Macitentan Newbury: Uses, Dosage & Side Effects

What Is Macitentan Newbury and What Is It Used For?

Macitentan Newbury contains the active substance macitentan, a dual endothelin receptor antagonist designed specifically for the treatment of pulmonary arterial hypertension (PAH). PAH is a serious, progressive, and life-threatening condition characterized by abnormally elevated 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 these arteries become thickened, stiff, and narrowed due to a combination of vasoconstriction, vascular smooth muscle cell proliferation, fibrosis, and in situ thrombosis. This progressive remodeling leads to a dramatic increase in pulmonary vascular resistance, which in turn forces the right ventricle to work significantly harder to pump blood through the lungs. Over time, this increased workload leads to right ventricular hypertrophy, dysfunction, and ultimately right heart failure.

The endothelin system plays a central role in the pathogenesis of PAH. Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known in human physiology. In healthy individuals, ET-1 is produced primarily by endothelial cells and acts on two receptor subtypes: ETA receptors (found predominantly on vascular smooth muscle cells, mediating vasoconstriction and cell proliferation) and ETB receptors (found on both endothelial cells, where they promote vasodilation via nitric oxide and prostacyclin release, and on smooth muscle cells, where they also mediate vasoconstriction). In patients with PAH, the endothelin system is markedly upregulated: plasma ET-1 concentrations are elevated, ET-1 immunoreactivity is increased in the pulmonary vasculature, and the balance of ETA/ETB receptor expression is altered. These changes contribute to sustained vasoconstriction, vascular remodeling, and fibrosis in the pulmonary circulation.

Macitentan was designed as a next-generation dual endothelin receptor antagonist with several pharmacological advantages over earlier agents in this class. It competitively blocks the binding of ET-1 to both ETA and ETB receptors with high affinity and sustained receptor binding properties. Tissue distribution studies have demonstrated that macitentan achieves high concentrations in pulmonary tissue, which is pharmacologically important for maximizing efficacy at the site of disease. Unlike bosentan, the first oral ERA approved for PAH, macitentan shows sustained receptor occupancy, meaning it remains bound to the endothelin receptors for a prolonged period, providing a more consistent pharmacological blockade throughout the dosing interval.

After oral administration, macitentan is extensively metabolized in the liver, primarily by cytochrome P450 enzyme CYP3A4 (with a minor contribution from CYP2C19), to form its major active metabolite, ACT-132577. This active metabolite is approximately 5-fold less potent than the parent compound at endothelin receptors but has a much longer half-life (approximately 48 hours compared with approximately 16 hours for macitentan), meaning it contributes meaningfully to the overall pharmacological effect. Steady-state plasma concentrations are reached by approximately day 3 for macitentan and by day 7 for ACT-132577.

Macitentan Newbury is indicated for the long-term treatment of PAH in adult patients of WHO functional class (FC) II to III, as monotherapy or in combination with other PAH-specific therapies. WHO functional class II describes patients with PAH who have slight limitation of physical activity — ordinary physical activity causes undue breathlessness, fatigue, chest pain, or near-syncope. WHO functional class III describes patients with marked limitation of physical activity, where less than ordinary activity causes these symptoms. The goal of macitentan therapy is to slow disease progression, reduce the risk of clinical worsening events (including hospitalizations), and improve or stabilize exercise capacity.

What Should You Know Before Taking Macitentan Newbury?

Before initiating treatment with Macitentan Newbury, your prescribing physician will conduct a thorough evaluation to ensure the medication is appropriate and safe for you. This evaluation typically includes a review of your medical history, current medications, liver function tests, hemoglobin levels, and — for women of childbearing potential — a pregnancy test. Understanding the contraindications, warnings, and precautions associated with macitentan is essential for safe and effective use of this medication.

Contraindications

Macitentan Newbury must not be used in the following situations:

• Pregnancy: Macitentan is classified as a known human teratogen. Animal studies have demonstrated severe embryo-fetal toxicity, including cardiovascular malformations (ventricular septal defects, abnormalities of the aortic arch) and mandibular/facial malformations at clinically relevant doses. Macitentan must not be initiated in pregnant women, and pregnancy must be excluded before starting treatment.
• Breastfeeding: It is not known whether macitentan or its active metabolite is excreted in human breast milk. Given the potential for serious adverse effects in breastfed infants, breastfeeding is contraindicated during treatment with macitentan.
• Severe hepatic impairment: Macitentan is extensively metabolized by the liver. In patients with severe hepatic impairment (Child-Pugh class C), systemic exposure to macitentan is significantly altered, and the drug should not be used.
• Hypersensitivity: Patients with a known hypersensitivity to macitentan, soy (the formulation contains soya lecithin), or any of the excipients should not take this medication.
• Baseline elevated aminotransferases: Treatment should not be initiated if baseline hepatic aminotransferases (AST and/or ALT) are greater than 3 times the upper limit of normal (ULN).

Warnings and Precautions

Several important warnings and precautions apply to the use of macitentan:

Hepatotoxicity: Elevations of liver aminotransferases (ALT and AST) have been observed in patients treated with endothelin receptor antagonists as a class. Although hepatotoxicity was not a prominent finding in the SERAPHIN trial for macitentan, cases of liver injury have been reported in post-marketing surveillance. Liver function tests should be performed before initiating treatment and should be repeated during treatment as clinically indicated. If aminotransferases rise above 3 times the ULN, or if elevations are accompanied by signs or symptoms of liver injury (such as jaundice, nausea, vomiting, fever, abdominal pain, or unusual fatigue), macitentan should be discontinued and not restarted unless another cause can be identified.

Anemia and hemoglobin decrease: Treatment with macitentan has been associated with a decrease in hemoglobin concentration. In the SERAPHIN trial, the incidence of a marked decrease in hemoglobin (>5 g/dL from baseline to <10 g/dL) was 8.7% in the macitentan 10 mg group compared with 3.4% in the placebo group. In most cases, the hemoglobin decrease occurred within the first few months of treatment and stabilized thereafter. Hemoglobin should be measured before initiation of treatment, after 1 month of treatment, and periodically thereafter. Initiation of treatment is not recommended in patients with severe anemia. If clinically significant anemia develops during treatment, appropriate evaluation and management are required.

Fluid retention and edema: Peripheral edema is a known class effect of endothelin receptor antagonists. In the SERAPHIN trial, edema was reported more frequently in macitentan-treated patients than in the placebo group. Patients should be monitored for signs and symptoms of fluid retention, particularly those with underlying heart failure or renal impairment. If clinically significant fluid retention develops, appropriate measures including diuretic therapy should be implemented.

Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur during treatment with macitentan, the possibility of associated PVOD should be considered. Should confirmatory investigations reveal PVOD, macitentan should be discontinued.

Pregnancy and Breastfeeding

Macitentan is classified as Pregnancy Category X (contraindicated in pregnancy) in the United States. In the European Union, it is contraindicated in women who are pregnant or who could become pregnant unless appropriate contraceptive measures are in place. The pregnancy prevention program for endothelin receptor antagonists requires that women of childbearing potential use at least one reliable method of contraception (preferably two methods), undergo pregnancy testing before treatment initiation and monthly during treatment, and receive counseling about the risks of pregnancy during therapy.

It is not known whether macitentan or its active metabolite ACT-132577 is excreted in human breast milk. In animal studies, macitentan and its metabolites were detected in the milk of lactating rats. Because of the potential risk to the breastfed infant, breastfeeding should be discontinued before initiating macitentan treatment.

Fertility: In male patients, endothelin receptor antagonists as a class have been associated with testicular atrophy and reduced spermatogenesis in animal studies. In the SERAPHIN trial, there were no significant differences in testosterone levels or semen parameters between treatment groups; however, the number of patients evaluated was limited. Male patients should be informed of these potential effects.

How Does Macitentan Newbury Interact with Other Drugs?

Understanding drug interactions is critical when prescribing macitentan, as the drug is extensively metabolized by the hepatic cytochrome P450 enzyme system. The primary enzyme responsible for macitentan metabolism is CYP3A4, with a minor contribution from CYP2C19. Co-administration of drugs that significantly alter CYP3A4 activity can substantially change macitentan plasma concentrations, potentially affecting both efficacy and safety.

Major Interactions

The following drug interactions are considered clinically significant and require either avoidance or dose adjustment:

Minor Interactions and Commonly Co-administered Drugs

Macitentan can generally be safely combined with the following medications commonly used in the management of PAH and associated comorbidities:

Unlike bosentan (a first-generation ERA), macitentan is not a clinically significant inducer of CYP enzymes at therapeutic concentrations. This means that macitentan is less likely to reduce the effectiveness of co-administered medications that are metabolized by CYP enzymes, including hormonal contraceptives. However, as a precaution, the use of at least one reliable contraceptive method is still required for women of childbearing potential taking macitentan, and dual contraception is recommended in many guidelines.

Macitentan is a substrate of organic anion transporting polypeptide (OATP) transporters. In vitro studies have shown that macitentan and its active metabolite ACT-132577 are neither significant inhibitors nor inducers of CYP enzymes or drug transporters (P-glycoprotein, OATP, BCRP) at clinically relevant concentrations. This favorable pharmacokinetic profile simplifies the management of PAH patients who typically require multiple concomitant medications.

What Is the Correct Dosage of Macitentan Newbury?

Macitentan Newbury should be taken as one 10 mg film-coated tablet once daily, swallowed whole with water. The tablet can be taken with or without food, as food does not significantly affect the bioavailability of macitentan. It is recommended to take the medication at approximately the same time each day to maintain consistent plasma levels. Treatment should be initiated and supervised by a physician experienced in the management of pulmonary arterial hypertension.

Adults

In the SERAPHIN trial, patients were randomized to receive macitentan 3 mg, 10 mg, or placebo. Only the 10 mg dose demonstrated a statistically significant reduction in the primary composite morbidity/mortality endpoint. For this reason, the 10 mg dose is the only approved dosage strength and the only recommended dose for PAH treatment. There is no evidence supporting dose escalation or dose reduction as therapeutic strategies.

Children

The safety and efficacy of macitentan in children and adolescents (under 18 years of age) have not been established. There are currently no data available from clinical trials in pediatric PAH patients. Macitentan Newbury is therefore not recommended for use in pediatric patients. Ongoing pediatric investigation plans may provide future data to inform potential pediatric use.

Elderly

No dose adjustment is required in elderly patients (65 years and older). In the SERAPHIN trial, approximately 14% of patients were aged 65 years or older, and no significant differences in safety or efficacy were observed in this subgroup compared with younger patients. However, as with all medications in elderly patients, treatment should be initiated with appropriate monitoring, taking into account the higher frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in this population.

Renal and Hepatic Impairment

Missed Dose

If you forget to take a dose of Macitentan Newbury, 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 scheduled dose at your regular time. Do not take a double dose to make up for a missed one. If you are unsure what to do, contact your doctor or pharmacist for advice. It is helpful to set a daily reminder or associate taking the tablet with a regular daily activity (such as brushing your teeth or eating breakfast) to help ensure consistent adherence.

Overdose

In clinical pharmacology studies, single doses of macitentan up to 600 mg (60 times the therapeutic dose) were administered to healthy volunteers. The primary effect observed was headache. In the event of an overdose, standard supportive measures should be taken as needed. Due to its high plasma protein binding, macitentan is unlikely to be significantly removed by dialysis. If overdose is suspected, contact your local poison control center or emergency department immediately.

What Are the Side Effects of Macitentan Newbury?

Like all medicines, Macitentan Newbury can cause side effects, although not everybody gets them. The safety profile of macitentan has been well characterized in the SERAPHIN trial and post-marketing surveillance involving thousands of patients worldwide. The side effects listed below are based on data from clinical trials and real-world experience. Most side effects are mild to moderate in severity and often resolve with continued treatment or appropriate management.

The frequency of side effects is categorized using standard medical terminology: very common (affects more than 1 in 10 people), common (affects 1 in 10 to 1 in 100 people), uncommon (affects 1 in 100 to 1 in 1,000 people), and rare (affects fewer than 1 in 1,000 people).

Anemia — A Key Class Effect

Anemia is one of the most clinically significant side effects of macitentan and endothelin receptor antagonists as a class. In the SERAPHIN trial, a decrease in hemoglobin to below 10 g/dL was reported in 13.2% of patients receiving macitentan 10 mg compared with 3.2% in the placebo group. The decrease in hemoglobin typically occurs within the first few months of treatment and generally stabilizes thereafter. The mechanism is thought to involve both hemodilution (due to fluid retention) and direct effects on erythropoiesis. Hemoglobin and hematocrit levels should be checked before starting treatment, at 1 month, and then at regular intervals (typically every 3 months) during treatment. If hemoglobin falls below 8 g/dL or if the patient develops symptomatic anemia, further evaluation (including iron studies and reticulocyte count) and management (iron supplementation, erythropoiesis-stimulating agents, or, in severe cases, transfusion) may be necessary.

Liver Safety

Although macitentan is associated with a lower rate of clinically significant hepatotoxicity compared with bosentan, liver function monitoring remains important. In the SERAPHIN trial, elevated aminotransferases (>3 times ULN) were reported in 3.4% of patients on macitentan 10 mg versus 4.5% on placebo, suggesting that the hepatotoxicity risk with macitentan is relatively low. However, post-marketing cases of hepatic injury have been reported, and periodic liver function testing is recommended, especially during the first year of treatment and whenever clinically indicated (e.g., if the patient develops symptoms suggestive of liver dysfunction).

When to Seek Medical Attention

You should contact your doctor or seek immediate medical attention if you experience any of the following while taking Macitentan Newbury:

• Unusual fatigue, weakness, shortness of breath, or pallor (could indicate significant anemia)
• Yellowing of the skin or eyes (jaundice), dark urine, or persistent abdominal pain (could indicate liver injury)
• Sudden worsening of breathing, development of pulmonary edema, or rapid weight gain with edema
• Signs of infection that are severe or persistent (high fever, productive cough, painful urination)
• Allergic reactions such as rash, hives, facial swelling, or difficulty breathing
• A positive pregnancy test while on treatment

How Should You Store Macitentan Newbury?

Proper storage of Macitentan Newbury ensures the medication maintains its potency and safety throughout its shelf life. Film-coated tablets should be stored at room temperature, not exceeding 30°C (86°F). The tablets should be kept in their original blister packaging until use to protect them from moisture and light. Do not store in the bathroom or near a kitchen sink where humidity may be high.

Keep the medication in a secure location out of the sight and reach of children and pets. Due to the serious teratogenic risk of macitentan, it is particularly important to prevent accidental exposure of pregnant women or women who may become pregnant. If the film coating of any tablet appears damaged, discolored, or if the tablet shows signs of deterioration, do not take it and consult your pharmacist.

Do not use Macitentan Newbury after the expiry date (EXP) printed on the carton and blister packaging. The expiry date refers to the last day of that month. Do not dispose of medications via wastewater or household waste. Return any unused or expired tablets to your pharmacy for proper disposal, in accordance with local environmental regulations. This helps protect the environment from pharmaceutical contamination.

What Does Macitentan Newbury Contain?

Each Macitentan Newbury film-coated tablet contains:

Active ingredient: Macitentan 10 mg per tablet.

Tablet core excipients: The inactive ingredients in the tablet core typically include lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone, magnesium stearate, and polysorbate 80. Soya lecithin may be included as a wetting agent. These excipients serve various pharmaceutical functions including binding, disintegration, lubrication, and ensuring uniform drug distribution within the tablet.

Film coating: The film coating typically contains polyvinyl alcohol, titanium dioxide (E171), talc, soya lecithin, and xanthan gum. The film coat provides the tablet with an even surface for ease of swallowing, protection from moisture, and contributes to the tablet's appearance and identification.

Tablet appearance: Macitentan Newbury 10 mg tablets are round, biconvex, white to off-white film-coated tablets, debossed with identification markings on one side. The tablets are supplied in blister packs contained within a cardboard carton.