Mesalamine

Description

Each mesalamine delayed-release tablet for oral administration contains 1.2 g of 5-aminosalicylic acid (5-ASA; mesalamine), an anti-inflammatory agent. Mesalamine is chemically designated as 5-amino-2-hydroxybenzoic acid, with a molecular formula of C₇H₇NO₃ and a molecular weight of 153.14. The tablet is coated with a pH-dependent polymer film that disintegrates at or above pH 6.8, typically in the terminal ileum, where mesalamine is released from the tablet core.

The core of the tablet comprises mesalamine along with hydrophilic and lipophilic excipients, facilitating the extended release of mesalamine. Inactive ingredients include sodium carboxymethylcellulose, carnauba wax, stearic acid, colloidal hydrated silica, sodium starch glycolate (type A), talc, magnesium stearate, methacrylic acid copolymer types A and B, triethylcitrate, titanium dioxide, red ferric oxide, and polyethylene glycol 6000.

Uses and Indications

Mesalamine delayed-release tablets are indicated for the induction and maintenance of remission in adult patients with mildly to moderately active ulcerative colitis. Additionally, these tablets are indicated for the treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg.

There are no teratogenic or nonteratogenic effects associated with mesalamine delayed-release tablets.

Dosage and Administration

Prior to initiating therapy with mesalamine delayed-release tablets, healthcare professionals should evaluate the patient's renal function and continue to monitor it periodically throughout the treatment. Mesalamine delayed-release tablets must be swallowed whole; they should not be split or crushed. It is recommended that these tablets be administered with food, and patients should be encouraged to drink an adequate amount of fluids.

For adults, the recommended dosage for the induction of remission is between 2.4 g to 4.8 g, which corresponds to two to four 1.2-g tablets taken once daily. For the maintenance of remission, the dosage is 2.4 g, equivalent to two 1.2-g tablets, taken once daily.

In pediatric patients weighing at least 24 kg who can swallow tablets whole, the recommended dosages for the treatment of mildly to moderately active ulcerative colitis are as follows:

• For patients weighing 24 kg to 35 kg:

  • Weeks 0 to 8: 2.4 g (two 1.2-g tablets) once daily

  • After Week 8: 1.2 g (one 1.2-g tablet) once daily

• For patients weighing greater than 35 kg to 50 kg:

  • Weeks 0 to 8: 3.6 g (three 1.2-g tablets) once daily

  • After Week 8: 2.4 g (two 1.2-g tablets) once daily

• For patients weighing greater than 50 kg:

  • Weeks 0 to 8: 4.8 g (four 1.2-g tablets) once daily

  • After Week 8: 2.4 g (two 1.2-g tablets) once daily

Contraindications

Use of mesalamine delayed-release tablets is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates, or to any of the components 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 delayed-release tablets and monitored periodically throughout the course of therapy. It is essential to evaluate the risks and benefits of mesalamine in patients with known renal impairment or those taking nephrotoxic medications. Should renal function deteriorate during treatment, mesalamine delayed-release tablets must be discontinued.

Healthcare professionals should be vigilant for signs of mesalamine-induced acute intolerance syndrome, as symptoms may closely resemble an exacerbation of ulcerative colitis. Monitoring for any worsening of symptoms is crucial, and treatment should be discontinued if acute intolerance syndrome is suspected.

Hypersensitivity reactions, which may include myocarditis and pericarditis, require immediate evaluation. If a hypersensitivity reaction is suspected, mesalamine delayed-release tablets should be discontinued without delay.

In patients with known liver impairment, careful consideration of the risks and benefits of mesalamine delayed-release tablets is necessary due to the potential for hepatic failure.

Severe cutaneous adverse reactions can occur; therefore, treatment should be stopped at the first indication of such reactions or any other signs of hypersensitivity, and further evaluation should be considered.

Mesalamine delayed-release tablets should be avoided in patients with upper gastrointestinal tract obstruction, including pyloric stenosis or other organic or functional obstructions.

Patients with pre-existing skin conditions should be advised about photosensitivity. It is recommended that they avoid sun exposure, wear protective clothing, and apply a broad-spectrum sunscreen when outdoors.

Cases of nephrolithiasis have been reported in patients using mesalamine. Notably, mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). To mitigate this risk, it is important to ensure adequate hydration during treatment.

The use of mesalamine may interfere with laboratory tests, particularly leading to spuriously elevated results when measuring urinary normetanephrine via liquid chromatography with electrochemical detection.

Regular assessment of renal function is advised at the beginning of treatment and periodically thereafter to ensure patient safety and treatment efficacy.

Side Effects

Most common adverse reactions observed in clinical trials and postmarketing experiences include a range of symptoms affecting various systems. In adult participants, the most frequently reported adverse reactions (≥2%) during treatment were headache, flatulence, liver function test abnormalities, abdominal pain, and diarrhea. Specifically, during the induction phase, headache was reported in 6% of patients, while flatulence occurred in 4%. Liver function test abnormalities were noted in less than 1% of patients, alongside other less common reactions such as alopecia and pruritus.

In the maintenance of remission phase, headache was again prevalent, affecting 3% of subjects, with liver function test abnormalities and abdominal pain each reported by 2% of participants. Diarrhea also occurred in 2% of patients. Other less common adverse reactions during this phase included abdominal distension, dyspepsia, back pain, rash, arthralgia, and fatigue, each affecting 1% of subjects.

In pediatric patients, the adverse reaction profile was similar to that of adults, with the most common reactions (≥5%) including abdominal pain, upper respiratory tract infection, vomiting, anemia, headache, and viral infection.

Postmarketing experiences have revealed additional serious adverse reactions. These include lupus-like syndrome, drug fever, and various cardiac disorders such as pericarditis and myocarditis. Gastrointestinal complications reported include cholecystitis, gastrointestinal bleeding, and perforated peptic ulcer. Hepatic adverse reactions have been significant, with cases of jaundice, hepatitis, and liver failure documented. Hematologic issues such as agranulocytosis and aplastic anemia have also been reported.

Neurological and psychiatric adverse reactions include peripheral neuropathy, Guillain-Barré syndrome, and transverse myelitis. Renal disorders such as renal failure and interstitial nephritis have been noted, alongside respiratory issues like interstitial lung disease and hypersensitivity pneumonitis. Dermatological reactions include severe cutaneous adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Patients should be monitored for renal function at the beginning of treatment and periodically thereafter, with discontinuation of therapy advised if renal function deteriorates. Mesalamine-induced acute intolerance syndrome may mimic an exacerbation of ulcerative colitis, necessitating treatment cessation if suspected. Hypersensitivity reactions, including myocarditis and pericarditis, warrant immediate discontinuation of mesalamine.

Patients with known liver impairment should be evaluated for the risks and benefits of treatment, and those with pre-existing skin conditions should be advised on sun exposure precautions due to the risk of photosensitivity. Adequate hydration is recommended to mitigate the risk of nephrolithiasis, which has been reported in association with mesalamine use. Additionally, the use of mesalamine may interfere with laboratory tests, leading to spuriously elevated results in certain assays.

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 azathioprine or 6-mercaptopurine is administered alongside this medication, there is an elevated risk of blood dyscrasias. Regular monitoring of complete blood cell counts and platelet counts is advised to detect any potential hematological abnormalities.

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 delayed-release tablets have been established for the treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg. Evidence supporting the use of mesalamine in this population includes data from adequate and well-controlled trials in adults, as well as a multicenter, randomized, double-blind, parallel group trial involving 105 pediatric patients aged 5 to 17 years.

The safety profile observed in pediatric patients was found to be similar to that of adults. However, the safety and effectiveness of mesalamine delayed-release tablets have not been established in patients weighing less than 24 kg.

Geriatric Use

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

Elderly patients may experience increased systemic exposures to mesalamine. Therefore, it is essential to monitor complete blood cell counts and platelet counts in this population during treatment. Additionally, when prescribing mesalamine delayed-release tablets to geriatric patients, healthcare providers should consider the greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

For induction therapy, it is advisable to consider starting at the low end of the dosing range for elderly patients to mitigate potential risks associated with higher doses.

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. However, it is important to note that adverse effects on maternal and fetal outcomes are associated with ulcerative colitis in pregnancy. Increased disease activity in women with ulcerative colitis has been linked to a higher risk of adverse pregnancy outcomes, including preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g), and small for gestational age infants at birth.

In animal reproduction studies, administration of oral mesalamine during organogenesis to pregnant rats and rabbits at doses 1.8 and 2.9 times, respectively, the maximum recommended human dose did not result in adverse developmental outcomes. Furthermore, there is no clear evidence that mesalamine exposure in early pregnancy is associated with an increased risk of major congenital malformations, including cardiac malformations.

The estimated background risk of major birth defects and miscarriage for the indicated populations remains unknown. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively.

It is important to consider that published epidemiologic studies have significant methodological limitations that may affect the interpretation of the data. These limitations include the inability to control for confounding factors such as underlying maternal disease, concomitant medication use, and incomplete information regarding the dose and duration of mesalamine use. Therefore, healthcare professionals should weigh the potential benefits of mesalamine treatment against the risks associated with untreated ulcerative colitis during pregnancy.

Lactation

Data from published literature indicate that mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, are present in human milk in small amounts. The relative infant doses (RID) for mesalamine are reported to be 0.1% or less. In lactation studies, maternal doses of mesalamine from various oral and rectal formulations ranged from 500 mg to 4.8 g daily. The average concentration of mesalamine in breast milk ranged from non-detectable to 0.5 mg/L, while the average concentration of N-acetyl-5-aminosalicylic acid ranged from 0.2 to 9.3 mg/L.

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 breastfeeding. Therefore, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for mesalamine delayed-release tablets 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. 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.

Renal Impairment

Mesalamine is substantially excreted by the kidneys, which increases the risk of toxic reactions in patients with impaired renal function. It is essential to evaluate renal function in all patients prior to the initiation of mesalamine delayed-release tablets therapy and to monitor renal function periodically during treatment.

Patients with known renal impairment, a history of renal disease, or those taking nephrotoxic drugs should be closely monitored for any signs of decreased renal function and mesalamine-related adverse reactions. The risks and benefits of continuing mesalamine therapy should be carefully assessed in these patients. If renal function deteriorates while on therapy, mesalamine delayed-release tablets should be discontinued.

Hepatic Impairment

Patients with hepatic impairment should be carefully evaluated for the risks and benefits of using mesalamine delayed-release tablets. Due to the potential for altered drug metabolism and clearance in individuals with compromised liver function, it is essential to consider the severity of the hepatic impairment when prescribing this medication.

Monitoring of liver function is recommended for patients receiving mesalamine, particularly in those with pre-existing liver conditions. Regular assessment of liver enzymes and overall liver health may be necessary to ensure patient safety and to identify any potential adverse effects related to hepatic function.

Healthcare providers should exercise caution and consider dosage adjustments based on the individual patient's liver function status, as the pharmacokinetics of mesalamine may be affected in this population.

Overdosage

In cases of overdosage with mesalamine delayed-release tablets, 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 end-organ damage, particularly affecting the renal and hepatic systems.

There is currently no specific antidote available for mesalamine overdose. However, conventional management strategies for salicylate toxicity may be employed effectively in instances of acute overdosage. Initial management should focus on gastrointestinal decontamination to limit 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 crucial to address any fluid and electrolyte imbalances that may arise. This can be achieved through the administration of appropriate intravenous fluids and electrolytes, ensuring the maintenance of adequate renal function throughout the treatment process.

It is important to note that mesalamine delayed-release tablets are designed to be pH-dependent, which should be taken into account when formulating a treatment plan for suspected overdose cases. Monitoring and supportive care are essential components of managing patients who have experienced an overdose of mesalamine.

Nonclinical Toxicology

In a 104-week dietary carcinogenicity study conducted in CD-1 mice, mesalamine administered at doses up to 2500 mg/kg/day did not demonstrate tumorigenic potential. This dose corresponds to 2.2 times the maximum recommended human dose based on a body surface area comparison for mesalamine delayed-release tablets. Similarly, a 104-week dietary carcinogenicity study in Wistar rats revealed that mesalamine at doses up to 800 mg/kg/day was also non-tumorigenic, representing 1.4 times the recommended human dose based on body surface area comparison.

No evidence of mutagenicity was identified in either an in vitro Ames test or an in vivo mouse micronucleus test. Additionally, assessments of fertility and reproductive performance in male and female rats indicated no adverse effects at oral doses of mesalamine up to 400 mg/kg/day, which is 0.7 times the maximum recommended human dose based on body surface area comparison.

Animal studies have indicated that the kidney is the primary target organ for mesalamine toxicity. In a 13-week oral toxicity study involving mice, as well as 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys, significant renal lesions were observed. In mice, daily oral doses of 2400 mg/kg resulted in renal lesions characterized by granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, daily oral doses of 250 mg/kg or higher led to nephrosis, papillary edema, and interstitial fibrosis.

Postmarketing Experience

During post-approval use of mesalamine delayed-release tablets and other mesalamine-containing products, various adverse reactions have been reported voluntarily or through surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Reports include lupus-like syndrome and drug fever.

Cardiac Disorders: Adverse events such as pericarditis, pericardial effusion, and myocarditis have been documented.

Gastrointestinal: Cases of cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, and perforated peptic ulcer have been identified.

Hepatic: Adverse reactions include jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, hepatotoxicity, and Kawasaki-like syndrome, which may involve changes in liver enzymes.

Hematologic: Instances of agranulocytosis and aplastic anemia have been reported.

Immune System Disorders: Anaphylactic reactions and angioedema have been noted.

Musculoskeletal and Connective Tissue Disorders: Myalgia and lupus-like syndrome have been observed.

Neurological/Psychiatric: Reports include peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis, and intracranial hypertension.

Renal Disorders: Adverse events such as renal failure, interstitial nephritis, nephrogenic diabetes insipidus, and nephrolithiasis have been documented.

Urine discoloration has been reported to occur ex-vivo due to contact of mesalamine, including its inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.

Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, and eosinophilic pneumonitis), as well as pleurisy/pleuritis, have been identified.

Skin: Adverse reactions include psoriasis, pyoderma gangrenosum, erythema nodosum, photosensitivity, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).

Urogenital: Reversible oligospermia has been reported.

Patient Counseling

Advise patients to take the medication exactly as prescribed by their healthcare provider. It is important for patients to understand the dosage and frequency of administration to ensure optimal therapeutic outcomes.

Inform patients about the potential side effects associated with the medication. Patients should be made aware of common side effects, as well as any serious adverse reactions that may require immediate medical attention. Encourage patients to report any unusual symptoms or side effects they experience while taking the medication.

Discuss the importance of adhering to the prescribed treatment regimen and the potential consequences of missed doses. Patients should be instructed on what to do if they miss a dose, including whether to take it as soon as they remember or to skip it if it is close to the time of the next dose.

Educate patients on any necessary lifestyle modifications or precautions that may enhance the effectiveness of the medication or reduce the risk of side effects. This may include dietary recommendations, activity restrictions, or the avoidance of certain substances.

Remind patients to inform their healthcare provider about all other medications they are taking, including over-the-counter drugs, supplements, and herbal products, to avoid potential drug interactions.

Encourage patients to keep all follow-up appointments with their healthcare provider to monitor their response to the medication and make any necessary adjustments to their treatment plan.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at room temperature, specifically within the range of 15°C to 25°C (59°F to 77°F). Temporary excursions up to 30°C (86°F) are permissible.

It is recommended to adhere to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature to ensure the integrity and efficacy of the product. Proper handling and storage conditions are essential for maintaining product quality.

Additional Clinical Information

Postmarketing experience has revealed a range of adverse events associated with the use of the medication. Clinicians should be aware of potential systemic reactions such as lupus-like syndrome and drug fever. Cardiac disorders may include pericarditis, pericardial effusion, and myocarditis. Gastrointestinal complications can manifest as cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, and perforated peptic ulcer.

Hepatic effects may present as jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, and hepatotoxicity, with Kawasaki-like syndrome noted for changes in liver enzymes. Hematologic issues such as agranulocytosis and aplastic anemia have also been reported. Immune system disorders may include anaphylactic reactions and angioedema. Musculoskeletal and connective tissue disorders can lead to myalgia and lupus-like syndrome. Neurological and psychiatric effects may involve peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis, and intracranial hypertension. Renal disorders reported include renal failure, interstitial nephritis, nephrogenic diabetes insipidus, and nephrolithiasis.

Additional observations include urine discoloration due to contact with hypochlorite-containing bleach, respiratory disorders such as interstitial lung disease and hypersensitivity pneumonitis, and skin reactions including psoriasis, pyoderma gangrenosum, erythema nodosum, photosensitivity, Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Urogenital effects may involve reversible oligospermia. Clinicians are advised to consult the Warnings and Precautions section for further details.

FDA Insert (PDF)

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

View full prescribing information (PDF)