Mesalamine

Description

Each mesalamine capsule is a delayed- and extended-release dosage form intended for oral administration. Each extended-release 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 formulation includes pellets composed of mesalamine within a polymer matrix, featuring an enteric coating that dissolves at a pH of 6 and above.

Inactive ingredients in the mesalamine extended-release capsules, USP, comprise ethyl cellulose, hypromellose, methacrylic acid copolymer, maize starch, sucrose, talc, and triethyl citrate. The capsule shell is formulated with FD&C blue #1, gelatin, purified water, sodium lauryl sulfate, and titanium dioxide. Additionally, the capsule is imprinted with black pharmaceutical ink and contains black iron oxide, potassium hydroxide, propylene glycol, purified water, and shellac. It is important to note that FDA-approved dissolution test specifications may differ from those established by the USP.

Uses and Indications

Mesalamine extended-release capsules are 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 absorption 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

Assessment of renal function is essential at the initiation of treatment with mesalamine and should be conducted periodically throughout the treatment course. Healthcare professionals must carefully evaluate the risks and benefits of therapy in patients with known renal impairment or those concurrently using nephrotoxic medications. If there is any deterioration in renal function, treatment should be discontinued.

Healthcare providers should be vigilant for symptoms indicative of Mesalamine-Induced Acute Intolerance Syndrome, which may mimic an exacerbation of ulcerative colitis. Continuous monitoring for worsening symptoms is crucial, and treatment should be halted if acute intolerance syndrome is suspected.

In cases where a hypersensitivity reaction is suspected, including but not limited to myocarditis and pericarditis, immediate evaluation of the patient is warranted, and mesalamine should be discontinued. Additionally, the risks and benefits of treatment should be assessed in patients with pre-existing liver impairment.

At the first signs or symptoms of severe cutaneous adverse reactions or any other indications of hypersensitivity, treatment should be discontinued, and further evaluation should be considered. Patients with existing skin conditions are advised to minimize sun exposure, wear protective clothing, and utilize 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 imperative to prevent stone formation.

Healthcare professionals should also be aware that the use of mesalamine may result in spuriously elevated test results when measuring urinary normetanephrine via liquid chromatography with electrochemical detection.

Regular laboratory assessments should include renal function tests at the beginning of treatment and periodically thereafter, as well as monitoring for any worsening symptoms associated with Mesalamine-Induced Acute Intolerance Syndrome. Liver function should also be evaluated in patients with known liver impairment to ensure safe use of the medication.

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 careful monitoring and management. Patients with renal impairment should have their renal function assessed at the beginning of treatment and periodically thereafter. It is essential to evaluate the risks and benefits in these patients, particularly those taking nephrotoxic drugs, and to discontinue treatment if renal function deteriorates.

Mesalamine-induced acute intolerance syndrome may present symptoms that are difficult to distinguish from an exacerbation of ulcerative colitis. Therefore, it is crucial to monitor for worsening symptoms and discontinue treatment if acute intolerance syndrome is suspected. Additionally, hypersensitivity reactions, which may include myocarditis and pericarditis, require immediate evaluation and discontinuation of the medication if such reactions are suspected.

Patients with known liver impairment should be evaluated for the risks and benefits of treatment, as hepatic failure has been reported. Severe cutaneous adverse reactions necessitate discontinuation of the medication at the first signs or symptoms, along with further evaluation for hypersensitivity.

Photosensitivity is another concern; patients with pre-existing skin conditions are advised to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. Furthermore, nephrolithiasis has been noted, with mesalamine-containing stones being undetectable by standard radiography or computed tomography (CT). Adequate fluid intake during treatment is recommended to mitigate this risk.

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.

In cases of overdosage, symptoms of salicylate toxicity may include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms such as headache, dizziness, confusion, and seizures. Severe salicylate intoxication can 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), may lead to an increased risk of nephrotoxicity. It is recommended 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 advised 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 extended-release capsules in pediatric patients have not been established. Therefore, caution is advised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and therapeutic outcomes in this population.

Geriatric Use

Clinical studies of mesalamine extended-release capsules 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 using 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 extended-release capsules. Additionally, when prescribing this medication 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 extended-release capsules 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 times 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 2,500 g), and small for gestational age at birth. While there is no clear evidence that mesalamine exposure in early pregnancy is linked to an increased risk of major congenital malformations, including cardiac malformations, the methodological limitations of existing epidemiologic studies, such as the inability to control for confounders like underlying maternal disease and concomitant medication use, as well as missing information on the dose and duration of mesalamine use, complicate the interpretation of these findings.

Healthcare professionals should consider these factors when prescribing mesalamine to pregnant patients and weigh the potential benefits against any risks, particularly in the context of the patient's disease activity and overall health.

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.

Hepatic Impairment

Patients with hepatic impairment should be carefully evaluated for the risks and benefits of treatment. It is essential to consider the degree of liver function compromise when determining the appropriateness of therapy. Monitoring of liver function tests may be necessary to assess the patient's condition and to guide treatment decisions. Adjustments to dosage or treatment regimens may be required based on the severity of hepatic impairment. Close observation is recommended to ensure patient safety and to mitigate potential adverse effects associated with compromised liver function.

Overdosage

In the event of an overdose of mesalamine extended-release capsules, which are classified as aminosalicylates, 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 cases of salicylate intoxication can result in significant electrolyte and blood pH imbalances, potentially leading to damage of vital organs, including the kidneys and liver. It is crucial for healthcare providers to recognize these risks promptly.

Currently, there is no specific antidote available for mesalamine overdose. However, conventional therapeutic approaches for managing salicylate toxicity may be beneficial in cases of 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.

Additionally, it is essential to correct any fluid and electrolyte imbalances that may arise. This can be achieved through the administration of appropriate intravenous fluids, ensuring that renal function is adequately maintained throughout the treatment process.

It is important to note that mesalamine extended-release capsules are a pH-dependent delayed-release formulation. This characteristic should be taken into account when devising a treatment plan for suspected overdose cases, as it may influence the pharmacokinetics of the drug and the timing of interventions.

Nonclinical Toxicology

Dietary mesalamine was evaluated for carcinogenic potential in both rats and mice. The results indicated that mesalamine was not carcinogenic at doses of up to 480 mg/kg/day in rats and 2,000 mg/kg/day in mice. These doses correspond to approximately 2.6 times and 5.4 times the recommended human dose of granulated mesalamine capsules, which is 1.5 g/day (equivalent to 30 mg/kg for a 50 kg individual or 1,110 mg/m²), respectively, when adjusted for body surface area.

In terms of mutagenicity, mesalamine demonstrated negative results in several 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.

No adverse effects on fertility or reproductive performance were observed in male and female rats administered oral doses of mesalamine up to 320 mg/kg, which is approximately 1.7 times the recommended human dose based on body surface area.

Animal studies, 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 doses of mesalamine were determined to be 800 mg/kg (approximately 2.2 times the recommended human dose based on body surface area) for mice and 1,800 mg/kg (approximately 9.7 times the recommended human dose based on body surface area) for rats, both of which resulted in gastrointestinal and renal toxicity.

At lower oral doses of 40 mg/kg/day (about 0.20 times the human dose based on body surface area), minimal to slight tubular injury was noted. Doses of 160 mg/kg/day (approximately 0.90 times the human dose based on body surface area) or higher in rats led to renal lesions, including tubular degeneration, tubular mineralization, and papillary necrosis. Similarly, oral doses of 60 mg/kg/day (about 1.1 times the human dose based on body surface area) or higher in dogs resulted in renal lesions characterized by 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, such as anaphylaxis, have also been documented, along with various skin reactions, including rash, pruritus, and urticaria. Hematologic reactions, specifically thrombocytopenia and leukopenia, have been observed, as well as respiratory reactions, including interstitial lung disease. Cardiovascular reactions, such as myocarditis and pericarditis, have been reported as well.

Additionally, postmarketing experience has revealed cases of serious gastrointestinal events, contributing to the overall safety profile of the product.

Patient Counseling

Healthcare providers should advise patients to swallow mesalamine extended-release capsules whole, without cutting, breaking, crushing, or chewing them. It is important to inform patients to avoid co-administration of these 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 ensure proper hydration. They can take mesalamine extended-release capsules without regard to meals, providing flexibility in their dosing schedule.

Additionally, healthcare providers should inform patients that their urine may become discolored reddish-brown while using mesalamine extended-release capsules, particularly when it 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, before any contact with surfaces or water, such as in the toilet.

Storage and Handling

The product is supplied in a bottle containing 120 capsules, equipped with a child-resistant closure. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F). Temporary excursions are permissible between 15°C and 30°C (59°F and 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity of the product.

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 Zydus Pharmaceuticals USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)