Balsalazide Disodium

RECENT MAJOR CHANGES Warnings and Precautions, Renal Impairment ( 5.1 ) 11/2022

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 )] .

3 DOSAGE FORMS AND STRENGTHS Balsalazide Disodium Capsules, USP are available as light orange opaque capsules containing 750 mg balsalazide disodium, USP and "54 795" printed in black ink on the cap and body, containing a yellow-orange powder. Capsules: 750 mg ( 3 )

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 )

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 (incidence ≥3%) are headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia. Adverse reactions in children were similar. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies 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 event 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/ …

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.

8 USE IN SPECIFIC POPULATIONS 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 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. 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-dete …

12.1 Mechanism of Action 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.

11 DESCRIPTION Each Balsalazide Disodium Capsules, USP contains 750 mg of balsalazide disodium, a prodrug that is enzymatically cleaved in the colon to produce mesalamine (5-aminosalicylic acid or 5-ASA), an aminosalicylate. Each capsule of balsalazide disodium (750 mg) is equivalent to 267 mg of mesalamine. Balsalazide disodium has the chemical name (E)-5-[[-4-[[(2-carboxyethyl)amino]carbonyl]phenyl]azo]-2-hydroxybenzoic acid, disodium salt, dihydrate. Its structural formula is: Molecular Weight: 437.32 Molecular Formula: C 17 H 13 N 3 O 6 Na 2 ●2H 2 O Balsalazide disodium is a stable orange to yellow crystalline powder. It is freely soluble in water and isotonic saline, sparingly soluble in methanol and ethanol and practically insoluble in all other organic solvents. Inactive Ingredients: Each hard gelatin capsule contains colloidal silicon dioxide and magnesium stearate. Additionally, the capsule shell contains gelatin, titanium dioxide, iron oxide yellow, and iron oxide red. The black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and water. The sodium content of each capsule is approximately 78.89 mg/ capsule (10.51%). chemstruc

10 OVERDOSAGE Balsalazide disodium capsules are 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Balsalazide Disodium Capsules, USP are available as white, opaque capsules imprinted “APO B750” in red ink. Balsalazide Disodium Capsules, USP are supplied as follows: Bottles of 30 (NDC 60505-2575-3) Bottles of 280 (NDC 60505-2575-7) Bottles of 350 (NDC 60505-2575-4) Unit Dose Blister Packs of 10 strips of 10 capsules (NDC 60505-2575-0) Storage Store at 20oC to 25oC (68oF to 77oF); excursions permitted between 15oC and 30oC (59oF and 86oF). See USP Controlled Room Temperature.