Macitentan Glenmark: Uses, Dosage & Side Effects

What Is Macitentan Glenmark and What Is It Used For?

Macitentan Glenmark is a generic formulation containing macitentan 10 mg as its active substance. Macitentan belongs to a class of medications known as endothelin receptor antagonists (ERAs). These drugs target the endothelin system, which plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH). Macitentan Glenmark is manufactured by Glenmark Pharmaceuticals and is bioequivalent to the originator product, Opsumit, which was developed by Actelion Pharmaceuticals (now part of Janssen Pharmaceutical Companies of Johnson & Johnson).

Pulmonary arterial hypertension is a serious, progressive, and life-threatening disease characterized by abnormally high blood pressure in the pulmonary arteries—the blood vessels that carry blood from the right side of the heart to the lungs. In PAH, the walls of the pulmonary arteries undergo pathological remodeling, becoming thickened, stiffened, and narrowed. This increased resistance forces the right ventricle of the heart to work harder to pump blood through the lungs, eventually leading to right heart failure if left untreated. Patients with PAH typically experience progressive breathlessness, fatigue, chest pain, dizziness, and reduced exercise tolerance.

The endothelin system is a key driver of the vascular abnormalities observed in PAH. Endothelin-1 (ET-1) is a 21-amino-acid peptide and one of the most potent endogenous vasoconstrictors known. In healthy individuals, ET-1 plays a physiological role in maintaining vascular tone, but in PAH, the endothelin system is pathologically overactivated. Plasma levels of ET-1 are markedly elevated in PAH patients, and ET-1 exerts its harmful effects through two receptor subtypes: the ET_A receptor (primarily located on vascular smooth muscle cells, mediating vasoconstriction and cell proliferation) and the ET_B receptor (found on both endothelial cells and smooth muscle cells, with a dual role in vasodilation via nitric oxide release and vasoconstriction when located on smooth muscle).

Macitentan is a dual endothelin receptor antagonist, meaning it blocks both ET_A and ET_B receptors. This dual blockade provides more comprehensive inhibition of the endothelin pathway compared with selective ET_A antagonists. By blocking ET-1 signaling at both receptor subtypes, macitentan reduces pulmonary vascular resistance, inhibits pathological vascular remodeling (proliferation and hypertrophy of smooth muscle cells), reduces inflammation, and decreases fibrosis in the pulmonary vasculature. These combined effects lead to improved pulmonary hemodynamics, increased exercise capacity, and delayed disease progression.

The clinical efficacy of macitentan was established in the landmark SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial. This was the largest event-driven, randomized, double-blind, placebo-controlled outcomes study ever conducted in PAH at the time of its publication. The SERAPHIN trial enrolled 742 patients across 151 centers in 39 countries, with a median treatment duration of approximately 115 weeks (over 2 years). The primary endpoint was the time from treatment initiation to the first occurrence of a composite endpoint of disease worsening or death:

• Worsening of PAH was defined as any of the following: a decrease in 6-minute walk distance (6MWD) of at least 15% from baseline confirmed by two consecutive tests, worsening of PAH symptoms (WHO Functional Class deterioration), or need for additional PAH therapy (intravenous or subcutaneous prostanoid therapy, or lung transplantation).
• Death from any cause during the study period.

The results were compelling: macitentan 10 mg reduced the risk of the composite morbidity/mortality endpoint by 45% compared with placebo (hazard ratio 0.55; 97.5% CI, 0.39–0.76; p < 0.001). The number needed to treat (NNT) to prevent one event over the study period was approximately 6. Importantly, the benefit was consistent across all prespecified subgroups, including patients already receiving background PAH therapy (phosphodiesterase-5 inhibitors such as sildenafil) and treatment-naive patients. Additionally, macitentan significantly improved 6-minute walk distance, WHO Functional Class, and hemodynamic parameters measured by right heart catheterization.

Macitentan is indicated for the long-term treatment of PAH in adult patients classified as WHO Functional Class II (mild symptoms with slight limitation of physical activity) or III (moderate symptoms with marked limitation of physical activity). It can be used as monotherapy or in combination with other PAH-specific therapies, particularly phosphodiesterase-5 (PDE-5) inhibitors. The 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension recommend initial combination therapy with an ERA and a PDE-5 inhibitor for most patients with newly diagnosed PAH, making macitentan a cornerstone of modern PAH management.

What Should You Know Before Taking Macitentan Glenmark?

Contraindications

Macitentan Glenmark must not be used in the following situations:

• Pregnancy: Macitentan is teratogenic and is strictly contraindicated during pregnancy. Animal studies have demonstrated severe developmental abnormalities, including cardiovascular and mandibular malformations, at clinically relevant doses. Any exposure during pregnancy can result in serious birth defects. Women must have a confirmed negative pregnancy test before initiating treatment.
• Women of childbearing potential not using reliable contraception: Women who could become pregnant must use at least two reliable methods of contraception during treatment and for at least one month after discontinuation of macitentan. Hormonal contraceptives alone are not considered sufficiently reliable when used with macitentan because of potential pharmacokinetic interactions; a barrier method should be used in combination.
• Severe hepatic impairment: Macitentan is extensively metabolized by the liver, and its use is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) due to the risk of accumulation and potential hepatotoxicity. Patients with moderate hepatic impairment should be treated with caution.
• Hypersensitivity: Do not use macitentan if you are allergic to the active substance or to any of the excipients listed in the composition section.
• Baseline hepatic aminotransferases greater than 3 times the upper limit of normal (ULN): Treatment should not be initiated in patients with significantly elevated liver enzymes at baseline.

Warnings and Precautions

Before and during treatment with Macitentan Glenmark, several important precautions should be discussed with your healthcare provider:

• Hepatotoxicity: Although clinically significant liver injury has been less commonly reported with macitentan compared with some older ERAs (such as bosentan), liver enzyme elevations can occur. Liver function tests (ALT, AST, bilirubin) should be performed before starting treatment and monitored periodically as clinically indicated. If sustained, clinically significant elevations of liver aminotransferases occur, or if elevations are accompanied by increases in bilirubin greater than 2 times the ULN, or by clinical symptoms of liver injury, macitentan should be discontinued.
• Anemia and hemoglobin decrease: Endothelin receptor antagonists, including macitentan, can cause a decrease in hemoglobin and hematocrit. In the SERAPHIN trial, a decrease in hemoglobin to below 10 g/dL was observed in approximately 8.7% of patients receiving macitentan 10 mg compared with 3.4% on placebo. Hemoglobin should be measured before starting treatment, after 1 month, and then periodically thereafter. Do not start macitentan in patients with severe anemia. If a clinically significant decrease in hemoglobin develops, further evaluation should be undertaken to determine the cause and need for specific treatment.
• Fluid retention and edema: PAH itself can cause fluid retention, but endothelin receptor antagonists may also contribute. Patients should be monitored for signs of fluid overload, including peripheral edema, ascites, and weight gain. If clinically significant fluid retention develops, further investigation is warranted to determine whether it is related to the underlying PAH or to macitentan treatment, and appropriate management should be initiated.
• Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema develop during treatment with macitentan, the possibility of associated pulmonary veno-occlusive disease should be considered. Macitentan and other vasodilators may significantly worsen the cardiovascular status of patients with PVOD. If PVOD is confirmed, macitentan should be discontinued.

Pregnancy and Breastfeeding

As detailed above, macitentan is absolutely contraindicated during pregnancy. The teratogenic potential of endothelin receptor antagonists is well established from preclinical studies and is a class effect. Women of childbearing potential must undergo monthly pregnancy testing during treatment. If pregnancy occurs despite contraceptive measures, macitentan must be stopped immediately and the patient should be referred to an obstetrician experienced in reproductive toxicology for counseling and monitoring.

It is not known whether macitentan or its active metabolite are excreted in human breast milk. In animal studies, macitentan and its metabolites were detected in the milk of lactating rats. Given the potential for serious adverse effects in the breastfed infant, breastfeeding is not recommended during treatment with macitentan. The decision to discontinue breastfeeding or to discontinue macitentan treatment should be made in consultation with your PAH specialist, weighing the importance of the drug to the mother and the potential risk to the infant.

Fertility

In male patients, macitentan may affect male fertility. Animal studies have shown that endothelin receptor antagonists can cause testicular tubular atrophy and impaired spermatogenesis. In the SERAPHIN trial, no formal fertility assessments were conducted in male participants. Male patients who are concerned about fertility should discuss this with their healthcare provider before starting treatment. Semen analysis may be considered in male patients planning to father children.

Driving and Operating Machinery

Macitentan may have a minor influence on the ability to drive and use machines. Dizziness, fatigue, and hypotension have been reported in some patients. Patients should be aware of how they respond to the medication before driving or operating heavy machinery. If you experience dizziness or fatigue while taking macitentan, refrain from these activities until symptoms resolve.

How Does Macitentan Glenmark Interact with Other Drugs?

Understanding drug interactions is crucial for the safe and effective use of macitentan, particularly because PAH patients often take multiple medications simultaneously. Macitentan is extensively metabolized in the liver, primarily by cytochrome P450 3A4 (CYP3A4), with a minor contribution from CYP2C19. This metabolic pathway means that drugs affecting CYP3A4 activity can significantly alter macitentan blood levels.

The active metabolite of macitentan, known as ACT-132577, retains approximately 20% of the pharmacological activity of the parent compound and has a longer half-life (approximately 48 hours). ACT-132577 is also primarily formed via CYP3A4, so interactions affecting CYP3A4 will impact both the parent drug and its active metabolite.

The interaction between macitentan and strong CYP3A4 inducers is particularly important. Rifampicin, a potent CYP3A4 inducer, reduces macitentan exposure by approximately 79%, which would significantly compromise its therapeutic efficacy. Therefore, co-administration of macitentan with strong CYP3A4 inducers (including rifampicin, carbamazepine, phenobarbital, phenytoin, and the herbal supplement St. John’s wort) should be avoided.

Conversely, strong CYP3A4 inhibitors such as ketoconazole can approximately double the exposure to macitentan. While no formal dose adjustment recommendation is provided for this interaction, patients receiving concomitant strong CYP3A4 inhibitors should be monitored more closely for macitentan-related adverse effects, including headache, anemia, and fluid retention.

Macitentan can be safely combined with PDE-5 inhibitors (sildenafil, tadalafil), which is clinically important because combination therapy with an ERA and a PDE-5 inhibitor is a recommended treatment strategy for PAH according to the 2022 ESC/ERS guidelines. In the SERAPHIN trial, approximately 64% of patients were receiving background PDE-5 inhibitor therapy, and the benefit of macitentan was consistent in this subgroup.

What Is the Correct Dosage of Macitentan Glenmark?

Macitentan Glenmark is available as a 10 mg film-coated tablet for oral administration. The dosing regimen is straightforward, with a single fixed dose for all adult patients. Treatment should always be initiated and supervised by a physician experienced in the management of pulmonary arterial hypertension, typically at a specialized PAH center.

Adults

The 10 mg once-daily dose was established as the optimal therapeutic dose in the SERAPHIN trial. In this trial, both 3 mg and 10 mg doses were studied. While the 3 mg dose showed some benefit, the 10 mg dose demonstrated a statistically significant and clinically meaningful reduction in the primary composite morbidity/mortality endpoint (45% risk reduction), which was the basis for regulatory approval. No dose titration is required when initiating treatment.

Children and Adolescents

The safety and efficacy of macitentan in children and adolescents under 18 years of age have not been established. Currently, macitentan is not approved for pediatric use. PAH in children requires specialized management, and other treatment options that have been studied in pediatric populations should be considered. Clinical trials investigating the use of macitentan in pediatric PAH are ongoing.

Elderly Patients

No dose adjustment is required for elderly patients (65 years and older). In the SERAPHIN trial, approximately 14% of patients were aged 65 or older. No overall differences in safety or efficacy were observed between older and younger patients. However, elderly patients may be more susceptible to the hemodynamic effects of macitentan (e.g., hypotension), and careful monitoring is advisable. There is limited experience in patients over 75 years of age.

Missed Dose

If you miss a dose of Macitentan Glenmark, take it as soon as you remember. However, if it is almost time for your next scheduled dose (within approximately 12 hours), skip the missed dose and take your next dose at the regular time. Do not take a double dose to make up for a missed one. Consistent daily dosing is important for maintaining steady therapeutic blood levels and optimal disease control. Consider setting a daily reminder (alarm or medication tracking app) to help maintain adherence.

Overdose

If you take more Macitentan Glenmark than prescribed, contact your doctor or local poison control center immediately. In clinical studies, single doses of up to 600 mg were administered to healthy volunteers. The most likely symptoms of overdose would be related to the pharmacological effects of the drug, including headache, nausea, vomiting, and hypotension. There is no specific antidote for macitentan overdose. Treatment is supportive, focusing on management of blood pressure and general supportive measures. Due to the high protein binding of macitentan (over 99%), dialysis is unlikely to be effective in removing the drug from the circulation.

What Are the Side Effects of Macitentan Glenmark?

Like all medicines, Macitentan Glenmark can cause side effects, although not everyone who takes it will experience them. The safety profile of macitentan has been well characterized through the SERAPHIN trial, its long-term extension study, and post-marketing surveillance covering more than a decade of clinical use since the originator product was first approved in 2013.

In the SERAPHIN trial, the overall discontinuation rate due to adverse events was 12.4% with macitentan 10 mg versus 13.6% with placebo, indicating that the drug is generally well tolerated. The most frequently reported adverse reactions that occurred more often with macitentan than placebo are listed below by frequency category.

Anemia is the most clinically significant hematological side effect of macitentan. In the SERAPHIN trial, hemoglobin concentrations decreased below 10 g/dL in 8.7% of patients on macitentan 10 mg versus 3.4% on placebo. The decrease in hemoglobin is believed to be related to the pharmacological action of endothelin receptor antagonists on erythropoiesis and fluid retention (hemodilution). Hemoglobin levels should be measured before treatment, at 1 month, and periodically thereafter. In most cases, anemia was mild and did not require treatment discontinuation. However, if hemoglobin drops significantly, further evaluation should be undertaken to rule out other causes (e.g., gastrointestinal bleeding) and to determine whether dose reduction or discontinuation is necessary.

Hepatic safety is an area of particular importance for endothelin receptor antagonists. The first-generation ERA, bosentan, was associated with a notable incidence of dose-dependent hepatotoxicity (elevated aminotransferases above 3 times ULN in approximately 11% of patients). In contrast, macitentan has demonstrated a significantly more favorable hepatic safety profile. In the SERAPHIN trial, the incidence of aminotransferase elevations above 3 times ULN was 3.4% with macitentan 10 mg versus 4.5% with placebo, indicating no excess hepatotoxicity compared with placebo. Nevertheless, liver function monitoring remains recommended as a precautionary measure.

Other side effects, including upper respiratory tract infections (nasopharyngitis, bronchitis, pharyngitis), are common but generally mild and self-limiting. Hypotension can occur, particularly in patients who are volume-depleted or taking other antihypertensive medications, and blood pressure should be monitored regularly during treatment.

How Should You Store Macitentan Glenmark?

Proper storage of Macitentan Glenmark is essential to ensure the medication maintains its quality, safety, and therapeutic effectiveness throughout its shelf life. As a film-coated tablet, macitentan is relatively stable under standard storage conditions, but certain precautions should be observed.

• Temperature: Store at room temperature, not exceeding 30°C (86°F). Do not refrigerate or freeze. Avoid storing the medication in areas with significant temperature fluctuations, such as near radiators, in direct sunlight, or in cars during hot weather.
• Moisture protection: Keep the tablets in the original blister packaging to protect them from moisture. Do not remove tablets from the blister pack until ready to take them. High humidity can compromise the integrity of the film coating and the active ingredient.
• Light protection: Store in the original carton when not in use to provide additional protection from light exposure.
• Keep out of reach of children: Store Macitentan Glenmark in a safe location inaccessible to children. Given its teratogenic properties, it is particularly important that this medication is stored securely and handled only by the intended patient.
• Expiration date: Do not use Macitentan Glenmark after the expiration date printed on the blister pack and outer carton (after “EXP”). The expiration date refers to the last day of that month. Dispose of expired medication properly—do not flush down the toilet or discard in household waste. Ask your pharmacist about local medication take-back programs or disposal guidelines.
• Handling precautions: Because macitentan is teratogenic, women who are pregnant or may become pregnant should avoid handling broken or crushed tablets. If a tablet is accidentally broken, avoid direct skin contact and clean any contaminated surfaces.

When traveling with Macitentan Glenmark, keep the medication in your hand luggage in its original packaging. Carry a copy of your prescription or a letter from your doctor confirming the need for this medication, as macitentan is a prescription-only medicine that may be subject to customs regulations in some countries.

What Does Macitentan Glenmark Contain?

Understanding the composition of your medication is important, particularly if you have known allergies or sensitivities to specific pharmaceutical ingredients. Below is a detailed description of the contents of Macitentan Glenmark.

Active Ingredient

The active substance is macitentan. Each film-coated tablet contains 10 mg of macitentan. Macitentan is chemically described as N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)pyrimidin-4-yl]-N’-propylsulfamide. It is a synthetic small molecule with a molecular weight of 588.27 g/mol and is practically insoluble in water.

Inactive Ingredients (Excipients)

Appearance and Pack Sizes

Macitentan Glenmark 10 mg film-coated tablets are white to off-white, round, biconvex tablets. They are supplied in blister packs. Pack sizes may vary by country but typically include 28 tablets (corresponding to a 4-week supply) or 30 tablets. Not all pack sizes may be marketed in every country.

Important Excipient Information

Macitentan Glenmark tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency, or glucose-galactose malabsorption should not take this medication. The tablets also contain sodium, but the amount per tablet is less than 1 mmol (23 mg), meaning they are essentially sodium-free. If you have any known intolerances or allergies to any of the listed excipients, inform your healthcare provider before starting treatment.