Mesalamine

Description

Each mesalamine delayed-release tablet, USP for oral administration contains 1.2 g of 5-aminosalicylic acid (5-ASA; mesalamine, USP), which serves as an anti-inflammatory agent. Mesalamine, USP is chemically designated as 5-amino-2-hydroxybenzoic acid. The structural formula of mesalamine is provided in the accompanying documentation.

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, USP is subsequently released from the tablet core.

Inactive ingredients in the formulation include ammonium hydroxide, colloidal silicon dioxide, copovidone, iron oxide black, iron oxide red, iron oxide yellow, magnesium stearate, methacrylic acid and methyl methacrylate copolymer, microcrystalline cellulose, polyethylene glycol 3350, polyvinyl alcohol, povidone, propylene glycol, shellac, sodium starch glycolate (type A), talc, titanium dioxide, and triethyl citrate.

The product meets the specifications outlined in USP Dissolution Test 3.

Uses and Indications

Mesalamine is indicated for the induction and maintenance of remission in adult patients with mildly to moderately active ulcerative colitis. Additionally, mesalamine is 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.

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 (equivalent to two to four 1.2 g tablets) taken once daily. For the maintenance of remission, the dosage is 2.4 g (two 1.2 g tablets) once daily.

In pediatric patients weighing at least 24 kg who are capable of swallowing 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 mesalamine therapy and monitored periodically throughout treatment. 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 therapy, mesalamine must be discontinued.

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

Hypersensitivity reactions, including myocarditis and pericarditis, necessitate immediate evaluation. Mesalamine should be discontinued if any signs of hypersensitivity are observed.

In patients with known liver impairment, a careful assessment of the risks and benefits of mesalamine use is required due to the potential for hepatic failure.

Severe cutaneous adverse reactions may occur; therefore, mesalamine should be discontinued at the first indication of such reactions or any other signs of hypersensitivity, with further evaluation considered.

Mesalamine is contraindicated in patients with upper gastrointestinal tract obstruction, including pyloric stenosis or other organic or functional obstructions.

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

Cases of nephrolithiasis have been reported in patients using mesalamine. It is important to note that mesalamine-containing stones are not detectable by standard radiography or computed tomography (CT). Adequate hydration should be ensured during treatment to mitigate this risk.

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 via liquid chromatography with electrochemical detection.

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

Side Effects

Most common adverse reactions observed in clinical trials include headache, flatulence, abnormal liver function tests, abdominal pain, and diarrhea in adults, with an incidence of 2% or greater. In pediatric patients, the most frequently reported adverse reactions (≥5%) are abdominal pain, upper respiratory tract infection, vomiting, anemia, headache, and viral infection.

Serious adverse reactions may occur, necessitating careful monitoring and evaluation. Patients with renal impairment should have their renal function assessed at the beginning of treatment and periodically thereafter. The risks and benefits of mesalamine should be evaluated in these patients, particularly those taking nephrotoxic drugs. Mesalamine should be discontinued if renal function deteriorates during therapy.

Mesalamine-induced acute intolerance syndrome may present symptoms that are difficult to distinguish from an exacerbation of ulcerative colitis. Patients should be monitored for worsening symptoms, and treatment should be discontinued if acute intolerance syndrome is suspected. Hypersensitivity reactions, which may include myocarditis and pericarditis, require immediate evaluation and discontinuation of mesalamine if suspected.

Patients with known liver impairment should be carefully evaluated for the risks and benefits of mesalamine use, 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.

Caution is advised in patients with upper gastrointestinal tract obstruction, such as pyloric stenosis, as mesalamine should be avoided in these cases. Additionally, patients with pre-existing skin conditions should be informed about the risk of photosensitivity and advised to take protective measures against sun exposure.

Nephrolithiasis has been reported in association with mesalamine use; however, mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Adequate hydration during treatment is essential 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 overdosage, symptoms of salicylate toxicity may manifest as nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms such as headache, dizziness, confusion, and seizures. Severe intoxication can result in electrolyte and blood pH imbalances, potentially leading to end-organ damage, including renal and liver impairment.

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 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 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 have been established for the treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg. Evidence supporting its use 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 similar to that reported in adults. However, the safety and effectiveness of mesalamine have not been established in patients weighing less than 24 kg.

Geriatric Use

Clinical trials of mesalamine 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, such as mesalamine delayed-release tablets, 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 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 systemic exposure and to account for the aforementioned factors.

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 during 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 2,500 g), and small for gestational age 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 mg/L 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 and any potential adverse effects on the breastfed child from the medication 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 calculated to be between 0 mg/kg/day to 0.075 mg/kg/day for mesalamine (RID 0% to 0.1%) and 0.03 mg/kg/day to 1.4 mg/kg/day for N-acetyl-5-aminosalicylic acid.

Renal Impairment

Renal function should be assessed at the beginning of treatment and periodically throughout the course of therapy in patients with renal impairment. It is important to evaluate the risks and benefits of mesalamine in these patients, particularly those who are also taking nephrotoxic drugs. If renal function deteriorates while on mesalamine therapy, the medication should be discontinued.

Additionally, cases of nephrolithiasis have been reported in patients using mesalamine, and it is noteworthy that mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). To mitigate potential risks, ensuring adequate hydration during treatment is essential.

Hepatic Impairment

Patients with hepatic impairment should be carefully evaluated for the risks and benefits of using mesalamine. Due to the potential for altered drug metabolism and excretion in this population, it is essential to consider the degree of liver function impairment when prescribing mesalamine.

Monitoring of liver function tests is recommended for patients with known liver impairment who are initiated on mesalamine therapy. Regular assessment of liver enzymes and overall liver function may be necessary to ensure patient safety and to adjust treatment as needed.

In cases of significant hepatic failure, the use of mesalamine may be contraindicated, and alternative therapies should be considered. The prescribing physician should exercise caution and make informed decisions based on the individual patient's liver function status.

Overdosage

In cases of mesalamine overdosage, symptoms may reflect those associated with salicylate toxicity. Healthcare professionals should be vigilant for signs such as nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and various neurologic manifestations, including 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 kidneys and liver.

Management of mesalamine overdosage does not have a specific antidote; however, conventional treatment strategies for salicylate toxicity may be applicable. Immediate actions should include gastrointestinal decontamination to limit further absorption of the drug. This may involve the use of activated charcoal if the patient presents within an appropriate time frame post-ingestion.

It is crucial to monitor and correct any fluid and electrolyte imbalances that may arise. The administration of intravenous fluids should be considered to maintain adequate hydration and renal function. Given that mesalamine is a pH-dependent, delayed-release formulation, this characteristic must be taken into account when devising a treatment plan for suspected overdose cases. Continuous monitoring of the patient's clinical status and laboratory parameters is essential to guide further management and ensure patient safety.

Nonclinical Toxicology

In a 104-week dietary carcinogenicity study conducted in CD-1 mice, mesalamine administered at doses up to 2,500 mg/kg/day did not demonstrate tumorigenic potential. This dose is approximately 2.2 times the maximum recommended human dose based on a body surface area comparison. 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, corresponding to 1.4 times the recommended human dose based on body surface area.

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.

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 2,400 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

The postmarketing experience for the drug associated with SPL code 90375-7 includes reports of additional adverse events received through voluntary reporting and surveillance programs. These events encompass a range of conditions, some of which are rare and may not have been observed during clinical trials.

Healthcare professionals and patients have reported various cases, contributing to the understanding of the drug's safety profile in a broader population. The nature of these reports varies, and while they provide valuable insights, the relationship between the drug and the reported events has not been definitively established.

Continued monitoring and evaluation of postmarketing data are essential to ensure ongoing safety and efficacy of the drug in the general population.

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 adherence to the prescribed treatment regimen. Emphasize that missing doses can affect the effectiveness of the therapy and may lead to complications.

Instruct patients to avoid certain activities or substances that may interact with the medication. This may include specific foods, alcohol, or other medications that could lead to adverse effects or reduced efficacy.

Encourage patients to maintain regular follow-up appointments to monitor their progress and any potential side effects. This will help ensure that the treatment remains effective and safe.

Remind patients to keep the medication out of reach of children and to store it according to the instructions provided, to prevent accidental ingestion or misuse.

Lastly, advise patients to consult their healthcare provider before making any changes to their medication regimen or if they have any questions or concerns regarding their treatment.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy 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 Actavis Pharma, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)