DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Balsalazide is indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. Safety and effectiveness of Balsalazide beyond 8 weeks in children (ages 5-17 years) and 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 Pediatric Dose
For treatment of active ulcerative colitis in pediatric patients, aged 5 to 17 years, the usual dose is EITHER:
Use of Balsalazide in the pediatric population for more than 8 weeks has not been evaluated in clinical trials. .
2.3 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 is available as beige capsules containing 750 mg Balsalazide and CZ imprinted in black.
Capsules: 750 mg (3)
Patients with hypersensitivity to salicylates or to any of the components of Balsalazide capsules or balsalazide metabolites. Hypersensitivity reactions may include, but are not limited to the following: anaphylaxis, bronchospasm, and skin reaction.
Patients with hypersensitivity to salicylates or to any of the components of Balsalazide capsules or balsalazide metabolites. Hypersensitivity reactions may include, but are not limited to the following: anaphylaxis, bronchospasm, and skin reaction. (4)
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. In the pediatric clinical trials, 4 out of 68 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.
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. .
6 ADVERSE REACTIONS
Most common adverse reactions are headache, abdominal pain, diarrhea, nausea, vomiting, respiratory infection, and arthralgia. Adverse reactions in children were similar. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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.
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 Balsalazide 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%). .
One patient who received Balsalazide 6.75 g/day and 3 patients who received Balsalazide 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.
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.
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.
In an in vitro study using human liver microsomes, balsalazide and its metabolites were not shown to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). (7)
8 USE IN SPECIFIC POPULATIONS
Renal impairment: Use Balsalazide with caution in patients with a history of renal disease.
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. 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 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
Use of Balsalazide in pediatric and adolescent patients 5 to 17 years of age for the treatment of mildly to moderately active ulcerative colitis is supported by:
Based on the limited data available, dosing can be initiated at either 6.75 or 2.25 g/day.
Safety and efficacy of Balsalazide in pediatric patients below the age of 5 years have not been established.
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.
Each Balsalazide capsule contains 750 mg of Balsalazide, 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 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 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 colloidal silicon dioxide and magnesium stearate. The sodium content of each capsule is approximately 86 mg.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Balsalazide 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 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.
Balsalazide capsules contain a powder of Balsalazide 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.
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.
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 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 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 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.
The binding of balsalazide to human plasma proteins was ≥99%.
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.
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-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 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.
In studies of pediatric patients with mild-to-moderate active ulcerative colitis receiving three 750 mg Balsalazide 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 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 carcinogenicity study, oral (dietary) Balsalazide 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 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, 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, was not genotoxic in Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, or the human lymphocyte chromosomal aberration test. Balsalazide 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
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.
A single oral dose of Balsalazide at 5 g/kg or 4-aminobenzoyl-ß-alanine, a metabolite of Balsalazide, 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. 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).
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 is available as beige capsules containing 750 mg Balsalazide and CZ imprinted in black.
NDC 65649-101-02 Bottles of 280 capsules.
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F)
17 PATIENT COUNSELING INFORMATION
17.1 Important Precautions Regarding Balsalazide
17.2 What Patients Should Know About Adverse Reactions
17.3 What Patients Should Know About Taking Balsalazide with Other Medication
Salix Pharmaceuticals, Inc., a division of
Valeant Pharmaceuticals North America LLC,
Bridgewater, NJ 08807 USA
Irvine, CA 92614
Balsalazide is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.
© Valeant Pharmaceuticals North America LLC
Product protected by U.S. Patent No. 7,452,872 and U.S. Patent No. 7,625,884
Please see www.salix.com for patent information.
Balsalazide pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Balsalazide available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Balsalazide destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Balsalazide Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Balsalazide pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Balsalazide?
Depending on the reaction of the Balsalazide after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Balsalazide not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Balsalazide addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Balsalazide, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Balsalazide consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology