MACITENTAN- macitentan_tablet

Endothelin (ET)-1 and its receptors (ET A B Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ET A B in vitro. 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 tablets 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 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. The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration. A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects. Absorption and Distribution The maximum plasma concentration of macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high fat breakfast. Macitentan may therefore be taken with or without food. Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects. Metabolism and Elimination Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with minor contributions of CYP2C8, CYP2C9, and CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces. Special Populations There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite. Renal Impairment Exposure to macitentan and its active metabolite in patients with severe renal impairment (CrCl 15 to 29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant. Hepatic Impairment Exposure to macitentan was 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 (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant. 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), sodiumtaurocholate 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 macitenta n 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: Sildenafil Hormonal contraceptives: BCRP Substrate drugs: image description.

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. 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.

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 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. 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.

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 Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 tablets 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 tablets 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 tablets 10 mg and placebo treatment groups (approximately 11%). Table 2 presents adverse reactions more frequent on macitentan tablets 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 The following adverse reactions have been identified during post-approval use of macitentan tablets. 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 Vascular disorders Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders: [see Warnings and Precautions (5. General disorders and administration site conditions [see Warnings and Precautions (5. Cardiac disorders.

Pregnancy ( 4. 1 Hypersensitivity ( 4. 2 Macitentan tablets may cause fetal harm when administered to a pregnant woman. Macitentan tablets are contraindicated in females who are pregnant. Macitentan tablets were 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)] Macitentan tablets is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product [see Adverse Reactions (6.

Lactation: Advise not to breastfeed. 2 Risk Summary Based on data from animal reproduction studies, macitentan tablets 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] [see Contraindications (4. 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. 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. 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 tablets advise women not to breastfeed during treatment with macitentan tablets. 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 tablets 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. The safety and effectiveness of macitentan tablets 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 tablets for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with macitentan tablets ( 7. 3 Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with macitentan tablets ( 7. 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 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)] 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)] [see Clinical Pharmacology (12. 3)] 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.

=15% decrease from baseline in 6 minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH. All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation. A critical secondary endpoint was time to PAH death or PAH hospitalization. The mean patient age was 46 years (14% were age 65 or above). Most patients were white (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively. Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%) and HIV (1%)]. At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of specific therapy for PAH. Study results are described for the placebo and macitentan tablets 10 mg groups. The median treatment durations were 101 and 118 weeks in the placebo and macitentan tablets 10 mg groups, respectively, up to a maximum of 188 weeks. Treatment with macitentan tablets 10 mg resulted in a 45% reduction (HR 0. 76; logrank p<0. 0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 3 and Figure 2). The beneficial effect of macitentan tablets 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment). Figure 2 Kaplan-Meier Estimates of the Occurrence of the Primary Endpoint Event in the SERAPHIN Study Table 3: Summary of Primary Endpoint Events *No patients experienced an event of lung transplantation or atrial septostomy in the placebo or macitentan tablets 10 mg treatment groups. Placebo N=250 n (%) Macitentan tablets 10 mg N=242 n (%) Patients with a primary endpoint event* 116 (46. 4) Component as first event Worsening PAH 93 (37. 4) Death 17 (6. 6) IV/SC prostanoid 6 (2. 4) Subgroup analyses were performed to examine their influence on outcome as shown in Figure 3. Consistent efficacy of macitentan tablets 10 mg on the primary endpoint was seen across subgroups of age, sex, race, etiology, by monotherapy or in combination with another PAH therapy, baseline 6MWD, and baseline WHO FC. Figure 3 Subgroup Analysis of the SERAPHIN Study Eo = Number of events macitentan tablets 10 mg; No = Number of patients randomized to macitentan tablets 10 mg Ep = Number of events placebo; Np = Number of patients randomized to placebo PAH related death or hospitalization for PAH was assessed as a secondary endpoint. The risk of PAH related death or hospitalization for PAH was reduced by 50% in patients receiving macitentan tablets 10 mg compared to placebo (HR 0. 75; logrank p<0. 0001) (Table 4 and Figure 4). Figure 4 Kaplan-Meier Estimates of the Occurrence of Death due to PAH or Hospitalization for PAH in SERAPHIN Table 4: Summary of Death due to PAH and Hospitalization due to PAH Placebo (N=250) n (%) Macitentan tablets 10 mg (N=242) n (%) Death due to PAH or hospitalization for PAH 84 (33. 7) Component as first event Death due to PAH 5 (2. 1) Hospitalization for PAH 79 (31. 6) Treatment with macitentan tablets 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97. 5% CI 3 to 41; p=0. 0078), with significant improvement in 6MWD by Month 3. 6MWD increased more in patients with worse baseline WHO Functional Class (37 meters and 12 meters placebo-corrected mean increase in WHO FC III/IV and FC I/II, respectively). The increase in 6MWD achieved with macitentan tablets was maintained for the duration of the study. Treatment with macitentan tablets 10 mg led to an improvement of at least one WHO Functional Class at Month 6 in 22% of patients compared to 13% of patients treated with placebo. Long-Term Treatment of PAH In long-term follow-up of patients who were treated with macitentan tablets 10 mg in the placebo-controlled study (N=242) and the open-label extension study, Kaplan-Meier estimates of survival at 1, 2, 5, and 7 years were 95%, 89%, 73%, and 63% respectively. The median exposure to macitentan tablets was 4. These uncontrolled observations do not allow comparison with a group not given macitentan tablets and cannot be used to determine the long term-effect of macitentan tablets on mortality. image description image description image description.">OVERDOSAGE
Macitentan tablets 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.
NONCLINICAL TOXICOLOGY
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 in vivo in vivo 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. In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans. There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at exposures of 12- to 116-fold the human exposure.
CLINICAL STUDIES
The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term (average duration of exposure approximately 2 years), placebo-controlled study in 742 patients with symptomatic [WHO functional class (FC) II-IV] PAH who were randomized to placebo (n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily. Patients were treated with macitentan tablets monotherapy or in combination with another PAH therapy. The primary study endpoint was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC) prostanoids, or "other worsening of PAH" during double-blind treatment plus 7 days. Other worsening was defined as all of the following: 1) a sustained >=15% decrease from baseline in 6 minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH. All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation. A critical secondary endpoint was time to PAH death or PAH hospitalization. The mean patient age was 46 years (14% were age 65 or above). Most patients were white (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively. Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%) and HIV (1%)]. At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of specific therapy for PAH. Study results are described for the placebo and macitentan tablets 10 mg groups. The median treatment durations were 101 and 118 weeks in the placebo and macitentan tablets 10 mg groups, respectively, up to a maximum of 188 weeks. Treatment with macitentan tablets 10 mg resulted in a 45% reduction (HR 0. 76; logrank p<0. 0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 3 and Figure 2). The beneficial effect of macitentan tablets 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment). Figure 2 Kaplan-Meier Estimates of the Occurrence of the Primary Endpoint Event in the SERAPHIN Study Table 3: Summary of Primary Endpoint Events *No patients experienced an event of lung transplantation or atrial septostomy in the placebo or macitentan tablets 10 mg treatment groups. Placebo N=250 n (%) Macitentan tablets 10 mg N=242 n (%) Patients with a primary endpoint event* 116 (46. 4) Component as first event Worsening PAH 93 (37. 4) Death 17 (6. 6) IV/SC prostanoid 6 (2. 4) Subgroup analyses were performed to examine their influence on outcome as shown in Figure 3. Consistent efficacy of macitentan tablets 10 mg on the primary endpoint was seen across subgroups of age, sex, race, etiology, by monotherapy or in combination with another PAH therapy, baseline 6MWD, and baseline WHO FC. Figure 3 Subgroup Analysis of the SERAPHIN Study Eo = Number of events macitentan tablets 10 mg; No = Number of patients randomized to macitentan tablets 10 mg Ep = Number of events placebo; Np = Number of patients randomized to placebo PAH related death or hospitalization for PAH was assessed as a secondary endpoint. The risk of PAH related death or hospitalization for PAH was reduced by 50% in patients receiving macitentan tablets 10 mg compared to placebo (HR 0. 75; logrank p<0. 0001) (Table 4 and Figure 4). Figure 4 Kaplan-Meier Estimates of the Occurrence of Death due to PAH or Hospitalization for PAH in SERAPHIN Table 4: Summary of Death due to PAH and Hospitalization due to PAH Placebo (N=250) n (%) Macitentan tablets 10 mg (N=242) n (%) Death due to PAH or hospitalization for PAH 84 (33. 7) Component as first event Death due to PAH 5 (2. 1) Hospitalization for PAH 79 (31. 6) Treatment with macitentan tablets 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97. 5% CI 3 to 41; p=0. 0078), with significant improvement in 6MWD by Month 3. 6MWD increased more in patients with worse baseline WHO Functional Class (37 meters and 12 meters placebo-corrected mean increase in WHO FC III/IV and FC I/II, respectively). The increase in 6MWD achieved with macitentan tablets was maintained for the duration of the study. Treatment with macitentan tablets 10 mg led to an improvement of at least one WHO Functional Class at Month 6 in 22% of patients compared to 13% of patients treated with placebo. Long-Term Treatment of PAH In long-term follow-up of patients who were treated with macitentan tablets 10 mg in the placebo-controlled study (N=242) and the open-label extension study, Kaplan-Meier estimates of survival at 1, 2, 5, and 7 years were 95%, 89%, 73%, and 63% respectively. The median exposure to macitentan tablets was 4. These uncontrolled observations do not allow comparison with a group not given macitentan tablets and cannot be used to determine the long term-effect of macitentan tablets on mortality. image description image description image description.

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