Mesalamine

Description

Each mesalamine delayed-release tablet, USP, for oral administration contains 1.2 g of 5-aminosalicylic acid (5-ASA; mesalamine), an anti-inflammatory agent. The chemical name for mesalamine is 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 colloidal silicon dioxide, magnesium stearate, carboxymethylcellulose sodium, sodium starch glycolate, hypromellose, microcrystalline cellulose, methacrylic acid-methyl methacrylate copolymer 1:1, methacrylic acid-methyl methacrylate copolymer 1:2, triethyl citrate, talc, polyvinyl alcohol, titanium dioxide, macrogol/PEG, iron oxide red, and iron oxide yellow. It is important to note that FDA-approved dissolution test specifications differ from those of the USP.

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 the use of 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 advised 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 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:

  • Week 0 to Week 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:

  • Week 0 to Week 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:

  • Week 0 to Week 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 halted if acute intolerance syndrome is suspected.

Hypersensitivity reactions, which may include myocarditis and pericarditis, necessitate 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 warranted due to the potential for hepatic failure.

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

Mesalamine delayed-release tablets are 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). Therefore, ensuring adequate hydration during treatment is critical to mitigate this risk.

Healthcare professionals should also 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 and effective management.

Side Effects

Most adverse reactions reported in clinical trials and postmarketing experiences can be categorized based on their seriousness and frequency.

Common adverse reactions observed in adult participants (≥2%) include headache, flatulence, liver function test abnormalities, abdominal pain, and diarrhea. In pediatric patients (≥5%), the most frequently reported reactions are abdominal pain, upper respiratory tract infection, vomiting, anemia, headache, and viral infection.

In clinical trials involving adults, headache was reported in 6% of participants receiving 2.4 g once daily and 3% of those receiving 4.8 g once daily, compared to less than 1% in the placebo group. Flatulence occurred in 4% of the 2.4 g group and 3% in the 4.8 g group, with similar rates in the placebo group. Liver function test abnormalities were noted in less than 1% of participants on 2.4 g daily and 2% on 4.8 g, while 1% of those on placebo experienced this reaction. Other common adverse reactions (≥1%) during maintenance of remission included abdominal pain (2%), diarrhea (2%), and liver function test abnormalities (2%).

Less common adverse reactions (<1%) reported in clinical trials included pancreatitis, which led to therapy discontinuation, as well as cardiac disorders such as tachycardia, gastrointestinal disorders including abdominal distention and colitis, and various skin disorders like acne and pruritus.

Postmarketing experiences have revealed serious adverse reactions, including lupus-like syndrome, drug fever, pericarditis, myocarditis, and gastrointestinal complications such as gastrointestinal bleeding and perforated peptic ulcer. Hepatic adverse reactions include jaundice, liver failure, and hepatotoxicity. Hematologic reactions such as agranulocytosis and aplastic anemia have also been reported. Neurological and psychiatric disorders, including peripheral neuropathy and Guillain-Barré syndrome, as well as renal disorders like renal failure and interstitial nephritis, have been documented.

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

Severe cutaneous adverse reactions should prompt discontinuation at the first signs or symptoms. Patients with known liver impairment should be evaluated for risks and benefits before treatment initiation. Additionally, patients are advised to avoid sun exposure due to the risk of photosensitivity and to ensure adequate hydration to prevent nephrolithiasis. It is important to note that this medication may interfere with laboratory tests, potentially leading to spuriously elevated results when measuring urinary normetanephrine.

Drug Interactions

Nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), may increase the risk of nephrotoxicity when administered concurrently. It is recommended to monitor renal function and observe for any mesalamine-related adverse reactions in patients receiving these agents.

Co-administration of azathioprine or 6-mercaptopurine is associated with an increased 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. This indication is supported by evidence 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 seen in 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. 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 during pregnancy.

In animal reproduction studies, oral administration of mesalamine during organogenesis in 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.

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.

In women with ulcerative colitis, increased disease activity has been linked to 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.

Data suggest that mesalamine exposure during early pregnancy (first trimester) and throughout pregnancy is not associated with an increased risk of major congenital malformations, including cardiac malformations. Reproductive studies conducted with mesalamine during organogenesis in rats and rabbits have shown no evidence of harm to the fetus at doses significantly higher than the maximum recommended human dose based on body surface area comparisons.

Healthcare professionals should consider these factors when prescribing mesalamine to pregnant patients and counsel them regarding the potential risks associated with 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. The average concentration of mesalamine in breast milk ranges from non-detectable to 0.5 mg/L, while the average concentration of N-acetyl-5-aminosalicylic acid ranges from 0.2 to 9.3 mg/L. Estimated daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day for mesalamine (RID 0% to 0.1%) 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 prevents a definitive assessment of the risk of mesalamine delayed-release tablets to a nursing infant. 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.

Caregivers should be advised to monitor breastfed infants for signs of diarrhea. Maternal doses of mesalamine in published lactation studies have varied from 500 mg to 4.8 g daily.

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 this population, it is essential to consider the degree of liver function compromise when prescribing this medication.

Monitoring of liver function tests may be warranted in patients with known liver impairment to ensure safety and efficacy. Adjustments to the dosage regimen may be necessary based on the severity of hepatic impairment, and clinicians should remain vigilant for any signs of adverse reactions associated with liver function changes.

Overdosage

In the event of an overdose of 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 intoxication with salicylates can result in significant electrolyte and blood pH imbalances, potentially leading to end-organ damage, particularly affecting the renal and hepatic systems. It is crucial to recognize these risks promptly to mitigate complications.

Currently, there is no specific antidote for mesalamine overdose. However, conventional management strategies for salicylate toxicity may be beneficial in cases of acute overdosage. Initial treatment 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.

In addition to decontamination, it is essential to correct 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 management process.

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

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 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 about 1.4 times the recommended human dose based on body surface area.

No evidence of mutagenicity was identified in both an in vitro Ames test and an in vivo mouse micronucleus test, indicating that mesalamine does not possess mutagenic properties.

Regarding reproductive toxicity, no adverse effects on fertility or reproductive performance were observed in male or female rats administered oral doses of mesalamine up to 400 mg/kg/day, which is approximately 0.7 times the maximum recommended human dose based on body surface area.

In animal studies assessing the toxicological profile of mesalamine, the kidney was identified as the primary target organ for toxicity. A 13-week oral toxicity study in mice, along with 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys, indicated that oral daily doses of 2,400 mg/kg in mice and 1,150 mg/kg in rats resulted in significant renal lesions. These included granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily 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: Cases of pericarditis, pericardial effusion, and myocarditis have been documented.

Gastrointestinal Disorders: Adverse events such as cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, and perforated peptic ulcer have been identified.

Hepatic Disorders: Instances of jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, hepatotoxicity, and Kawasaki-like syndrome with changes in liver enzymes have been reported.

Hematologic Disorders: Reports of agranulocytosis and aplastic anemia have been noted.

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

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

Neurological/Psychiatric Disorders: Cases of peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis, and intracranial hypertension have been documented.

Renal Disorders: Reports include renal failure, interstitial nephritis, nephrogenic diabetes insipidus, and nephrolithiasis.

Urine discoloration has been observed 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 reported.

Skin Disorders: Adverse reactions such as 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) have been identified.

Urogenital Disorders: 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 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, ensuring its stability and effectiveness.

Finally, advise patients to consult their healthcare provider if they have any questions or concerns regarding their treatment, including any changes in their health status or new medications they may be considering.

Storage and Handling

The product is supplied in an HDPE bottle equipped with a child-resistant closure. It should be stored at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), with permissible excursions between 15ºC to 30ºC (59ºF to 86ºF). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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 issues reported include jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, and hepatotoxicity, with some cases resembling Kawasaki-like syndrome.

Hematologic concerns involve agranulocytosis and aplastic anemia, while immune system disorders may present as anaphylactic reactions and angioedema. Musculoskeletal and connective tissue disorders include myalgia and lupus-like syndrome. Neurological and psychiatric effects can range from peripheral neuropathy to Guillain-Barré syndrome, transverse myelitis, and intracranial hypertension. Renal disorders reported include renal failure, interstitial nephritis, nephrogenic diabetes insipidus, and nephrolithiasis. Additionally, urine discoloration may occur ex-vivo due to contact with hypochlorite-containing bleach. Respiratory issues such as interstitial lung disease and hypersensitivity pneumonitis, along with skin reactions like psoriasis, pyoderma gangrenosum, and severe cutaneous adverse reactions (SJS/TEN, DRESS, AGEP), have also been documented. Lastly, reversible oligospermia has been noted in the urogenital category.

FDA Insert (PDF)

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

View full prescribing information (PDF)