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 disodium capsules beyond 8 weeks in children (ages 5 years 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) ].

4 CONTRAINDICATIONS Balsalazide disodium capsules are contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or to any of the components of balsalazide disodium capsules or balsalazide metabolites [see Warnings and Precautions (5.3) , Adverse Reactions (6.2) , Description (11) ] . Known or suspected hypersensitivity to salicylates, aminosalicylates, or any of the components of balsalazide disodium capsules or balsalazide metabolites. ( 4 , 5.3 )

5 WARNINGS AND PRECAUTIONS Renal Impairment: Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. Discontinue if renal function deteriorates. ( 5.1 , 7.1 , 8.6 ) Mesalamine-Induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis; monitor for worsening symptoms; discontinue treatment if acute intolerance syndrome is suspected. ( 5.2 ) Hypersensitivity Reactions, including Myocarditis and Pericarditis: Evaluate patients immediately and discontinue if a hypersensitivity reaction is suspected. ( 5.3 ) Hepatic Failure: Evaluate the risks and benefits in patients with known liver impairment. ( 5.4 ) Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation ( 5.5 ) Upper Gastrointestinal Tract Obstruction : Avoid in patients with pyloric stenosis or other organic or functional obstruction. ( 5.6 ) Photosensitivity : Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. ( 5.7 ) Nephrolithiasis : Stones containing mesalamine, the active moiety in balsalazide disodium capsules, are undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with balsalazide disodium capsules. ( 5.8 ) Interference with Laboratory Tests : Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. ( 5.9 ) 5.1 Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as balsalazide disodium capsules that release mesalamine into the gastrointestinal tract. Evaluate renal function prior to initiation of balsalazide disodium capsules and periodically while on therapy. Evaluate the risks and benefits of using balsalazide disodium capsules in patients with known renal impairment, a history of renal disease or taking nephrotoxic drugs. Discontinue balsalazide disodium capsules if renal function deteriorates while on therapy [see Drug Interactions (7.1) , Use in Specific Populations (8.6) ] . 5.2 Mesalamine-Induced Acute Intolerance Syndrome Balsalazide is converted to mesalamine, which has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with balsalazide disodium capsules. 5.3 Hypersensitivity Reactions Some patients have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to balsalazide disodium capsules or to other compounds that contain or are converted to mesalamine. Mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue balsalazide disodium capsules if an alternative etiology for the signs and symptoms cannot be established. 5.4 Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Because balsalazide is converted to mesalamine, evaluate the risks and benefits of using balsalazide disodium capsules in patients with known liver impairment. 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine, the active moiety of balsalazide disodium capsules [see Adverse Reactions (6.2)]. Discontinue balsalazide disodium capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.6 Upper Gastrointestinal Tract Obstruction Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of balsalazide disodium capsules, which would delay mesalamine release in the colon. Avoid balsalazide disodium capsules in patients at risk of upper gastrointestinal tract obstruction. 5.7 Photosensitivity Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. 5.8 Nephrolithiasis Cases of nephrolithiasis have been reported with the use of mesalamine, the active moiety of balsalazide disodium capsules, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with balsalazide disodium capsules. 5.9 Interference with Laboratory Tests Use of balsalazide disodium capsules, which is converted to mesalamine, may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5- ASA). Consider an alternative, selective assay for normetanephrine.

7 DRUG INTERACTIONS Nephrotoxic Agents including NSAIDs: Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine- related adverse reactions. ( 7.1 ) Azathioprine or 6-Mercaptopurine: Increased risk of blood disorders; monitor complete blood cell counts and platelet counts. ( 7.2 ) 7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs), may increase the risk of renal reactions. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1) ]. 7.2 Azathioprine or 6-Mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of balsalazide disodium capsules and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. 7.3 Interference with Urinary Normetanephrine Measurements Use of balsalazide disodium capsules, which is converted to mesalamine, may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions (5.9) ] . Consider an alternative, selective assay for normetanephrine.

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 Zydus Pharmaceuticals (USA) at 1-877-993-8779 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 disodium in 4 controlled trials. In the 4 controlled clinical trials patients receiving a balsalazide disodium 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 disodium 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 disodium Patients in Controlled Trials Adverse reactions occurring in at least 1% of balsalazide disodium patients which were less frequent than placebo for the same adverse reaction were not included in the table. Adverse Reaction balsalazide disodium capsules 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 years to 17 years with mildly to moderately active ulcerative colitis who received 6.75 g/day or 2.25 g/day balsalazide disodium 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 disodium 6.75 g/day and 3 patients who received balsalazide disodium 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 disodium 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) ]

8.1 Pregnancy Risk Summary Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of balsalazide disodium, during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations) . In animal reproduction studies, there were no adverse developmental effects observed after oral administration of balsalazide disodium in pregnant rats and rabbits during organogenesis at doses up to 2.4 and 4.7 times, respectively, the maximum recommended human dose (MRHD) (see Data) . 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 embryo/fetal risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Data Human Data Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of balsalazide disodium, during early pregnancy (first trimester) and throughout pregnancy have not reliably informed an association of mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is no clear evidence that mesalamine exposure in early pregnancy is associated with an increased risk in major congenital malformations, including cardiac malformations. Published epidemiologic studies have important methodological limitations which hinder interpretation of the data, including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant medications, and missing information on the dose and duration of use for mesalamine products. Animal Data Reproduction studies were performed in rats and rabbits following administration of balsalazide during organogenesis at oral doses up to 2 g/kg/day, 2.4 and 4.7 times the MRHD based on body surface area for the rat and rabbit, respectively, and revealed no adverse embryofetal developmental effects due to balsalazide disodium.