Mesalamine

Description

Each mesalamine extended-release capsule, USP is a delayed- and extended-release dosage form intended for oral administration. Each capsule contains 0.375 g of mesalamine USP (5-amino-salicylic 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 include ethylcellulose, FD&C Green No. 3, gelatin, hypromellose, methacrylic acid copolymer type C, sugar spheres (corn starch and sucrose), talc, titanium dioxide, and triethyl citrate. The black imprinting ink utilized contains black iron oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. This product meets the USP Dissolution Test 2 standards.

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. It is essential that the capsules be swallowed whole; they must not be cut, broken, crushed, or chewed. Co-administration with antacids should be avoided to ensure optimal efficacy. Patients are advised to drink an adequate amount of fluids while on this medication. Mesalamine extended-release capsules can be taken without regard to meals.

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

Renal function should be assessed at the initiation of treatment with mesalamine and monitored periodically throughout the course of therapy. In patients with known renal impairment or those taking nephrotoxic medications, a careful evaluation of the risks and benefits is essential. If there is any deterioration in renal function, discontinuation of mesalamine is warranted.

Healthcare professionals should be vigilant for symptoms indicative of mesalamine-induced acute intolerance syndrome, which may mimic an exacerbation of ulcerative colitis. Monitoring for worsening symptoms is crucial, and treatment should be discontinued if acute intolerance syndrome is suspected.

Hypersensitivity reactions, including but not limited to myocarditis and pericarditis, require immediate evaluation. If a hypersensitivity reaction is suspected, mesalamine should be discontinued without delay.

In patients with known liver impairment, a thorough assessment of the risks and benefits of continuing treatment with mesalamine is necessary.

Severe cutaneous adverse reactions can occur; therefore, treatment should be stopped at the first signs or symptoms of such reactions or any other indications of hypersensitivity. Further evaluation may be required in these cases.

Patients should be advised about the risk of photosensitivity. Those with pre-existing skin conditions should take precautions to avoid sun exposure, including wearing protective clothing and applying a broad-spectrum sunscreen when outdoors.

It is important to note that mesalamine can contribute to the formation of nephrolithiasis, with mesalamine-containing stones being undetectable by standard radiography or computed tomography (CT). To mitigate this risk, patients should be encouraged to maintain adequate fluid intake during treatment.

Additionally, healthcare professionals should be aware that the use of mesalamine may interfere with laboratory tests, specifically leading to spuriously elevated results when measuring urinary normetanephrine using liquid chromatography with electrochemical detection.

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 have also been reported and require careful monitoring. Renal impairment is a significant concern; renal function should be assessed at the beginning of treatment and periodically thereafter. It is essential to evaluate the risks and benefits in patients with known renal impairment or those taking nephrotoxic drugs, with discontinuation of treatment advised if renal function deteriorates.

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 crucial, and treatment should be discontinued if acute intolerance syndrome is suspected. Hypersensitivity reactions, which may include myocarditis and pericarditis, necessitate immediate evaluation and discontinuation of the medication if such reactions are suspected.

Patients with known liver impairment should be carefully evaluated for the risks and benefits of treatment due to the potential for hepatic failure. Additionally, severe cutaneous adverse reactions can occur; treatment should be discontinued at the first signs or symptoms of such reactions or any other signs of hypersensitivity, with further evaluation considered.

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

Furthermore, 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 salicylate toxicity due to overdosage, symptoms 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), with this medication may lead to an increased risk of nephrotoxicity. It is advisable to monitor renal function closely, as well as to observe for any mesalamine-related adverse reactions.

Additionally, the use of azathioprine or 6-mercaptopurine in conjunction with this medication may elevate the risk of blood disorders. Regular monitoring of complete blood cell counts and platelet counts is recommended to ensure patient safety and to detect any potential hematological complications early.

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

Safety and effectiveness of mesalamine extended-release capsules 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 needed to determine appropriate dosing and 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.

Due to these findings, it is essential to monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine extended-release capsules. Additionally, when prescribing this medication to geriatric 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 with 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 indicate 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. There is no clear evidence suggesting that mesalamine exposure during early pregnancy is linked to an increased risk of major congenital malformations, including cardiac malformations. However, it is important to recognize that published epidemiologic studies have significant methodological limitations that complicate data interpretation, such as the inability to control for confounding factors like underlying maternal disease and concomitant medication use, as well as incomplete information regarding the dose and duration of mesalamine use.

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), with no evidence of fetal harm attributed to mesalamine.

Lactation

Data from published literature indicate that mesalamine and its metabolite, N-acetyl 5-aminosalicylic acid, are present in human milk in small amounts, with relative infant doses (RID) of 2% or less. Maternal doses of mesalamine from various oral and rectal formulations have ranged from 500 mg to 4.8 g daily. The average concentration of mesalamine in breast milk has been reported to range from non-detectable to 0.5 mg/L, while the average concentration of N-acetyl-5-aminosalicylic acid in milk has ranged from 0.2 to 9.3 mg/L. Based on these concentrations, estimated daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day (RID 0 to 0.1%) for mesalamine and 0.03 to 1.4 mg/kg/day for N-acetyl-5-aminosalicylic acid.

There have been case reports of diarrhea in breastfed infants exposed to mesalamine. However, there is no information available regarding the effects of mesalamine on milk production. The lack of clinical data during lactation limits the ability to clearly determine the risk of mesalamine to an infant during this period. Therefore, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for mesalamine extended-release capsules and any potential adverse effects on the breastfed child from mesalamine or from the underlying maternal condition.

Caregivers should be advised to monitor breastfed infants for signs of diarrhea.

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 in these patients, particularly those with known renal impairment or those taking nephrotoxic drugs. Continuous monitoring of renal function is recommended, and treatment should be discontinued if there is any deterioration in renal function.

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, and close monitoring is recommended to ensure patient safety and therapeutic efficacy.

Overdosage

In cases of overdosage with mesalamine extended-release capsules, which are classified as aminosalicylates, healthcare professionals should be vigilant for symptoms indicative of salicylate toxicity. Common manifestations include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and various neurologic symptoms 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. It is crucial for healthcare providers to recognize these potential outcomes and act promptly.

Currently, there is no specific antidote available for mesalamine overdose. However, conventional treatment strategies 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.

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, which will also help maintain adequate renal function during the management of the overdose.

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 timing and effectiveness of therapeutic interventions.

Nonclinical Toxicology

Dietary mesalamine was evaluated for carcinogenic potential in both rats and mice. In these studies, mesalamine did not demonstrate carcinogenicity 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 and 5.4 times the recommended human dose of granulated mesalamine capsules, which is 1.5 g/day, based on body surface area.

In terms of mutagenicity, mesalamine was found to be negative 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.

Regarding reproductive toxicity, 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 in mice and 1,800 mg/kg in rats, which are approximately 2.2 and 9.7 times the recommended human dose, respectively, based on body surface area. These high doses resulted in gastrointestinal and renal toxicity.

At lower oral doses of 40 mg/kg/day, which is 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 or higher, approximately 0.90 times the human dose, led to renal lesions in rats, including tubular degeneration, tubular mineralization, and papillary necrosis. Similarly, in dogs, oral doses of 60 mg/kg/day or higher, about 1.1 times the human dose, resulted in renal lesions such as tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with mesalamine extended-release capsules. These include mesalamine-induced acute intolerance syndrome, severe cutaneous adverse reactions, hypersensitivity reactions, and various blood disorders.

Patients are advised to be aware of the signs and symptoms of these reactions. They should discontinue the use of mesalamine extended-release capsules and promptly report any new or worsening symptoms to their healthcare provider.

Patient Counseling

Patients should be instructed to swallow the mesalamine extended-release capsules whole and to avoid cutting, breaking, crushing, or chewing them. It is important to advise patients against the co-administration of these capsules with antacids. Patients should also be encouraged to drink an adequate amount of fluids during treatment.

Mesalamine extended-release capsules can be taken without regard to meals. Patients may notice that their urine becomes discolored reddish-brown while taking the medication, particularly when it comes into contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, patients should be advised to monitor their urine flow and report to their healthcare provider only if the urine is discolored upon leaving the body, prior to contact with any surface or water.

Patients should be informed that mesalamine extended-release capsules may decrease renal function, especially in those with known renal impairment or those taking nephrotoxic drugs, including NSAIDs. Periodic monitoring of renal function will be performed while they are on therapy, and patients should be advised to complete all blood tests ordered by their healthcare provider.

Healthcare providers should inform patients of the signs and symptoms of hypersensitivity reactions. Patients should be instructed to discontinue the use of mesalamine extended-release capsules and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome, which may include cramping, abdominal pain, bloody diarrhea, fever, headache, and rash, or any other symptoms suggestive of mesalamine-induced hypersensitivity.

Patients with known liver disease should be informed about the signs and symptoms of worsening liver function and advised to report any such signs or symptoms to their healthcare provider. Additionally, patients should be made aware of the signs and symptoms of severe cutaneous adverse reactions. They should be instructed to stop taking mesalamine extended-release capsules and report to their healthcare provider at the first appearance of a severe cutaneous adverse reaction or any other sign of hypersensitivity.

For patients with pre-existing skin conditions, it is advisable to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. Patients should also be instructed to drink an adequate amount of fluids during treatment to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of a kidney stone, such as severe side or back pain or blood in the urine.

Elderly patients and those taking azathioprine or mercaptopurine should be informed of the risk for blood disorders and the necessity for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Patients should be advised to complete all blood tests ordered by their healthcare provider.

Storage and Handling

The product is supplied in a tight, light-resistant container, compliant with USP standards, and equipped with a child-resistant closure. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

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

View full prescribing information (PDF)