Macitentan

The standard recommended dosage for macitentan in adults is 10 mg taken orally once daily.

Clinical trials, specifically the SERAPHIN study, evaluated both 3 mg and 10 mg doses. While both doses showed efficacy compared to placebo, the 10 mg dose demonstrated a more robust effect on reducing the risk of morbidity and mortality events. Consequently, 10 mg has become the global standard dose. There is generally no need for dose titration (starting low and increasing); patients typically start and remain on the 10 mg dose unless side effects require a change in management.

The safety and effectiveness of macitentan in pediatric patients (under the age of 18) have not been fully established. While some off-label use may occur in specialized pediatric pulmonary centers, macitentan is not currently FDA-approved for use in children. Clinical trials in pediatric populations are ongoing to determine appropriate weight-based dosing and safety profiles.

Renal Impairment

No dosage adjustment is required for patients with renal impairment, including those with severe renal impairment. Macitentan has not been extensively studied in patients undergoing dialysis, so caution is advised in this specific sub-population.

Hepatic Impairment

No dosage adjustment is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, macitentan has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Because other drugs in this class have been associated with liver injury, macitentan is generally not recommended for use in patients with severe hepatic impairment or those with elevated liver transaminases (greater than 3 times the upper limit of normal) prior to starting treatment.

Elderly Patients

No overall differences in safety or effectiveness have been observed between patients over 65 and younger patients. No dose adjustment is necessary based solely on age, although clinicians should be mindful of the higher frequency of decreased hepatic, renal, or cardiac function in the elderly.

• Consistency: Take macitentan at the same time every day to maintain steady levels of the drug in your bloodstream.
• With or Without Food: Macitentan can be taken with or without food. Taking it with a meal may help if you experience mild stomach upset.
• Administration: Swallow the tablet whole. Do not crush, chew, or break the tablet, as this may affect how the drug is absorbed and could increase the risk of side effects.
• Storage: Store the medication at room temperature (20°C to 25°C or 68°F to 77°F) in its original container to protect it from moisture.

If you miss a dose of macitentan, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and return to your regular schedule. Do not take two doses at once to make up for a missed one. If you miss multiple doses, contact your healthcare provider for guidance, as consistency is vital for managing PAH.

Symptoms of macitentan overdose may include severe headache, nausea, vomiting, or a significant drop in blood pressure (hypotension).

In the event of an overdose:

1. 1Contact your local Poison Control Center or seek emergency medical attention immediately.
2. 2Provide the medical team with the exact dose taken and the time of ingestion.
3. 3Treatment is generally supportive, as there is no specific antidote for macitentan. Because macitentan is highly protein-bound, dialysis is unlikely to be effective in removing the drug from the system.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking this medication without medical guidance, as sudden discontinuation can lead to a rapid worsening of pulmonary hypertension symptoms.

In clinical trials, the following side effects were reported most frequently by patients taking macitentan:

• Anemia (Low Red Blood Cell Count): This is a known class effect of endothelin receptor antagonists. It typically occurs within the first few weeks of treatment. You may feel more tired than usual, short of breath, or pale. Your doctor will monitor your hemoglobin levels via blood tests.
• Nasopharyngitis and Pharyngitis: Inflammation of the nose and throat, similar to a common cold. Symptoms include a runny nose, sneezing, and sore throat.
• Bronchitis: Inflammation of the bronchial tubes, which may cause a persistent cough and mucus production.
• Headache: Often described as a dull ache or pressure. This usually improves as the body adjusts to the medication.
• Influenza (Flu): Patients may be more susceptible to viral respiratory infections while on macitentan.
• Urinary Tract Infection (UTI): Symptoms include a frequent urge to urinate or a burning sensation during urination.

• Edema (Fluid Retention): Swelling of the ankles, feet, or legs. This is common in PAH patients but can be exacerbated by macitentan. It may require the initiation or adjustment of diuretic therapy (water pills).
• Hypotension (Low Blood Pressure): This may cause dizziness or lightheadedness, especially when standing up quickly.
• Nasal Congestion: A feeling of 'stuffiness' in the nose without other cold symptoms.

• Hypersensitivity Reactions: Rare cases of rash, itching, or swelling of the face and tongue.
• Sperm Count Reduction: In studies of similar drugs, a decrease in sperm count was observed. It is possible that macitentan may affect male fertility.

> Warning: Stop taking Macitentan and call your doctor immediately if you experience any of these symptoms.

• Signs of Liver Injury: While macitentan has a lower incidence of liver toxicity than older drugs in its class, it can still cause liver problems. Watch for yellowing of the skin or eyes (jaundice), dark urine, severe pain in the upper right stomach, or unusual nausea and vomiting.
• Severe Anemia: If you experience extreme fatigue, fainting, or a rapid heart rate, your hemoglobin may have dropped significantly.
• Pulmonary Edema (Fluid in the Lungs): If you experience sudden, severe shortness of breath, especially when lying flat, it may be a sign of pulmonary veno-occlusive disease (PVOD). If PVOD is confirmed, macitentan must be discontinued.
• Severe Fluid Retention: Rapid weight gain (e.g., more than 3-5 pounds in a few days) or severe swelling that interferes with movement.

• Hepatotoxicity Monitoring: Long-term use requires periodic monitoring of liver enzymes to ensure the drug is not causing cumulative damage to the liver.
• Hemoglobin Stability: Most decreases in hemoglobin occur early, but long-term monitoring is necessary to ensure levels remain within a safe range for heart function.
• Potential for Decreased Fertility: Men should be aware that long-term use of ERAs has been linked to decreased sperm counts in some clinical observations.

Macitentan carries a Black Box Warning for Embryo-Fetal Toxicity.

Summary of Warning:

• Do not use macitentan during pregnancy because it can cause major birth defects.
• Pregnancy must be excluded before starting treatment, monthly during treatment, and for one month after stopping treatment.
• Females of reproductive potential must use highly effective contraception during treatment and for one month after the final dose.
• Because of these risks, macitentan is only available through the Macitentan REMS program.

Report any unusual symptoms to your healthcare provider immediately. Regular blood work is a standard part of macitentan therapy to catch side effects before they become serious.

Macitentan is a high-risk medication that requires careful clinical supervision. It is exclusively indicated for Pulmonary Arterial Hypertension (PAH) and should not be used for other forms of high blood pressure. Patients must be enrolled in the REMS program to receive the drug. It is vital to never share this medication with others, especially women of childbearing age, due to the extreme risk of birth defects.

EMBRYO-FETAL TOXICITY: Macitentan is contraindicated in pregnancy. In animal studies, macitentan was found to be teratogenic (causing birth defects) even at low doses. For all female patients of reproductive potential, a negative pregnancy test is required before initiation. Monthly pregnancy tests are mandatory throughout the duration of treatment. Patients must commit to using acceptable forms of contraception (such as an IUD, tubal sterilization, or a combination of hormonal and barrier methods) while taking macitentan.

• Hepatotoxicity (Liver Toxicity): Although macitentan did not show significant liver enzyme elevations in the SERAPHIN trial, other endothelin receptor antagonists (like bosentan) are known to cause liver injury. Healthcare providers should obtain liver enzyme tests (ALT and AST) and bilirubin levels before starting macitentan and repeat them as clinically indicated.
• Fluid Retention: Peripheral edema and fluid retention are known effects of ERAs. If clinically significant fluid retention develops, with or without weight gain, the cause must be determined (e.g., macitentan use or underlying heart failure) and treated appropriately with diuretics.
• Hemoglobin Reduction: Decreases in hemoglobin concentration and hematocrit have occurred. These decreases usually happen within the first weeks of therapy and then stabilize. Monitoring is recommended at baseline and periodically thereafter.
• Pulmonary Veno-Occlusive Disease (PVOD): If signs of pulmonary edema occur when starting macitentan, the physician should consider the possibility of associated PVOD. If confirmed, the drug should be stopped immediately as it can worsen the condition.
• Decreased Sperm Counts: Macitentan, like other ERAs, may have an adverse effect on spermatogenesis. Male patients should be counseled about potential effects on fertility.

Patients on macitentan require a structured monitoring schedule:

1. 1Pregnancy Tests (Females of Reproductive Potential): Monthly.
2. 2Hemoglobin/Hematocrit: Baseline, at 1 month, and periodically thereafter (e.g., every 3-6 months).
3. 3Liver Function Tests (ALT/AST/Bilirubin): Baseline and when symptoms of liver injury occur.
4. 4Weight and Edema: Regular self-monitoring for sudden weight gain or swelling.

Macitentan generally does not interfere with the ability to drive or operate machinery. However, since PAH itself can cause dizziness or fainting (syncope), and macitentan can occasionally cause low blood pressure or headaches, patients should assess their reaction to the medication before engaging in these activities.

There is no direct pharmacological interaction between macitentan and alcohol. However, alcohol can cause vasodilation and lower blood pressure, which may compound the blood-pressure-lowering effects of macitentan. Excessive alcohol use can also strain the liver, which is a concern for patients on ERAs. Moderation is advised.

Do not stop taking macitentan abruptly. Abrupt withdrawal of PAH medications can lead to "rebound" pulmonary hypertension, where the blood pressure in the lungs rises rapidly, potentially leading to a life-threatening crisis. If the drug must be stopped, it should be done under the strict supervision of a cardiologist or pulmonologist.

> Important: Discuss all your medical conditions, including any history of liver disease or anemia, with your healthcare provider before starting Macitentan.

• Strong CYP3A4 Inducers: Drugs like Rifampin, St. John's Wort, Phenytoin, and Carbamazepine should be avoided. These substances significantly increase the activity of the enzyme that breaks down macitentan. This leads to a dramatic reduction in macitentan blood levels (up to 80% reduction), making the treatment ineffective and increasing the risk of PAH progression.

• Strong CYP3A4 Inhibitors: Medications such as Ketoconazole, Itraconazole, Ritonavir, and Clarithromycin can increase the exposure to macitentan. While a dose adjustment is not always mandatory, the risk of side effects (like anemia and edema) increases significantly. Patients on these combinations should be monitored closely for signs of toxicity.
• Other PAH Medications: When used with other vasodilators (like Sildenafil or Nitrates), there is an additive effect on lowering blood pressure. While often used intentionally in combination therapy, it requires careful monitoring for symptomatic hypotension (dizziness).

• Moderate CYP3A4 Inhibitors/Inducers: Drugs like erythromycin or fluconazole may slightly alter macitentan levels. Most patients tolerate these combinations well, but clinical monitoring is advised.
• Hormonal Contraceptives: While macitentan does not significantly reduce the efficacy of oral contraceptives (unlike bosentan), the absolute requirement for pregnancy prevention means patients should still discuss their specific birth control method with their doctor to ensure maximum protection.

• Grapefruit Juice: Grapefruit is a known inhibitor of CYP3A4. Consuming large amounts of grapefruit or grapefruit juice may increase the levels of macitentan in the blood, potentially increasing the risk of side effects. It is generally best to avoid large quantities of grapefruit while on this medication.
• High-Fat Meals: Clinical studies show that high-fat meals do not significantly change the absorption of macitentan. It can be taken safely with any type of meal.

• St. John’s Wort: As a potent inducer of CYP3A4, this herbal supplement can lower macitentan levels to sub-therapeutic ranges. It should be strictly avoided.
• Garlic/Ginkgo/Ginseng: These supplements may have mild blood-thinning or vasodilatory effects. While not strictly contraindicated, patients should inform their doctor if they use them regularly.

Macitentan does not typically interfere with standard laboratory chemistry or imaging tests. However, it will cause a predictable decrease in Hemoglobin and Hematocrit values on a Complete Blood Count (CBC). Clinicians should be aware that these changes are drug-induced and not necessarily indicative of internal bleeding.

Mechanism of Interactions

The primary mechanism for macitentan interactions is the CYP3A4 enzymatic pathway. Because macitentan relies on this enzyme for both its clearance and the formation of its active metabolite, any substance that 'speeds up' (induces) or 'slows down' (inhibits) this enzyme will directly impact how much medicine is in the patient's body.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter cold medicines and vitamins.

Macitentan must NEVER be used in the following circumstances:

1. 1Pregnancy: Macitentan is highly teratogenic. It can cause severe birth defects or fetal death. This is an absolute contraindication with no exceptions. Any woman who becomes pregnant must stop the drug immediately and contact her doctor.
2. 2Hypersensitivity: Patients with a known severe allergy to macitentan or any of the inactive ingredients in the tablet (such as lactose, microcrystalline cellulose, or magnesium stearate) must not take the drug. Signs of hypersensitivity include angioedema (swelling of the face/throat) and anaphylaxis.
3. 3Severe Hepatic Impairment: Patients with Child-Pugh Class C liver disease should not use macitentan, as the drug's safety has not been established in this group and the risk of further liver injury is high.

These conditions require a careful risk-benefit analysis by a specialist:

• Pre-existing Anemia: If a patient has a very low hemoglobin level before starting (e.g., < 10 g/dL), the doctor may choose to treat the anemia first, as macitentan will likely lower the level further.
• Pulmonary Veno-Occlusive Disease (PVOD): If a patient is suspected of having PVOD, ERAs like macitentan can cause life-threatening pulmonary edema. Use is generally avoided unless the diagnosis of PAH is certain.
• Severe Hypotension: In patients with very low baseline blood pressure, the vasodilatory effects of macitentan could lead to fainting or compromised organ perfusion.

There is a theoretical risk of cross-sensitivity between different endothelin receptor antagonists. If a patient had a severe allergic reaction to Bosentan (Tracleer) or Ambrisentan (Letairis), they should be monitored with extreme caution if starting macitentan, or an alternative class of medication should be considered.

> Important: Your healthcare provider will evaluate your complete medical history, including liver function and pregnancy status, before prescribing Macitentan.

Macitentan is classified as Pregnancy Category X (under the older system) and carries a high risk of embryo-fetal toxicity.

• Teratogenicity: Animal studies showed cardiovascular and facial malformations in offspring.
• Mandatory REMS: All females, regardless of whether they believe they can get pregnant, must be assessed for "reproductive potential." Those who can get pregnant must have a negative pregnancy test every single month to receive their refill.
• Contraception: Two forms of reliable contraception are required unless an IUD or tubal ligation is present.

It is not known whether macitentan or its metabolites pass into human breast milk. However, because many drugs are excreted in milk and because of the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended while taking macitentan. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Macitentan is not approved for use in patients under 18 years of age. While PAH does occur in children, the safety and efficacy of macitentan in this population are still being studied in clinical trials (such as the TOMORROW study). Pediatric dosing is not standardized and should only be managed by a pediatric PAH specialist.

In the SERAPHIN trial, approximately 14% of patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. However, elderly patients are more likely to have decreased hepatic or renal function and may be taking other medications (polypharmacy), increasing the risk of drug interactions. No specific dose adjustment is needed, but close monitoring for fluid retention is advised.

• Mild to Severe: No dose adjustment is required. The pharmacokinetics of macitentan are not significantly altered by kidney function.
• End-Stage Renal Disease (ESRD): There is limited data for patients on dialysis. Use should be approached with caution in this group.

• Mild to Moderate (Child-Pugh A/B): No dose adjustment is required.
• Severe (Child-Pugh C): Use is not recommended.
• Baseline Elevations: Macitentan should not be started if liver transaminases (ALT/AST) are > 3 times the upper limit of normal.

> Important: Special populations require individualized medical assessment. Always inform your specialist about your plans for pregnancy or any changes in your kidney or liver health.

Macitentan is a non-peptide, potent, dual endothelin receptor antagonist (ERA). It works by competitively inhibiting the binding of endothelin-1 (ET-1) to both Endothelin-A ($ET_A$) and Endothelin-B ($ET_B$) receptors.

• $ET_A$ Receptors: Located primarily on vascular smooth muscle cells; their activation causes potent vasoconstriction and cell proliferation.
• $ET_B$ Receptors: Located on both endothelial cells (where they mediate ET-1 clearance and the release of nitric oxide) and smooth muscle cells (where they cause vasoconstriction).

By blocking these receptors, macitentan prevents the harmful effects of excess ET-1, leading to vasodilation in the pulmonary arteries and preventing the structural remodeling of the blood vessels.

Macitentan shows high affinity and sustained occupancy of the endothelin receptors in human pulmonary arterial smooth muscle cells. The clinical effect is a decrease in pulmonary vascular resistance (PVR) and an increase in cardiac index. Unlike some other ERAs, macitentan has high lipophilicity, which allows it to penetrate deeply into the vascular tissues where the receptors are located. This results in a long duration of action, supporting its once-daily efficacy.

| Parameter | Value |

|---|---|

| Bioavailability | ~74% (estimated) |

| Protein Binding | >99% (Albumin) |

| Half-life | 16 hours (Parent) / 48 hours (Metabolite) |

| Tmax | 8 hours |

| Metabolism | CYP3A4 (Major), CYP2C19 (Minor) |

| Excretion | Renal 50%, Fecal 24% |

• Molecular Formula: $C_{19}H_{20}Br_2N_6O_4S$
• Molecular Weight: 588.27 g/mol
• Solubility: Insoluble in water; slightly soluble in methanol and ethanol.
• Structure: It is a sulfamide derivative. The presence of the bromine atoms and the specific sulfamide structure contributes to its high potency and tissue distribution properties.

Macitentan is classified as an Endothelin Receptor Antagonist [EPC]. It is part of a therapeutic class used specifically for pulmonary hypertension. Other drugs in this class include Bosentan and Ambrisentan. Macitentan is distinguished by its dual antagonism and its specific pharmacokinetic profile that allows for once-daily dosing without the frequent liver monitoring required by some older ERAs.