BOSENTAN

Bosentan, an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula: Bosentan has a molecular weight of 569.63 and a molecular formula of C 27 H 29 N 5 O 6 S•H 2 O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive. Bosentan is available as a 32 mg tablet for oral suspension and contains the following excipients: microcrystalline cellulose, dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, tutti fruitti flavor, aspartame, acesulfame potassium and magnesium stearate. Each dispersible tablet contains 1.85 mg of phenylalanine. Each dispersible tablet contains 33.045 mg of bosentan monohydrate, equivalent to 32 mg anhydrous bosentan. chemical-structure

Bosentan is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) [see Clinical Studies (14.1) ] . in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability. Bosentan is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) ( 1 ). in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability ( 1 ).

• Patients older than 12 years of age: initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after 4 weeks ( 2.2 ). • Patients 12 years of age and younger: dosage is based on weight, see Table 1 ( 2.2 ). • Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3 x Upper Limit of Normal (ULN) ( 2.1 ). 2.1 Required Monitoring Healthcare professionals who prescribe bosentan tablets for oral suspension must enroll in the Bosentan REMS Program and must comply with the required monitoring to minimize the risks associated with bosentan [see Warnings and Precautions (5.3) ] . Obtain a pregnancy test in females of reproductive potential prior to bosentan treatment, monthly during treatment and one month after stopping bosentan. Initiate treatment with bosentan in females of reproductive potential only after a negative pregnancy test [see Boxed Warning , Contraindications (4.1) , Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3) ] . Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage Administer bosentan orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity. Table 1: Dosing Recommendations Initial 4 weeks Maintenance (after 4 weeks) Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily Patients ≤12 years of age ≥4-8 kg ˃8-16 kg ˃16-24 kg ˃24-40 kg 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily 2.3 Administration Bosentan tablets for oral suspension (dispersible tablets) should be administered orally twice daily. Disperse tablets for oral suspension, or dispersible tablet half, in a minimal amount of water immediately before administration. Store divided dispersible tablet pieces at 20 ºC to 25 ºC (68 ºF to 77 ºF) in the opened blister for up to 7 days. 2.4 Dosage Adjustments for Aminotransferase Elevations If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2. Discontinue bosentan if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or bilirubin ≥2xUpper Limit of Normal (ULN). There is no experience with the reintroduction of bosentan in these circumstances. Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3xULN ALT/AST levels Treatment and monitoring recommendations > 3 and ≤ 5xULN Confirm by another aminotransferase test; if confirmed, - in adults and pediatric patients >12 years and >40 kg , reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pretreatment values, treatment may continue or be reintroduced at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. - in all other pediatric patients, interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days. > 5 and ≤ 8xULN Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, - in adults and pediatric patients >12 years and >40 kg , consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. - in all other pediatric patients , consider reintroduction at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days. > 8xULN Stop treatment permanently. There is no experience with reintroduction of bosentan in these circumstances. 2.5 Use with Ritonavir Co-administration of Bosentan in Patients on Ritonavir In patients who have been receiving ritonavir for at least 10 days, start bosentan at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1) ] . Co-administration of Ritonavir in Patients on Bosentan Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1) ] . 2.6 Use in Patients with Pre-existing Hepatic Impairment Avoid initiation of bosentan in patients with aminotransferases >3xULN. No dose adjustment is required in patients with mildly impaired liver function [see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

• Pregnancy ( 4.1 ) • Use with Cyclosporine A ( 4.2 ) • Use with Glyburide ( 4.3 ) • Hypersensitivity ( 4.4 ) 4.1 Pregnancy Use of bosentan is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping bosentan [see Boxed Warning , Warnings and Precautions (5.2) , Drug Interactions (7.2) , Use in Specific Populations (8.1) ] . 4.2 Use with Cyclosporine A Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan and cyclosporine A is contraindicated [see Cytochrome P450 Drug Interactions (7.1) ] . 4.3 Use with Glyburide An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and bosentan is contraindicated [see Cytochrome P450 Drug Interactions (7.1) ] . 4.4 Hypersensitivity Bosentan is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema [see Adverse Reactions (6.2) , Description (11) ] .

The following important adverse reactions are described elsewhere in the labeling: • Hepatotoxicity [see Boxed Warning , Warnings and Precautions (5.1) ] • Embryo-fetal Toxicity [see Boxed Warning , Warnings and Precautions (5.2) ] • Fluid Retention [see Warnings and Precautions (5.4) ] Common adverse reactions (≥15%) for the dispersible tablet are upper respiratory tract infections and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 practice. Safety data on bosentan were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with PAH and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years; and n=39 for more than 2 years). Exposure of PAH patients (n=328) to bosentan ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months). Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with PAH were more frequent on bosentan (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on bosentan was abnormal liver function. The adverse drug events that occurred in ≥ 3% of the bosentan-treated patients and were more common on bosentan in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3: Table 3. Adverse Events* Occurring in ≥3% of Patients Treated with Bosentan 125-250 mg Twice Daily and More Common on Bosentan in Placebo-Controlled Studies in Pulmonary Arterial Hypertension Adverse Event Bosentan n = 258 Placebo n = 172 No. % No. % Respiratory Tract Infection** 56 22% 30 17% Headache 39 15% 25 14% Edema 28 11% 16 9% Chest Pain 13 5% 8 5% Syncope 12 5% 7 4% Flushing 10 4% 5 3% Hypotension 10 4% 3 2% Sinusitis 9 4% 4 2% Arthralgia 9 4% 3 2% Serum Aminotransferases, abnormal 9 4% 3 2% Palpitations 9 4% 3 2% Anemia 8 3% - - *Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. **Respiratory Tract Infection combines the terms "Nasopharyngitis", "Upper Respiratory Tract Infection" and "Respiratory Tract Infection". Combined data from Study 351, BREATHE-1 and EARLY Bosentan was evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH. Decreased Sperm Counts An open-label, single-arm, multicenter, safety study evaluated the effect on testicular function of bosentan 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as bosentan have an adverse effect on spermatogenesis. Decreases in Hemoglobin and Hematocrit Treatment with bosentan can cause a dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment. The overall mean decrease in hemoglobin concentration for adult bosentan-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan treatment and haemoglobin levels stabilized by 4–12 weeks of bosentan treatment. In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in haemoglobin occurred in 3% compared to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan treatment. During the course of treatment, the hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. In a pooled analysis of pediatric patients (N=100) with PAH treated with bosentan, a decrease in hemoglobin levels to < 10 g/dL from baseline was reported in 11% of patients. There was no decrease to < 8 g/dL. 6.2 Postmarketing Experience There have been several postmarketing reports of angioedema associated with the use of bosentan. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing bosentan. The following additional adverse reactions have been reported during the post approval use of bosentan. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to bosentan exposure: Unexplained hepatic cirrhosis [see Boxed Warning ] Liver failure [see Boxed Warning ] Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4) ] Thrombocytopenia Rash Jaundice Anemia requiring transfusion Neutropenia and leukopenia Nasal congestion Autoimmune hepatitis

• Cytochrome P450: Coadministration of bosentan with drugs metabolized by CYP2C9 and CYP3A can increase exposure to bosentan and/or the coadministered drug ( 4.2 , 4.3 , 7.1 ). • Hormonal contraceptives: Bosentan use decreases contraceptive exposure and reduces effectiveness ( 7.2 ). 7.1 Cytochrome P450 Drug Interactions Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see Pharmacokinetics (12.3) ] . Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with bosentan is not recommended. Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when bosentan is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, bosentan is not expected to increase the plasma concentrations of drugs metabolized by these enzymes. Figure 1. CYP3A induction-mediated effect of bosentan on other drugs Figure 2. Effect of other drugs on bosentan figure 1 figure 2 7.2 Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when bosentan is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan [see Use in Specific Populations (8.3) ] . An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.