Mesalamine

Description

Mesalamine Rectal Suspension, USP Enema, is a disposable unit containing 60 mL of a suspension formulated for rectal administration. The active ingredient is mesalamine, also known as 5-aminosalicylic acid (5-ASA), with a chemical structure represented by the empirical formula C₇H₇NO₃ and a molecular weight of 153.14. Each enema unit delivers 4 grams of mesalamine.

The formulation includes several inactive ingredients: carbomer 974P, edetate disodium, potassium acetate, potassium metabisulfite, purified water, and xanthan gum, with sodium benzoate included as a preservative. The enema unit features an applicator tip that is protected by a polyethylene cover and lubricated with USP white petrolatum. Additionally, the unit is designed with a one-way valve to prevent backflow of the dispensed product.

Uses and Indications

Mesalamine rectal suspension enema is indicated for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis, or proctitis in adults.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The recommended dosage of mesalamine rectal suspension enema is one rectal instillation of 4 grams, administered once daily. It is preferable to administer the enema at bedtime, allowing for retention for approximately eight hours. The duration of treatment may vary from 3 to 6 weeks, depending on the patient's symptoms and sigmoidoscopic findings.

This formulation is intended for rectal use only. Healthcare professionals should ensure that patients are instructed on the proper technique for administration to maximize therapeutic efficacy and minimize discomfort.

Contraindications

Use of mesalamine rectal suspension enema is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, sulfites, or any other components of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Hypersensitivity reactions may occur with the use of mesalamine rectal suspension enema, particularly due to the presence of potassium metabisulfite, which can lead to sulfite-related reactions. Additionally, sulfasalazine-associated reactions, such as myocarditis and pericarditis, have been reported. Healthcare professionals should evaluate patients immediately and discontinue the mesalamine rectal suspension enema if a hypersensitivity reaction is suspected.

Renal function must be assessed at the initiation of treatment and monitored periodically throughout therapy. It is crucial to evaluate the risks and benefits of mesalamine rectal suspension enema in patients with known renal impairment or those taking nephrotoxic medications. Should renal function deteriorate during treatment, the mesalamine rectal suspension enema should be discontinued.

Healthcare providers should be vigilant for signs of mesalamine-induced acute intolerance syndrome, which may present as cramping, acute abdominal pain, bloody diarrhea, fever, headache, and rash. If such symptoms arise, treatment should be discontinued immediately.

In patients with known liver impairment, the risks and benefits of using mesalamine rectal suspension enema should be carefully evaluated. Furthermore, at the first indication of severe cutaneous adverse reactions or other signs of hypersensitivity, the medication should be discontinued, and further evaluation should be considered.

Patients are advised to avoid sun exposure if they have pre-existing skin conditions, as photosensitivity may occur. Additionally, 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 essential to mitigate this risk.

Mesalamine may interfere with laboratory tests, specifically leading to elevated urinary normetanephrine test results. As such, healthcare professionals should be aware of this potential interference when interpreting laboratory findings.

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

Side Effects

Patients receiving mesalamine rectal suspension enema may experience a range of adverse reactions. The most common adverse reactions, occurring in 1% or more of patients, include gas/flatulence, flu-like symptoms, fever, leg or joint pain, hemorrhoids, rectal pain, and hair loss.

Serious adverse reactions may include hypersensitivity reactions, which can manifest as sulfite-related reactions or sulfasalazine-associated reactions such as myocarditis and pericarditis. It is crucial to evaluate patients immediately and discontinue the mesalamine rectal suspension enema if a hypersensitivity reaction is suspected. Additionally, mesalamine-induced acute intolerance syndrome may occur, characterized by cramping, acute abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash. Treatment should be discontinued if this syndrome is suspected.

Severe cutaneous adverse reactions have also been reported. In such cases, discontinuation of the medication at the first signs or symptoms is recommended, along with further evaluation. Furthermore, cases of nephrolithiasis have been documented in patients using mesalamine. Notably, mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT), thus adequate hydration during treatment is essential.

Patients should be aware that mesalamine may interfere with laboratory tests, specifically leading to elevated urinary normetanephrine test results. Renal function should be assessed at the beginning of treatment and periodically thereafter, with discontinuation of the mesalamine rectal suspension enema if renal function deteriorates. Caution is advised in patients with known liver impairment, and the risks and benefits of using mesalamine should be evaluated in these individuals.

It is important to note that clinical trials of mesalamine rectal suspension enema did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, reports from uncontrolled clinical studies and postmarketing data suggest a higher incidence of blood dyscrasias, such as agranulocytosis, neutropenia, and pancytopenia, in patients aged 65 years and older compared to younger adults. Patients with known or suspected hypersensitivity to salicylates, aminosalicylates, sulfites, or any other ingredients in mesalamine rectal suspension enema should also be closely monitored.

Drug Interactions

The concomitant use of nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs), may lead to an increased risk of nephrotoxicity. It is advisable to monitor renal function closely and observe for any mesalamine-related adverse reactions in patients receiving these medications.

When azathioprine or 6-mercaptopurine is administered alongside this drug, there is an elevated risk of blood dyscrasias. Regular monitoring of complete blood cell counts and platelet counts is recommended 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 in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, were not adequately represented in clinical trials of mesalamine rectal suspension enema, making it difficult to ascertain whether they respond differently compared to younger patients. However, reports from uncontrolled clinical studies and postmarketing surveillance indicate a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia, in geriatric patients receiving mesalamine-containing products. This increased risk may be associated with factors such as ulcerative colitis, the use of interacting medications, or diminished renal function.

Given these considerations, it is advisable to monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine rectal suspension enema. Additionally, healthcare providers should be mindful of the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concurrent diseases or other drug therapies in this population when prescribing mesalamine rectal suspension enema.

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, mesalamine was administered to rats and rabbits during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, without revealing any evidence of harm to the embryo or fetus. Additionally, 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 background risk of major birth defects and miscarriage for the indicated population remains unknown, as 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 miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

It is essential to consider that published epidemiologic studies have important methodological limitations that may hinder the interpretation of the data. These limitations include the inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications, as well as missing information on 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. 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 rectal suspension enema to an infant during breastfeeding. Therefore, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for mesalamine rectal suspension enema 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.

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 rectal suspension enema in patients with known renal impairment or those taking nephrotoxic drugs. If renal function deteriorates while on therapy, mesalamine rectal suspension enema should be discontinued. Additionally, cases of nephrolithiasis have been reported with the use of mesalamine; these mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Therefore, 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 rectal suspension enema. Due to the potential for altered drug metabolism and excretion in individuals with compromised liver function, close monitoring is recommended. Healthcare providers should assess liver function prior to initiating treatment and periodically during therapy to ensure patient safety and efficacy of the medication. Adjustments to the dosage may be necessary based on the severity of liver impairment and the patient's overall clinical status.

Overdosage

In the event of an overdose of mesalamine rectal suspension enema, which is classified as an aminosalicylate, 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 complications, including electrolyte and blood pH imbalances, as well as potential involvement of other organs, notably the kidneys and liver.

Currently, there is no specific antidote available for mesalamine overdose. However, conventional therapeutic approaches for managing salicylate toxicity may be beneficial in cases of acute overdosage. Recommended management strategies include gastrointestinal tract decontamination to minimize further absorption of the drug.

Additionally, it is crucial to address any fluid and electrolyte imbalances that may arise. This can be achieved through the administration of appropriate intravenous therapy, which also aids in maintaining adequate renal function. Continuous monitoring and supportive care are essential to ensure patient safety and recovery.

Nonclinical Toxicology

In a 2-year carcinogenicity study conducted in Wistar rats, administration of mesalamine at doses up to 320 mg/kg/day, which is approximately 0.78 times the maximum recommended human dose based on body surface area comparison, did not result in an increased incidence of neoplastic lesions compared to controls.

Mesalamine was evaluated for mutagenicity and demonstrated no mutagenic effects in Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, and TA1538. Additionally, no reverse mutations were observed in an assay using E. coli strain WP2UVRA. Genotoxicity assessments, including an in vivo mouse micronucleus assay at a dose of 600 mg/kg and an in vivo sister chromatid exchange assay at doses up to 610 mg/kg, also indicated no evidence of genotoxicity. Furthermore, mesalamine did not affect fertility in rats at doses up to 320 mg/kg/day.

Preclinical studies identified the kidney as the primary target organ for mesalamine toxicity. Adverse changes in renal function were noted in rats following a single oral dose of 600 mg/kg, while no such changes were observed at a dose of 200 mg/kg. Gross kidney lesions, including papillary necrosis, were documented after a single oral dose exceeding 900 mg/kg and after intravenous doses greater than 214 mg/kg.

In a 13-week oral (gavage) study in rats, the high dose of 640 mg/kg/day resulted in fatalities likely due to renal failure, with dose-related renal lesions such as papillary necrosis and multifocal tubular injury observed in most rats receiving this high dose, as well as in males receiving a lower dose of 160 mg/kg/day. However, renal lesions were not present in the female rats at the 160 mg/kg/day dose. Minimal tubular epithelial damage was noted in males at the 40 mg/kg/day dose, which was reversible.

A six-month oral study in dogs established a no-observable adverse effect level for mesalamine at 40 mg/kg/day, while doses of 80 mg/kg/day and higher resulted in renal pathology similar to that observed in rats. In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys was observed at doses of 100 mg/kg/day and above after 52 weeks, with an increased incidence of kidney degeneration and hyalinization of basement membranes and Bowman's capsule noted at the same dose level after 127 weeks.

In a 12-month eye toxicity study in dogs, Keratoconjunctivitis Sicca (KCS) was observed at oral doses of 40 mg/kg/day and above. The oral preclinical studies utilized a highly bioavailable suspension, facilitating absorption throughout the gastrointestinal tract.

Postmarketing Experience

No postmarketing experience details are available in the provided text.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, specifically the Instructions for Use, to ensure they understand the proper administration and usage of the medication. This information is crucial for maximizing the benefits of the treatment and minimizing potential risks. Providers should encourage patients to ask questions if they have any uncertainties regarding the instructions or their treatment plan.

Storage and Handling

The product is supplied in a foil-wrapped unit containing seven bottles. Each bottle is intended for single use. It is essential that once the foil-wrapped unit is opened, all enemas are used promptly as directed by the physician to ensure efficacy.

Storage conditions require the product to be maintained at a controlled room temperature of 20°C to 25°C (68°F to 77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F).

It is important to note that the contents of enemas removed from the foil pouch may darken over time. While slight darkening does not affect the potency of the product, any enema exhibiting dark brown contents should be discarded to ensure patient safety.

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 Padagis Israel Pharmaceuticals Ltd. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)