MACITENTAN

1 INDICATIONS AND USAGE Macitentan tablets are endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults to reduce the risks of disease progression and hospitalization for PAH ( 1.1 ). 1.1 Pulmonary Arterial Hypertension Macitentan tablets are an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adults to reduce the risks of disease progression and hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%) [see Clinical Studies ( 14.1 )] .

2 DOSAGE AND ADMINISTRATION 10 mg once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended ( 2.1 ). 2.1 Recommended Dosage The recommended dosage of macitentan tablets are 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended. 2.2 Pregnancy Testing in Females of Reproductive Potential Exclude pregnancy before initiating treatment with macitentan tablets in females of reproductive potential [see Boxed Warning, Contraindications ( 4.1 ), Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.3 )] .

5 WARNINGS AND PRECAUTIONS 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, macitentan 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 macitentan. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of therapy with macitentan. 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 macitentan. When pregnancy is detected, discontinue use as soon as possible [see Dosage and Administration ( 2.2 ), Contraindications ( 4.1 ), 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 macitentan in PAH is shown in Table 1. Table 1 Incidence of Elevated Aminotransferases in the SERAPHIN Study Macitentan 1 0 mg Placebo ( N=242 ) (N =2 4 9 ) > 3 x ULN 3.4 % 4.5% > 8 x ULN 2.1% 0.4% In the placebo-controlled study of macitentan, discontinuations for hepatic adverse events were 3.3% in the macitentan 10 mg group vs. 1.6% for placebo. Obtain liver enzyme tests prior to initiation of macitentan and repeat during treatment as clinically indicated [see Adverse Reactions ( 6.2 )] . 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 x ULN, or by clinical symptoms of hepatotoxicity, discontinue macitentan. Consider re initiation of macitentan 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 macitentan in PAH, the incidence of edema was 21.9% in the macitentan 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 macitentan in patients with pulmonary hypertension because of left ventricular dysfunction, more patients in the macitentan 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 macitentan, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported [see Adverse Reactions ( 6.2 )] . Monitor for signs of fluid retention after macitentan initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as macitentan or underlying heart failure, and the possible need to discontinue macitentan. 5.4 Hemoglobin Decrease Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with macitentan. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of macitentan in PAH, macitentan 10 mg caused a mean decre…

4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Pregnancy Macitentan may cause fetal harm when administered to a pregnant woman. Macitentan is contraindicated in females who are pregnant. Macitentan was consistently shown to have teratogenic effects when administered to animals. If macitentan is used during pregnancy, advise the patient of the potential risk to a fetus [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . 4.2 Hypersensitivity Macitentan is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product [see Adverse Reactions ( 6.2 )] .

7 DRUG INTERACTIONS Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid coadministration with macitentan ( 7.1 , 12.3 ). Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid coadministration with macitentan ( 7.2 , 12.3 ). Moderate dual CYP3A4 and CYP2C9 inhibitors (fluconazole, amiodarone) or use of combined CYP3A4 and CYP2C9 inhibitors may increase exposure to macitentan: avoid co-administration with macitentan ( 7.3 , 12.3 ). 7.1 Strong CYP3A4 Inducers Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of macitentan with strong CYP3A4 inducers should be avoided [see Clinical Pharmacology ( 12.3 )] . 7.2 Strong CYP3A4 Inhibitors Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of macitentan with strong CYP3A4 inhibitors [see Clinical Pharmacology ( 12.3 )] . Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment [see Clinical Pharmacology ( 12.3 )] . 7.3 Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic (PBPK) modeling. Avoid concomitant use of macitentan with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology ( 12.3 )] . Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with macitentan should also be avoided [see Clinical Pharmacology ( 12.3 )] .

4.1 Pregnancy Macitentan may cause fetal harm when administered to a pregnant woman. Macitentan is contraindicated in females who are pregnant. Macitentan was consistently shown to have teratogenic effects when administered to animals. If macitentan is used during pregnancy, advise the patient of the potential risk to a fetus [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, macitentan 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 the mother and the fetus associated with pulmonary arterial hypertension in pregnancy [see Clinical Considerations] . Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as macitentan have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. Macitentan was teratogenic in rabbits and rats at all doses tested. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus [see Contraindications ( 4.1 )] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor. Data Animal Data In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.

8.2 Lactation Risk Summary There are no data on the presence of macitentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breastfed infants from macitentan advise women not to breastfeed during treatment with macitentan.

6 ADVERSE REACTIONS 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 ). To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Safety data for macitentan were obtained primarily from one placebo-controlled clinical study in 742 patients with PAH (SERAPHIN study) [see Clinical Studies ( 14.1 )] . The exposure to macitentan in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment discontinuations because of adverse events was similar across macitentan 10 mg and placebo treatment groups (approximately 11%). Table 2 presents adverse reactions more frequent on macitentan than on placebo by ≥ 3%. Table 2 Adverse Reactions Adverse Reaction Macitentan 10 mg Placebo ( N=242 ) (N=249) (%) (%) Anemia 13 3 Nasopharyngitis/pharyngitis 20 13 Bronchitis 12 6 Headache 14 9 Influenza 6 2 Urinary tract infection 9 6 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of macitentan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders : hypersensitivity reactions (angioedema, pruritus and rash) Vascular disorders: flushing Respiratory, thoracic and mediastinal disorders : nasal congestion Gastrointestinal disorders: Elevations of liver aminotransferases (ALT, AST) and liver injury have been reported with macitentan use; in most cases alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis). Endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Warnings and Precautions ( 5.2 )]. General disorders and administration site conditions : edema/fluid retention. Cases of edema and fluid retention occurred within weeks of starting macitentan, some requiring intervention with a diuretic, fluid management or hospitalization for decompensated heart failure [see Warnings and Precautions ( 5.3 )] . Cardiac disorders : symptomatic hypotension