Balsalazide Disodium (Page 3 of 6)

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

Renal: renal failure, interstitial nephritis, nephrolithiasis [see Warnings and Precautions (5.1, 5.8)]

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)]

7 DRUG INTERACTIONS

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 (5.8)]. Consider an alternative, selective assay for normetanephrine.

8 USE IN SPECIFIC POPULATIONS

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 increase 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 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 [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 capsules 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 compare to younger patients taking mesalamine-containing products. Balsalazide disodium capsules are converted into mesalamine in the colon. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with balsalazide disodium capsules. 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)].

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