Usage
- Macitentan is prescribed for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults and children weighing at least 40 kg. It is used to delay disease progression and reduce the risk of hospitalization for PAH.
- Pharmacological classification: Endothelin Receptor Antagonist (ERA)
- Mechanism of action: Macitentan competitively and reversibly antagonizes endothelin-1 (ET-1) at both endothelin A (ETA) and endothelin B (ETB) receptors. ET-1 is a potent vasoconstrictor and smooth muscle mitogen that plays a key role in the pathogenesis of PAH. By blocking the binding of ET-1 to its receptors, macitentan prevents the vasoconstricting and proliferative effects of ET-1, thereby decreasing pulmonary vascular resistance and improving pulmonary hemodynamics.
Alternate Names
- International Nonproprietary Name (INN): Macitentan
- Brand Name: Opsumit, Opsynvi (in combination with tadalafil)
How It Works
- Pharmacodynamics: Macitentan lowers pulmonary arterial pressure and pulmonary vascular resistance by blocking the effects of endothelin-1. This leads to improved cardiac output and exercise tolerance in PAH patients.
- Pharmacokinetics: Macitentan is administered orally and is absorbed well. It is extensively metabolized primarily by CYP3A4 with minor contributions from CYP2C9 and other hepatic enzymes. The major metabolic pathway involves oxidation and dealkylation. The primary route of elimination is via the feces. The half-life is approximately 16 hours.
- Mode of action: Macitentan competitively inhibits the binding of ET-1 to ETA and ETB receptors on vascular smooth muscle cells, leading to vasodilation.
- Receptor binding: Binds to ETA and ETB receptors.
- Enzyme inhibition: Does not significantly inhibit or induce CYP enzymes at clinical doses.
- Elimination pathways: Primarily hepatic metabolism followed by biliary/fecal excretion. Minor renal elimination.
Dosage
Standard Dosage
Adults:
- 10 mg once daily orally. No titration is required. It can be taken with or without food.
Children:
- For children weighing at least 40 kg, the recommended dose is 10 mg once daily.
- Children less than 40 kg require dose adjustment based on their body weight, ideally under expert clinical advice. Dispersible tablets of lower dose strength are available for younger children.
Special Cases:
- Elderly Patients: No dose adjustment is required. However, use with caution in patients over 75 years old due to limited clinical experience.
- Patients with Renal Impairment: No dose adjustment is required. Use is not recommended for patients undergoing dialysis. Avoid use in patients with severe renal impairment (creatinine clearance 15-29 mL/min).
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild or moderate hepatic impairment. Do not initiate in patients with severe hepatic impairment or clinically significant elevated hepatic aminotransferases (> 3 × ULN).
- Patients with Comorbid Conditions: Use Opsynvi (macitentan and tadalafil) cautiously in patients with certain conditions, such as left ventricular outflow tract obstruction and hypotension.
Clinical Use Cases
Macitentan is specifically indicated for chronic management of PAH and not typically used for short-term management in acute clinical situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency scenarios.
Dosage Adjustments
- Renal/hepatic dysfunction: As described above, dosage modifications may be necessary for patients with moderate to severe renal or hepatic impairment.
- Metabolic disorders or genetic polymorphisms: No specific dose adjustments based on metabolic disorders or genetic polymorphisms are currently recommended, but clinical judgment is advised.
Side Effects
Common Side Effects
- Anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, urinary tract infection, peripheral edema.
Rare but Serious Side Effects
- Hepatotoxicity, liver failure, decreases in hemoglobin (sometimes requiring transfusion), pulmonary edema (especially in patients with pulmonary veno-occlusive disease), hypersensitivity reactions.
Long-Term Effects
- Decreased sperm count, chronic liver disease progression (if pre-existing).
Adverse Drug Reactions (ADR)
- Angioedema, hepatitis, jaundice, significant hemoglobin reduction.
Contraindications
- Pregnancy, hypersensitivity to macitentan, use in women of childbearing potential not using reliable contraception, breastfeeding, severe hepatic impairment, baseline hepatic aminotransferases > 3 × ULN.
Drug Interactions
- Strong CYP3A4 inducers (e.g., rifampin): Avoid concomitant use due to significantly reduced macitentan exposure.
- Strong CYP3A4 inhibitors (e.g., ketoconazole): Avoid concomitant use due to increased macitentan exposure. Consider alternative PAH treatments.
- Moderate dual inhibitors of CYP3A4 and CYP2C9: Avoid concomitant use.
- Hormonal contraceptives: No clinically significant interaction.
- Many other drug interactions are possible, including with PDE5 inhibitors, so a full drug interaction check should be performed.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: X. Macitentan is contraindicated in pregnancy due to the risk of serious birth defects. Strict contraception is required during and for one month after treatment.
- Breastfeeding: Macitentan is contraindicated during breastfeeding as it is unknown if it is excreted in breast milk. Women must not breastfeed while taking this drug.
Drug Profile Summary
- Mechanism of Action: ERA, blocks ET-1 binding to ETA and ETB receptors, leading to vasodilation and reduced pulmonary vascular resistance.
- Side Effects: Anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, UTI, peripheral edema; rarely, hepatotoxicity, liver failure, pulmonary edema.
- Contraindications: Pregnancy, hypersensitivity, women of childbearing potential not using reliable contraception, breastfeeding, severe hepatic impairment, elevated aminotransferases.
- Drug Interactions: Strong CYP3A4 inducers/inhibitors, moderate dual inhibitors of CYP3A4/CYP2C9.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Adults and children ≥40 kg: 10 mg once daily. Dose adjustment required for children <40 kg.
- Monitoring Parameters: Liver function tests (LFTs), hemoglobin levels, signs of fluid retention, pregnancy tests (for women of childbearing potential).
Popular Combinations
- Tadalafil: The combination of macitentan and tadalafil (Opsynvi) is FDA-approved for PAH and provides synergistic effects on pulmonary hemodynamics and exercise capacity.
Precautions
- General Precautions: Monitor LFTs before and during treatment. Assess for signs of fluid retention. Monitor hemoglobin levels. Women of childbearing potential must follow the Opsumit REMS program requirements.
- Specific Populations: Pregnancy: Contraindicated. Breastfeeding: Contraindicated.
- Children & Elderly: No dose adjustment is typically required but clinical judgment is advised.
- Lifestyle Considerations: Advise patients about the potential impact on driving or operating machinery due to side effects such as headache or dizziness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Macitentan?
A: For adults and children weighing at least 40 kg, the standard dose is 10 mg orally once daily. For children weighing less than 40 kg, dosage adjustments based on body weight are required.
Q2: How does Macitentan differ from other ERAs?
A: Macitentan has a dual ETA and ETB receptor antagonism profile, whereas some other ERAs are selective for ETA receptors. It also has once-daily dosing, which can enhance patient compliance.
Q3: What are the most common side effects of Macitentan?
A: Common side effects include headache, nasopharyngitis/pharyngitis, bronchitis, anemia, influenza, and urinary tract infections.
Q4: Are there any contraindications to using Macitentan?
A: Yes. Macitentan is contraindicated in pregnancy, women of childbearing potential not using reliable contraception, breastfeeding mothers, and patients with severe hepatic impairment or significantly elevated liver enzymes.
Q5: What monitoring is required for patients on Macitentan?
A: Monitor liver function tests (LFTs) before and during treatment, hemoglobin levels, signs of fluid retention, and pregnancy tests for women of reproductive potential.
Q6: Can Macitentan be used in combination with other PAH therapies?
A: Yes, it can be used in combination with other PAH-specific medications such as PDE5 inhibitors (e.g., tadalafil in Opsynvi) or inhaled prostanoids when clinically indicated.
Q7: What should be done in case of a missed dose?
A: The patient should take the missed dose as soon as possible. However, if it is close to the next scheduled dose, they should skip the missed dose and take the next dose at the regular time. Double dosing should be avoided.
Q8: What are the key patient counseling points for Macitentan?
A: Counsel patients about the importance of adhering to strict contraception during and for one month following treatment, potential side effects, the need for regular monitoring, and the importance of reporting any new or worsening symptoms.
A: Primarily via hepatic metabolism by CYP3A4 with minor contributions from CYP2C9 and other enzymes.
