Balsalazide

Balsalazide is a 5-Aminosalicylic acid derivative belonging to anti-inflammatory agent.

Balsalazide is an aminosalicylate used for the treatment of ulcerative colitis.

In a 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 µghr/mL to 0.480 µghr/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. Mainly excreted via faeces (approximately 65%, as mesalazine, 4-aminobenzoyl-β-alanine or N-acetylated metabolites); urine, (approximately 25%, as N-acetylated metabolites); <1% via urine or faeces (as unchanged drug). Elimination half-life: 6-9 hours (as N-acetylated metabolites); approximately 1 hours (mesalazine).

Balsalazide shows common side effects like Headache, abdominal pain, upset stomach, diarrhoea, vomiting, joint or muscle pain, difficulty falling or staying asleep, tiredness, gas, runny nose, coughing, loss of appetite, constipation, dry mouth.

Balsalazide is available in the form of Oral Tablet and Oral Capsule.

Balsalazide is available in India, US, Canada, Russia, China, Japan, New Zealand, Singapore, France, and Australia.

Balsalazide belongs to the anti-inflammatory agent acts as a 5-Aminosalicylic acid.

The mechanism of action of 5-aminosalicylic acid is unknown but appears exert its anti-inflammatory effects locally (in the GI tract) rather than systemically. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways (catalyzes the formation of prostaglandin precursors from arachidonic acid), and through the lipoxygenase pathways (catalyzes the formation of leukotrienes and hydroxy eicosatetraenoic acids from arachidonic acid and its metabolites), is increased in patients with chronic inflammatory bowel disease. Therefore, it is possible that 5-aminosalicylic acid diminishes inflammation by blocking production of arachidonic acid metabolites in the colon through both the inhibition of cyclooxygenase and lipoxygenase.

The onset and duration of action of Balsalazide is not clinically established.

The Tmax of Balsalazide is approximately 1-2 hours (capsule) and 0.5hour (tablet).

Balsalazide is available in the form of Oral Tablet and Oral Capsule.

Balsalazide tablet is taken orally, usually in divided dose.

Balsalazide is a prodrug that is used in the treatment of ulcerative colitis. Balsalazide should be used with caution in children since the safety and efficacy of use are varied based on the dosage form of Balsalazide.

Balsalazide is a 5-Aminosalicylic acid derivative belonging to anti-inflammatory agent.

Balsalazide is a prodrug, converted by bacterial azoreduction to 5-aminosalicylic acid (mesalamine, active), 4-aminobenzoyl-β-alanine (inert), and their metabolites. 5-aminosalicylic acid may decrease inflammation by blocking the production of arachidonic acid metabolites topically in the colon mucosa.

Balsalazide is approved for use in the following clinical indications

• Ulcerative colitis, remission induction

Balsalazide is an aminosalicylate used to treat ulcerative colitis.

• Ulcerative colitis, remission maintenance (off-label use)

• Ulcerative colitis, remission induction

Adult Dose

Capsule: 2.25 g 3 times daily for 8 to 12 weeks.

Tablet: Males: 3.3 g twice daily for up to 8 weeks.

Pediatric Dose

Children ≥5 years and Adolescents ≤17 years

Capsules: 2.25 g (three 750 mg capsules) 3 times daily (total daily dose: 6.75 g/day) for up to 8 weeks or 750 mg (one capsule) 3 times daily (total daily dose: 2.25 g/day) for up to 8 weeks.

Adolescents ≥18 years

Capsule: 2.25 g (three 750 mg capsules) 3 times daily (total daily dose: 6.75 g/day) for up to 8 to 12 weeks.

Tablet: Males: 3.3 g (three 1.1 g tablets) twice daily (total daily dose: 6.6 g/day) for up to 8 weeks.

• Ulcerative colitis, remission maintenance (off-label use)

Capsule: 1.5 or 3 g twice daily for 6 to 12 months

Balsalazide is available in various strengths as 750mg and 1.1g.

Balsalazide is available in the form of Oral Tablet and Oral Capsule.

Balsalazide is contraindicated in patients with

• Hypersensitivity to balsalazide or its metabolites, amino salicylates, salicylates, or any component of the formulation.

• Dermatologic reactions

Severe cutaneous adverse reactions, including acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. If a reaction occurs, discontinue immediately and consider further evaluation.

• Hypersensitivity reactions

Mesalamine-induced hypersensitivity reactions have been reported and may include internal organ involvement, such as hepatitis, myocarditis, pericarditis, nephritis, hematologic abnormalities, and/or pneumonitis. Monitor for signs and symptoms of hypersensitivity; discontinue treatment if hypersensitivity occurs.

• Intolerance syndrome

May cause an acute intolerance syndrome (cramping, acute abdominal pain, bloody diarrhea; sometimes fever, headache, rash); may be hard to discern from an exacerbation; monitor for worsening of symptoms and discontinue immediately if syndrome occurs or is suspected.

• Photosensitivity

Use with caution in patients with pre-existing skin conditions (including atopic dermatitis and atopic eczema); severe photosensitivity reactions have been reported. Use skin protection (protective clothing and broad-spectrum sunscreen) and avoid prolonged exposure to sunlight and ultraviolet light.

• Renal effects

Renal impairment (including minimal change disease, acute and chronic interstitial nephritis, and renal failure) has been reported. A renal function evaluation is recommended prior to initiation of therapy and periodically during treatment. Evaluate risk versus benefit in patients with renal impairment, history of renal disease, or concurrently taking nephrotoxic medications. Cases of nephrolithiasis (including stones with 100% mesalamine content) have occurred with mesalamine use. Stones may be radiotransparent and undetectable by standard imaging. Ensure patients are adequately hydrated during therapy.

It is not known if balsalazide is present in breast milk. Mesalamine, 5-aminosalicylic acid, is the active metabolite of balsalazide. Mesalamine is present in breast milk; refer to the mesalamine monograph for additional information. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Breastfed infants should be monitored for diarrhea.

Balsalazide is not recommended for use in pregnant women unless necessary. All the risks and benefits should be considered before taking Balsalazide. The tablet form of this medicine is not recommended for use in females.

Common

● Abdominal pain, upper abdominal pain, Headache, Abdominal cramps, anorexia, constipation, diarrhea, dyspepsia, exacerbation of ulcerative colitis, flatulence, hematochezia, nausea, stomatitis, vomiting, xerostomia, Dysmenorrhea, urinary tract infection, Anemia, Influenza, Fatigue, insomnia, Arthralgia, musculoskeletal pain, myalgia, Cough, flu-like symptoms, nasopharyngitis, pharyngitis, pharyngolaryngeal pain, respiratory tract infection, rhinitis, Fever.

Rare

● Facial edema, increased blood pressure, increased heart rate, Erythema nodosum, skin rash, Bowel urgency, fecal impaction, gastroenteritis, gastroesophageal reflux disease, Increased serum aspartate aminotransferase, Dizziness, lethargy, malaise, pain, Back pain, Dyspnea, Swelling.

• 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.

• 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 and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

• Interference With Urinary Normetanephrine Measurements

Use of Balsalazide, which is converted to mesalamine, may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. Consider an alternative, selective assay for normetanephrine.

The common side effects of Balsalazide include the following

Common side effects

● Headache, abdominal pain, upset stomach, diarrhoea, vomiting, joint or muscle pain, difficulty falling or staying asleep, tiredness, gas, runny nose, coughing, loss of appetite, constipation, dry mouth.

Rare side effects

● Chest tightness, Shortness of breath, Difficulty in breathing.

• Pregnancy

Pregnancy Category B

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. 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.

• Nursing Mothers

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.

• Pediatric Use

The safety and effectiveness of Balsalazide 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 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. The safety and effectiveness of Balsalazide in pediatric patients below the age of 5 years have not been established.

• Geriatric Use

Clinical trials of Balsalazide did not include enough subjects aged 65 years and over to determine whether they respond differently than younger subjects. Reports from uncontrolled clinical studies and post marketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia, in patients who were 65 years or older compared to younger patients taking mesalamine-containing products. Balsalazide is converted into mesalamine in the colon. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with Balsalazide. 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.

Balsalazide is an aminosalicylate, and symptoms of salicylate toxicity include nausea, vomiting and abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) damage. There is no specific antidote for balsalazide overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent of further absorption. Proper medical care should be sought immediately with appropriate supportive care, including the possible use of emesis, cathartics, and activated charcoal to prevent further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function.

Pharmacodynamic

Balsalazide is a prodrug that has little or no pharmacologic activity until it is enzymatically cleaved in the colon to produce mesalamine (5-aminosalicylic acid), an anti-inflammatory drug indicated for the treatment of mildly to moderately active ulcerative colitis. 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 intert 4-aminobenzoyl-(beta)-alanine. As a result, the spectrum of pharmacologic activity of balsalazide is similar to that of mesalamine.

Pharmacokinetics

• Absorption

In a 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 µghr/mL to 0.480 µghr/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.

• Excretion

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 subjects, 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.

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