Balsalazide Disodium

1 INDICATIONS AND USAGE Balsalazide disodium capsules are indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. Limitations of Use: Safety and effectiveness of balsalazide disodium capsules beyond 8 weeks in pediatric patients 5 years to 17 years of age and 12 weeks in adults have not been established. Balsalazide disodium capsules are an aminosalicylate indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. ( 1 ) Limitations of Use: Safety and effectiveness of balsalazide beyond 8 weeks in children (ages 5 to 17 years) and 12 weeks in adults have not been established. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration Instructions: Evaluate renal function before initiating therapy with balsalazide disodium capsules. ( 2.1 ) Swallow capsules whole. Do not cut, break, crush or chew. ( 2.1 ) For patients who cannot swallow intact capsules, the capsules may be opened and sprinkled on applesauce, then chewed and swallowed immediately. ( 2.1 ) Teeth and/or tongue staining may occur when administered sprinkled on applesauce. ( 2.1 ) Drink an adequate amount of fluids. ( 2.1 , 5.8 ) Take balsalazide disodium capsules with or without food. ( 2.1 ) Dosage: Adults: The recommended dosage is 2.25 g (three 750 mg capsules) three times daily for 8 weeks. Some adult patients required treatment for up to 12 weeks in clinical trials. ( 2.2 ) Pediatric Patients 5 Years to 17 Years of Age: The recommended dosage is either : 2.25 g (three 750 mg capsules) three times for up to 8 weeks. OR: 750 mg (one capsule) three times daily for up to 8 weeks. ( 2.2 ) 2.1 Important Preparation and Administration Instructions Evaluate renal function before initiating therapy with balsalazide disodium capsules [see Warnings and Precaution ( 5.1 )] . Swallow balsalazide disodium capsules whole. Do not cut, break, crush or chew the capsules. For patients who cannot swallow intact capsules, balsalazide disodium capsules may also be administered by opening the capsule and sprinkling the capsule contents on applesauce. If the capsules are opened for sprinkling, color variation of the powder inside the capsules ranges from orange to yellow and is expected due to color variation of the active pharmaceutical ingredient. Place a small amount (approximately 10 mL) of applesauce into a clean container. Carefully open the capsules. Sprinkle the capsule contents on the applesauce. Mix the capsule contents with the applesauce. The contents may be chewed, if necessary. Consume the entire amount of applesauce mixture immediately. Do not store the applesauce mixture for future use. Teeth and/or tongue staining may occur in some patients when administered sprinkled on applesauce. Drink an adequate amount of fluids [see Warnings and Precautions ( 5.8 )] . Take balsalazide disodium capsules with or without food [see Clinical Pharmacology ( 12.3 )] . 2.2 Recommended Dosage in Adults and Pediatric Patients 5 Years to 17 Years of Age Adults: The recommended dosage in adults is 2.25 g (three 750 mg capsules) three times daily for up to 8 weeks. Some patients in the adult clinical trials required treatment for up to 12 weeks. Pediatric Patients 5 Years to 17 Years of Age: The recommended dosage in pediatric patients 5 years to 17 years of age is either : 2.25 g (three 750 mg capsules) three times daily for up to 8 weeks; OR: 750 mg (one capsule) three times daily for up to 8 weeks. Use of balsalazide disodium capsules in the pediatric population for more than 8 weeks has not been evaluated in clinical trials [see Clinical Studies ( 14 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Renal Impairment [see Warnings and Precautions ( 5.1 )] Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions ( 5.2 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] Hepatic Failure [see Warnings and Precautions ( 5.4 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.5 )] Upper Gastrointestinal Tract Obstruction [see Warnings and Precautions ( 5.6 )] Photosensitivity [see Warnings and Precautions ( 5.7 )] Nephrolithiasis [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (≥3%) are: headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia. Adverse reactions in pediatric patients were similar. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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. Adult Ulcerative Colitis: During clinical development, 259 adult patients with active ulcerative colitis were exposed to 6.75 g/day balsalazide in 4 controlled trials. In the 4 controlled clinical trials patients receiving a balsalazide dose of 6.75 g/day most frequently reported the following adverse reactions: headache (8%), abdominal pain (6%), diarrhea (5%), nausea (5%), vomiting (4%), respiratory infection (4%), and arthralgia (4%). Withdrawal from therapy due to adverse reactions was comparable among patients on balsalazide and placebo. Adverse reactions reported by 1% or more of patients who participated in the 4 well-controlled, Phase 3 trials are presented by treatment group (Table 1). The number of placebo patients (35), however, is too small for valid comparisons. Some adverse reactions, such as abdominal pain, fatigue, and nausea were reported more frequently in women than in men. Abdominal pain, rectal bleeding, and anemia can be part of the clinical presentation of ulcerative colitis. Table 1: Adverse Reactions Occurring in ≥1% of Adult Balsalazide Patients in Controlled Trials Adverse reactions occurring in at least 1% of balsalazide patients which were less frequent than placebo for the same adverse reaction were not included in the table. Adverse Reaction Balsalazide 6.75 g/day [N=259] Placebo [N=35] Abdominal pain 16 (6%) 1 (3%) Diarrhea 14 (5%) 1 (3%) Arthralgia 9 (4%) 0% Rhinitis 6 (2%) 0% Insomnia 6 (2%) 0% Fatigue 6 (2%) 0% Flatulence 5 (2%) 0% Fever 5 (2%) 0% Dyspepsia 5 (2%) 0% Pharyngitis 4 (2%) 0% Coughing 4 (2%) 0% Anorexia 4 (2%) 0% Urinary tract infection 3 (1%) 0% Myalgia 3 (1%) 0% Flu-like disorder 3 (1%) 0% Dry mouth 3 (1%) 0% Cramps 3 (1%) 0% Constipation 3 (1%) 0% Pediatric Ulcerative Colitis: In a clinical trial in 68 pediatric patients aged 5 to 17 years with mildly to moderately active ulcerative colitis who received 6.75 g/day or 2.25 g/day balsalazide for 8 weeks, the most frequently reported adverse reactions were headache (15%), abdominal pain upper (13%), abdominal pain (12%), vomiting (10%), diarrhea (9%), colitis ulcerative (6%), nasopharyngitis (6%), and pyrexia (6%) [see Table 2 ] . One patient who received balsalazide 6.75 g/day and 3 patients who received balsalazide 2.25 g/day discontinued treatment because of adverse reactions. In addition, 2 patients in each dose group discontinued because of a lack of efficacy. Adverse reactions reported by 3% or more of pediatric patients within either treatment group in the Phase 3 trial are presented in Table 2. Table 2: Treatment-Emergent Adverse Reactions Reported by ≥3% of Patients in Either Treatment Group in a Controlled Study of 68 Pediatric Patients Balsalazide Adverse Reaction 6.75 g/day [N = 33] 2.25 g/day [N = 35] Total [N = 68] Headache 5 (15%) 5 (14%) 10 (15%) Abdominal pain upper 3 (9%) 6 (17%) 9 (13%) Abdominal pain 4 (12%) 4 (11%) 8 (12%) Vomiting 1 (3%) 6 (17%) 7 (10%) Diarrhea 2 (6%) 4 (11%) 6 (9%) Colitis ulcerative 2 (6%) 2 (6%) 4 (6%) Nasopharyngitis 3 (9%) 1 (3%) 4 (6%) Pyrexia 0 (0%) 4 (11%) 4 (6%) Hematochezia 0 (0%) 3 (9%) 3 (4%) Nausea 0 (0%) 3 (9%) 3 (4%) Influenza 1 (3%) 2 (6%) 3 (4%) Fatigue 2 (6%) 1 (3%) 3 (4%) Stomatitis 0 (0%) 2 (6%) 2 (3%) Cough 0 (0%) 2 (6%) 2 (3%) Pharyngolaryngeal pain 2 (6%) 0 (0%) 2 (3%) Dysmenorrhea 2 (6%) 0 (0%) 2 (3%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of balsalazide, or other products which contain or are metabolized to mesalamine. 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. Cardiovascular and Vascular: Myocarditis, pericarditis, vasculitis [see Warnings and Precautions ( 5.3 )] Respiratory: pleural effusion, pneumonia (with and without eosinophilia), alveolitis, pleurisy/pleuritis Renal: renal failure, interstitial nephritis, nephrolithiasis [see Warnings and Precautions ( 5.1 , 5.8 )] Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach Gastrointestinal: pancreatitis Dermatologic: pruritus, alopecia Hepatic: hepatotoxicity, elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure, Kawasaki-like syndrome including hepatic dysfunction Skin: SJS/TEN, DRESS, and AGEP [see Warnings and Precautions ( 5.5 )]

12.3 Pharmacokinetics Balsalazide disodium capsules contain a powder of balsalazide disodium that is insoluble in acid and designed to be delivered to the colon as the intact prodrug. Upon reaching the colon, bacterial azoreductases cleave the compound to release 5-ASA, the therapeutically active portion of the molecule, and 4-aminobenzoyl-β-alanine. The 5-ASA is further metabolized to yield N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), a second key metabolite. Absorption: In a study of adult patients with ulcerative colitis, who received balsalazide, 1.5 g twice daily, for over 1 year, systemic drug exposure, based on mean AUC values, was up to 60 times greater (0.008 mcg·hr/mL to 0.480 mcg·hr/mL) when compared to that obtained in healthy subjects who received the same dose. Effect of Food : The plasma pharmacokinetics of balsalazide and its key metabolites from a crossover study in healthy subjects are summarized in Table 3. In this study, a single oral dose of balsalazide 2.25 g was administered to healthy volunteers as intact capsules (3 x 750 mg) under fasting conditions, as intact capsules (3 x 750 mg) after a high-fat meal, and unencapsulated (3 x 750 mg) as sprinkles on applesauce. Table 3: Plasma Pharmacokinetics for Balsalazide and Key Metabolites (5-ASA and N-Ac-5-ASA) with Administration of Balsalazide Following a Fast, a High-Fat Meal, and Drug Contents Sprinkled on Applesauce (Mean ± SD) Fasting N=17 High-fat Meal N=17 Sprinkled N=17 C max (mcg/mL) Balsalazide 0.51 ± 0.32 0.45 ± 0.39 0.21 ± 0.12 5-ASA 0.22 ± 0.12 0.11 ± 0.136 0.29 ± 0.17 N-Ac-5-ASA 0.88 ± 0.39 0.64 ± 0.534 1.04 ± 0.57 AUC last (mcg·hr/mL) Balsalazide 1.35 ± 0.73 1.52 ± 1.01 0.87 ± 0.48 5-ASA 2.59 ± 1.46 2.10 ± 2.58 2.99 ± 1.70 N-Ac-5-ASA 17.8 ± 8.14 17.7 ± 13.7 20.0 ± 11.4 T max (h) Balsalazide 0.8 ± 0.85 1.2 ± 1.11 1.6 ± 0.44 5-ASA 8.2 ± 1.98 22.0 ± 8.23 8.7 ± 1.99 N-Ac-5-ASA 9.9 ± 2.49 20.2 ± 8.94 10.8 ± 5.39 A relatively low systemic exposure was observed under all three administered conditions (fasting, fed with high-fat meal, sprinkled on applesauce), which reflects the variable, but minimal absorption of balsalazide disodium and its metabolites. The data indicate that both C max and AUC last were lower, while T max was markedly prolonged, under fed (high-fat meal) compared to fasted conditions. Moreover, the data suggest that dosing balsalazide disodium as a sprinkle or as a capsule provides highly variable, but relatively similar mean pharmacokinetic parameter values. No inference can be made as to how the systemic exposure differences of balsalazide and its metabolites in this study might predict the clinical efficacy under different dosing conditions (i.e., fasted, fed with high-fat meal, or sprinkled on applesauce) since clinical efficacy after balsalazide disodium administration is presumed to be primarily due to the local effects of 5-ASA on the colonic mucosa [see Dosage and Administration ( 2.1 )] . Distribution: The binding of balsalazide to human plasma proteins was ≥99%. Elimination: Metabolism : The products of the azoreduction of this compound, 5-ASA and 4-aminobenzoyl-β-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces. Excretion: Following single-dose administration of 2.25 g balsalazide (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively. In a multiple-dose study in healthy subjects receiving a balsalazide dose of two 750 mg capsules twice daily (3 g/day) for 10 days, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.1%, 0%, and 11.3%, respectively. During this study, subjects received their morning dose 0.5 hours after being fed a standard meal, and subjects received their evening dose 2 hours after being fed a standard meal. In a study with 10 healthy subjects, 65% of a single 2.25-gram dose of balsalazide was recovered as 5-ASA, 4-aminobenzoyl-β-alanine, and the N-acetylated metabolites in feces, while <1% of the dose was recovered as parent compound. In a study that examined the disposition of balsalazide in patients who were taking 3 to 6 g of balsalazide daily for more than 1 year and who were in remission from ulcerative colitis, less than 1% of an oral dose was recovered as intact balsalazide in the urine. Less than 4% of the dose was recovered as 5-ASA, while virtually no 4-aminobenzoyl-β-alanine was detected in urine. The mean urinary recovery of N-Ac-5-ASA and N-acetyl-4-aminobenzoyl-β-alanine comprised <16% and <12% of the balsalazide dose, respectively. No fecal recovery studies were performed in this population. Use in Specific Populations: Pediatric Patients : In studies of pediatric patients with mild-to-moderate active ulcerative colitis receiving three 750 mg balsalazide capsules 3 times daily (6.75 g/day) for 8 weeks, steady state was reached within 2 weeks, as observed in adult patients. Likewise, the pharmacokinetics of balsalazide, 5-ASA, and N-Ac-5-ASA were characterized by very large inter-patient variability, which is also similar to that seen in adult patients. The prodrug moiety, balsalazide, appeared to exhibit dose-independent (i.e., dose-linear) kinetics in children, and the systemic exposure parameters (C max and AUC 0-8 ) increased in an almost dose-proportional fashion after the 6.75 g/day versus the 2.25 g/day doses. However, the absolute magnitude of these exposure parameters was greater relative to adults. The C max and AUC 0-8 observed in pediatric patients were 26% and 102% greater than those observed in adult patients at the 6.75 g/day dosage level. In contrast, the systemic exposure parameters for the active metabolites, 5-ASA and N-Ac-5‑ASA, in pediatric patients increased in a less than dose-proportional manner after the 6.75 g/day dose versus the 2.25 g/day dose. Additionally, the magnitude of these exposure parameters was decreased for both metabolites relative to adults. For the metabolite of key safety concern from a systemic exposure perspective, 5-ASA, the C max and AUC 0-8 observed in pediatric patients were 67% and 64% lower than those observed in adult patients at the 6.75 g/day dosage level. Likewise, for N-Ac-5-ASA, the C max and AUC 0-8 observed in pediatric patients were 68% and 55% lower than those observed in adult patients at the 6.75 g/day dosage level. All pharmacokinetic studies with balsalazide are characterized by large variability in the plasma concentration versus time profiles for balsalazide and its metabolites, thus half-life estimates of these analytes are indeterminate. Drug Interaction Studies: In Vitro Data : In an in vitro study using human liver microsomes, balsalazide and its metabolites [5-aminosalicylic acid (5-ASA), N‑acetyl-5-aminosalicylic acid (N-Ac-5-ASA), 4-aminobenzoyl-β-alanine (4-ABA) and N-acetyl-4-aminobenzoyl-β-alanine (N-Ac-4-ABA)] were not shown to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). Therefore, balsalazide and its metabolites are not expected to inhibit the metabolism of other drugs which are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.