Balsalazide Disodium: Package Insert and Label Information

BALSALAZIDE DISODIUM — balsalazide disodium capsule
Physicians Total Care, Inc.

1 INDICATIONS AND USAGE

Balsalazide Disodium Capsules are indicated for the treatment of mildly to moderately active ulcerative colitis in adults. Safety and effectiveness of Balsalazide Disodium Capsules beyond 12 weeks in adults have not been established.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dose

For treatment of active ulcerative colitis in adult patients, the usual dose is three 750 mg balsalazide capsules to be taken 3 times a day (6.75 g per day) for up to 8 weeks. Some patients in the adult clinical trials required treatment for up to 12 weeks.

2.2 Administration Alternatives

Balsalazide capsules may also be administered by carefully opening the capsule and sprinkling the capsule contents on applesauce. The entire drug/applesauce mixture should be swallowed immediately; the contents may be chewed, if necessary, since contents of balsalazide are NOT coated beads/granules. Patients should be instructed not to store any drug/applesauce mixture for future use.

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.

Teeth and/or tongue staining may occur in some patients who use balsalazide in sprinkle form with food.

3 DOSAGE FORMS AND STRENGTHS

Balsalazide Disodium Capsules are available as light orange opaque capsules containing 750 mg balsalazide disodium and “54 795” imprinted in black ink on the cap and body, containing a yellow-orange powder.

4 CONTRAINDICATIONS

Patients with hypersensitivity to salicylates or to any of the components of Balsalazide Disodium Capsules or balsalazide metabolites. Hypersensitivity reactions may include, but are not limited to the following: anaphylaxis, bronchospasm, and skin reaction.

5 WARNINGS AND PRECAUTIONS

5.1 Exacerbations of Ulcerative Colitis

In the adult clinical trials, 3 out of 259 patients reported exacerbation of the symptoms of ulcerative colitis.

Observe patients closely for worsening of these symptoms while on treatment.

5.2 Pyloric Stenosis

Patients with pyloric stenosis may have prolonged gastric retention of balsalazide capsules.

5.3 Renal

Renal toxicity has been observed in animals and patients given other mesalamine products. Therefore, caution should be exercised when administering balsalazide to patients with known renal dysfunction or a history of renal disease. [See 13 NONCLINICAL TOXICOLOGY (13.2)]

6 ADVERSE REACTIONS

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 6.75 g/day (N=259) Placebo (N=35)
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%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of balsalazide in clinical practice: myocarditis, pericarditis, vasculitis, pruritus, pleural effusion, pneumonia (with and without eosinophilia), alveolitis, renal failure,interstitial nephritis, pancreatitis, and alopecia.

Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to balsalazide.

Hepatic

Postmarketing adverse reactions of hepatotoxicity have been reported for products which contain (or are metabolized to) mesalamine, including 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. Some of these cases were fatal; however, no fatalities associated with these adverse reactions were reported in balsalazide clinical trials. One case of Kawasaki-like syndrome which included hepatic function changes was also reported, however, this adverse reaction was not reported in balsalazide clinical trials.

7 DRUG INTERACTIONS

In an in vitro study using human liver microsomes, balsalazide and its metabolites [5-aminosalicylic acid (5-ASA), N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), 4-aminobenzoyl-ß-alanine (4-ABA) and N-acetyl-4-aminobenzoyl-ß–alanine (N-Ac-4-ABA)] were not shown to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). Therefore, balsalazide and its metabolites are not expected to inhibit the metabolism of other drugs which are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. Reproduction studies were performed in rats and rabbits at oral doses up to 2 g/kg/day, 2.4 and 4.7 times the recommended human dose based on body surface area for the rat and rabbit, respectively, and revealed no evidence of impaired fertility or harm to the fetus due to balsalazide disodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether balsalazide disodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when balsalazide is administered to a nursing woman.

8.4 Pediatric Use

Pediatric use information is protected by marketing exclusivity.

10 OVERDOSAGE

No case of overdose has occurred with balsalazide. A 3-year-old boy is reported to have ingested 2 g of another mesalamine product. He was treated with ipecac and activated charcoal with no adverse reactions.

If an overdose occurs with balsalazide, treatment should be supportive, with particular attention to correction of electrolyte abnormalities.

11 DESCRIPTION

Each Balsalazide Disodium 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 anti-inflammatory drug. Each capsule of balsalazide (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:

structural formula
(click image for full-size original)

Molecular Weight: 437.32

Molecular Formula: C17 H13 N3 O6 Na2 •2H2 O

Balsalazide disodium is a stable, odorless orange to yellow microcrystalline 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 ammonium hydroxide, colloidal silicon dioxide, FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, gelatin, iron oxide black, isopropyl alcohol, magnesium stearate, n-butyl alcohol, propylene glycol, shellac, and titanium dioxide. The sodium content of each capsule is approximately 79 mg.

12 CLINICAL PHARMACOLOGY

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-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 unknown, but appears to be local to the colonic mucosa rather than systemic. 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 chronic inflammatory bowel disease, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites in the colon.

12.3 Pharmacokinetics

Balsalazide capsules contain a powder of balsalazide disodium that is insoluble in acid and designed to be delivered to the colon as the intact prodrug. Upon reaching the colon, bacterial azoreductases cleave the compound to release 5-ASA, the therapeutically active portion of the molecule, and 4-aminobenzoyl-ß-alanine. The 5-ASA is further metabolized to yield N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), a second key metabolite.

Absorption

The plasma pharmacokinetics of balsalazide and its key metabolites from a crossover study in healthy volunteers are summarized in Table 2. In this study, a single oral dose of balsalazide 2.25 g was administered to healthy volunteers as intact capsules (3 x 750 mg) under fasting conditions, as intact capsules (3 x 750 mg) after a high-fat meal, and unencapuslated (3 x 750 mg) as sprinkles on applesauce.

Table 2: Plasma Pharmacokinetics for Balsalazide and Key Metabolites (5-ASA and N-Ac-5-ASA) with Administration of Balsalazide Following a Fast, a High-Fat Meal, and Drug Contents Sprinkled on Applesauce (Mean ± SD)
Fasting (N=17) High-Fat Meal (N=17) Sprinkled (N=17)
Cmax (mcg/mL)
Balsalazide 0.51 ± 0.32 0.45 ± 0.39 0.21 ± 0.12
5-ASA 0.22 ± 0.12 0.11 ± 0.136 0.29 ± 0.17
N-Ac-5-ASA 0.88 ± 0.39 0.64 ± 0.534 1.04 ± 0.57
AUClast (mcg·hr/mL)
Balsalazide 1.35 ± 0.73 1.52 ± 1.01 0.87 ± 0.48
5-ASA 2.59 ± 1.46 2.1 ± 2.58 2.99 ± 1.7
N-Ac-5-ASA 17.8 ± 8.14 17.7 ± 13.7 20 ± 11.4
Tmax (h)
Balsalazide 0.8 ± 0.85 1.2 ± 1.11 1.6 ± 0.44
5-ASA 8.2 ± 1.98 22 ± 8.23 8.7 ± 1.99
N-Ac-5-ASA 9.9 ± 2.49 20.2 ± 8.94 10.8 ± 5.39

A relatively low systemic exposure was observed under all three administered conditions (fasting, fed with high-fat meal, sprinkled on applesauce), which reflects the variable, but minimal absorption of balsalazide disodium and its metabolites. The data indicate that both Cmax and AUClast were lower, while Tmax was markedly prolonged, under fed (high-fat meal) compared to fasted conditions. Moreover, the data suggest that dosing balsalazide disodium as a sprinkle or as a capsule provides highly variable, but relatively similar mean pharmacokinetic parameter values. No inference can be made as to how the systemic exposure differences of balsalazide and its metabolites in this study might predict the clinical efficacy under different dosing conditions (i.e., fasted, fed with high-fat meal, or sprinkled on applesauce) since clinical efficacy after balsalazide disodium administration is presumed to be primarily due to the local effects of 5-ASA on the colonic mucosa.

In a separate study of adult patients with ulcerative colitis, who received balsalazide, 1.5 g twice daily, for over 1 year, systemic drug exposure, based on mean AUC values, was up to 60 times greater (0.008 mcg·hr/mL to 0.48 mcg·hr/mL) when compared to that obtained in healthy subjects who received the same dose.

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