Mesalamine

Description

Each mesalamine capsule is a delayed- and extended-release dosage form intended for oral administration. Each capsule contains 0.375 g of mesalamine, USP (5-aminosalicylic acid, 5-ASA), an aminosalicylate, with a molecular weight of 153.14 and a molecular formula of C₇H₇NO₃. The extended-release capsules contain granules of mesalamine embedded in a polymer matrix, featuring an enteric coating that dissolves at a pH of 6 and above.

The inactive ingredients in the mesalamine extended-release capsules include microcrystalline cellulose, hypromellose, colloidal silicon dioxide, ethyl acrylate and methyl methacrylate 2:1 copolymer, magnesium stearate, methacrylic acid and methyl methacrylate 1:1 copolymer, talc, triethyl citrate, titanium dioxide, and hypromellose phthalate. The capsule shell is composed of titanium dioxide, FD&C Blue 1, FD&C Red 40, and gelatin, and is printed with edible black ink containing shellac, black iron oxide, and potassium hydroxide. The formulation meets USP Dissolution Test 5.

Uses and Indications

Mesalamine extended-release capsule is indicated for the maintenance of remission of ulcerative colitis in adults.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The recommended dosage of mesalamine extended-release capsules is 1.5 g, which corresponds to four 0.375 g capsules, administered once daily in the morning.

Prior to initiating therapy, healthcare professionals should evaluate the patient's renal function to ensure safety and efficacy. The capsules must be swallowed whole; they should not be cut, broken, crushed, or chewed, as this may affect the release mechanism of the medication.

Co-administration with antacids is not advised, as it may interfere with the therapeutic effects of mesalamine. Patients should be encouraged to drink an adequate amount of fluids while on this medication. Mesalamine extended-release capsules can be taken without regard to meals, allowing for flexibility in administration.

Contraindications

Use of mesalamine extended-release capsules is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or any component of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Healthcare professionals are advised to conduct a thorough assessment of renal function at the initiation of treatment with mesalamine and to continue monitoring renal function periodically throughout the course of therapy. This is particularly crucial for patients with known renal impairment or those concurrently using nephrotoxic medications. In cases where renal function deteriorates, it is imperative to discontinue treatment.

Symptoms indicative of Mesalamine-Induced Acute Intolerance Syndrome may closely resemble an exacerbation of ulcerative colitis. Therefore, healthcare providers should remain vigilant for any worsening of symptoms and discontinue treatment if acute intolerance syndrome is suspected.

In addition, immediate evaluation and discontinuation of mesalamine are warranted if a hypersensitivity reaction is suspected, which may include serious conditions such as myocarditis and pericarditis. The risks and benefits of continuing treatment should be carefully weighed in patients with pre-existing liver impairment.

Healthcare professionals should also be alert to the potential for severe cutaneous adverse reactions or other signs of hypersensitivity. Treatment should be stopped at the first indication of these reactions, and further evaluation should be considered.

Patients with existing skin conditions should be counseled to minimize sun exposure, wear protective clothing, and apply a broad-spectrum sunscreen when outdoors to mitigate the risk of skin reactions.

It is important to note that mesalamine-containing stones are not detectable through standard radiographic techniques or computed tomography (CT). Therefore, ensuring adequate fluid intake during treatment is essential to prevent stone formation.

General precautions include the awareness that the use of mesalamine may result in spuriously elevated test results when measuring urinary normetanephrine via liquid chromatography with electrochemical detection.

Regular assessment of renal function is recommended at the beginning of treatment and periodically thereafter, particularly for patients with known renal impairment or those taking nephrotoxic drugs. In the event of any hypersensitivity reactions, immediate medical evaluation is necessary, and treatment should be discontinued.

Side Effects

Patients may experience a range of adverse reactions during treatment. The most common adverse reactions, occurring in 3% or more of participants, include headache, diarrhea, upper abdominal pain, nausea, and nasopharyngitis.

Serious adverse reactions warrant immediate attention. Patients should be monitored for renal impairment, with renal function assessed at the beginning of treatment and periodically thereafter. Treatment should be discontinued if renal function deteriorates. Additionally, mesalamine-induced acute intolerance syndrome may present symptoms that are difficult to distinguish from an exacerbation of ulcerative colitis; therefore, monitoring for worsening symptoms is essential, and treatment should be halted if acute intolerance syndrome is suspected.

Hypersensitivity reactions, which may include myocarditis and pericarditis, require immediate evaluation and discontinuation of treatment if suspected. Patients with known liver impairment should be carefully evaluated for the risks and benefits of treatment, as hepatic failure has been reported. Severe cutaneous adverse reactions necessitate discontinuation at the first signs or symptoms, along with consideration for further evaluation.

Patients should also be advised about the risk of nephrolithiasis, as mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Adequate fluid intake during treatment is crucial to mitigate this risk. Furthermore, patients with pre-existing skin conditions should be cautioned about photosensitivity, recommending the use of protective clothing and broad-spectrum sunscreen when outdoors.

It is important to note that the use of mesalamine may interfere with laboratory tests, leading to spuriously elevated results when measuring urinary Normetanephrine by liquid chromatography with electrochemical detection.

Patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or any component of mesalamine extended-release capsules should not use this medication. Symptoms of salicylate toxicity, which include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (such as headache, dizziness, confusion, and seizures), should be monitored closely. Severe salicylate intoxication may result in electrolyte and blood pH imbalances, potentially leading to damage to other organs, including the kidneys and liver.

Drug Interactions

The concomitant use of nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), with this medication may lead to an increased risk of nephrotoxicity. It is advisable to monitor renal function closely and observe for any mesalamine-related adverse reactions.

When administered alongside azathioprine or 6-mercaptopurine, there is an elevated risk of blood disorders. Regular monitoring of complete blood cell counts and platelet counts is recommended to detect any potential hematological complications.

Packaging & NDC

The table below lists all NDC Code configurations of Mesalamine, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of mesalamine in pediatric patients have not been established. Therefore, caution should be exercised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and outcomes in this population.

Geriatric Use

Clinical studies of mesalamine did not include a sufficient number of subjects aged 65 years and older to determine whether these elderly patients respond differently than younger subjects. However, reports from uncontrolled clinical studies and postmarketing surveillance have indicated a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia, in patients aged 65 years and older compared to their younger counterparts receiving mesalamine-containing products.

Given these findings, it is essential to monitor complete blood cell counts and platelet counts in geriatric patients during treatment with mesalamine. Additionally, when prescribing mesalamine to elderly patients, healthcare providers should consider the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may affect treatment outcomes. Careful assessment and monitoring are recommended to ensure the safety and efficacy of mesalamine in this population.

Pregnancy

Published data from meta-analyses, cohort studies, and case series regarding the use of mesalamine during pregnancy have not consistently demonstrated an association between mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of oral mesalamine during organogenesis to pregnant rats and rabbits at doses 1.7 and 5.4 times, respectively, the maximum recommended human dose did not result in adverse developmental outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated populations remains unknown. It is important to note that adverse outcomes in pregnancy can occur regardless of maternal health or medication use. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2 to 4% and 15 to 20%, respectively.

In women with ulcerative colitis, published data suggest that increased disease activity is associated with a higher risk of adverse pregnancy outcomes, which may include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g), and small for gestational age infants at birth. Furthermore, data indicate that mesalamine exposure during early pregnancy (first trimester) and throughout pregnancy does not appear to be associated with an increased risk of major congenital malformations, including cardiac malformations.

Reproductive studies involving mesalamine during organogenesis have been conducted in rats at oral doses up to 320 mg/kg/day (approximately 1.7 times the recommended human dose based on body surface area comparison) and in rabbits at doses up to 495 mg/kg/day (approximately 5.4 times the recommended human dose based on body surface area comparison), revealing no evidence of harm to the fetus due to mesalamine.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion of this medication in breast milk or its effects on breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment should have their renal function assessed at the beginning of treatment and periodically throughout the course of therapy. It is essential to evaluate the risks and benefits of treatment in patients with known renal impairment or those taking nephrotoxic drugs, with close monitoring of renal function. If there is any deterioration in renal function, discontinuation of the treatment is recommended.

Additionally, ensuring adequate fluid intake during treatment is crucial to prevent nephrolithiasis, as mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT).

Hepatic Impairment

Patients with hepatic impairment should be carefully evaluated for the risks and benefits of treatment. It is essential to assess liver function prior to initiating therapy and to monitor liver parameters throughout the course of treatment. Adjustments to dosage may be necessary based on the severity of liver impairment. Close monitoring of liver function tests is recommended to ensure patient safety and to mitigate potential adverse effects associated with compromised liver function.

Overdosage

In cases of mesalamine overdosage, healthcare professionals should be vigilant for symptoms indicative of salicylate toxicity. These symptoms may include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and various neurologic manifestations such as headache, dizziness, confusion, and seizures.

Severe salicylate intoxication can result in significant complications, including electrolyte and blood pH imbalances, which may lead to damage of vital organs, particularly the kidneys and liver. Therefore, prompt recognition and management of these symptoms are critical.

There is currently no specific antidote for mesalamine overdose. However, conventional therapeutic approaches for salicylate toxicity may be beneficial in managing acute overdosage. Initial management should focus on gastrointestinal decontamination to prevent further absorption of the drug. This may involve the use of activated charcoal, provided that the patient presents within an appropriate time frame post-ingestion.

It is essential to correct any fluid and electrolyte imbalances that may arise due to the overdose. This can be achieved through the administration of appropriate intravenous fluids, which will also help maintain adequate renal function during the management of the overdose.

Additionally, it is important to consider that mesalamine is a pH-dependent delayed-release formulation. This characteristic should be taken into account when treating a suspected overdose, as it may influence the timing and effectiveness of therapeutic interventions.

Nonclinical Toxicology

No information is available regarding teratogenic effects associated with mesalamine.

Non-teratogenic effects were observed in studies where no impact on fertility or reproductive performance was noted in male and female rats administered oral mesalamine at doses up to 320 mg/kg, which is approximately 1.7 times the recommended human dose based on body surface area.

Dietary mesalamine demonstrated no carcinogenic potential in rats at doses as high as 480 mg/kg/day, nor in mice at 2,000 mg/kg/day. These doses correspond to approximately 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg for a 50 kg body weight or 1,110 mg/m²), respectively, based on body surface area. Additionally, mesalamine was found to be negative in several genotoxicity assays, including the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.

Animal studies involving mesalamine, including 13-week and 26-week oral toxicity studies in rats, as well as 26-week and 52-week oral toxicity studies in dogs, identified the kidney as the primary target organ for mesalamine toxicity. Lethal outcomes were observed in mice and rats following single oral doses of 800 mg/kg (approximately 2.2 times the recommended human dose based on body surface area) and 1,800 mg/kg (approximately 9.7 times the recommended human dose based on body surface area), respectively, leading to gastrointestinal and renal toxicity.

In rats, oral doses of 40 mg/kg/day (about 0.20 times the human dose based on body surface area) resulted in minimal to slight tubular injury, while doses of 160 mg/kg/day (approximately 0.90 times the human dose based on body surface area) or higher induced renal lesions, including tubular degeneration, tubular mineralization, and papillary necrosis. Similarly, in dogs, oral doses of 60 mg/kg/day (approximately 1.1 times the human dose based on body surface area) or higher also led to renal lesions, such as tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions reported voluntarily or through surveillance programs. These include pancreatitis, hepatic failure, renal failure, and colitis. Allergic reactions have been noted, including anaphylaxis, as well as various skin reactions such as rash, pruritus, and urticaria. Hematologic reactions reported include thrombocytopenia and leukopenia. Additionally, respiratory reactions, specifically interstitial lung disease, have been documented. Cardiovascular reactions, including myocarditis and pericarditis, have also been observed.

Further safety updates from postmarketing experience indicate reports of serious gastrointestinal events, including bowel obstruction and perforation.

Patient Counseling

Healthcare providers should advise patients to swallow mesalamine extended-release capsules whole and to avoid cutting, breaking, crushing, or chewing the capsules to ensure proper medication delivery. It is important to inform patients that they should not co-administer mesalamine extended-release capsules with antacids, as this may affect the medication's efficacy.

Patients should be encouraged to drink an adequate amount of fluids while taking this medication to maintain hydration. Additionally, healthcare providers can inform patients that mesalamine extended-release capsules can be taken without regard to meals, providing flexibility in their dosing schedule.

Healthcare providers should also discuss the possibility of urine discoloration, which may appear reddish-brown while taking mesalamine extended-release capsules. This discoloration can occur when urine comes into contact with surfaces or water treated with hypochlorite-containing bleach. Patients should be instructed to observe their urine flow and to report to their healthcare provider only if they notice discolored urine upon leaving the body, prior to any contact with surfaces or water, such as in the toilet.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 25°C (77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F), in accordance with USP guidelines for controlled room temperature.

Care should be taken to ensure that the product is kept in its original container to maintain stability and integrity. Special handling requirements should be observed to prevent exposure to extreme temperatures or conditions that may compromise the product's quality.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Mesalamine as submitted by Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)