Macitentan Devatis

What Is Macitentan Devatis and What Is It Used For?

Quick Answer: Macitentan Devatis is a dual endothelin receptor antagonist (ERA) used to treat pulmonary arterial hypertension (PAH) in adults. It reduces the abnormally elevated blood pressure in the pulmonary arteries, slows disease progression, and improves the ability to exercise.

Macitentan Devatis contains the active substance macitentan, which 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 development and progression of pulmonary arterial hypertension. The endothelin-1 peptide is one of the most potent vasoconstrictors found in the human body, and in patients with PAH, its levels are pathologically elevated, contributing to the narrowing and remodelling of pulmonary blood vessels.

Pulmonary arterial hypertension is a serious and progressive condition characterised by abnormally high blood pressure in the arteries that carry blood from the heart to the lungs. Over time, this elevated pressure forces the right side of the heart to work harder, eventually leading to right heart failure if left untreated. PAH can be idiopathic (of unknown cause), heritable, or associated with conditions such as connective tissue diseases (notably systemic sclerosis), congenital heart disease, HIV infection, or portal hypertension.

Macitentan differs from earlier endothelin receptor antagonists such as bosentan in several important ways. It was specifically designed for enhanced tissue targeting and sustained receptor binding. Unlike bosentan, macitentan has demonstrated tissue penetration properties that allow it to reach the pulmonary vasculature more effectively. Additionally, macitentan produces an active metabolite (ACT-132577) that also blocks endothelin receptors, providing prolonged pharmacological activity with an effective half-life of approximately 48 hours.

The efficacy of macitentan was established in the pivotal SERAPHIN trial (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), one of the largest and longest randomised controlled trials ever conducted in PAH. This event-driven, double-blind, placebo-controlled study enrolled 742 patients across 151 centres in 39 countries. Macitentan 10 mg demonstrated a 45% reduction in the composite endpoint of morbidity and mortality 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.

What Should You Know Before Taking Macitentan Devatis?

Quick Answer: Before starting Macitentan Devatis, your doctor must confirm you are not pregnant, check your liver function and haemoglobin levels, and review all other medications you take. This drug is strictly contraindicated in pregnancy and in patients with severe liver impairment.

Contraindications

Macitentan Devatis must not be used in the following situations:

• Pregnancy: Macitentan is teratogenic (causes birth defects) based on animal data. It is classified as Pregnancy Category X and is absolutely contraindicated in pregnant women or women who may become pregnant
• Severe hepatic impairment: Patients with severe liver disease (Child-Pugh class C) must not take this medication, as macitentan is extensively metabolised by the liver
• Baseline elevated liver aminotransferases: Patients with ALT or AST levels greater than 3 times the upper limit of normal should not start treatment
• Hypersensitivity: Known allergy to macitentan or any of the excipients in the formulation
• Breastfeeding: It is unknown whether macitentan is excreted in human breast milk; breastfeeding is not recommended during treatment

Warnings and Precautions

Several important precautions apply to all patients considering or receiving macitentan therapy. Your prescribing physician will evaluate these factors carefully before initiating treatment and throughout the course of therapy.

Hepatotoxicity: Although macitentan has shown a lower incidence of liver injury compared to some older ERAs, liver enzyme elevations can occur. Liver function tests (ALT, AST, bilirubin) should be measured before starting treatment and then periodically as clinically indicated. If unexplained, clinically significant elevations in aminotransferases occur, or if elevations are accompanied by symptoms of liver injury (such as jaundice, nausea, vomiting, fever, abdominal pain, or unusual fatigue), treatment should be stopped and not restarted.

Anaemia and haemoglobin decrease: Macitentan causes a decrease in haemoglobin concentration and haematocrit. In the SERAPHIN trial, the incidence of a haemoglobin decrease to below 10 g/dL was 8.7% in the macitentan 10 mg group compared to 3.4% in the placebo group. Haemoglobin should be checked before starting treatment, at regular intervals during treatment (e.g., after 1 month, then every 3 months), and as clinically indicated thereafter. Initiation of macitentan is not recommended in patients with severe anaemia. If a clinically significant decrease in haemoglobin occurs, investigate the cause and consider whether treatment should continue.

Fluid retention and oedema: Endothelin receptor antagonists, including macitentan, can cause fluid retention. Patients should be monitored for signs of fluid overload, particularly those with underlying ventricular dysfunction. If clinically significant fluid retention develops, consider additional diuretic therapy or, if severe, discontinue macitentan.

Pulmonary veno-occlusive disease (PVOD): Cases of pulmonary oedema have been reported with vasodilators used in PAH, and this may be a sign of underlying PVOD. If pulmonary oedema develops, the possibility of PVOD should be considered. If confirmed, macitentan should be discontinued.

Pregnancy and Breastfeeding

If pregnancy occurs during treatment, macitentan must be stopped immediately and the patient referred for specialist obstetric care. Healthcare providers and patients should report any pregnancy exposure to the relevant pharmacovigilance authorities. Breastfeeding is not recommended during treatment, as it is not known whether macitentan or its metabolites are excreted in human breast milk.

Fertility: In animal studies, macitentan has been shown to affect male reproductive organs, including testicular tubular atrophy at high doses. The clinical significance in humans is uncertain, but male patients should be informed of these findings. Sperm count monitoring may be considered in male patients who are concerned about fertility.

How Does Macitentan Devatis Interact with Other Drugs?

Quick Answer: Macitentan is metabolised primarily by CYP3A4 and to a lesser extent by CYP2C9. Strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase macitentan exposure approximately 2-fold, while strong CYP3A4 inducers (e.g. rifampicin) significantly reduce its levels. Co-administration with strong CYP3A4 inducers should be avoided.

Understanding drug interactions is critical for the safe use of Macitentan Devatis, particularly as patients with PAH often require multiple medications. Macitentan undergoes extensive hepatic metabolism primarily through the cytochrome P450 enzyme CYP3A4 (with minor contribution from CYP2C9), producing the active metabolite ACT-132577. Any drug that significantly alters CYP3A4 activity can therefore affect macitentan blood levels and clinical efficacy.

Major Interactions

The following drug interactions are considered clinically significant and may require dose adjustment, enhanced monitoring, or avoidance of co-administration:

Minor Interactions

Moderate CYP3A4 inhibitors (such as fluconazole, erythromycin, diltiazem, verapamil) may modestly increase macitentan exposure. While no dose adjustment is typically required, patients should be monitored for increased side effects. Macitentan does not significantly inhibit or induce major CYP enzymes at therapeutic concentrations, reducing its potential to alter the metabolism of other co-administered drugs.

Warfarin and anticoagulants: In vitro and clinical studies indicate that macitentan does not have a clinically relevant effect on the pharmacokinetics or anticoagulant activity of warfarin. However, given the serious nature of anticoagulation therapy, INR should still be monitored regularly in patients taking warfarin concurrently.

Sildenafil and tadalafil: Macitentan does not significantly alter the pharmacokinetics of phosphodiesterase-5 (PDE-5) inhibitors, and these drugs are commonly used in combination for PAH treatment without dose adjustment. The SERAPHIN trial included patients on background PDE-5 inhibitor therapy, and the benefit of macitentan was maintained in this population.

What Is the Correct Dosage of Macitentan Devatis?

Quick Answer: The recommended dose of Macitentan Devatis is one 10 mg film-coated tablet taken once daily by mouth, with or without food. There is no dose titration required. The tablet should be swallowed whole and not crushed, split, or chewed.

Adults

There is no specific requirement regarding food intake, as food does not significantly affect the bioavailability of macitentan. However, taking the tablet at a consistent time each day helps maintain steady blood levels and promotes adherence. Treatment should be continued long-term unless clinically indicated otherwise, as PAH is a chronic progressive disease.

Hepatic impairment: No dose adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh class A or B). However, macitentan is contraindicated in patients with severe hepatic impairment (Child-Pugh class C). Given its extensive hepatic metabolism, patients with any degree of liver dysfunction should be monitored more closely.

Renal impairment: No dose adjustment is required for patients with renal impairment, including those with severe renal insufficiency. However, clinical experience in patients on dialysis is limited, and caution is warranted in this population as blood pressure changes may be more pronounced.

Children and Adolescents

Elderly Patients

Missed Dose

If a dose of Macitentan Devatis 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 should be resumed. Patients should never take a double dose to make up for a missed one. Given the long half-life of macitentan (approximately 16 hours) and its active metabolite (approximately 48 hours), a single missed dose is unlikely to have an immediate clinical impact, but consistent adherence is important for optimal disease management.

Overdose

There is limited clinical experience with macitentan overdose. In healthy volunteers, single doses up to 600 mg have been administered. Expected symptoms of overdose would include headache, nausea, and vomiting, along with pronounced vasodilatory effects such as hypotension and potentially syncope. There is no specific antidote for macitentan. In the event of an overdose, supportive measures should be instituted as needed, including monitoring of vital signs and management of hypotension with intravenous fluids and vasopressors if necessary. Macitentan is highly protein-bound and is unlikely to be removed by haemodialysis.

What Are the Side Effects of Macitentan Devatis?

Quick Answer: The most common side effects of Macitentan Devatis include anaemia (decreased haemoglobin), headache, nasopharyngitis, bronchitis, and urinary tract infections. Anaemia is the most clinically significant side effect and requires regular blood monitoring. Serious but rare side effects include hepatotoxicity and severe hypotension.

Like all medicines, Macitentan Devatis can cause side effects, although not everybody gets them. The safety profile of macitentan has been extensively characterised in the SERAPHIN trial and post-marketing surveillance. The incidence of side effects described below is based on clinical trial data involving over 700 patients treated with macitentan 10 mg.

When to seek immediate medical attention: Contact your doctor or seek emergency care immediately if you experience signs of a serious allergic reaction (swelling of face, lips, tongue, or throat; difficulty breathing), unexplained jaundice (yellowing of skin or eyes), extreme fatigue with dark urine (signs of liver problems), or symptoms of severe anaemia (extreme pallor, chest pain at rest, shortness of breath disproportionate to your usual symptoms).

Many of the mild side effects, particularly headache and nasopharyngitis, tend to improve over the first few weeks of treatment as the body adjusts to the medication. Your doctor may advise symptomatic treatment for headache (e.g., paracetamol) during this initial period. It is important to continue taking macitentan as prescribed and not to stop without consulting your doctor, as abrupt discontinuation may lead to worsening of PAH symptoms.

How Should You Store Macitentan Devatis?

Quick Answer: Store Macitentan Devatis at room temperature below 30°C (86°F) in the original packaging. Protect from moisture. Keep out of the sight and reach of children. Do not use after the expiry date printed on the packaging.

Proper storage of Macitentan Devatis is essential to ensure the medication remains effective and safe throughout its shelf life. The following guidelines should be observed:

• Temperature: Store at room temperature, not exceeding 30°C (86°F). Do not refrigerate or freeze
• Packaging: Keep the tablets in the original blister packaging to protect them from moisture
• Light: Protect from excessive light exposure; store in the outer carton when not in use
• Children: Keep out of the sight and reach of children. Given the teratogenic potential, special care must be taken to prevent accidental exposure
• Expiry: Do not use Macitentan Devatis after the expiry date stated on the carton and blister. The expiry date refers to the last day of that month
• Disposal: Do not dispose of medicines via wastewater or household waste. Return unused or expired medication to a pharmacy for proper disposal

If you notice any changes in the appearance of the tablets (discolouration, crumbling, unusual odour), do not take them and consult your pharmacist. Tablets that have been removed from the blister packaging but not taken should be discarded and not returned to the blister.

What Does Macitentan Devatis Contain?

Quick Answer: Each Macitentan Devatis 10 mg film-coated tablet contains 10 mg of the active substance macitentan. The tablets also contain various inactive ingredients (excipients) that provide the tablet structure, coating, and stability.

Active substance: Each film-coated tablet contains 10 mg macitentan.

Excipients (inactive ingredients):

Tablet core: Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone, magnesium stearate, polysorbate 80.

Film coating: Polyvinyl alcohol, titanium dioxide (E171), talc, soya lecithin, xanthan gum.

Appearance: Macitentan Devatis 10 mg tablets are white to off-white, round, biconvex, film-coated tablets. They are supplied in blister packs.

Pharmacokinetics: After oral administration, macitentan is absorbed with a peak plasma concentration (Tmax) reached approximately 8 hours post-dose. The absolute bioavailability is not known but is estimated to be moderate. Macitentan is highly protein-bound (greater than 99%), primarily to albumin and to a lesser extent to alpha-1 acid glycoprotein. It is metabolised primarily by CYP3A4, with a minor contribution from CYP2C9, to form the active metabolite ACT-132577 (approx. 50% of parent pharmacological activity). The elimination half-life of macitentan is approximately 16 hours, while the active metabolite has a half-life of approximately 48 hours, supporting once-daily dosing.