be undertaken to determine the cause and the need for specific treatment.
- Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur during treatment, the possibility of PVOD should be considered. Vasodilators, including ERAs, may significantly worsen the condition of patients with PVOD. Macitentan should be discontinued if PVOD is confirmed.
- Fluid retention and edema: ERAs as a class are associated with fluid retention and peripheral edema. If clinically significant fluid retention develops (with or without weight gain), further evaluation should be performed. The need for additional diuretic therapy or adjustment of existing diuretic doses should be considered.
- Blood pressure reduction: Macitentan has vasodilatory effects that can lower systemic blood pressure. In patients who are already hypotensive, this may lead to symptomatic hypotension. Blood pressure should be monitored, particularly at the start of treatment and in patients on antihypertensive medications.
- Male fertility: Endothelin receptor antagonists as a class may affect spermatogenesis. Effects on testicular function have been observed in animal studies with macitentan and other ERAs. While the clinical relevance in humans is uncertain, the possibility of impaired male fertility should be discussed.
- Renal impairment: Limited data are available in patients with severe renal impairment. Caution is advised and close monitoring recommended in this population. Dialysis is unlikely to be effective in removing macitentan due to its high protein binding.
Pregnancy and Breastfeeding
Macitentan is classified as a teratogen and is absolutely contraindicated during pregnancy. In animal reproductive toxicity studies, macitentan caused teratogenic effects at all doses tested, including cardiovascular malformations and fusion of the mandible. The doses at which these effects occurred were at clinically relevant plasma exposures. There are no adequate and well-controlled studies in pregnant women, but the strong preclinical evidence of teratogenicity means that human risk is presumed to be significant.
Women of childbearing potential must have a confirmed negative pregnancy test (serum or urine, with a sensitivity of at least 25 mIU/mL) before initiation of therapy and at monthly intervals during treatment. The prescribing physician should ensure that the patient understands the teratogenic risk, the need for reliable contraception, and the need for monthly pregnancy testing. If pregnancy occurs during treatment, macitentan must be discontinued immediately.
It is not known whether macitentan or its active metabolite ACT-132577 are excreted in human breast milk. In animal studies, macitentan and its metabolites were detected in milk. A risk to the breastfed child cannot be excluded, and therefore breastfeeding must be discontinued during treatment with Macitentan Accord.
Driving and Operating Machinery
Macitentan may cause side effects such as headache and hypotension that could affect the ability to drive or operate machinery. Patients should be aware of how they react to the medication before driving or using machines. The underlying condition (PAH) may also impair physical functioning and exercise tolerance, which should be considered when assessing fitness to drive.
How Does Macitentan Accord Interact with Other Drugs?
Macitentan is primarily metabolized by cytochrome P450 enzymes CYP3A4 and, to a lesser extent, CYP2C19. The active metabolite ACT-132577 is formed through oxidative depropylation. Medications that significantly inhibit or induce CYP3A4 can therefore alter the plasma concentrations of macitentan and its active metabolite, potentially affecting efficacy and safety. Unlike the first-generation ERA bosentan, macitentan does not significantly induce CYP enzymes and is therefore less likely to cause drug interactions as a perpetrator.
Major Interactions
| Interacting Drug | Effect | Clinical Significance |
|---|---|---|
| Ketoconazole (strong CYP3A4 inhibitor) | Approximately 2-fold increase in macitentan exposure | Avoid concomitant use with strong CYP3A4 inhibitors |
| Ritonavir and other HIV protease inhibitors | Significant increase in macitentan plasma levels via strong CYP3A4 inhibition | Avoid concomitant use; consider alternative PAH therapy |
| Rifampicin (strong CYP3A4 inducer) | Approximately 79% reduction in macitentan exposure; 54% reduction in active metabolite | Avoid concomitant use – substantial loss of efficacy |
| St. John’s Wort (herbal CYP3A4 inducer) | Significant reduction in macitentan plasma levels | Avoid concomitant use; may render macitentan ineffective |
| Carbamazepine, phenytoin, phenobarbital | Predicted reduction in macitentan exposure via CYP3A4 induction | Avoid concomitant use; consider alternative anticonvulsants |
Minor Interactions and No-Dose-Adjustment Combinations
| Interacting Drug | Effect | Clinical Guidance |
|---|---|---|
| Sildenafil (PDE5 inhibitor) | No clinically significant pharmacokinetic interaction | Can be combined safely; commonly used combination in PAH |
| Warfarin (anticoagulant) | No significant effect on INR or warfarin pharmacokinetics | No dose adjustment needed; monitor INR per standard practice |
| Cyclosporine A (moderate CYP3A4 inhibitor) | Modest increase in macitentan exposure (not clinically significant at typical doses) | No dose adjustment at standard cyclosporine doses; monitor |
| Hormonal contraceptives | Macitentan does not affect contraceptive hormone levels | Unlike bosentan, macitentan does not reduce contraceptive efficacy |
Unlike the first-generation ERA bosentan, macitentan does not significantly induce CYP enzymes. This means macitentan does not reduce the effectiveness of hormonal contraceptives and has fewer drug-drug interactions overall. This is a clinically important advantage, particularly for female patients of childbearing potential who must use reliable contraception during treatment.
What Is the Correct Dosage of Macitentan Accord?
Macitentan Accord must be prescribed and monitored by a physician experienced in the management of pulmonary arterial hypertension. Treatment should be initiated and supervised at a specialist PAH center to ensure appropriate patient selection, monitoring, and follow-up.
Adults
Standard Adult Dose
10 mg once daily, taken orally with or without food. The tablet should be swallowed whole with water. It is recommended to take the tablet at approximately the same time each day to maintain consistent plasma levels. Macitentan is available as a single strength (10 mg), and this is the only dose that has demonstrated efficacy in the pivotal SERAPHIN trial. There is no evidence supporting the use of lower doses for maintenance therapy.
Treatment with macitentan is intended to be long-term and continuous. PAH is a chronic disease requiring ongoing therapy, and abrupt discontinuation may lead to clinical deterioration. Patients should be counseled about the importance of adherence to daily dosing and should not stop treatment without consulting their physician.
Children and Adolescents
Pediatric Use
The safety and efficacy of macitentan in children and adolescents under 18 years of age have not been established. No pediatric dosing recommendations can be made, and macitentan is not indicated for use in the pediatric population.
Elderly Patients
Elderly (≥65 years)
No dose adjustment is required based on age alone. Clinical experience in patients aged 75 years and older is limited. Macitentan should be used with caution in elderly patients, taking into account the greater frequency of decreased hepatic, renal, and cardiac function, as well as concomitant disease and other drug therapy.
Hepatic and Renal Impairment
Dose Adjustments for Organ Impairment
Mild or moderate hepatic impairment (Child-Pugh Class A or B): No dose adjustment is required. However, liver function should be assessed before initiation and as clinically indicated during treatment.
Severe hepatic impairment (Child-Pugh Class C): Contraindicated. Macitentan has not been studied in this population.
Mild, moderate, or severe renal impairment: No dose adjustment is required. However, experience in patients with severe renal impairment is limited, and macitentan should be used with caution. Dialysis is not expected to be effective in removing macitentan due to its high protein binding (>99%).
Missed Dose
If a dose is missed, it should be taken as soon as remembered unless it is close to the time of the next scheduled dose. In that case, the missed dose should be skipped and the regular dosing schedule resumed. Do not take a double dose to make up for a missed one. Patients should be advised to set a daily reminder to help ensure consistent dosing.
Overdose
There is limited experience with overdose of macitentan. In healthy volunteers, single doses up to 600 mg (60 times the therapeutic dose) were administered during clinical pharmacology studies. The primary symptoms of overdose are expected to be related to the pharmacological effects of the drug, including headache, nausea, and vomiting, as well as potential significant hypotension. In the event of overdose, standard supportive measures should be taken. Due to the high degree of protein binding, dialysis is unlikely to effectively remove macitentan from the circulation. There is no specific antidote.
The 10 mg once-daily dose is the only dose shown to reduce morbidity and mortality in the SERAPHIN trial. Do not adjust the dose without consulting your PAH specialist. The tablet must be swallowed whole and must not be split, crushed, or chewed, as this may alter the drug’s release characteristics.
What Are the Side Effects of Macitentan Accord?
Like all medicines, Macitentan Accord can cause side effects, although not everybody gets them. The side effect profile of macitentan has been extensively characterized in clinical trials involving more than 900 PAH patients, with the SERAPHIN trial providing the most comprehensive safety data from long-term exposure (median treatment duration of approximately 2 years). The side effects observed with macitentan are largely consistent with the pharmacological class of endothelin receptor antagonists and the underlying PAH disease.
Below are the side effects reported with macitentan, organized by frequency based on clinical trial data. Frequency categories are defined as: very common (≥1/10 patients), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and rare (<1/1,000).
Very Common
- Nasopharyngitis (common cold symptoms, sore throat, nasal congestion)
- Headache
- Anemia / decreased hemoglobin
- Bronchitis (infection of the airways)
Common
- Pharyngitis (sore throat, inflammation of the throat)
- Influenza (flu-like illness)
- Urinary tract infection
- Hypotension (low blood pressure)
- Nasal congestion
- Edema / fluid retention (swelling in the legs, ankles, or feet)
- Elevated liver enzymes (AST, ALT)
Uncommon
- Allergic reactions (rash, pruritus, urticaria)
- Leukopenia (decreased white blood cell count)
- Thrombocytopenia (decreased platelet count)
- Flushing (warmth and redness of the face)
Rare
- Hepatic injury with significantly elevated aminotransferases
- Angioedema (swelling of the face, lips, tongue, or throat)
- Severe hypersensitivity reactions
Anemia: A Key Safety Concern
Decreased hemoglobin and anemia are among the most clinically significant side effects of macitentan. In the SERAPHIN trial, hemoglobin concentration decreased to below 10 g/dL in 8.7% of patients receiving macitentan 10 mg compared to 3.4% of those receiving placebo. The decrease in hemoglobin is thought to be related to the pharmacological action of endothelin receptor blockade and is generally dose-dependent. The mechanism involves dilutional effects (fluid retention), as well as possible direct effects on erythropoiesis.
Hemoglobin levels typically decrease within the first few months of treatment and then stabilize. However, in some patients, the decrease can be clinically significant and may require intervention, including blood transfusion in rare cases. Hemoglobin and hematocrit should be checked before treatment initiation, after one month, every three months thereafter, and as clinically indicated. Initiating macitentan in patients with severe pre-existing anemia is not recommended.
Hepatic Effects
While macitentan has a more favorable hepatic safety profile compared to the first-generation ERA bosentan (which carries a specific hepatotoxicity warning and requires monthly liver function monitoring), cases of elevated liver aminotransferases have been reported. In the SERAPHIN trial, the incidence of aminotransferase elevations greater than 3x ULN was comparable between the macitentan and placebo groups. Nonetheless, hepatotoxicity remains a class concern for ERAs, and liver function should be assessed before starting treatment. If clinically significant liver enzyme elevations occur, treatment should be reassessed.
When to Seek Medical Attention
Contact your doctor or seek medical attention immediately if you experience any of the following during treatment with Macitentan Accord:
- Signs of liver problems: unexplained nausea, vomiting, right upper abdominal pain, unusual fatigue, loss of appetite, jaundice (yellowing of the skin or eyes), or dark-colored urine
- Signs of severe anemia: extreme tiredness, pallor, shortness of breath at rest or on minimal exertion, rapid heartbeat, dizziness, or fainting
- Signs of infection: fever, chills, persistent sore throat, or other signs that do not resolve
- Signs of fluid overload: rapid weight gain, new or worsening swelling of the legs, ankles, or abdomen, or worsening shortness of breath (may indicate right heart failure progression)
- Signs of severe allergic reaction: rash, swelling of the face, lips, tongue, or throat, or difficulty breathing
- Signs of possible pregnancy: missed period or any suspicion of pregnancy
If you experience any side effects, including those not listed here, talk to your doctor or pharmacist. You can also report side effects directly to your national pharmacovigilance authority (e.g., the Yellow Card Scheme in the UK, MedWatch in the US, or the EMA EudraVigilance system in the EU). By reporting side effects, you can help provide more information on the safety of this medicine.
How Should You Store Macitentan Accord?
Proper storage of medication is essential to maintain its effectiveness and safety throughout its shelf life. Macitentan Accord should be stored in its original blister packaging to protect it from moisture and light. The specific storage conditions are as follows:
- Temperature: Store below 30°C (86°F). Do not refrigerate or freeze.
- Packaging: Keep the tablets in the original blister packaging until immediately before use. Do not transfer to a different container.
- Light and moisture: The original packaging provides protection from light and moisture. Store in a dry place.
- Children: Keep out of the sight and reach of children. Macitentan is a teratogenic medication and accidental exposure must be prevented.
- Expiry date: Do not use this medicine after the expiry date stated on the carton and blister. The expiry date refers to the last day of that month.
Do not dispose of medications via household waste or wastewater. Ask your pharmacist how to dispose of medicines you no longer use. Proper disposal helps protect the environment and prevents accidental exposure. Given the teratogenic nature of macitentan, proper disposal is particularly important to prevent inadvertent exposure of pregnant women or women of childbearing potential.
What Does Macitentan Accord Contain?
Active Ingredient
The active substance in Macitentan Accord is macitentan. Each film-coated tablet contains 10 mg of macitentan. Macitentan (chemical name: N-[5-(4-bromophenyl)-6-[2-[(5-bromopyrimidin-2-yl)oxy]ethoxy]pyrimidin-4-yl]-N′-propylsulfamide) is a sulfonamide derivative with a molecular weight of 588.27 g/mol. It acts as a dual endothelin receptor antagonist with approximately 100-fold selectivity for ETA over ETB receptors.
Inactive Ingredients (Excipients)
The inactive ingredients serve essential pharmaceutical functions including binding the tablet, facilitating disintegration, aiding swallowing, and protecting the tablet from degradation. The typical excipients found in macitentan film-coated tablets include:
- Tablet core: Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), povidone (K-30), magnesium stearate, poloxamer 188
- Film coating: Polyvinyl alcohol, titanium dioxide (E171), talc, soya lecithin, xanthan gum
Macitentan Accord tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
Appearance
Macitentan Accord 10 mg tablets are white to off-white, round, biconvex film-coated tablets. They are supplied in aluminum-aluminum blister packs containing 15 or 30 film-coated tablets.
Frequently Asked Questions About Macitentan Accord
Macitentan Accord is a generic version of Opsumit, both containing the same active substance (macitentan 10 mg). As a generic medicine, Macitentan Accord has demonstrated bioequivalence to the originator product through rigorous regulatory review, meaning it provides the same plasma concentration profile and therapeutic effect. The differences are limited to the manufacturer, certain inactive ingredients, and typically the cost (generics are usually less expensive). Both products are equally effective and safe for the treatment of pulmonary arterial hypertension.
Macitentan reaches steady-state plasma concentrations within approximately 3 days of once-daily dosing, and its active metabolite ACT-132577 reaches steady state after about 8 days. However, the clinical benefits of treatment develop gradually over weeks to months. In the SERAPHIN trial, improvements in exercise capacity (6-minute walk distance) were observed from around week 12, and the full benefit on morbidity and mortality outcomes was established over a median follow-up of approximately 2 years. PAH is a chronic condition requiring long-term treatment, and patients should not expect immediate symptom relief.
There is no specific contraindication regarding alcohol consumption during macitentan treatment. However, alcohol can lower blood pressure and may add to the blood-pressure-lowering effect of macitentan, potentially increasing the risk of dizziness, lightheadedness, or fainting. Alcohol can also affect liver function, which is a concern given the hepatic metabolism of macitentan. It is advisable to limit alcohol intake and discuss with your doctor what level of alcohol consumption, if any, is appropriate for your situation.
You should not stop taking Macitentan Accord without consulting your doctor. While there is no formal rebound effect described in the prescribing information, abrupt discontinuation of PAH-targeted therapy may lead to clinical deterioration of the underlying disease. PAH is a chronic, progressive condition, and continuous treatment is necessary to maintain the therapeutic benefit. If treatment needs to be stopped for any reason, this should be done under medical supervision with careful monitoring and consideration of alternative therapy.
No. Unlike the first-generation ERA bosentan, macitentan does not induce hepatic CYP enzymes and therefore does not reduce the effectiveness of hormonal contraceptives (including oral contraceptive pills, patches, or rings). This is a significant clinical advantage because women of childbearing potential treated with macitentan must use reliable contraception due to the drug’s teratogenic risk. Hormonal contraceptives remain effective when used with macitentan. Nevertheless, many physicians recommend using two methods of contraception simultaneously for maximum protection.
Macitentan, bosentan, and ambrisentan all belong to the endothelin receptor antagonist (ERA) class but differ in important ways. Bosentan (Tracleer) is a first-generation dual ERA that requires monthly liver function monitoring and reduces hormonal contraceptive efficacy. Ambrisentan (Volibris/Letairis) is a selective ETA receptor antagonist with less hepatotoxicity risk but limited to ETA blockade. Macitentan is a second-generation dual ERA designed for enhanced tissue penetration and sustained receptor binding, with a more favorable hepatic safety profile than bosentan and the only ERA with morbidity-mortality outcomes data from the SERAPHIN trial.
References
- European Medicines Agency (EMA). Opsumit (macitentan) – Summary of Product Characteristics. Last updated 2025. Available at: EMA – Opsumit.
- U.S. Food and Drug Administration (FDA). Opsumit (macitentan) – Prescribing Information. Revised 2024. Available at: FDA – Opsumit Label.
- Pulido T, Adzerikho I, Channick RN, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013;369(9):809–818. doi:10.1056/NEJMoa1213917.
- Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618–3731. doi:10.1093/eurheartj/ehac237.
- Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. 2019;53(1):1801889. doi:10.1183/13993003.01889-2018.
- World Health Organization. WHO Model List of Essential Medicines – 23rd List (2023). Available at: WHO Essential Medicines.
- British National Formulary (BNF). Macitentan. National Institute for Health and Care Excellence (NICE). Available at: BNF – Macitentan.
- Klinger JR, Elliott CG, Levine DJ, et al. Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. Chest. 2019;155(3):565–586. doi:10.1016/j.chest.2018.11.030.
Editorial Team
Medical Content
iMedic Medical Editorial Team – Specialists in Pulmonary Vascular Medicine and Clinical Pharmacology
Medical Review
iMedic Medical Review Board – Independent review according to international guidelines (ESC/ERS, EMA, FDA, WHO)
Evidence Standard
Level 1A – Based on systematic reviews and randomized controlled trials (SERAPHIN trial)
Independence
No pharmaceutical company funding or sponsorship. All content is editorially independent.
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