WARNING: EMBRYO-FETAL TOXICITY Macitentan is contraindicated for use during pregnancy because it may cause fetal harm based on animal data [see Contraindications (4.1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ] . Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with macitentan. Advise use of effective contraception before the initiation of treatment, during treatment, and for one month after stopping treatment with macitentan [see Dosage and Administration (2.2) , Use in Specific Populations (8.3) ] . When pregnancy is detected, discontinue macitentan as soon as possible [see Warnings and Precautions (5.1) ] . WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Based on animal data, macitentan may cause fetal harm if used during pregnancy. ( 4.1 , 5.1 , 8.1 ) Females of reproductive potential: exclude pregnancy before start of treatment. Prevent pregnancy prior to initiation of treatment, during treatment and for one month after treatment by using effective methods of contraception. ( 2.2 , 8.3 ) When pregnancy is detected, discontinue macitentan as soon as possible. ( 5.1 )
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warnings and cautions
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 10 mg (N=242) Placebo (N=249) > 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. Post-marketing 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 decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the macitentan 10 mg group and in 3.4% of the placebo group. Decreases in hemoglobin seldom require transfusion. Initiation of macitentan is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated [see Adverse Reactions (6.1) ] . 5.5 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD) Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue macitentan. 5.6 Decreased Sperm Counts Macitentan, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1) ] .
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 Amneal Pharmaceuticals LLC at 1-877-835-5472 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 (N=242) (%) Placebo (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 Post-marketing Experience The following adverse reactions have been identified during post-approval 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