Macitentan

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-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) ] .

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 is 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 )].

Tablets: 10 mg, white to off-white, round, biconvex film-coated tablet. Engraved “APO” on one side, “M” over “10” on the other side. Tablet: 10 mg ( 3 )

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 )].

Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with macitentan tablets ( 7.1 , 12.3 ). Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with macitentan tablets ( 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 tablets ( 7.3 , 12 .3 ).

7.1 Strong CYP3A4 Inducers Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of macitentan tablets 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 tablets 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 tablets 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 tablets should also be avoided [see Clinical Pharmacology ( 12.3 )] .

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 Apotex Corp. at 1-800-706-5575 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 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

Macitentan has 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.

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 tablets 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.

8.3 Females and Males of Reproductive Potential Based on data from animal reproductive toxicity studies, macitentan tablets 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 tablets. 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 tablets should use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with macitentan tablets 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. Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Actelion Pharmaceuticals US, Inc.’s Opsumit (macitentan) tablets. However, due to Actelion Pharmaceuticals US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use Of the total number of subjects in the clinical study of macitentan for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

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 tablets 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.

8.3 Females and Males of Reproductive Potential Based on data from animal reproductive toxicity studies, macitentan tablets 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 tablets. 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 tablets should use an effective method of contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with macitentan tablets 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)] .

The safety and effectiveness of macitentan in pediatric patients have not been established for the treatment of PAH. Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Actelion Pharmaceuticals US, Inc.’s Opsumit (macitentan) tablets. However, due to Actelion Pharmaceuticals US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Of the total number of subjects in the clinical study of macitentan for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Macitentan tablets are 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 20 Br 2 N 6 O 4 S and a molecular weight of 588.28. Macitentan is achiral and has the following structural formula: Macitentan is a white to off-white powder that is soluble in dimethyl sulfoxide and slightly soluble in methanol. 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, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing polyethylene glycol 8000, polyvinyl alcohol, talc and titanium dioxide. chemicalstructure.jpg

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.

Pulmonary Hemodynamics The clinical efficacy study in patients with pulmonary arterial hypertension assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with macitentan 10 mg (N=57) achieved a median reduction of 37% (95% CI 22 to 49) in pulmonary vascular resistance and an increase of 0.6 L/min/m 2 (95% CI 0.3 to 0.9) in cardiac index compared to placebo (N=67). Cardiac Electrophysiology In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval.

, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively. Mutagenesis Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats. Impairment of Fertility Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.

17 PATIENT COUNSELING INFORMATION Advise patient to read FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity Counsel female patients of reproductive potential about the need to use effective methods of contraception prior to initiation of treatment with macitentan tablets, during treatment and for one month after treatment discontinuation. Females of reproductive potential should have a negative pregnancy test prior to treatment with macitentan tablets [see Contraindications ( 4.1 ), and Use in Specific Populations ( 8.1 , 8.3 )]. Patients should be instructed to contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed. Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. Review the Medication Guide with female patients. Lactation Advise women not to breastfeed during treatment with macitentan tablets [see Use in Specific Populations ( 8.2 )]. Hepatotoxicity Some members of this pharmacological class are hepatotoxic. Educate patients on signs of hepatotoxicity. Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching [see Warnings and Precautions ( 5.2 )]. Fluid Retention Educate patients on signs of fluid retention. Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs [see Warnings and Precautions ( 5.3 )].

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]. Keep out of reach of children.