Macitentan AccordPharma
Endothelin receptor antagonist for pulmonary arterial hypertension (PAH)
Quick Facts About Macitentan AccordPharma
Key Takeaways About Macitentan AccordPharma
- Treats pulmonary arterial hypertension: Macitentan is a dual endothelin receptor antagonist proven to reduce morbidity and mortality in PAH patients (SERAPHIN trial)
- Strictly contraindicated in pregnancy: Macitentan is teratogenic and must not be used during pregnancy; reliable contraception and monthly pregnancy tests are mandatory
- Regular blood monitoring required: Hemoglobin levels and liver function tests must be checked before and during treatment due to risk of anemia and hepatotoxicity
- Can be combined with other PAH therapies: Often used as part of combination therapy with phosphodiesterase-5 inhibitors or prostacyclin analogs
- Simple once-daily dosing: One 10 mg tablet taken once daily, with or without food, at approximately the same time each day
What Is Macitentan AccordPharma and What Is It Used For?
Macitentan AccordPharma is a prescription medication containing the active substance macitentan, a dual endothelin receptor antagonist (ERA) used to treat pulmonary arterial hypertension (PAH) in adult patients classified as WHO Functional Class II to III. It works by blocking the effects of endothelin-1, a naturally occurring substance that causes blood vessels in the lungs to narrow and thicken.
Pulmonary arterial hypertension is a serious and progressive condition characterized by abnormally elevated blood pressure in the pulmonary arteries — the blood vessels that carry blood from the heart to the lungs. In PAH, the walls of these arteries become thickened, stiff, and narrowed, forcing the right side of the heart to work progressively harder to pump blood through the lungs. Over time, this increased workload can lead to right heart failure if left untreated.
Endothelin-1 (ET-1) is one of the most potent vasoconstrictors produced in the human body. In patients with PAH, endothelin-1 levels are significantly elevated, contributing to the vasoconstriction, proliferation of smooth muscle cells, fibrosis, and inflammation that drive disease progression. Macitentan works by blocking both the ETA and ETB endothelin receptors with sustained receptor binding, thereby reducing the harmful effects of excessive endothelin-1 signaling in the pulmonary vasculature.
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 large multicenter, double-blind, randomized controlled trial involving 742 patients with PAH. The SERAPHIN trial demonstrated that macitentan 10 mg significantly reduced the composite endpoint of morbidity and mortality by 45% compared to placebo (hazard ratio 0.55; 97.5% CI: 0.39-0.76; p < 0.001) over a median treatment duration of approximately 115 weeks.
Macitentan AccordPharma is a generic version of the originator product, containing the same active substance (macitentan) at the same strength (10 mg) in a bioequivalent formulation. It is approved for use as monotherapy or in combination with other PAH treatments, including phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil or tadalafil, and prostacyclin analogs. Current ESC/ERS guidelines recommend initial combination therapy for most PAH patients, making macitentan an important component of modern PAH treatment strategies.
What Should You Know Before Taking Macitentan AccordPharma?
Before starting macitentan, your doctor must confirm that you are not pregnant (if applicable), check your liver function and hemoglobin levels, and review all other medications you are taking. Macitentan is absolutely contraindicated in pregnancy due to severe teratogenic risks, and certain drug interactions must be carefully managed.
Contraindications
Macitentan must not be used in the following situations:
- Pregnancy: Macitentan is classified as a known teratogen. Animal studies have demonstrated severe birth defects including cardiovascular and mandibular abnormalities. There is no safe dose during pregnancy.
- Women of childbearing potential not using reliable contraception: Women who could become pregnant must use at least one highly effective method of contraception (or two complementary methods) during treatment and for one month after discontinuation.
- Breastfeeding: It is not known whether macitentan is excreted in human breast milk. Due to the potential for serious adverse effects in the nursing infant, breastfeeding must be discontinued before starting treatment.
- Severe hepatic impairment: Patients with severe liver dysfunction (Child-Pugh Class C) must not receive macitentan, as drug metabolism is significantly impaired and the risk of hepatotoxicity is substantially increased.
- Baseline liver aminotransferases >3x ULN: If alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are more than three times the upper limit of normal before treatment, macitentan should not be initiated.
- Hypersensitivity: Known allergy to macitentan or any of the excipients in the formulation.
Warnings and Precautions
Several important warnings apply to treatment with macitentan that both patients and healthcare providers must be aware of:
Hepatotoxicity: Endothelin receptor antagonists as a class have been associated with liver injury. Although macitentan has demonstrated a more favorable hepatic safety profile compared to earlier ERAs such as bosentan, cases of elevated liver enzymes and hepatic injury have been reported. Liver function tests (ALT and AST) should be obtained before initiating therapy and monitored periodically during treatment. If clinically significant liver enzyme elevations occur (exceeding 3 times the upper limit of normal), or if elevations are accompanied by symptoms of liver injury (nausea, vomiting, fever, abdominal pain, jaundice, or unusual fatigue), treatment should be discontinued and not restarted.
Anemia and decreased hemoglobin: Macitentan causes a dose-dependent decrease in hemoglobin concentration. In the SERAPHIN trial, decreases in hemoglobin to below 10 g/dL occurred in 8.7% of patients receiving macitentan 10 mg compared to 3.4% in the placebo group. Hemoglobin levels should be measured before treatment initiation, at months 1 and 3, and periodically thereafter. Treatment initiation is not recommended in patients with severe anemia (hemoglobin <8 g/dL). If a clinically significant decrease in hemoglobin occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
Pulmonary veno-occlusive disease (PVOD): If patients develop signs of pulmonary edema during treatment with macitentan, the possibility of associated PVOD should be considered. If PVOD is confirmed, treatment should be discontinued, as vasodilators may significantly worsen the cardiovascular status of patients with PVOD.
Fluid retention: Peripheral edema is a recognized effect of endothelin receptor antagonists. In the SERAPHIN trial, edema and fluid retention were reported more frequently in the macitentan group. Patients should be monitored for signs of fluid overload, particularly those with underlying right heart failure.
Pregnancy and Breastfeeding
Macitentan is classified in Pregnancy Category X — it must not be used during pregnancy under any circumstances. Preclinical studies in animals have shown that macitentan produces teratogenic effects at all doses tested, including malformations of the head, mouth, face, and large blood vessels. These findings are consistent with the teratogenic effects observed with other endothelin receptor antagonists.
Women of childbearing potential must have a negative pregnancy test (serum or urine beta-hCG) prior to starting treatment, and a pregnancy prevention program should be implemented. Reliable contraception must be used consistently during treatment and for at least one month after the last dose. Monthly pregnancy testing is strongly recommended throughout the duration of therapy. If pregnancy is suspected or confirmed at any point, treatment must be stopped immediately, and the patient should be referred for specialist obstetric counseling regarding the potential risks to the fetus.
There is no data on the presence of macitentan or its metabolites in human breast milk. In animal studies, macitentan and its active metabolite were detected in the milk of lactating rats. Given the potential for serious adverse effects in nursing infants, a decision should be made to either discontinue breastfeeding or discontinue macitentan, taking into account the importance of the drug to the mother. In practice, breastfeeding should be discontinued before starting macitentan.
Fertility: In male patients, endothelin receptor antagonists may affect spermatogenesis. In preclinical studies, macitentan was associated with testicular tubular atrophy in animals at high doses. Male patients should be counseled about this potential effect, although the clinical significance in humans at the therapeutic dose remains uncertain.
How Does Macitentan AccordPharma Interact with Other Drugs?
Macitentan is metabolized primarily by CYP3A4 and CYP2C19 enzymes. Strong CYP3A4 inhibitors increase macitentan exposure, while strong CYP3A4 inducers significantly decrease it. Concomitant use with strong CYP3A4 inducers such as rifampicin is not recommended. Careful dose monitoring is required with other interacting medications.
Understanding drug interactions with macitentan is essential for safe and effective treatment. Macitentan undergoes extensive hepatic metabolism, primarily through cytochrome P450 enzymes CYP3A4 and, to a lesser extent, CYP2C19. The major active metabolite, ACT-132577, is formed via oxidative depropylation and accounts for approximately 40% of the pharmacological activity. Both the parent compound and the active metabolite are highly protein-bound (>99%).
Major Interactions
| Interacting Drug | Effect | Clinical Recommendation |
|---|---|---|
| Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) | Approximately 2-fold increase in macitentan exposure; increased risk of adverse effects | Avoid concomitant use; if unavoidable, close monitoring for adverse effects is required |
| Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John's Wort) | Approximately 79% decrease in macitentan exposure (with rifampicin); significantly reduced efficacy | Concomitant use is not recommended; may render macitentan ineffective |
| Cyclosporine A | Increases macitentan steady-state exposure by approximately 10%; increases active metabolite by approximately 48% | Use with caution; monitor for increased adverse effects, particularly hepatotoxicity |
Minor Interactions and Considerations
| Interacting Drug | Effect | Clinical Recommendation |
|---|---|---|
| Sildenafil (PDE-5 inhibitor) | No clinically significant pharmacokinetic interaction; combination is common in PAH | No dose adjustment needed; combination therapy is standard practice |
| Warfarin | Macitentan does not significantly affect warfarin pharmacokinetics or INR | No dose adjustment needed; routine INR monitoring is still recommended |
| Hormonal contraceptives | Macitentan does not affect the pharmacokinetics of oral contraceptives | No dose adjustment needed; hormonal contraception remains effective |
| Moderate CYP3A4 inhibitors (fluconazole, erythromycin, diltiazem) | May moderately increase macitentan exposure | Use with caution; monitor for adverse effects |
It is important to inform your healthcare provider about all medications you are taking, including prescription drugs, over-the-counter medicines, herbal supplements, and dietary products. Some herbal products, particularly St. John's Wort (Hypericum perforatum), are potent CYP3A4 inducers and can substantially reduce the effectiveness of macitentan. Grapefruit juice, while a mild CYP3A4 inhibitor, is not expected to cause clinically significant interactions at normal consumption levels, but excessive intake should be avoided.
What Is the Correct Dosage of Macitentan AccordPharma?
The recommended dose of Macitentan AccordPharma is one 10 mg tablet taken orally once daily, with or without food. The tablet should be swallowed whole and should not be split, crushed, or chewed. There is only one approved dosage strength for clinical use.
Adults
Standard Adult Dose
The recommended and only approved dose of macitentan for the treatment of PAH in adults is 10 mg once daily. The tablet should be taken at approximately the same time each day. It may be taken with or without food, as food does not significantly affect the bioavailability of macitentan. The tablet should be swallowed whole with water — do not break, crush, or chew the tablet.
There is no dose titration required with macitentan. Unlike some other PAH medications that require gradual dose escalation, macitentan is started at the full therapeutic dose of 10 mg daily from treatment initiation. The efficacy of macitentan was established at this dose in the SERAPHIN trial, which showed significant reduction in the composite endpoint of morbidity and mortality. A lower dose of 3 mg was also studied in the SERAPHIN trial but did not demonstrate a statistically significant benefit on the primary composite endpoint, confirming that 10 mg is the appropriate therapeutic dose.
Treatment with macitentan should be continued for as long as the patient derives clinical benefit. PAH is a chronic, progressive disease, and long-term treatment is typically necessary. In the SERAPHIN trial, the median treatment duration was approximately 115 weeks (over 2 years), and efficacy was maintained throughout the treatment period. Discontinuation of macitentan should be done gradually and under medical supervision, as abrupt cessation of PAH therapy may lead to clinical deterioration.
Special Populations
| Population | Recommended Dose | Notes |
|---|---|---|
| Adults (18+ years) | 10 mg once daily | Standard dose; no titration needed |
| Elderly (≥65 years) | 10 mg once daily | No dose adjustment required based on age alone; clinical experience in patients >75 years is limited |
| Mild hepatic impairment (Child-Pugh A) | 10 mg once daily | No dose adjustment; monitor liver function closely |
| Moderate hepatic impairment (Child-Pugh B) | 10 mg once daily | No dose adjustment; enhanced liver function monitoring recommended |
| Severe hepatic impairment (Child-Pugh C) | Contraindicated | Do not use; insufficient data and increased risk of hepatotoxicity |
| Renal impairment | 10 mg once daily | No dose adjustment needed; limited experience in severe renal impairment or dialysis |
| Children and adolescents (<18 years) | Not recommended | Safety and efficacy have not been established in pediatric patients |
Missed Dose
If you miss a dose of macitentan, take it as soon as you remember on the same day. If you do not remember until the next day, skip the missed dose and take the next dose at your regular scheduled time. Do not take a double dose to make up for a missed dose. If you frequently forget to take your medication, consider setting a daily reminder alarm or using a pill organizer to help maintain adherence. Consistent daily dosing is important for maintaining stable drug levels and optimal therapeutic effect.
Overdose
In the event of an overdose, standard supportive measures should be taken as appropriate. Macitentan is highly protein-bound (>99%), and therefore hemodialysis is unlikely to be effective for removal of the drug from the systemic circulation. There is no specific antidote for macitentan overdose. Symptoms of overdose may include severe hypotension, headache, nausea, vomiting, and potentially liver injury. In clinical studies, single doses of up to 600 mg have been administered to healthy volunteers without life-threatening effects, though headache, nausea, and vomiting were reported. If an overdose is suspected, contact your local poison control center or emergency medical services immediately.
What Are the Side Effects of Macitentan AccordPharma?
Like all medicines, macitentan can cause side effects, although not everybody gets them. The most commonly reported side effects include anemia (decreased hemoglobin), headache, nasopharyngitis, bronchitis, and urinary tract infections. Serious side effects include significant anemia, liver injury, and hypotension.
The safety profile of macitentan has been extensively characterized in clinical trials, most notably the SERAPHIN study involving 742 patients. Side effects are categorized below by frequency, ranging from very common to rare. It is important to report any new or worsening symptoms to your healthcare provider, as some side effects may require dose adjustment, additional treatment, or discontinuation of macitentan.
Very Common
- Anemia or decreased hemoglobin
- Headache
- Nasopharyngitis (common cold symptoms)
- Bronchitis
Common
- Urinary tract infection
- Pharyngitis (sore throat)
- Influenza (flu-like symptoms)
- Peripheral edema (swelling of ankles/legs)
- Hypotension (low blood pressure)
- Nasal congestion
- Elevated liver enzymes (ALT/AST)
- Flushing
Uncommon
- Hepatotoxicity (liver injury)
- Leukopenia (low white blood cell count)
- Allergic reactions (rash, pruritus)
- Symptomatic hypotension (dizziness, fainting)
Rare
- Severe hepatic injury requiring hospitalization
- Severe anemia requiring blood transfusion
- Angioedema
Anemia deserves special attention as it is one of the most clinically significant side effects of macitentan. In the SERAPHIN trial, a decrease in hemoglobin to below 10 g/dL was observed in 8.7% of patients taking macitentan 10 mg, compared to 3.4% of patients receiving placebo. Most cases of hemoglobin decrease occurred within the first few months of treatment and stabilized thereafter. The mechanism is believed to involve both hemodilution (fluid redistribution) and a direct suppressive effect on erythropoiesis. Baseline hemoglobin should be measured before initiating treatment, and monitoring should be performed at 1 month, 3 months, and periodically during treatment. Patients with pre-existing anemia should be managed appropriately before starting macitentan.
Hepatotoxicity: While macitentan has shown a more favorable hepatic safety profile compared to bosentan (another ERA), liver enzyme elevations have been reported. In the SERAPHIN trial, elevations of ALT/AST greater than 3 times the upper limit of normal occurred in 3.4% of macitentan-treated patients compared to 4.5% in the placebo group. Despite this favorable comparison, patients should be aware of symptoms that may indicate liver injury, including unexplained nausea, vomiting, right upper abdominal pain, fatigue, jaundice (yellowing of the skin or eyes), and dark urine. If any of these symptoms occur, seek medical attention immediately.
Edema and fluid retention: Endothelin receptor antagonists can cause fluid retention and peripheral edema. Patients should monitor their weight regularly and report any sudden weight gain, increased swelling of the ankles or legs, or worsening shortness of breath, as these may indicate fluid overload requiring medical attention.
How Should You Store Macitentan AccordPharma?
Store Macitentan AccordPharma at room temperature below 30°C (86°F) in the original packaging to protect from moisture. Keep out of reach and sight of children. Do not use after the expiry date printed on the packaging.
Proper storage of medications is essential to maintain their efficacy and safety throughout the treatment period. Macitentan AccordPharma film-coated tablets should be stored under the following conditions:
- Temperature: Store below 30°C (86°F). Do not freeze. Avoid exposure to excessive heat or direct sunlight.
- Moisture protection: Keep the tablets in the original blister packaging until the time of use to protect from moisture. Do not transfer tablets to pill organizers for extended periods unless used within a few days.
- Child safety: Store in a location that is out of the reach and sight of children. Given the teratogenic potential of macitentan, extra care should be taken to prevent accidental exposure, particularly to women of childbearing potential and pregnant women.
- Expiry date: Do not use the tablets after the expiry date printed on the blister pack and outer carton. The expiry date refers to the last day of that month.
- Disposal: Do not dispose of unused medicines via household waste or wastewater. Return unused or expired tablets to your pharmacy for proper disposal in accordance with local requirements. This helps protect the environment.
If tablets have been exposed to conditions outside the recommended storage parameters (for example, left in a hot car or exposed to significant moisture), do not use them and consult your pharmacist about whether replacement is needed.
What Does Macitentan AccordPharma Contain?
Each Macitentan AccordPharma film-coated tablet contains 10 mg of the active substance macitentan. The tablet also contains inactive ingredients (excipients) that are essential for the manufacturing process, stability, and bioavailability of the medication.
The complete composition of Macitentan AccordPharma 10 mg film-coated tablets includes:
Active substance:
- Macitentan 10 mg per tablet
Tablet core excipients:
- Lactose monohydrate — filler/diluent
- Microcrystalline cellulose — binder and filler
- Sodium starch glycolate — disintegrant to aid tablet dissolution
- Povidone — binder
- Magnesium stearate — lubricant for manufacturing process
- Polysorbate 80 — wetting agent
Film coating:
- Polyvinyl alcohol — film-forming agent
- Titanium dioxide (E171) — opacifier and colorant
- Talc — anti-tack agent
- Lecithin (soya) — emulsifier
- Xanthan gum — viscosity modifier
Appearance: Macitentan AccordPharma 10 mg tablets are white to off-white, round, biconvex film-coated tablets. The tablets are supplied in PVC/PE/PVDC-aluminium blister packs.
Frequently Asked Questions About Macitentan AccordPharma
Macitentan AccordPharma is a generic version that contains the same active substance (macitentan 10 mg) as the originator product. It has been demonstrated to be bioequivalent, meaning it delivers the same amount of active drug into the bloodstream at the same rate. The European Medicines Agency requires generic medicines to meet strict quality, safety, and efficacy standards before approval. The only differences may be in the inactive ingredients (excipients) and the appearance of the tablets, but these do not affect the therapeutic performance of the medicine.
There are no specific interaction studies between macitentan and alcohol. However, both alcohol and macitentan can affect liver function and lower blood pressure. Excessive alcohol consumption may increase the risk of hepatotoxicity and hypotension. It is advisable to limit alcohol intake during treatment and discuss your drinking habits with your doctor. If you experience dizziness, lightheadedness, or nausea, you should avoid alcohol entirely.
Macitentan reaches steady-state plasma concentrations within approximately 3 days of once-daily dosing. However, the full clinical benefit in terms of improved exercise capacity and disease stabilization may take several weeks to months to become apparent. In the SERAPHIN trial, the benefits of treatment were demonstrated over a median follow-up of approximately 115 weeks. PAH treatment is a long-term commitment, and patients should not discontinue treatment due to a lack of immediate improvement without consulting their physician.
Regular monitoring during treatment with macitentan includes: (1) Hemoglobin and hematocrit levels — before starting, at 1 month, 3 months, and periodically thereafter; (2) Liver function tests (ALT, AST) — before starting and during treatment as clinically indicated; (3) Pregnancy tests — monthly for women of childbearing potential; (4) Blood pressure — regular monitoring, especially during initial treatment; (5) Signs and symptoms of fluid retention (weight, edema). Your specialist will determine the exact monitoring schedule based on your clinical situation.
Yes. In fact, current ESC/ERS guidelines recommend combination therapy for most PAH patients. Macitentan is commonly used in combination with phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil or tadalafil. In the SERAPHIN trial, approximately 64% of patients were receiving background PAH therapy, most commonly PDE-5 inhibitors, and the benefit of macitentan was observed regardless of background therapy. Triple combination therapy (ERA + PDE-5 inhibitor + prostacyclin analog) may also be considered in patients with inadequate clinical response to dual therapy.
If you experience side effects, contact your prescribing specialist or PAH nurse for advice. Many common side effects (headache, mild nasal congestion) may improve over time as your body adjusts to the medication. Do not stop taking macitentan without medical advice, as abrupt discontinuation can lead to clinical deterioration. For serious side effects such as signs of liver injury (jaundice, dark urine, abdominal pain), significant shortness of breath, severe swelling, or signs of a serious allergic reaction, seek immediate medical attention. You should also report any side effects to your national adverse drug reaction reporting system.
References and Medical Sources
This article is based on the following peer-reviewed sources and official guidelines:
- 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 (SERAPHIN Trial)
- European Medicines Agency (EMA). Macitentan Summary of Product Characteristics (SmPC). European Public Assessment Report (EPAR). Last updated 2024.
- U.S. Food and Drug Administration (FDA). Macitentan Prescribing Information. Reference ID: 4883542.
- 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.
- 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.
- World Health Organization (WHO). WHO Model List of Essential Medicines. 23rd list, 2023.
- Sidharta PN, van Giersbergen PLM, Halabi A, Dingemanse J. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977-984.
Editorial Team
This article has been written and reviewed by qualified medical professionals with expertise in pulmonology, cardiology, and clinical pharmacology.
Medical Editorial Team
Board-certified specialists in pulmonary medicine, cardiology, and clinical pharmacology. All content follows international guidelines (ESC/ERS, EMA, FDA, WHO) and the GRADE evidence framework.
Medical Review Board
Independent review panel ensuring accuracy, currency, and adherence to evidence-based medicine principles. All claims are verified against primary sources and current guidelines.