BALSALAZIDE DISODIUM
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balsalazide disodium capsule
Roxane Laboratories, Inc
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FULL PRESCRIBING INFORMATION
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]
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 four controlled, Phase 3 trials are presented by treatment group in 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.
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| 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 in clinical practice of products which contain (or are metabolized to) mesalamine. 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 mesalamine.
Hepatic
Postmarketing adverse reactions of hepatotoxicity have been reported, 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.
Several cases of alopecia in patients taking balsalazide have been reported.
7 DRUG INTERACTIONS
No drug interaction studies have been conducted for balsalazide.
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:
Molecular Weight: 437.32
Molecular Formula: C17H13N3O6Na2•2H2O
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 86 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.
| 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.
Distribution
The binding of balsalazide to human plasma proteins was ≥99%.
Metabolism
The products of the azoreduction of this compound, 5-ASA and 4-aminobenzoyl-ß-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces.
Elimination
Following single-dose administration of 2.25 g balsalazide (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.2%, 0.22% and 10.2%, respectively.
In a multiple-dose study in healthy subjects receiving a balsalazide dose of two 750 mg capsules twice daily (3 g/day) for 10 days, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.1%, 0%, and 11.3%, respectively. During this study, subjects received their morning dose 0.5 hours after being fed a standard meal, and subjects received their evening dose 2 hours after being fed a standard meal.
In a study with 10 healthy volunteers, 65% of a single 2.25 g dose of balsalazide was recovered as 5-ASA, 4-aminobenzoyl-ß-alanine, and the N-acetylated metabolites in feces, while <1% of the dose was recovered as parent compound.
In a study that examined the disposition of balsalazide in patients who were taking 3 to 6 g of balsalazide daily for more than 1 year and who were in remission from ulcerative colitis, less than 1% of an oral dose was recovered as intact balsalazide in the urine. Less than 4% of the dose was recovered as 5-ASA, while virtually no 4-aminobenzoyl-ß-alanine was detected in urine. The mean urinary recovery of N-Ac-5-ASA and N-acetyl-4-aminobenzoyl-ß-alanine comprised <16% and <12% of the balsalazide dose, respectively. No fecal recovery studies were performed in this population.
All pharmacokinetic studies with balsalazide are characterized by large variability in the plasma concentration versus time profiles for balsalazide and its metabolites, thus half-life estimates of these analytes are indeterminate.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month rat (Sprague Dawley) carcinogenicity study, oral (dietary) balsalazide disodium at doses up to 2 g/kg/day was not tumorigenic. For a 50 kg person of average height this dose represents 2.4 times the recommended human dose on a body surface area basis. Balsalazide disodium was not genotoxic in the following in vitro or in vivo tests: Ames test, human lymphocyte chromosomal aberration test, and mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, or mouse micronucleus test. However, it was genotoxic in the in vitro Chinese hamster lung cell (CH V79/HGPRT) forward mutation test.
4-aminobenzoyl-ß-alanine, a metabolite of balsalazide disodium, was not genotoxic in the Ames test and the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test but was positive in the human lymphocyte chromosomal aberration test. N-acetyl-4-aminobenzoyl-ß-alanine, a conjugated metabolite of balsalazide disodium, was not genotoxic in Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, or the human lymphocyte chromosomal aberration test. Balsalazide disodium at oral doses up to 2 g/kg/day, 2.4 times the recommended human dose based on body surface area, was found to have no effect on fertility and reproductive performance in rats.
13.2 Animal Toxicology and/or Pharmacology
Renal Toxicity
In animal studies conducted at doses up to 2000 mg/kg (approximately 21 times the recommended 6.75 g/day dose on a mg/kg basis for a 70 kg person), balsalazide demonstrated no nephrotoxic effects in rats or dogs.
Overdosage
A single oral dose of balsalazide disodium at 5 g/kg or 4-aminobenzoyl-ß-alanine, a metabolite of balsalazide disodium, at 1 g/kg was non-lethal in mice and rats. No symptoms of acute toxicity were seen at these doses.
14 CLINICAL STUDIES
14.1 Adult Studies
Two randomized, double-blind studies were conducted in adults. In the first trial, 103 patients with active mild-to-moderate ulcerative colitis with sigmoidoscopy findings of friable or spontaneously bleeding mucosa were randomized and treated with balsalazide 6.75 g/day or balsalazide 2.25 g/day. The primary efficacy endpoint was reduction of rectal bleeding and improvement of at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician’s global assessment [PGA]). Outcome assessment for rectal bleeding at each interim period (week 2, 4, and 8) encompassed a 4-day period (96 hours). Results demonstrated a statistically significant difference between high and low doses of balsalazide (Figure 1).
Figure 1: Percentage of Patients Improved at 8 Weeks
A second study, conducted in Europe, confirmed findings of symptomatic improvement.
14.2 Pediatric Studies
A clinical trial was conducted comparing two doses (6.75 g/day and 2.25 g/day) of balsalazide in 68 pediatric patients (age 5 to 17, 23 males and 45 females) with mildly to moderately active ulcerative colitis. 28 /33 (85%) patients randomized to 6.75 g/day and 25/35 (71%) patients randomized to 2.25 g/day completed the study. The primary endpoint for this study was the proportion of subjects with clinical improvement (defined as a reduction of at least 3 points in the Modified Sutherland Ulcerative Colitis Activity Index [MUCAI] from baseline to 8 weeks). Fifteen (45%) patients in the balsalazide 6.75 g/day group and 13 (37%) patients in the balsalazide 2.25 g/day group showed this clinical improvement. In both groups, patients with higher MUCAI total scores at baseline were likely to experience greater improvement.
Rectal bleeding improved in 64% of patients treated with balsalazide 6.75 g/day and 54% of patients treated with balsalazide 2.25 g/day. Colonic mucosal appearance upon endoscopy improved in 61% of patients treated with balsalazide 6.75 g/day and 46% of patients treated with balsalazide 2.25 g/day.
16 HOW SUPPLIED/STORAGE AND HANDLING
Balsalazide Disodium Capsules are supplied as light orange opaque capsules containing 750 mg blasalazide disodium and "54 795" printed in black ink on the cap and body, containing a yellow-orange powder.
0054-0079-28 750 mg, light orange opaque capsules, bottle of 280
Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]
17 PATIENT COUNSELING INFORMATION
17.1 Important Precautions Regarding Balsalazide
- Instruct patients not to take balsalazide if they have a hypersensitivity to salicylates (e.g., aspirin).
- Patients should be instructed to contact their health care provider under the following circumstances:
- If they experience a worsening of their ulcerative colitis symptoms.
- If they are diagnosed with pyloric stenosis, because balsalazide capsules may be slow to pass through their digestive tract.
- If they are diagnosed with renal dysfunction. Damage to the kidney has been observed in people given medications similar to balsalazide.
17.2 What Patients Should Know About Adverse Reactions
- In adult clinical trials the most common adverse reactions were headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia.
- Inform patients that this listing of adverse reactions is not complete and not all adverse reactions can be anticipated. If appropriate, a more comprehensive list of adverse reactions can be discussed with patients.
17.3 What Patients Should Know About Taking Balsalazide with Other Medication
- Drug interactions with balsalazide have not been studied.
10003708/02 Revised September 2007
©RLI, 2007
Package Label - Balsalazide disodium capsules
750 mg - 280 Capsules
NDC 0054-0079-28
Rx Only
Roxane Laboratories, Inc
| BALSALAZIDE DISODIUM
balsalazide disodium capsule |
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA077806 | 12/28/2007 | |
| Labeler - Roxane Laboratories, Inc (058839929) |
| Registrant - Roxane Laboratories, Inc (058839929) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Boehringer Ingelheim Roxane Inc | 128407710 | MANUFACTURE | |