Macitentan STADA

What Is Macitentan STADA and What Is It Used For?

Macitentan STADA 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 pathophysiology of pulmonary arterial hypertension. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is overproduced in patients with PAH. When ET-1 binds to receptors on the smooth muscle cells of pulmonary arteries, it causes the vessels to constrict and promotes pathological remodelling of the vessel walls, leading to progressively increasing pulmonary vascular resistance and right heart failure.

Macitentan is a dual receptor antagonist, meaning it blocks both the ET_A and ET_B receptors. The ET_A receptor, predominantly found on vascular smooth muscle cells, mediates vasoconstriction and cell proliferation. The ET_B receptor has a dual role: on endothelial cells it promotes vasodilation and ET-1 clearance, while on smooth muscle cells it contributes to vasoconstriction. By blocking both receptors, macitentan comprehensively counteracts the harmful effects of excess ET-1 in the pulmonary vasculature.

Compared to earlier ERAs such as bosentan, macitentan was specifically designed to achieve superior tissue penetration and sustained receptor binding. Its lipophilic properties allow it to penetrate more effectively into the diseased pulmonary arterial wall, and its slow dissociation from endothelin receptors results in a prolonged duration of action. Macitentan also produces an active metabolite, ACT-132577, which itself has pharmacological activity and contributes to the overall therapeutic effect, with a half-life of approximately 48 hours.

Macitentan STADA is indicated for the long-term treatment of PAH in adult patients classified as WHO functional class II (mild limitation of physical activity) or class III (marked limitation of physical activity). It is approved both as monotherapy and in combination with other PAH-specific therapies, including phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil or tadalafil. The efficacy and safety of combination therapy have been well-established in clinical trials, and international guidelines from the ESC/ERS (European Society of Cardiology/European Respiratory Society) now recommend initial or sequential combination therapy for most PAH patients.

The pivotal evidence for macitentan comes from the SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, one of the largest randomised, double-blind, placebo-controlled outcome studies ever conducted in PAH. This trial enrolled 742 patients across 151 centres in 39 countries and demonstrated that macitentan 10 mg significantly reduced the composite endpoint of morbidity and mortality by 45% compared to placebo over a median treatment duration of approximately 2 years. Notably, this benefit was observed regardless of whether patients were already receiving background PAH therapy.

What Should You Know Before Taking Macitentan STADA?

Contraindications

Macitentan STADA must not be used in several important clinical situations. The most critical contraindication is pregnancy. Macitentan, like all endothelin receptor antagonists, has been shown to be teratogenic in animal studies, causing severe malformations of the head, face, and major blood vessels. For this reason, macitentan carries a Pregnancy Category X classification and is absolutely contraindicated in women who are pregnant or who may become pregnant without using reliable contraception.

Other contraindications include hypersensitivity to macitentan or any of the excipients, severe hepatic impairment (Child-Pugh class C) with or without cirrhosis, and baseline values of liver aminotransferases (AST and/or ALT) greater than 3 times the upper limit of normal. Patients with these conditions should not receive macitentan under any circumstances.

Warnings and Precautions

Several important warnings and precautions apply to the use of macitentan. Liver function should be assessed before initiating treatment and monitored periodically thereafter. While macitentan has a more favourable hepatic safety profile than bosentan (which requires monthly liver function monitoring), cases of liver injury have been reported with ERA therapy. Treatment should be discontinued if clinically significant liver enzyme elevations occur, particularly if accompanied by symptoms such as jaundice, nausea, vomiting, fever, or abdominal pain.

Haemoglobin and haematocrit levels should be measured before starting treatment, at 1 month and 3 months after initiation, and periodically thereafter. Endothelin receptor antagonists, including macitentan, have been associated with decreases in haemoglobin concentration. In the SERAPHIN trial, clinically significant decreases in haemoglobin (below 10 g/dL) occurred in 8.7% of patients receiving macitentan 10 mg compared to 3.4% in the placebo group. In most cases, the decrease occurred within the first few months and stabilised thereafter. Blood transfusion was required in some patients.

Macitentan has not been studied in patients with pulmonary hypertension associated with idiopathic pulmonary fibrosis (WHO Group 3 PH). Its use in this population is not recommended, as vasodilator therapy may worsen gas exchange in these patients. Macitentan should also be used with caution in patients with significant anaemia, patients on anticoagulant therapy, and elderly patients due to limited clinical experience.

Pregnancy and Breastfeeding

Macitentan is classified as Pregnancy Category X. Animal reproductive toxicology studies have demonstrated teratogenicity at all doses tested. Malformations observed include cardiovascular and mandibular abnormalities. There are no adequate data on the use of macitentan in pregnant women, but based on the mechanism of action (endothelin receptor blockade is critical for foetal development) and animal data, human teratogenicity is presumed.

Women of childbearing potential must not start treatment without a negative pregnancy test. They must use reliable contraception during treatment and for one month after discontinuation. Hormonal contraceptives may be used but should not be the sole method; a barrier method should be added since macitentan may reduce the efficacy of hormonal contraceptives. Monthly pregnancy testing during treatment is strongly recommended.

It is not known whether macitentan or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, breastfeeding should be discontinued during treatment with macitentan. The decision to discontinue breastfeeding or to discontinue macitentan should take into account the benefit of therapy for the mother.

How Does Macitentan STADA Interact with Other Drugs?

Macitentan is extensively metabolised in the liver, primarily by cytochrome P450 enzymes CYP3A4 and, to a lesser extent, CYP2C19. Its active metabolite ACT-132577 is formed via oxidative depropylation. Because of this metabolic pathway, drugs that significantly affect CYP3A4 activity can alter macitentan and metabolite plasma concentrations, potentially affecting efficacy or safety.

Understanding these interactions is essential for safe prescribing, particularly since PAH patients frequently receive multiple concurrent medications for their underlying condition, comorbidities, and associated symptoms. The following table summarises the most clinically relevant interactions documented in the prescribing information and post-marketing experience.

Major Interactions

Other Interactions of Note

It is important to inform your doctor or pharmacist about all medicines you are currently taking, including over-the-counter drugs, herbal supplements (especially St John's wort), and vitamins. Some herbal products can significantly affect CYP3A4 activity and thus alter macitentan levels. Grapefruit juice, a moderate CYP3A4 inhibitor, should be consumed with caution during treatment.

What Is the Correct Dosage of Macitentan STADA?

Adults

Macitentan is available only in the 10 mg strength, which is the single approved dose. In the SERAPHIN trial, both 3 mg and 10 mg doses were evaluated; however, only the 10 mg dose demonstrated a statistically significant reduction in the composite morbidity-mortality endpoint. Therefore, the 3 mg dose is not approved for clinical use. Patients should not split or crush the tablet.

For patients with mild to moderate hepatic impairment (Child-Pugh class A or B), no dose adjustment is necessary based on pharmacokinetic data. However, macitentan is contraindicated in severe hepatic impairment (Child-Pugh class C). Similarly, for patients with renal impairment, including those with an estimated glomerular filtration rate (eGFR) as low as 15 mL/min/1.73 m², no dose adjustment is required. There are limited data in patients on dialysis, and macitentan is not expected to be dialysable due to its high protein binding (>99%).

Children and Adolescents

Elderly Patients

Missed Dose

If you miss a dose of Macitentan STADA, take it as soon as you remember on the same day. If it is already close to the time for your next scheduled dose, skip the missed dose and take your next dose at the regular time. Do not take two doses on the same day to make up for a missed dose. Consistency in daily dosing is important for maintaining stable blood levels of the medication and its active metabolite.

Overdose

In clinical studies, single doses of macitentan up to 600 mg (60 times the approved dose) have been administered to healthy volunteers. The most commonly observed adverse effects at supratherapeutic doses were headache, nausea, and vomiting. In the event of overdose, standard supportive measures should be taken as needed. Due to macitentan's very high plasma protein binding (>99%), haemodialysis is unlikely to be effective in removing the drug.

If overdose is suspected, contact a poison control centre or emergency medical services immediately. There is no specific antidote for macitentan. Treatment should be symptomatic and supportive, with close monitoring of blood pressure, heart rate, and fluid status. Liver function and haemoglobin should also be monitored in the days following an overdose.

What Are the Side Effects of Macitentan STADA?

Like all medicines, Macitentan STADA can cause side effects, although not everybody experiences them. The side effect profile of macitentan has been well characterised in the SERAPHIN trial and in post-marketing surveillance. The following classification follows the standard medical frequency categories established by the Council for International Organizations of Medical Sciences (CIOMS).

The most clinically significant side effect associated with macitentan is a decrease in haemoglobin concentration (anaemia). This is a class effect of endothelin receptor antagonists and is thought to be related to both haemodilution (fluid retention) and a potential direct effect on erythropoiesis. In the SERAPHIN trial, haemoglobin concentration decreased to below 10 g/dL in 8.7% of patients on macitentan 10 mg versus 3.4% on placebo. Most decreases were mild to moderate in severity and occurred within the first few months of treatment.

Patients should be aware that some side effects, particularly upper respiratory tract infections and mild headache, are common during the initial weeks of treatment and often improve with time. However, any new or worsening symptoms should be reported to your prescribing physician. Regular monitoring appointments are an important part of treatment with macitentan, allowing your healthcare team to detect and manage side effects early.

Reporting suspected side effects is important for ongoing drug safety monitoring. In the European Union, patients and healthcare professionals can report suspected adverse reactions through the national pharmacovigilance system. In the United Kingdom, reports can be made via the Yellow Card Scheme. In the United States, the FDA MedWatch programme accepts reports of adverse events.

How Should You Store Macitentan STADA?

Macitentan STADA tablets should be stored at a temperature not exceeding 30°C (86°F). Keep the tablets in the original blister packaging until ready to take, as this helps protect them from moisture and light degradation. Do not transfer the tablets to a different container.

As with all medications, Macitentan STADA must be kept out of the sight and reach of children. This is particularly important for macitentan given its teratogenic potential. Even a single tablet could pose a risk if ingested by a child or by a woman who is pregnant. Store the medication in a secure location.

Do not use Macitentan STADA after the expiry date printed on the blister and carton (EXP). The expiry date refers to the last day of the indicated month. Do not use the medicine if you notice any visible signs of deterioration such as discolouration or damaged packaging. Do not dispose of medicines via household waste or wastewater. Ask your pharmacist about proper disposal through local take-back programmes to help protect the environment.

What Does Macitentan STADA Contain?

The active substance in Macitentan STADA is macitentan. Each film-coated tablet contains precisely 10 mg of macitentan. Macitentan is a synthetic small molecule with the chemical name N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)pyrimidin-4-yl]-N'-propylsulfamide. It has a molecular weight of 588.27 g/mol and appears as a white to off-white crystalline powder.

The other ingredients (excipients) in the tablet core typically include lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone K-30, magnesium stearate, and polysorbate 80. These excipients serve various functions: lactose monohydrate and microcrystalline cellulose act as fillers, sodium starch glycolate is a disintegrant that helps the tablet break down in the gastrointestinal tract, povidone K-30 is a binder, magnesium stearate is a lubricant, and polysorbate 80 is a surfactant that aids in dissolution.

The film coating contains polyvinyl alcohol, titanium dioxide (E171), macrogol/PEG, talc, lecithin (soya), and iron oxide yellow (E172). This coating provides a smooth surface for ease of swallowing, protects the active ingredient from moisture and light, and gives the tablet its characteristic appearance. Patients with known allergies to soya or peanut should inform their doctor, as lecithin derived from soya is present in the film coating. Patients with lactose intolerance should also be aware that the tablet contains lactose monohydrate.

Macitentan STADA tablets are round, biconvex, film-coated tablets approximately 9 mm in diameter. They are available in blister packs containing 28 or 30 tablets, corresponding to one month of treatment. Not all pack sizes may be marketed in every country.

Medical Editorial Team