Mesalamine

Description

The active ingredient in mesalamine rectal suspension, USP enema, is mesalamine, also known as 5-aminosalicylic acid (5-ASA). Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid, with an empirical formula of C7H7NO3 and a molecular weight of 153.14. Mesalamine rectal suspension, USP enema is supplied as a suspension for rectal administration, with each enema unit containing 4 grams of mesalamine. Inactive ingredients include carbomer 934P, edetate disodium, potassium acetate, potassium metabisulfite, purified water, xanthan gum, and sodium benzoate, which is added as a preservative.

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, USP 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 the therapeutic effect 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 individuals with such sensitivities.

Warnings and Precautions

Patients receiving mesalamine rectal suspension enema should be closely monitored for potential hypersensitivity reactions, including those related to sulfite and sulfasalazine. The presence of potassium metabisulfite in the formulation may lead to sulfite-related reactions. In cases where a hypersensitivity reaction is suspected, immediate evaluation is warranted, and the mesalamine rectal suspension enema should be discontinued.

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

Healthcare professionals 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 halted immediately.

In patients with known liver impairment, a careful assessment of the risks and benefits of mesalamine rectal suspension enema is essential, as hepatic failure may complicate treatment. Additionally, any signs or symptoms of severe cutaneous adverse reactions or other hypersensitivity manifestations necessitate the discontinuation of the medication and further evaluation.

Patients should be advised to avoid sun exposure, particularly if they have pre-existing skin conditions that may exacerbate photosensitivity. Furthermore, cases of nephrolithiasis associated with mesalamine use have been reported. It is important to note that mesalamine-containing stones are not detectable through standard radiography or computed tomography (CT). Therefore, ensuring adequate hydration during treatment is critical to mitigate this risk.

General precautions include the potential for mesalamine to interfere with laboratory tests, specifically leading to elevated urinary normetanephrine test results. Regular assessment of renal function is recommended at the beginning of treatment and periodically throughout the course of therapy to ensure patient safety.

Side Effects

Most common adverse reactions occurring in patients receiving mesalamine rectal suspension enema include gas/flatulence, flu, fever, leg/joint pain, hemorrhoids, rectal pain, and hair loss, with an incidence of 1% or greater.

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. Discontinuation of therapy is recommended at the first signs or symptoms of such reactions or any other indications of hypersensitivity, with consideration for further evaluation.

Nephrolithiasis has been reported in patients using mesalamine, with mesalamine-containing stones being undetectable by standard radiography or computed tomography (CT). Patients should be advised to maintain adequate hydration during treatment to mitigate this risk.

Mesalamine may interfere with laboratory tests, leading to elevated urinary normetanephrine test results.

Additional considerations include the assessment of renal function at the beginning of treatment and periodically thereafter, as mesalamine rectal suspension enema should be discontinued if renal function deteriorates. In patients with known liver impairment, the risks and benefits of using mesalamine should be carefully evaluated.

Reports from uncontrolled clinical studies and postmarketing surveillance indicate a higher incidence of blood dyscrasias, such as agranulocytosis, neutropenia, and pancytopenia, in patients aged 65 years or older receiving mesalamine-containing products compared to younger adult patients.

Patients with known or suspected hypersensitivity to salicylates, aminosalicylates, sulfites, or any other ingredients in mesalamine rectal suspension enema should not receive this treatment.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 patients aged 65 years and older 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 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 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 approximately 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 confounding factors such as underlying maternal disease, concomitant medication use, and missing 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

No specific information is available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion in breast milk or its effects on breastfed infants. Healthcare professionals should consider this lack of information when advising lactating mothers.

Renal Impairment

Patients with renal impairment should have their renal function assessed at the beginning of treatment and periodically during therapy. 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.

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 therapeutic efficacy. Adjustments to the dosage may be necessary based on the severity of liver impairment and the patient's overall clinical status.

Overdosage

In cases of mesalamine overdose, symptoms indicative of salicylate toxicity may manifest, including nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, headache, dizziness, confusion, and seizures. Healthcare professionals should be vigilant for these signs, as they can vary in severity.

Severe salicylate intoxication can result in significant complications, including electrolyte and blood pH imbalances, which may lead to renal and liver involvement. It is crucial to monitor these parameters closely in affected patients.

Currently, there is no specific antidote available for mesalamine overdose. Management should focus on conventional therapy for salicylate toxicity, which may involve gastrointestinal tract decontamination to prevent further absorption of the drug. This can include methods such as activated charcoal administration, provided 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 therapy. Maintaining adequate renal function is also a critical component of the management strategy in cases of overdose, necessitating careful monitoring and supportive care.

Nonclinical Toxicology

In a 2-year carcinogenicity study conducted in Wistar rats administered 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, there was no observed increase in the incidence of neoplastic lesions compared to controls. Additionally, mesalamine was found to be non-mutagenic in various Salmonella typhimurium tester strains (TA98, TA100, TA1535, TA1537, TA1538) and did not induce reverse mutations in an assay using E. coli strain WP2UVRA. Furthermore, there was no evidence of genotoxicity in an in vivo mouse micronucleus assay at a dose of 600 mg/kg, nor in an in vivo sister chromatid exchange assay at doses up to 610 mg/kg. Mesalamine did not affect fertility in rats at doses up to 320 mg/kg/day.

Preclinical studies have 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 lower 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, 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 female rats at the 160 mg/kg/day dose. Minimal tubular epithelial damage was noted in male rats at 40 mg/kg/day, which was reversible.

In a six-month oral study in dogs, the no-observable adverse effect level for mesalamine was determined to be 40 mg/kg/day, while doses of 80 mg/kg/day and higher resulted in renal pathology similar to that observed in rats. A combined 52-week toxicity and 127-week carcinogenicity study in rats revealed degeneration of the kidneys at doses of 100 mg/kg/day and above, with increased incidences of kidney degeneration and hyalinization of basement membranes and Bowman's capsule noted at the same doses over the 127-week period. Additionally, 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 specific postmarketing experience details have been reported. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Instructions for Use) thoroughly. It is important to inform them that mesalamine rectal suspension enema may decrease renal function, particularly in individuals with known renal impairment or those taking nephrotoxic drugs. Periodic monitoring of renal function will be conducted during therapy, and patients should be encouraged to complete all blood tests ordered by their healthcare provider.

Patients must be instructed to discontinue the use of mesalamine rectal suspension enema and report to their healthcare provider if they experience new or worsening symptoms of acute intolerance syndrome, which may include cramping, abdominal pain, bloody diarrhea, fever, headache, and rash, or any other symptoms suggestive of mesalamine-induced hypersensitivity. Those with known liver disease should be advised to contact their healthcare provider if they notice any signs or symptoms indicative of worsening liver function.

It is essential to inform patients about the signs and symptoms of severe cutaneous adverse reactions. They should be instructed to stop taking mesalamine rectal suspension enema and report to their healthcare provider at the first appearance of a severe cutaneous adverse reaction or any other sign of hypersensitivity. Patients with pre-existing skin conditions should be advised to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.

Patients should be instructed to maintain adequate fluid intake during treatment to minimize the risk of kidney stone formation. They should also be advised to contact their healthcare provider if they experience signs or symptoms of a kidney stone, such as severe side or back pain or blood in the urine. Elderly patients and those taking azathioprine or 6-mercaptopurine should be informed of the risk for blood disorders and the necessity for periodic monitoring of complete blood cell counts and platelet counts while on therapy. They should be encouraged to complete all blood tests ordered by their healthcare provider.

Patients should be made aware that mesalamine rectal suspension enema may cause staining of direct contact surfaces, including fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Therefore, it is advisable to administer the product in a suitable location.

Instructions for administration include shaking the bottle to ensure the suspension is homogeneous, removing the protective sheath from the applicator tip, and lying on the left side with the lower leg extended and the upper right leg flexed forward for balance, or alternatively, getting into the knee-chest position. Patients should be instructed to gently insert the applicator tip into the rectum, pointing toward the umbilicus, and to steadily squeeze the bottle to discharge the medication. It is recommended that patients administer the enema at bedtime with the objective of retaining it throughout the night.

Lastly, patients should be informed that urine may become discolored reddish-brown while taking mesalamine rectal suspension enema when it comes into contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, patients should be advised to monitor their urine flow and report to their healthcare provider only if the urine is discolored upon leaving the body, before contact with any surface or water (e.g., in the toilet).

Storage and Handling

The product is supplied in a foil-wrapped unit containing seven bottles. It is essential to store the product at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), with permissible excursions between 15ºC to 30ºC (59ºF to 86ºF) in accordance with USP Controlled Room Temperature guidelines.

Once the foil-wrapped unit is opened, all enemas should be utilized promptly as directed by a physician. 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 enemas exhibiting dark brown contents should be discarded.

Additional Clinical Information

Use of mesalamine may result in spuriously elevated urinary normetanephrine test results due to the similarity in chromatograms between normetanephrine and mesalamine's main metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Clinicians should consider utilizing an alternative, selective assay for accurate measurement of normetanephrine.

Patients with pre-existing skin conditions, such as atopic dermatitis and atopic eczema, have reported experiencing more severe photosensitivity reactions. It is recommended that these patients avoid sun exposure, wear protective clothing, and apply a broad-spectrum sunscreen when outdoors to mitigate the risk of adverse reactions.

FDA Insert (PDF)

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

View full prescribing information (PDF)