OPSUMIT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for OPSUMIT (OPSUMIT).
Macitentan is an endothelin receptor antagonist (ERA) that blocks binding of endothelin-1 (ET-1) to ETA and ETB receptors in pulmonary vascular smooth muscle and endothelium, reducing vasoconstriction and proliferation.
| Metabolism | Primarily metabolized by cytochrome P450 (CYP) 3A4, with minor contributions from CYP2C19 and CYP2C9; forms active metabolite (ACT-132577) which contributes to pharmacological activity. |
| Excretion | Primarily fecal (approximately 66%) as unchanged drug and active metabolite; renal excretion accounts for about 34% (mostly as metabolites). |
| Half-life | Terminal elimination half-life is approximately 16 hours (range 6–30 hours) for macitentan; the active metabolite (ACT-132577) has a half-life of about 48 hours, contributing to sustained pharmacodynamic effects. |
| Protein binding | Macitentan: ~99% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 50 L (0.7 L/kg for a 70 kg adult). Large Vd indicates extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 70% (not significantly affected by food). |
| Onset of Action | Oral: Clinical effects on exercise capacity (6-minute walk distance) are observed within 4 weeks; hemodynamic improvements are seen as early as 3 months. |
| Duration of Action | Dosing interval is once daily due to prolonged activity of the metabolite; effect on pulmonary hemodynamics is maintained over 24 hours with once-daily dosing. |
10 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (GFR ≥15 mL/min). Not recommended in severe renal impairment (GFR <15 mL/min) or dialysis. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C). No dose adjustment required for mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. |
| Pediatric use | Not approved for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended; use with caution due to age-related hepatic and renal decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for OPSUMIT (OPSUMIT).
| Breastfeeding | It is not known whether macitentan is excreted in human breast milk. However, due to the potential for serious adverse reactions in nursing infants (e.g., hepatotoxicity, teratogenicity), women should not breastfeed during treatment with OPSUMIT and for at least one month after the last dose. The milk-to-plasma ratio is unknown. |
| Teratogenic Risk | OPSUMIT (macitentan) is contraindicated in pregnancy. It is an endothelin receptor antagonist associated with major congenital malformations (e.g., craniofacial, cardiovascular) and fetal death when administered during pregnancy. In animal studies, fetal toxicity was observed at all doses tested. The risk extends throughout all trimesters due to the drug's mechanism of action and prolonged half-life. |
■ FDA Black Box Warning
Due to risks of hepatotoxicity and birth defects, OPSUMIT is available only through a restricted program called the OPSUMIT Risk Evaluation and Mitigation Strategy (REMS). Embryofetal toxicity: OPSUMIT may cause fetal harm when administered to a pregnant woman; pregnancy must be excluded before initiation, monthly during treatment, and 1 month after discontinuation.
| Serious Effects |
["Pregnancy (must be excluded before use)","Hypersensitivity to macitentan or any excipients"]
| Precautions | ["Hepatotoxicity: Monitor liver aminotransferases and bilirubin prior to initiation and monthly thereafter.","Fluid retention: Peripheral edema and fluid overload may occur, especially in elderly and those with comorbidities.","Hemoglobin decrease: Monitor hemoglobin levels; reductions may require dose adjustment.","Pulmonary veno-occlusive disease: If signs of pulmonary edema occur, consider PVOD.","Fertility impairment: May impair male fertility."] |
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| Fetal Monitoring | Women of childbearing potential must have a negative pregnancy test before initiation of therapy, monthly during treatment, and one month after discontinuation. Effective contraception must be used during treatment and for one month after stopping. If pregnancy occurs, OPSUMIT should be discontinued immediately and the patient counseled regarding the risk to the fetus. |
| Fertility Effects | In animal studies, macitentan caused testicular tubular atrophy and reduced fertility in males at clinically relevant exposures. Effects on human fertility are unknown but should be considered. In females, there was an increased incidence of ovarian cysts observed in animal studies; however, clinical significance is uncertain. |