GIAZO® (balsalazide disodium) tablets

GIAZO® (balsalazide disodium) tablets

GIAZO® (balsalazide disodium)

Each GIAZO tablet contains 1.1 g of balsalazide disodium, an orally available prodrug that is enzymatically cleaved to produce mesalamine (5-aminosalicylic acid, 5-ASA), an aminosalicylate. 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, odorless, orange to yellow, microcrystalline powder. It is insoluble in acid, but soluble at a pH of at least 4.5. 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 tablet contains hypromellose, magnesium stearate, and Opadry II Yellow. The sodium content of each tablet is approximately 126 mg.

INDICATIONS AND USAGE

GIAZO is indicated for the treatment of mildly to moderately active ulcerative colitis in male patients 18 years of age and older.

Limitations of Use:

  • Effectiveness of GIAZO in the treatment of female patients was not demonstrated in clinical trials
  • Safety and effectiveness of GIAZO therapy beyond 8 weeks have not been established.

Mechanism of Action

Balsalazide is a prodrug of mesalamine (5-aminosalicylic acid, 5-ASA). 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

The recommended dosage is 3.3 g (three 1.1 g tablets) orally twice daily with or without food for up to 8 weeks. Drink an adequate amount of fluids.

CONTRAINDICATIONS

GIAZO is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates or their metabolites, or to any of the components of GIAZO tablets.

WARNINGS AND PRECAUTIONS

Renal Impairment: Renal impairment, including minimal change disease, acute and chronic interstitial nephritis and renal failure, has been reported in patients given products that release mesalamine in the gastrointestinal tract. Evaluate renal function prior to initiation of GIAZO and periodically while on therapy. Evaluate the risks and benefits of using GIAZO 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. In controlled clinical trials with GIAZO in adults with ulcerative colitis, 7% of male patients reported exacerbation of the symptoms of ulcerative colitis. 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 GIAZO.

Hypersensitivity Reactions: Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to GIAZO 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 GIAZO 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 administered mesalamine. Because balsalazide is converted to mesalamine, evaluate the risks and benefits of GIAZO in patients 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), acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine, the active moiety of GIAZO. Discontinue GIAZO at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

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.

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

Sodium Content of GIAZO: Each 1.1 g tablet of GIAZO contains 126 mg of sodium. The recommended dosage of GIAZO (6.6 g/day) provides about 756 mg of sodium per day. Take the sodium content of GIAZO into consideration when administering to patients on a sodium-restricted diet or those at risk for developing congestive heart failure.

Interference with Laboratory Tests: Use of GIAZO, 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 mesalamine’s main metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

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 GIAZO 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 GIAZO, 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 of GIAZO, 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 outcomes associated with ulcerative colitis in pregnancy.

Lactation: 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. There are case reports 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 the risk of GIAZO to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GIAZO and any potential adverse effects on the breastfed child from GIAZO or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness of GIAZO in pediatric patients have not been established.

Geriatric Use: Clinical trials of GIAZO 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. GIAZO is converted into mesalamine in the colon. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with GIAZO. 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 GIAZO.

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

GIAZO 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 intoxication with salicylates 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.