Macitentan

Macitentan is used for: Pulmonary arterial hypertension

Oral Pulmonary arterial hypertension Adult: As mono- or in combination therapy, in patients with WHO functional class II and III PAH (idiopathic, heritable, associated with connective tissue diseases or with corrected simple congenital heart disease): 10 mg once daily. Hepatic impairment Mild, moderate, or severe (Child-Pugh Class A, B, and C): No dosage modification needed System exposure decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment respectively (not considered clinically relevant)

Renal impairment Severe (CrCl 15-29 mL/min): No dosage modification needed Systemic exposure to macitentan and its active metabolite were increased by 30% and 60% respectively (not considered clinically relevant)

May be taken with or without food

History of hypersensitivity reaction to drug or excipients. Severe hepatic impairment (with or without cirrhosis) or clinically significant elevated baseline values of hepatic aminotransferases (>3 times the upper limit of normal). Women of childbearing potential who are not using reliable contraception. Pregnancy and lactation.

Patient with pulmonary veno-occlusive disease, anaemia, severe chronic heart disease. Severe renal (including patients on dialysis) and moderate hepatic impairment. If pulmonary edema occurs, consider the possibility of associated pulmonary veno-occlusive disease, and if confirmed, discontinue drug. Decreases in hemoglobin concentration and hematocrit reported; decreases in hemoglobin seldom require transfusion; initiation of therapy is not recommended in patients with severe anemia; measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated. Obtain pregnancy test prior to initiation of therapy, monthly during treatment, and 1 month after stopping treatment. Monitor ALT and AST, Hb and haematocrit levels prior to treatment and as clinically indicated. Monitor for signs of hepatic injury, significant peripheral oedema.

Pregnancy Based on data from animal reproduction studies, therapy may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy; there are risks to mother and fetus associated with pulmonary arterial hypertension in pregnancy; there are limited data on use in pregnant women; the drug was teratogenic in rabbits and rats at all doses tested; if drug is used during pregnancy, or if patient becomes pregnant while taking this drug, advise the patient of risk to a fetus In patients with pulmonary arterial hypertension, pregnancy is associated with increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor Pregnancy testing Verify pregnancy status of females of reproductive potential prior to initiating therapy, monthly during treatment and one month after stopping treatment; the patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected; if pregnancy test is positive, the physician and patient must discuss risks to her, the pregnancy, and fetus Contraception Female patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after stopping Patients may choose 1 highly effective form of contraception (intrauterine devices [IUD], contraceptive implants, or tubal sterilization) or a combination of methods (hormone method with a barrier method or 2 barrier methods) If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method Infertility Based on findings in animals, drug may impair fertility in males of reproductive potential; not known whether effects on fertility would be reversible Therapy may have an adverse effect on spermatogenesis; counsel men about potential effects on fertility Lactation There are no data on presence of macitentan in human milk, effects on breastfed infant, or on milk production; because of potential for serious adverse reactions in breastfed infants advise women not to breastfeed during treatment

Decreased serum concentrations with strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin). Increased serum concentrations with strong CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, ritonavir).

Side effects of Macitentan : >10% Nasopharyngitis (20%) Headache (14%) Anemia (13%) Bronchitis (12%) 1-10% Urinary tract infection (9%) Hemoglobin <10 g/dL (8.7%) Influenza (6%) Elevated aminotransferases >3 x ULN (3.4%) Elevated aminotransferases >8 x ULN (2.1%)

Endothelin receptor antagonist (ERA); prevents binding of endothelin (ET)-1 to both ET-A and ET-B receptors with high affinity to ET receptors in pulmonary arterial smooth muscle cells; active metabolite 20% as potent as parent compound.