OPSUMIT

The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration. A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects. Absorption and

DistributionThe maximum plasma concentration of macitentan is achieved about 8 hours after...

14.1 Pulmonary Arterial Hypertension The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term (average duration of exposure approximately 2 years), placebo-controlled study in 742 patients with symptomatic [WHO functional class (FC) II–IV] PAH who were randomized to placebo (n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily. Patients were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. The primary study endpoint was time to the first occurrence of death, a significant morbid...

Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal Toxicity [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Fluid Retention [see Warnings and Precautions (5.3) ] Decrease in Hemoglobin [see Warnings and Precautions (5.4) ] Most common adverse reactions (more frequent than placebo by ≥3%) are anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection ( 6.1 )....

Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Pregnancy OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is contraindicated in females who are pregnant. OPSUMIT was consistently shown to have teratogenic effects when administered to animals. If OPSUMIT is used during pregnancy, advise the patient of the potential risk to a fetus [see Warnings and Precautions (5.1) and U...

ERAs cause hepatotoxicity and liver failure. Obtain baseline liver enzymes and monitor as clinically indicated ( 5.2 ). Fluid retention may require intervention ( 5.3 ). Decreases in hemoglobin ( 5.4 ). Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment ( 5.5 ). Decreases in sperm count have been observed in patients taking ERAs ( 5.6 ). 5.1 Embryo-fetal Toxicity Based on data from animal reproduction studies, OPSUMIT may cause fetal harm when ...

7 DRUG INTERACTIONS Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with OPSUMIT ( 7.1 , 12.3 ). Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.2 , 12.3 ) . Moderate dual CYP3A4 and CYP2C9 inhibitors (fluconazole, amiodarone) or use of combined CYP3A4 and CYP2C9 inhibitors may inc...