Macitentan

RECENT MAJOR CHANGES Boxed Warning 4/2025 Dosage and Administration ( 2.2 ) 4/2025 Warnings and Precautions ( 5.1 ) 4/2025 Warnings and Precautions ( 5.2 ) Removal 4/2025

1 INDICATIONS AND USAGE 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 ( 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 to 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) ].

3 DOSAGE FORMS AND STRENGTHS Macitentan Tablets are available containing 10 mg of macitentan. • The 10 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and MC over 10 on the other side. • Tablet: 10 mg ( 3 )

4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Pregnancy Macitentan tablets may cause fetal harm when administered to a pregnant woman. Macitentan tablets are contraindicated in females who are pregnant. Macitentan was consistently shown to have teratogenic effects when administered to animals. If macitentan tablets are 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 tablets are contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product [see Adverse Reactions ( 6.2 )].

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 Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) 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 Tablets 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 Postmarketing 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

7 DRUG INTERACTIONS • Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with macitentan ( 7.1 , 12.3 ). • Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration 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) ].

Drug Interactions In Vitro Studies At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes. Macitentan is not a substrate or inhibitor of multi-drug resistance protein (P-gp, MDR-1). The active metabolite of macitentan also is not an inhibitor of P-gp/MDR-1 at clinically relevant concentrations. Macitentan and its active metabolite are not expected to have significant interaction with drug transporters such as organic anion transporting polypeptide (OATP1B1, OATP1B3), multidrug and toxin extrusion protein (MATE-1, MATE-2K), bile salt export pump (BSEP), sodium-taurocholate co-transporting polypeptide (NTCP), organic cation transporter (OCT-1, OCT-3), organic anion transporter (OAT-1, OAT-3) or BCRP transporter at clinically relevant plasma concentrations. In Vivo Studies Effect of other drugs on macitentan The effect of other drugs on macitentan and its active metabolite are studied in healthy subjects and are shown in Figure 1 below. Figure 1: Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole [see Drug Interactions (7.2) ] . PBPK modeling and simulations based analysis showed that a moderate dual inhibitor of CYP3A4 and CYP2C9 such as fluconazole (400 mg once daily) is predicted to increase macitentan exposure approximately 4-fold without relevant effect on the exposure to its active metabolite [see Drug Interactions (7.3) ] . Effect of macitentan on other drugs Warfarin: Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR). Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant. Hormonal contraceptives: Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl estradiol 35 μg). BCRP substrate drugs: Macitentan 10 mg once daily did not affect the pharmacokinetics of concomitant use o …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed ( 8.2 ). 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 2-4% and 15-20%, 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. 8.3 Females and Males of Reproductive Potential Based on data from animal reproductive toxicity studies, macitentan can cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1) and Use in Specific Populations (8.1) ]. Pregnancy Testing Verify that patients who can become pregnant are not pregnant prior to initiating macitentan. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient should discuss the risks to the pregnancy and the fetus. Contraception Patients who can become pregnant who are using macitentan should use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with macitentan to prevent pregnancy [see Warnings and Precautions (5.1) ] . Infertility Based on findings in animals, macitentan may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , and Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of macitentan in pediatric patients have not been established for the treatment of PAH. Macitentan was evaluated in 148 ped …

12.1 Mechanism of Action Endothelin (ET)-1 and its receptors (ET A and ET B ) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ET A and ET B receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro . The clinical impact of dual endothelin blockage is unknown.

11 DESCRIPTION Macitentan is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’- propylsulfamide. It has a molecular formula of C 19 H 2 0Br 2 N 6 O 4 S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula: Macitentan is a white to off-white powder that is freely soluble in dichloromethane and N,N dimethyl formamide, soluble in acetone, very slightly soluble in methanol and practically insoluble in ethanol and water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive. Macitentan tablets are available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, poloxamer 188, povidone, sodium stearyl fumarate. The tablets are film-coated with a coating material containing lecithin (soya), polyvinyl alcohol, talc, titanium dioxide and xanthan gum. macitentan structure

10 OVERDOSAGE Macitentan tablets have been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.

16 HOW SUPPLIED/STORAGE AND HANDLING Macitentan tablets are 10 mg white to off-white, round biconvex film-coated tablet debossed with “ M1 ” on one side and plain on other side. 15 count (5x3 unit-dose) PVC/PE/PVDC aluminium foil child resistant blisters in carton (NDC 47335-070-15) 30 count white high-density polyethylene bottle with child-resistant closure in carton, (NDC 47335-070-30) Store at 20° C to 25° C (68° F to 77° F). Excursions are permitted between 15° C and 30° C (59° F and 86° F). [See USP Controlled Room Temperature]. This package is child-resistant. Keep out of reach of children.