Balsalazide

Name: Balsalazide

Side effects

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 COLAZAL in 4 controlled trials.

In the 4 controlled clinical trials patients receiving a COLAZAL 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 COLAZAL 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 COLAZAL Patients in Controlled Trials*

Adverse Reaction COLAZAL 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%
*Adverse reactions occurring in at least 1% of Colazal patients which were less frequent than placebo for the same event were not included in the table.

Pediatric Ulcerative Colitis

In a clinical trial in 68 pediatric patients aged 5 to 17 years with mildly to moderately active ulcerative colitis who received 6.75 g/day or 2.25 g/day COLAZAL for 8 weeks, the most frequently reported adverse reactions were headache (15%), abdominal pain upper (13%), abdominal pain (12%), vomiting (10%), diarrhea (9%), colitis ulcerative (6%), nasopharyngitis (6%), and pyrexia (6%). [see Table 2]

One patient who received COLAZAL 6.75 g/day and 3 patients who received COLAZAL 2.25 g/ day discontinued treatment because of adverse reactions. In addition, 2 patients in each dose group discontinued because of a lack of efficacy.

Adverse reactions reported by 3% or more of pediatric patients within either treatment group in the Phase 3 trial are presented in Table 2.

Table 2: Treatment-Emergent Adverse Reactions Reported by ≥ 3% of Patients in Either Treatment Group in a Controlled Study of 68 Pediatric Patients

Adverse Reaction COLAZAL 6.75 g/day
[N=33]
2.25 g/day
[N=35]
Total
[N=68]
Headache 5 (15%) 5 (14%) 10 (15%)
Abdominal pain upper 3 (9%) 6 (17%) 9 (13%)
Abdominal pain 4 (12%) 4 (11%) 8 (12%)
Vomiting 1 (3%) 6 (17%) 7 (10%)
Diarrhea 2 (6%) 4 (11%) 6 (9%)
Colitis ulcerative 2 (6%) 2 (6%) 4 (6%)
Nasopharyngitis 3 (9%) 1 (3%) 4 (6%)
Pyrexia 0 (0%) 4 (11%) 4 (6%)
Hematochezia 0 (0%) 3 (9%) 3 (4%)
Nausea 0 (0%) 3 (9%) 3 (4%)
Influenza 1 (3%) 2 (6%) 3 (4%)
Fatigue 2 (6%) 1 (3%) 3 (4%)
Stomatitis 0 (0%) 2 (6%) 2 (3%)
Cough 0 (0%) 2 (6%) 2 (3%)
Pharyngolaryngeal pain 2 (6%) 0 (0%) 2 (3%)
Dysmenorrhea 2 (6%) 0 (0%) 2 (3%)

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 COLAZAL clinical trials. One case of Kawasaki-like syndrome which included hepatic function changes was also reported, however, this adverse reaction was not reported in COLAZAL clinical trials.

Clinical pharmacology

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-s-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.

Pharmacokinetics

COLAZAL 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 3. In this study, a single oral dose of COLAZAL 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 unencapsulated (3 x 750 mg) as sprinkles on applesauce.

Table 3: Plasma Pharmacokinetics for Balsalazide and Key Metabolites (5—ASA and N-Ac-5- ASA) with Administration of COLAZAL 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 (μg/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 (μghr/mL)
  Balsalazide 1.35 ± 0.73 1.52 ± 1.01 0.87 ± 0.48
  5-ASA 2.59 ± 1.46 2.10 ± 2.58 2.99 ± 1.70
  N-Ac-5-ASA 17.8 ± 8.14 17.7 ± 13.7 20.0 ± 11.4
Tmax (h)
  Balsalazide 0.8 ± 0.85 1.2 ± 1.11 1.6 ± 0.44
  5-ASA 8.2 ± 1.98 22.0 ± 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 μg•hr/mL to 0.480 μg•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 COLAZAL (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively.

In a multiple-dose study in healthy subjects receiving a COLAZAL 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-gram dose of COLAZAL 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 3-6 g of COLAZAL 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-s-alanine comprised < 16% and < 12% of the balsalazide dose, respectively. No fecal recovery studies were performed in this population.

Pediatric Population

In studies of pediatric patients with mild-to-moderate active ulcerative colitis receiving three 750 mg COLAZAL capsules 3 times daily (6.75 g/day) for 8 weeks, steady state was reached within 2 weeks, as observed in adult patients. Likewise, the pharmacokinetics of balsalazide, 5-ASA, and N-Ac-5-ASA were characterized by very large inter-patient variability, which is also similar to that seen in adult patients.

The pro-drug moiety, balsalazide, appeared to exhibit dose-independent (i.e., dose-linear) kinetics in children, and the systemic exposure parameters (Cmax and AUC0-8) increased in an almost dose-proportional fashion after the 6.75 g/day versus the 2.25 g/day doses. However, the absolute magnitude of these exposure parameters was greater relative to adults. The Cmax and AUC0-8 observed in pediatric patients were 26% and 102% greater than those observed in adult patients at the 6.75 g/ day dosage level. In contrast, the systemic exposure parameters for the active metabolites, 5-ASA and N-Ac-5-ASA, in pediatric patients increased in a less than dose-proportional manner after the 6.75 g/ day dose versus the 2.25 g/day dose. Additionally, the magnitude of these exposure parameters was decreased for both metabolites relative to adults. For the metabolite of key safety concern from a systemic exposure perspective, 5-ASA, the Cmax and AUC0-8 observed in pediatric patients were 67% and 64% lower than those observed in adult patients at the 6.75 g/day dosage level. Likewise, for N-Ac-5-ASA, the Cmax and AUC0-8 observed in pediatric patients were 68% and 55% lower than those observed in adult patients at the 6.75 g/day dosage level.

All pharmacokinetic studies with COLAZAL are characterized by large variability in the plasmaconcentration versus time profiles for balsalazide and its metabolites, thus half-life estimates of these analytes are indeterminate.

Animal Toxicology

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), COLAZAL 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.

Clinical Studies

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 COLAZAL (Figure 1).

Figure 1: Percentage of Patients Improved at 8 weeks

A second study, conducted in Europe, confirmed findings of symptomatic improvement.

Pediatric Studies

A clinical trial was conducted comparing two doses (6.75 g/day and 2.25 g/day) of COLAZAL 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 COLAZAL 6.75 g/ day group and 13 (37%) patients in the COLAZAL 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 COLAZAL 6.75 g/day and 54% of patients treated with COLAZAL 2.25 g/day. Colonic mucosal appearance upon endoscopy improved in 61% of patients treated with COLAZAL 6.75 g/day and 46% of patients treated with COLAZAL 2.25 g/day.

Pharmacology

Mechanism of Action

Metabolized to mesalamine by intestinal flora

Mesalamine (5-aminosalicylic acid) has anti-inflammatory effect; active component of sulfasalazine, specific MOA unknown; probably inhibits prostaglandin & leukotrienes synthesis & release in colon

Absorption

Bioavailability: Low absorption

Onset: 10 days to 2 wk

Peak Plasma Time: 1-2 hr

Distribution

Protein Bound: 99%

Vd: mesalamine: 0.2 L/kg

Metabolism

Following oral administration, balsalazide passes intact into colon where it is cleaved by intestinal flora to form mesalamine and 4-aminobenzoyl-b-alanine

Mesalamine is rapidly acetylated in colon wall and liver, independent of pt. acetylator status, into N-acetyl-5-aminosalycylic acid

Metabolites: mesalamine (active), N-acetyl-5-aminosalycylic acid (inactive), 4-aminobenzoyl-b-alanine (inactive)

Elimination

Half-Life: Undetermined due to large intersubject variability

Excretion: Feces (as metabolites) >65%; urine (as metabolites) >25%

Patient Handout

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Balsalazide Brand Names

Balsalazide may be found in some form under the following brand names:

  • Colazal

  • Giazo

Balsalazide Drug Class

Balsalazide is part of the drug class:

  • Aminosalicylic acid and similar agents

What is the most important information I should know about balsalazide?

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What should I avoid while taking balsalazide?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

What other drug's will affect balsalazide?

Other drugs may interact with balsalazide, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

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.

Balsalazide - Clinical Pharmacology

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-β-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 or 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.

Pharmacokinetics

Balsalazide disodium 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-β-alanine. The 5-ASA is further metabolized to yield Nacetyl-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 3. 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 unencapsulated (3 x 750 mg) as sprinkles on applesauce.

 Table 3: 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 2.10 ± 2.58 2.99 ± 1.70
   N-Ac-5-ASA 17.8 ± 8.14 17.7 ± 13.7 20.0 ± 11.4
Tmax (h)
   Balsalazide 0.8 ± 0.85 1.2 ± 1.11 1.6 ± 0.44
   5-ASA 8.2 ± 1.98 22.0 ± 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 0.480 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-β-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 0.20%, 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-gram dose of Balsalazide was recovered as 5-ASA, 4-aminobenzoyl-β-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-β-alanine was detected in urine. The mean urinary recovery of N-Ac-5-ASA and N-acetyl-4-aminobenzoyl-β-alanine comprised <16% and <12% of the Balsalazide dose, respectively. No fecal recovery studies were performed in this population.

Pediatric Population
In studies of pediatric patients with mild-to-moderate active ulcerative colitis receiving three 750 mg Balsalazide disodium capsules 3 times daily (6.75 g/day) for 8 weeks, steady state was reached within 2 weeks, as observed in adult patients. Likewise, the pharmacokinetics of Balsalazide, 5-ASA, and N-Ac-5-ASA were characterized by very large inter-patient variability, which is also similar to that seen in adult patients.

The pro-drug moiety, Balsalazide, appeared to exhibit dose-independent (i.e., doselinear) kinetics in children, and the systemic exposure parameters (Cmax and AUC0 to 8) increased in an almost dose-proportional fashion after the 6.75 g/day versus the 2.25 g/day doses. However, the absolute magnitude of these exposure parameters was greater relative to adults. The Cmax and AUC0 to 8 observed in pediatric patients were 26% and 102% greater than those observed in adult patients at the 6.75 g/day dosage level. In contrast, the systemic exposure parameters for the active metabolites, 5-ASA and N-Ac- 5-ASA, in pediatric patients increased in a less than dose-proportional manner after the 6.75 g/day dose versus the 2.25 g/day dose. Additionally, the magnitude of these exposure parameters was decreased for both metabolites relative to adults. For the metabolite of key safety concern from a systemic exposure perspective, 5-ASA, the Cmax and AUC0 to 8 observed in pediatric patients were 67% and 64% lower than those observed in adult patients at the 6.75 g/day dosage level. Likewise, for N-Ac-5-ASA, the Cmax and AUC0 to 8 observed in pediatric patients were 68% and 55% lower than those observed in adult patients at the 6.75 g/day dosage level.

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.

How Supplied/Storage and Handling

Balsalazide Disodium Capsules, USP are available as white, opaque capsules imprinted “APO B750” in red ink.

Balsalazide Disodium Capsules, USP are supplied as follows:

Bottles of 280 (NDC 42291-157-28). 

Storage

Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º and 30ºC (59º and 86ºF).

See USP Controlled Room Temperature.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as disodium:

Colazal: 750 mg

Generic: 750 mg

Tablet, Oral, as disodium:

Giazo: 1.1 g

Usual Adult Dose for Ulcerative Colitis - Active

Mildly to moderately active:
Capsules: 2250 mg orally 3 times a day for up to 8 weeks
In clinical trials, some patients required treatment for up to 12 weeks.

Tablets:
Male patients: 3.3 g orally twice a day for up to 8 weeks
Female patients: Effectiveness has not been established.

Balsalazide Levels and Effects while Breastfeeding

Summary of Use during Lactation

Although no information exists on the excretion of balsalazide into breastmilk, it is metabolized to the active drug mesalamine. A few cases of diarrhea have been reported in infants exposed to mesalamine, although the rate is not high. Most experts consider mesalamine derivatives to be safe during breastfeeding.[1][2][3][4] If balsalazide is required by the mother, it is not a reason to discontinue breastfeeding, but observe breastfed infants for diarrhea.

Drug Levels

Balsalazide is a prodrug that liberates the active drug, mesalamine (5-aminosalicylic acid; 5-ASA), in the gastrointestinal tract. Mesalamine is metabolized to N-acetyl-5-ASA which is inactive in treating inflammatory bowel disease, but its possible effects on the breastfed infant are unknown.

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

The active metabolite of balsalazide, mesalamine, was probably responsible for diarrhea in a 6-week-old whose diarrhea recurred 4 times after rechallenge of the mother 4 times during breastfeeding.[5]

Diarrhea has also been reported anecdotally by some nursing mothers taking mesalamine,[6] but a small controlled study reported only in abstract form found no higher rate of diarrhea in the breastfed infants of mothers taking mesalamine than in control infants.[7]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Mesalamine, Sulfasalazine

References

1. Nielsen OH, Maxwell C, Hendel J. IBD medications during pregnancy and lactation. Nat Rev Gastroenterol Hepatol. 2014;11:116-27. PMID: 23897285

2. Mahadevan U, Matro R. Care of the pregnant patient with inflammatory bowel disease. Obstet Gynecol. 2015;126:401-12. PMID: 26241432

3. Nguyen GC, Seow CH, Maxwell C et al. The Toronto Consensus Statements for the Management of IBD in Pregnancy. Gastroenterology. 2016;150:734-57. PMID: 26688268

4. van der Woude CJ, Ardizzone S, Bengtson MB et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis. 2015;9:107-24. PMID: 25602023

5. Nelis GF. Diarrhoea due to 5-aminosalicylic acid in breast milk. Lancet. 1989;333:383. Letter. PMID: 2563532

6. Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol. 1993;168:1393-9. PMID: 8498418

7. Moretti ME, Spiczynski Y, Hashemi G et al. Prospective follow-up of infants exposed to 5-aminosalicylic acid containing drugs through maternal milk. J Clin Pharmacol. 1998;38:867. Abstract.

Balsalazide Identification

Substance Name

Balsalazide

CAS Registry Number

82101-18-6

Drug Class

Anti-Inflammatory Agents, Non-Steroidal

Gastrointestinal Agents

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