MACITENTAN
Clinical safety rating: avoid
Contraindicated (not allowed)
Endothelin receptor antagonist (ERA) that blocks the binding of endothelin-1 (ET-1) to ETA and ETB receptors, thereby inhibiting vasoconstriction and smooth muscle proliferation.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19 and CYP2C9; undergoes oxidative metabolism followed by glucuronidation. |
| Excretion | Biliary/fecal (major, 93% as metabolites) and renal (3% unchanged, <5% of dose in urine). |
| Half-life | Terminal elimination half-life is 11–22 hours in healthy subjects; in pulmonary arterial hypertension patients, mean half-life is approximately 13 hours. |
| Protein binding | Highly protein bound (98–99%), primarily to albumin and α1-acid glycoprotein. |
| Volume of Distribution | Approximately 0.3 L/kg (range 0.2–0.4 L/kg), reflecting distribution into total body water. |
| Bioavailability | Absolute oral bioavailability is about 65% (40–85% range) in healthy subjects; absorption is not affected by food. |
| Onset of Action | Oral: maximal plasma concentrations reached within 2–4 hours; clinical effect (e.g., hemodynamic improvement) observed within 4–6 weeks of chronic dosing. |
| Duration of Action | Plasma concentrations sustain therapeutic levels over 24 hours with once-daily dosing; clinical duration of pulmonary vasodilation extends beyond 24 hours after steady state is achieved. |
10 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min). Not recommended in severe renal impairment (eGFR <30 mL/min) or dialysis. |
| Liver impairment | Contraindicated in patients with Child-Pugh class B or C hepatic impairment. No dose adjustment for Child-Pugh class A (use caution and monitor closely). |
| Pediatric use | Safety and efficacy not established in pediatric patients; no specific weight-based dosing available. |
| Geriatric use | No dose adjustment recommended based on age; monitor liver function tests and fluid status closely due to potential increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inducers may decrease efficacy Contraindicated in pregnancy due to fetal toxicity.
| Breastfeeding | It is unknown whether macitentan is excreted in human breast milk. However, due to the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment. No M/P ratio is available. |
| Teratogenic Risk | Macitentan is contraindicated in pregnancy. Based on animal studies and its mechanism (endothelin receptor antagonism), there is a high risk of fetal harm, including teratogenicity (cardiovascular and skeletal malformations) and fetal death. Risk applies throughout pregnancy; no trimester is safe. Effective contraception is required before initiation and during treatment. |
■ FDA Black Box Warning
WARNING: EMBRYOFETAL TOXICITY. Do not administer to a pregnant female because it may cause fetal harm. Females of reproductive potential must be tested for pregnancy before starting treatment, monthly during treatment, and 1 month after stopping treatment.
| Common Effects | Headache Bronchitis inflammation of the airways Nasopharyngitis inflammation of the throat and nasal passages Anemia low number of red blood cells Urinary tract infection Influenza |
| Serious Effects |
Pregnancy (absolute). Pre-existing hepatic impairment (Child-Pugh class A, B, C) or aminotransferases >3× ULN at baseline. Severe anemia (hemoglobin <8 g/dL). Concomitant use with cyclosporine A or strong CYP3A4 inhibitors (e.g., ketoconazole). Lactation (relative).
| Precautions | Hepatotoxicity: Elevations of aminotransferases (AST, ALT) and bilirubin; monitor liver enzymes monthly. Fluid retention (may require diuretic adjustment). Decreased hemoglobin and hematocrit (monitor for anemia). Pulmonary veno-occlusive disease (discontinue if signs). |
Loading safety data…
| Fetal Monitoring | Pregnancy testing must be performed prior to initiation, monthly during treatment, and one month after discontinuation. Liver function tests should be monitored as macitentan is associated with hepatotoxicity. Hemoglobin and hematocrit should be checked periodically due to risk of anemia. Blood pressure should be monitored for hypotension. |
| Fertility Effects | In animal studies, macitentan caused testicular tubular atrophy and reduced sperm counts, potentially impairing male fertility. Effects on female fertility are not well studied, but based on its mechanism, ovarian function may be affected. Reversibility is unknown. |