Macitentan - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS ERAs cause hepatotoxicity and liver failure.

Obtain baseline liver enzymes and monitor as clinically indicated .

Fluid retention may require intervention .

Decreases in hemoglobin .

Pulmonary edema in patients with pulmonary veno-occlusive disease.

If confirmed, discontinue treatment .

Decreases in sperm count have been observed in patients taking ERAs .

5.1 Embryo-fetal Toxicity Based on data from animal reproduction studies, OPSUMIT may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy.

The available human data for ERAs do not establish the presence or absence of major birth defects related to the use of OPSUMIT.

Advise patients who can become pregnant of the potential risk to a fetus.

Obtain a pregnancy test prior to initiation of therapy with OPSUMIT.

Advise patients who can become pregnant to use effective contraceptive methods prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with OPSUMIT.

When pregnancy is detected, discontinue use as soon as possible [see Dosage and Administration , Contraindications , and Use in Specific Populations (8.1 , 8.3) ] .

5.2 Hepatotoxicity ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure.

The incidence of elevated aminotransferases in the study of OPSUMIT in PAH is shown in Table 1.

Table 1: Incidence of Elevated Aminotransferases in the SERAPHIN Study OPSUMIT 10 mg (N=242) Placebo (N=249) >3 × ULN 3.4% 4.5% >8 × ULN 2.1% 0.4% In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events were 3.3% in the OPSUMIT 10 mg group vs.

Obtain liver enzyme tests prior to initiation of OPSUMIT and repeat during treatment as clinically indicated [see Adverse Reactions ] .

Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).

If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT.

Consider re-initiation of OPSUMIT when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

5.3 Fluid Retention Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs.

In the placebo-controlled study of OPSUMIT in PAH, the incidence of edema was 21.9% in the OPSUMIT 10 mg group and 20.5% in the placebo group.

Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment.

In a small study of OPSUMIT in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the OPSUMIT group developed significant fluid retention and had more hospitalizations because of worsening heart failure compared to those randomized to placebo.

Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported [see Adverse Reactions ] .