COLAZAL® (balsalazide disodium) capsules

COLAZAL® (balsalazide disodium) capsules

COLAZAL®

Each COLAZAL capsule 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 COLAZAL (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.

Molecular Weight: 437.32

Molecular Formula: C17H13N3O6Na2●2H2O

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. The sodium content of each capsule is approximately 86 mg.

INDICATIONS AND USAGE

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

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-ß-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.

DOSAGE AND ADMINISTRATION

  • Evaluate renal function before initiating therapy with COLAZAL
  • Swallow COLAZAL capsules whole. Do not cut, break, crush or chew the capsules.
  • For patients who cannot swallow intact capsules, COLAZAL 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 COLAZAL 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 COLAZAL in the pediatric population for more than 8 weeks has not been evaluated in clinical trials

CONTRAINDICATIONS

COLAZAL is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or to any of the components of COLAZAL capsules or balsalazide metabolites.

WARNINGS AND PRECAUTIONS

Renal Impairment: Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has beenreported in patients given products such as COLAZAL that release mesalamine into the gastrointestinal tract. Evaluaterenal function prior to initiation of COLAZAL and periodically while on therapy. Evaluate the risks and benefits of usingCOLAZAL in patients with known renal impairment, a history of renal disease or taking nephrotoxic drugs.

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. Symptomsinclude cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash.

Monitor patients forworsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinuetreatment with COLAZAL.

Hypersensitivity Reactions: Some patients have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to COLAZAL orto 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 COLAZAL if an alternative etiology for the signs and symptoms cannot be established.

Hepatic Failure: There have been reports of hepatic failure in patients with pre-existing liver disease who have been administeredmesalamine. Because balsalazide is converted to mesalamine, evaluate the risks and benefits of using COLAZAL inpatients with known liver impairment.

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 COLAZAL.

Upper Gastrointestinal Tract Obstruction: Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastricretention of COLAZAL, which would delay mesalamine release in the colon. Avoid COLAZAL in patients at risk ofupper gastrointestinal tract obstruction.

Photosensitivity: Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severephotosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrumsunscreen when outdoors.

Nephrolithiasis: Cases of nephrolithiasis have been reported with the use of mesalamine, the active moiety of COLAZAL, 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 COLAZAL.

Interference with Laboratory Tests: Use of COLAZAL, which is converted to mesalamine, may lead to spuriously elevated test results when measuringurinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in thechromatograms of normetanephrine and the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

Adverse drug reactions

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

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

DRUG INTERACTIONS

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 COLAZAL 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 COLAZAL, 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.

USE IN SPECIFIC POPULATIONS

Pregnancy: Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety ofCOLAZAL, during pregnancy have not reliably informed an association with mesalamine and major birth defects,miscarriage, or adverse maternal or fetal outcomes. There are adverse effects on maternal and fetal outcomesassociated with ulcerative colitis in pregnancy.

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.

Lactation: Data from published literature report the presence of mesalamine and its metabolite, N acetyl-5 aminosalicylic acid, inhuman milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine. There are casereports of diarrhea in breastfed infants exposed to mesalamine. 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 therisk of COLAZAL to an infant during lactation; therefore, the developmental and health benefits of breastfeeding shouldbe considered along with the mother’s clinical need for COLAZAL and any potential adverse effects on the breastfedchild from COLAZAL or from the underlying maternal condition.

Advise the caregiver to monitor breastfed infants for diarrhea.

Pediatric Use: The safety and effectiveness of COLAZAL has been established for the treatment of mildly to moderately activeulcerative colitis in pediatric and adolescent patients 5 years to 17 years of age. Use of COLAZAL for this indication issupported by evidence from adequate and well-controlled clinical studies in adults with additional pharmacokinetic andsafety data in pediatric patients aged 5 years to 17 years.

Renal Impairment: Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to COLAZAL, 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 COLAZAL 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.

OVERDOSAGE

COLAZAL 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.

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