Balsalazide Disodium Drug Information

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.

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.

Important Preparation and

Administration Instructions Evaluate renal function before initiating therapy with balsalazide disodium capsules . 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 . Take balsalazide disodium capsules with or without food .

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 .

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, 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 Placebo 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%) . 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 2.25 g/day Total 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%)

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 Respiratory: pleural effusion, pneumonia (with and without eosinophilia), alveolitis, pleurisy/pleuritis Renal: renal failure, interstitial nephritis, nephrolithiasis 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

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 .

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.

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 . Consider an alternative, selective assay for normetanephrine.

• 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 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, 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.

Pediatric Use The safety and effectiveness of balsalazide disodium capsules 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 capsules 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 . Based on the limited data available, dosing can be initiated at either 6.75 or 2.25 g/day . The safety and effectiveness of balsalazide disodium capsules in pediatric patients below the age of 5 years have not been established.

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 . Known or suspected hypersensitivity to salicylates, aminosalicylates, or any of the components of balsalazide disodium capsules or balsalazide metabolites.

Balsalazide disodium is an aminosalicylate, and symptoms of salicylate toxicity include: nausea, vomiting and abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) damage. There is no specific antidote for balsalazide overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent further absorption. Proper medical care should be sought immediately with appropriate supportive care, including the possible use of emesis, cathartics, and activated charcoal to prevent further absorption.

Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function.