Opsumit: Uses, Dosage & Side Effects

What Is Opsumit and What Is It Used For?

Opsumit contains the active substance macitentan, a medicine belonging to the class of endothelin receptor antagonists (ERAs). It is licensed for the long-term treatment of pulmonary arterial hypertension (PAH) in adults classified as WHO Functional Class II or III. Following paediatric approvals in multiple regions, it is also indicated in children aged 2 years and older with PAH. PAH is a rare, progressive, and life-limiting disease of the small pulmonary arteries, in which the vessels become narrowed, stiffened, and remodelled. The resulting increase in pulmonary vascular resistance places a heavy burden on the right side of the heart and, if untreated, leads to right heart failure.

Endothelin-1 is a naturally occurring peptide hormone produced by the cells lining the blood vessels (endothelial cells). In healthy lungs, endothelin signalling is tightly regulated. In PAH, however, endothelin-1 levels are markedly elevated, and the hormone contributes to excessive vasoconstriction (narrowing of the pulmonary arteries), abnormal proliferation of smooth muscle cells, inflammation, and deposition of fibrotic tissue within the vessel walls. Macitentan binds with high affinity to the two endothelin receptor subtypes, ET_A and ET_B, and prevents endothelin-1 from activating them. By doing so, Opsumit addresses one of the three main pathogenic pathways in PAH (the endothelin pathway), complementing drugs that target the nitric oxide and prostacyclin pathways.

Within the World Health Organization classification, pulmonary hypertension is divided into five groups based on underlying cause. Opsumit is specifically indicated for WHO Group 1 (pulmonary arterial hypertension), which includes idiopathic PAH, heritable PAH, drug- and toxin-induced PAH, PAH associated with connective tissue diseases (for example systemic sclerosis), PAH associated with congenital heart disease with repaired shunts, PAH associated with HIV infection, and PAH associated with portal hypertension. Opsumit is not indicated for pulmonary hypertension due to left heart disease (Group 2), chronic lung disease and/or hypoxia (Group 3), or chronic thromboembolic pulmonary hypertension (CTEPH, Group 4) outside of specialist settings, except where specifically approved.

The clinical evidence supporting Opsumit’s approval rests largely on the SERAPHIN trial – a randomised, double-blind, placebo-controlled event-driven outcome study in 742 patients with symptomatic PAH. In SERAPHIN, macitentan 10 mg once daily reduced the risk of the primary composite morbidity/mortality endpoint (worsening of PAH, initiation of intravenous or subcutaneous prostanoid therapy, lung transplantation, atrial septostomy, or death) by 45% compared with placebo. It was the first endothelin receptor antagonist to demonstrate a significant benefit on such a long-term composite outcome, not just short-term exercise capacity. Additional benefits were observed for 6-minute walking distance, WHO functional class, and PAH hospitalisation rates.

Beyond monotherapy, macitentan is widely used as part of upfront or sequential combination therapy with a phosphodiesterase type 5 inhibitor (such as tadalafil or sildenafil) or a soluble guanylate cyclase stimulator (riociguat), and with prostacyclin-pathway agents. Current European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines and other international consensus statements recommend combination PAH therapy for most newly diagnosed intermediate- or high-risk patients, with Opsumit commonly selected as the endothelin pathway component because of its once-daily dosing and favourable liver-safety profile compared with older ERAs such as bosentan.

What Should You Know Before Taking Opsumit?

Contraindications

There are specific situations in which Opsumit must not be taken. Understanding these absolute contraindications is essential before starting therapy.

• Pregnancy: Opsumit is contraindicated in pregnancy. Endothelin receptor antagonists as a class have been shown to cause serious birth defects (teratogenic effects) in animal studies, including severe malformations of the heart and great vessels, the head and face, and limbs. A negative pregnancy test is mandatory before initiating therapy.
• Women of child-bearing potential not using reliable contraception: Opsumit must not be prescribed to women who can become pregnant unless two reliable methods of contraception are in place throughout treatment and for at least 1 month after the last dose.
• Breastfeeding: Macitentan and/or its metabolites may be excreted in breast milk. Because of potential serious adverse reactions in breastfed infants, breastfeeding is contraindicated during treatment with Opsumit.
• Severe hepatic impairment: Opsumit must not be used in patients with severe hepatic impairment (with or without cirrhosis, Child-Pugh C), because of the risk of further liver injury and accumulation of the drug.
• Elevated aminotransferases at baseline: Patients with baseline ALT or AST greater than 3 times the upper limit of normal (>3 × ULN) should not start treatment until liver enzymes have returned to acceptable levels.
• Hypersensitivity: Do not take Opsumit if you are allergic to macitentan, soya, or any of the other ingredients.

Warnings and Precautions

Before and during treatment with Opsumit, inform your doctor if any of the following apply to you:

• Hepatotoxicity: Like other endothelin receptor antagonists, Opsumit can cause elevations of liver enzymes. Although clinically significant hepatotoxicity was uncommon in SERAPHIN (less frequent than seen historically with bosentan), rare cases of symptomatic liver injury have been reported in post-marketing surveillance. Liver function tests (ALT, AST, bilirubin) should be obtained before starting treatment and monitored periodically thereafter as clinically indicated. Stop Opsumit if sustained, unexplained, clinically relevant ALT or AST elevations occur, or if enzyme elevations are accompanied by an increase in bilirubin ≥2 × ULN, or by symptoms such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy.
• Decrease in haemoglobin and haematocrit: Dose-dependent reductions in haemoglobin concentration and haematocrit have been observed with Opsumit. In the SERAPHIN study, about 13% of patients treated with 10 mg developed a decrease in haemoglobin to less than 10 g/dL. Initiation is not recommended in patients with severe anaemia. Haemoglobin should be measured before starting treatment and during therapy as clinically indicated.
• Pulmonary oedema with pulmonary veno-occlusive disease (PVOD): If signs of pulmonary oedema develop when Opsumit is used, the possibility of underlying PVOD should be considered, and discontinuation of Opsumit may be required. PVOD is a rare form of PH that can be worsened by pulmonary vasodilators.
• Fluid retention: Peripheral oedema has been observed with Opsumit. A clinical evaluation to identify the cause (medication effect versus worsening heart failure, for example) and the possible need for specific treatment or discontinuation is warranted if oedema develops.
• Heart failure: Opsumit should be used with caution in patients with severe heart failure, as volume retention and worsening of failure may occur.
• Hypotension: Endothelin receptor antagonists can cause hypotension (low blood pressure). Symptoms may include dizziness, lightheadedness, or fainting, particularly when standing up quickly. Dose adjustment of other blood-pressure-lowering medicines may be necessary.
• Soya allergy: Opsumit tablets contain soya lecithin. Do not take Opsumit if you are allergic to soya.
• Lactose intolerance: Opsumit tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take Opsumit.
• Renal impairment: No dose adjustment is required for patients with renal impairment. However, patients on dialysis were not studied, and experience in severe renal impairment is limited; use with caution.
• Surgery and anaesthesia: Tell your anaesthetist or surgeon that you are taking Opsumit, as the drug can interact with anaesthetic agents and other peri-operative medications.

Your doctor will perform regular blood tests (haemoglobin and liver enzymes), pregnancy tests in women of reproductive potential, and clinical assessments to monitor for these potential complications throughout treatment.

Pregnancy, Contraception and Breastfeeding

Opsumit is strictly contraindicated in pregnancy. Macitentan has not been directly studied in pregnant women for obvious ethical reasons, but every endothelin receptor antagonist tested in animal reproductive toxicity studies has produced serious birth defects. Effects observed in animals include malformations of the cardiovascular system, the head and face, and the lower jaw, as well as foetal loss. There is no known safe dose during any trimester of pregnancy.

Before starting Opsumit, female patients of reproductive potential must have a negative serum or urine pregnancy test (sensitive to at least 25 mIU/mL hCG) within 24 hours of the first dose, and must agree to use two reliable forms of contraception throughout treatment and for at least 1 month after the last dose. Acceptable methods include a combination of:

• A reliable hormonal method (combined oral contraceptive, progestogen-only pill, injectable, implant, vaginal ring, or patch) – recognising that the efficacy of hormonal contraception has not been formally studied with macitentan and should not be used as the sole method;
• A reliable non-hormonal method (copper intrauterine device or barrier method such as a diaphragm or condom);
• Or two independent barrier methods (for example a condom plus a diaphragm with spermicide).

Male sterilisation (vasectomy) of the partner, if confirmed by documented azoospermia, may also be considered as one highly effective method. Tubal sterilisation or an intrauterine system releasing levonorgestrel are alternatives. Pregnancy tests must be repeated monthly during treatment and 1 month after stopping. If pregnancy is confirmed or suspected, Opsumit must be stopped immediately and the patient referred to a specialist for risk assessment and counselling.

Because it is unknown whether macitentan passes into human breast milk, and because of potential serious adverse reactions in nursing infants, breastfeeding during Opsumit therapy is not permitted.

Data on effects on male fertility are limited. Macitentan, like other ERAs, may reduce sperm count. Men who wish to father a child in the future should discuss fertility preservation options (for example sperm cryopreservation) with their doctor before starting treatment.

Driving and Operating Machinery

Opsumit can cause headache, hypotension, and dizziness, each of which may impair your ability to drive or operate machinery. If you experience any of these symptoms, do not drive or use machines until they have resolved. The effect on driving ability is expected to be minor to moderate, but individual reactions vary.

Important Information About Ingredients

Opsumit 10 mg film-coated tablets contain lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. The tablets also contain soya lecithin as part of the film coating. If you are allergic to soya, do not take this medicine. Each tablet contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’.

How Does Opsumit Interact with Other Drugs?

Drug interactions with Opsumit are primarily driven by cytochrome P450 3A4 (CYP3A4), the main enzyme responsible for converting macitentan to its active metabolite ACT-132577 and, to a lesser extent, for eliminating the parent drug. Because both the parent drug and its metabolite contribute to the pharmacological effect, interactions can alter either the efficacy or the safety of Opsumit. Macitentan itself is not a clinically relevant inhibitor or inducer of CYP enzymes, transporters, or multidrug resistance-associated proteins at therapeutic doses, so it has a favourable interaction profile compared with older ERAs such as bosentan.

Major Interactions

Minor and Clinically Relevant Interactions

You should always tell your doctor and pharmacist about every medicine you are taking or plan to take, including prescription drugs, over-the-counter products, vitamins, herbal supplements, and recreational substances. Seemingly harmless products such as St John’s wort (used for mild depression) can markedly reduce Opsumit’s efficacy, while grapefruit juice can subtly increase its levels. A pharmacist-led medication review before starting treatment and at every dose change is good practice in PAH care.

What Is the Correct Dosage of Opsumit?

Opsumit is supplied as round, white, film-coated tablets containing 10 mg of macitentan. It is taken orally once daily and must be swallowed whole with water. The tablet should not be split, crushed, or chewed. Opsumit may be taken with or without food, which simplifies adherence in patients already taking multiple PAH medications. Treatment should be initiated and supervised by a physician experienced in the management of pulmonary arterial hypertension.

Adults

Children and Adolescents

Opsumit is indicated for paediatric patients aged 2 years and older with PAH in many regions, including the European Union and the United States, based on data from the TOMORROW paediatric programme and bridging pharmacokinetic and efficacy evidence. Dosing is weight-based using a dedicated paediatric formulation (dispersible tablets for reconstitution) in younger children, with the standard 10 mg tablet used once the child is sufficiently heavy.

Elderly Patients

No specific dose adjustment is required in patients over 65 years of age. Clinical experience in patients over 75 years is more limited, and co-existing conditions and polypharmacy are more common, so elderly patients should be monitored particularly carefully for hypotension, oedema, and drug interactions.

Special Populations

• Renal impairment: No dose adjustment is needed, including in end-stage renal disease. However, data in severe renal impairment and in patients on haemodialysis are limited. Use with caution and monitor blood pressure, as these patients may be more prone to hypotension and anaemia.
• Hepatic impairment: No dose adjustment is required in mild or moderate hepatic impairment (Child-Pugh A or B). Opsumit is contraindicated in severe hepatic impairment (Child-Pugh C) and in patients with baseline ALT or AST >3 × ULN.
• Dialysis: Macitentan has high plasma protein binding and is not expected to be removed by haemodialysis. Give the dose at the same time each day, independent of dialysis sessions.

Missed Dose

If you forget to take a dose of Opsumit, take it as soon as you remember on the same day. Do not take a double dose to make up for the forgotten one. If it is almost time for your next dose, skip the missed one and carry on with your usual dosing schedule. Persistent difficulty remembering doses should be discussed with your doctor or pharmacist, who may suggest tools such as a weekly pill organiser or a reminder app.

Overdose

In healthy volunteer studies, single doses of macitentan up to 900 mg were investigated and produced mild to moderate adverse effects including headache, nausea, and vomiting, but no life-threatening events. There is no specific antidote for macitentan overdose. Management is supportive and may include symptomatic treatment of hypotension, cardiovascular monitoring, and intensive care if needed. Because of the high plasma protein binding (>99%) of macitentan, haemodialysis is unlikely to be effective at removing the drug. If you or someone else has taken too much Opsumit, contact your poison centre or emergency medical services immediately. Bring the packaging with you to the hospital.

Stopping Opsumit

Do not stop taking Opsumit without talking to your doctor first. Abrupt discontinuation of endothelin receptor antagonists in PAH can lead to rapid clinical deterioration, including right heart failure. If Opsumit must be stopped (for example because of pregnancy, severe side effects, or a switch to another ERA), your PAH centre will coordinate the transition, monitor closely, and may start alternative therapy. Patients must continue contraception for at least 1 month after the final dose.

What Are the Side Effects of Opsumit?

Like all medicines, Opsumit can cause side effects, although not everyone gets them. Most side effects are mild to moderate and may improve over time. However, a small number of side effects are serious and require prompt medical attention. Your medical team will monitor you during every follow-up visit and through regular blood tests.

When to Seek Urgent Medical Attention

Contact your doctor immediately, or go to the emergency department, if you experience any of the following while taking Opsumit:

• Signs of liver injury: unusual tiredness, loss of appetite, nausea, vomiting, yellowing of the skin or whites of the eyes (jaundice), dark-coloured urine, pale stools, abdominal pain (especially in the upper right), or persistent fever.
• Symptoms of severe anaemia: extreme tiredness, shortness of breath with minimal exertion, pale skin, rapid heartbeat, dizziness on standing, or fainting.
• Pulmonary oedema: new or suddenly worsening shortness of breath, coughing up pink or frothy sputum, inability to lie flat, or waking up at night gasping for air. These symptoms may indicate worsening PAH or pulmonary veno-occlusive disease and require urgent evaluation.
• Severe allergic reaction (anaphylaxis): sudden onset of widespread rash, facial or throat swelling, wheezing, chest tightness, or collapse. This is a medical emergency – call your local emergency number.
• Suspected pregnancy: if there is any possibility that you are pregnant, stop Opsumit and contact your doctor straight away.

You can also report suspected side effects to your national pharmacovigilance authority – for example, the EMA EudraVigilance system in the European Union, the FDA MedWatch program in the United States, or the MHRA Yellow Card Scheme in the United Kingdom – to help monitor the ongoing benefit-risk profile of Opsumit.

How Should Opsumit Be Stored?

Proper storage of Opsumit is important to maintain potency and safety throughout the shelf life. The following instructions apply to the commercially available 10 mg tablet:

• Temperature: Store below 30°C (86°F). Protect from freezing.
• Original packaging: Keep the tablets in the original blister pack or bottle to protect them from light and moisture.
• Safety: Keep Opsumit out of the sight and reach of children. Even a single tablet can be harmful to a small child.
• Expiry: Do not use Opsumit after the expiry date stated on the carton and blister. The expiry date refers to the last day of that month.
• Inspection: Do not use the tablet if it is broken, discoloured, or the blister pack is damaged.
• Bathroom storage: Avoid storing Opsumit in the bathroom or other humid areas, as moisture can affect the tablets.

Do not dispose of unused or expired Opsumit via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures help protect the environment and prevent accidental exposure to others.

What Does Opsumit Contain?

Active Substance

The active substance is macitentan. Each film-coated tablet contains 10 mg of macitentan. Macitentan is a non-peptide, orally active, dual endothelin receptor antagonist developed from bosentan with improved selectivity and tissue-penetration properties, resulting in longer receptor occupancy and once-daily dosing.

Inactive Ingredients (Excipients)

Tablet core:

• Lactose monohydrate
• Microcrystalline cellulose (E460)
• Sodium starch glycolate (Type A)
• Povidone K30 (E1201)
• Magnesium stearate (E572)
• Polysorbate 80 (E433)

Film coating:

• Polyvinyl alcohol (E1203)
• Titanium dioxide (E171)
• Talc (E553b)
• Soya lecithin (E322)
• Xanthan gum (E415)

Appearance and Pack Sizes

Opsumit 10 mg film-coated tablets are round, biconvex, white to off-white, approximately 5.5 mm in diameter, with “10” debossed on both sides. They are supplied in white high-density polyethylene (HDPE) bottles with polypropylene child-resistant closures containing a silica gel desiccant, or in PVC/PE/PVDC aluminium blister packs. Pack sizes include 15 tablets (blister), 30 tablets (blister or bottle), and 90 tablets (bottle). Not all pack sizes may be marketed in every country.

Marketing Authorisation Holder and Manufacturer

Opsumit was originally developed by Actelion Pharmaceuticals Ltd. and is now marketed worldwide by Janssen-Cilag International NV (a Johnson & Johnson company) following Janssen’s acquisition of Actelion. Manufacturing is performed by Actelion Manufacturing GmbH, Lorrach, Germany, and by other approved facilities in the Janssen network. Details of the local representative are listed in the patient information leaflet accompanying the product.