Balsalazide Disodium

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 beyond 8 weeks in pediatric patients 5 years to 17 years of age and 12 weeks in adults have not been established. Balsalazide is 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 )

Balsalazide disodium capsules, USP are available as opaque white capsules containing 750 mg balsalazide disodium, imprinted with “APO B750” in red ink. Capsules: 750 mg ( 3 )

Balsalazide disodium capsules is 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 )

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.

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 Apotex at 1-800-706-5575 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 Reaction Balsalazide Capsules 6.75 g/day [N=259] Placebo [N=35] Abdominal pain Diarrhea Arthralgia Rhinitis Insomnia Fatigue Flatulence Fever Dyspepsia Pharyngitis Coughing Anorexia Urinary tract infection Myalgia Flu-like disorder Dry mouth Cramps Constipation 16 (6%) 14 (5%) 9 (4%) 6 (2%) 6 (2%) 6 (2%) 5 (2%) 5 (2%) 5 (2%) 4 (2%) 4 (2%) 4 (2%) 3 (1%) 3 (1%) 3 (1%) 3 (1%) 3 (1%) 3 (1%) 1 (3%) 1 (3%) 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% *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. 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 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 )]

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 )

Geriatric Patients: Increased risk of blood dyscrasias; monitor blood cell counts and platelet counts. ( 8.5 )

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, 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 2,500 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, 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.

8.2 Lactation Risk Summary Data from published literature report the presence of mesalamine and its metabolite, N acetyl-5 aminosalicylic acid, in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine (see Data). There are case reports of diarrhea in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of balsalazide to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for balsalazide and any potential adverse effects on the breastfed child from balsalazide or from the underlying maternal condition. Clinical Considerations Advise the caregiver to monitor breastfed infants for diarrhea. Data In published lactation studies, maternal mesalamine doses from various oral and rectal mesalamine formulations and products ranged from 500 mg to 4.8 g daily. The average concentration of mesalamine in milk ranged from non-detectable to 0.5 mg/L. The average concentration of N-acetyl-5-aminosalicylic acid in milk ranged from 0.2 to 9.3 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day (RID 0 to 0.1%) of mesalamine and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid.

8.4 Pediatric Use The safety and effectiveness of balsalazide disodium has been established for the treatment of mildly to moderately active ulcerative colitis in pediatric and adolescent patients 5 years to 17 years of age. Use of balsalazide disodium for this indication is supported by evidence from adequate and well-controlled clinical studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 5 years to 17 years [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies (14.2)]. Based on the limited data available, dosing can be initiated at either 6.75 or 2.25 g/day [see Dosage and Administration ( 2.2 )]. The safety and effectiveness of balsalazide disodium capsules in pediatric patients below the age of 5 years have not been established.

8.5 Geriatric Use Clinical trials of balsalazide disodium did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia, in patients who were 65 years or older compared to younger patients taking mesalamine-containing products. Balsalazide disodium is converted into mesalamine in the colon. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with balsalazide disodium. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients when prescribing balsalazide disodium capsules [see Use in Specific Populations ( 8.6 )].

8.6 Renal Impairment Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to balsalazide disodium, which is converted to mesalamine, may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on balsalazide disodium capsules therapy. Monitor patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions. Discontinue balsalazide disodium capsules if renal function deteriorates while on therapy [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.2 ), Drug Interactions ( 7.1 )].

Balsalazide disodium is delivered intact to the colon where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalamine, which is the therapeutically active portion of the molecule, and the 4-aminobenzoyl-β-alanine carrier moiety. The carrier moiety released when balsalazide disodium is cleaved is only minimally absorbed and is largely inert. The mechanism of action of 5-ASA is not fully understood, but appears to be a local anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites in the colon.