Macitentan

Approved Indications:

• Pulmonary Arterial Hypertension (PAH) (WHO Group I):
  Macitentan is indicated for the treatment of pulmonary arterial hypertension (PAH) in adults classified as WHO functional class II–III. It is used to delay disease progression and reduce PAH-related hospitalizations. It may be used as monotherapy or in combination with other PAH therapies such as phosphodiesterase-5 inhibitors or prostanoids.

Clinically Accepted Off-Label Uses:

• PAH associated with congenital heart disease:
  Used in select patients, including those with Eisenmenger syndrome.
• Systemic sclerosis-associated PAH:
  Sometimes used off-label in connective tissue disease-related PAH to improve exercise capacity and delay clinical worsening.

Adults:

• Recommended Dose: 10 mg orally once daily, with or without food.

Pediatrics:

• Safety and efficacy in children have not been established. Not approved for use in pediatric patients.

Elderly:

• No dosage adjustment is required based solely on age, although hepatic and renal functions should be monitored due to age-related changes.

Renal Impairment:

• Mild to moderate impairment: No dosage adjustment needed.
• Severe impairment: Use with caution; clinical data are limited.

Hepatic Impairment:

• Mild impairment (Child-Pugh A): No adjustment needed.
• Moderate to severe impairment (Child-Pugh B or C): Contraindicated due to increased systemic exposure and hepatotoxicity risk.

Route of Administration:

• Oral. Tablets should be swallowed whole once daily.

Duration of Treatment:

• Long-term use, based on clinical evaluation of disease status and treatment response.

Macitentan is a dual endothelin receptor antagonist that selectively inhibits both ETA and ETB receptors. Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen that plays a major role in the pathogenesis of pulmonary arterial hypertension. By preventing ET-1 from binding to its receptors on pulmonary vascular smooth muscle cells, macitentan reduces vasoconstriction, cellular proliferation, fibrosis, and inflammation in the pulmonary vasculature. This results in decreased pulmonary vascular resistance, improved exercise tolerance, and delayed progression of PAH.

• Absorption: Oral bioavailability is approximately 74%. Peak plasma concentrations are reached in about 8 hours after dosing.
• Distribution: Volume of distribution is around 50 L. Macitentan is >99% bound to plasma proteins.
• Metabolism: Extensively metabolized in the liver, primarily by CYP3A4 to form an active metabolite (ACT-132577), which contributes to efficacy.
• Elimination:
• Parent drug half-life: ~16 hours
• Active metabolite half-life: ~48 hours
• Excretion: ~50% via urine and ~25% via feces

• Pregnancy:
  FDA Pregnancy Category X. Contraindicated in pregnancy due to the risk of fetal harm, including birth defects and fetal death. Females of reproductive potential must use highly effective contraception and undergo monthly pregnancy testing during treatment.
• Lactation:
  It is unknown whether macitentan or its metabolites are excreted in human breast milk. Due to the potential for serious adverse effects in infants, breastfeeding is not recommended during macitentan therapy.

• Primary Class: Endothelin Receptor Antagonist (ERA)
• Subclass: Dual ETA/ETB receptor antagonist
• Generation: Second-generation ERA (more selective and longer-acting than earlier agents such as bosentan)

• Known hypersensitivity to macitentan or any of its components
• Pregnancy
• Moderate or severe hepatic impairment (Child-Pugh B or C)
• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole)
• Severe anemia

• Hepatotoxicity: Elevations in liver enzymes may occur. Liver function tests should be monitored before and during treatment. Discontinue if ALT or AST >3x ULN with bilirubin >2x ULN.
• Anemia: A dose-dependent decrease in hemoglobin may occur. Monitor hemoglobin levels before starting and periodically thereafter.
• Fluid Retention: May cause peripheral edema or weight gain. Monitor fluid status, especially in patients with heart failure.
• Teratogenicity: Strict contraception and pregnancy testing required during use. Macitentan is part of a Risk Evaluation and Mitigation Strategy (REMS) in some countries.
• Pulmonary Veno-Occlusive Disease (PVOD): Avoid use in patients suspected of having PVOD due to risk of pulmonary edema.
• Monitoring Requirements:
• Baseline and monthly liver function tests
• Monthly pregnancy tests
• Periodic hemoglobin and hematocrit levels

Common (≥10%):

• Anemia
• Nasopharyngitis
• Headache
• Bronchitis
• Edema
• Fatigue

Less Common but Serious:

• Elevated hepatic transaminases
• Hypotension
• Hepatotoxicity
• Reduced sperm count

Rare:

• Agranulocytosis
• Pulmonary edema (especially in PVOD)
• Severe rash or hypersensitivity reactions

• Strong CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir): Increase macitentan exposure → Avoid concomitant use.
• Strong CYP3A4 Inducers (e.g., rifampin, carbamazepine): Decrease macitentan exposure → Avoid if possible.
• Hormonal Contraceptives: Effectiveness may be reduced; use additional barrier methods.
• Warfarin and other anticoagulants: No significant interaction, but monitor INR if used concurrently.
• Alcohol: May increase risk of liver toxicity and hypotension.

Enzyme Involvement:

• Metabolized primarily via CYP3A4
• Weak inhibitor of CYP2C19

• ESC/ERS Guidelines (2022): Macitentan is recommended as part of initial combination therapy for PAH with improved survival benefits when combined with tadalafil.
• REMS Updates (FDA): Reinforced contraception and pregnancy monitoring requirements under the REMS program.
• Expanded Use in CTD-PAH: Endorsement of macitentan in systemic sclerosis-associated PAH based on new data demonstrating long-term efficacy and safety.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions allowed between 15°C and 30°C.
• Humidity & Light: Protect from moisture and direct light.
• Handling Instructions:
• Store in the original package.
• Keep out of reach of children.
• No refrigeration or shaking required.
• Do not crush or split tablets.