Macipah10 mg

Established / FDA-Approved Indication

Macipah is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults, to delay disease progression and reduce the risk of hospitalization for PAH. Disease progression events in the pivotal trial included death, atrial septostomy, lung transplantation, initiation of intravenous or subcutaneous prostanoid therapy, and worsening of PAH.

Macipah may be used as monotherapy or in combination with other approved PAH therapies (for example, phosphodiesterase-5 inhibitors), consistent with current pulmonary hypertension treatment guidelines that support combination therapy for many patients.

Not Established

Macipah is not approved and not recommended for other forms of pulmonary hypertension (e.g., WHO Groups 2, 3, 4, or 5) or for any indication outside PAH; such use would be off-label and is not supported by adequate evidence.

Macipah is an orally active endothelin receptor antagonist (ERA) that blocks both endothelin type A (ET_A) and type B (ET_B) receptors. It is used long-term in adults with pulmonary arterial hypertension to slow disease progression. Macipah is taken once daily as a film-coated tablet and is metabolized to a pharmacologically active metabolite that contributes to its prolonged effect.

Endothelin-1 (ET-1) and its receptors (ET_A and ET_B) mediate vasoconstriction, fibrosis, and cell proliferation in the pulmonary vasculature, and are involved in the pathogenesis of pulmonary arterial hypertension. macitentan binds to and blocks both ET_A and ET_B receptors, inhibiting endothelin-1-mediated vasoconstriction and vascular smooth muscle proliferation, which lowers pulmonary vascular resistance.

macitentan is extensively metabolized to a pharmacologically active metabolite that has a long elimination half-life and contributes substantially to the overall effect, allowing once-daily dosing.

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort): significantly decrease plasma concentrations of Macipah, which may reduce its effectiveness; coadministration should generally be avoided.
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin): significantly increase plasma concentrations of Macipah, raising the risk of adverse effects; coadministration should generally be avoided.
• Other antihypertensive agents and PDE5 inhibitors: concomitant use with drugs that lower blood pressure may increase the risk of hypotension; blood pressure should be monitored, although combination with PDE5 inhibitors for PAH is an established treatment strategy under specialist supervision.

Common side effects of Macipah (occurring more often than with placebo) include:

• Anemia / decreased hemoglobin
• Headache
• Nasopharyngitis and pharyngitis (upper respiratory infection)
• Bronchitis and influenza-like illness
• Urinary tract infection
• Peripheral edema / fluid retention

Less common but serious effects include liver enzyme elevation or hepatotoxicity, severe anemia requiring transfusion, and pulmonary edema in patients with underlying pulmonary veno-occlusive disease (see Precautions and Warnings).

Boxed Warning - Embryo-Fetal Toxicity: Macipah must not be used during pregnancy. Animal studies have shown that Macipah causes birth defects and fetal harm. Females of reproductive potential must have a negative pregnancy test before starting Macipah, monthly during treatment, and use two reliable forms of contraception during treatment and for one month after stopping, unless permanent sterilization has been performed. If pregnancy occurs during treatment with Macipah, treatment must be stopped immediately and a physician consulted.

Lactation: It is not known whether Macipah passes into human breast milk. Because of the potential for serious adverse effects in a nursing infant, a decision should be made to discontinue breastfeeding or discontinue Macipah, taking into account the importance of treatment to the mother; use only under close medical supervision.

• Hepatotoxicity: Cases of liver injury have been reported with Macipah. Liver function should be evaluated before starting treatment and periodically or if symptoms of liver injury (nausea, jaundice, dark urine, right upper quadrant pain) occur.
• Fluid retention: Peripheral edema and fluid retention may occur, particularly in the first weeks of treatment with Macipah; patients with pre-existing volume overload should be monitored and managed appropriately.
• Decreased hemoglobin / anemia: Macipah can decrease hemoglobin. Hemoglobin should be checked before starting treatment, at one month, and periodically thereafter; consider dose interruption if a clinically significant fall occurs.
• Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur after starting Macipah, the possibility of underlying PVOD should be considered; if confirmed, Macipah should be discontinued.
• Hepatic/renal impairment: Use with caution and only under specialist supervision in severe hepatic or renal impairment (see Dosage and Administration).

• Pregnancy: Contraindicated - see Contraindications and Pregnancy and Lactation.
• Lactation: Use only if clearly needed, under medical supervision - see Pregnancy and Lactation.
• Pediatric patients: Safety and efficacy of standard Macipah tablets not established under 18 years; a weight-based dispersible tablet is used in some settings for children 2 years and older under specialist care.
• Elderly patients: No overall differences in safety or effectiveness have been observed compared with younger adults; no dose adjustment is required based on age alone.
• Hepatic impairment: No adjustment needed in mild-moderate impairment; not recommended in severe impairment.
• Renal impairment: No adjustment needed in mild-moderate impairment; use with caution in severe impairment or dialysis.

Endothelin Receptor Antagonists (ERAs)

macitentan acts as a dual antagonist of endothelin type A (ET_A) and type B (ET_B) receptors, which are found on vascular smooth muscle and endothelial cells of the pulmonary arteries. By blocking these receptors, macitentan prevents endothelin-1-induced vasoconstriction and proliferation of vascular smooth muscle, thereby reducing pulmonary vascular resistance and right ventricular workload in pulmonary arterial hypertension. Its active circulating metabolite has a long half-life, sustaining receptor blockade over a 24-hour dosing interval.

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