Mesalamine

Description

The active ingredient in Mesalamine Suppository USP, 1,000 mg for rectal use is mesalamine USP, also known as mesalazine or 5-aminosalicylic acid (5-ASA). Chemically, mesalamine, USP is 5-amino-2-hydroxybenzoic acid and is classified as an aminosalicylate. Each mesalamine rectal suppository USP contains 1,000 mg of mesalamine, USP in a base of hard fat. The empirical formula is C7H7NO3, with a molecular weight of 153.14.

Uses and Indications

Mesalamine suppositories are indicated in adults for the treatment of mildly to moderately active ulcerative proctitis.

There are no teratogenic or nonteratogenic effects associated with the use of mesalamine suppositories.

Dosage and Administration

The recommended adult dosage of mesalamine suppositories is 1,000 mg, administered rectally once daily at bedtime for a duration of 3 to 6 weeks. The safety and effectiveness of mesalamine beyond 6 weeks have not been established.

Prior to initiating therapy with mesalamine suppositories, healthcare professionals should evaluate the patient's renal function and continue to monitor it periodically throughout the treatment.

It is important to instruct patients not to cut or break the suppository prior to administration. Patients should also be advised to drink an adequate amount of fluids to support overall hydration. After insertion, the suppository should be retained for one to three hours, or longer if possible, to maximize therapeutic effect.

Contraindications

Use is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates, as well as to any ingredients in the formulation. This is due to the potential for severe allergic reactions in these individuals.

Warnings and Precautions

Healthcare professionals should carefully evaluate the risks and benefits of mesalamine treatment in patients with known renal impairment or those taking nephrotoxic medications. It is essential to monitor renal function closely in these patients. Should there be any deterioration in renal function, mesalamine suppositories must be discontinued.

Symptoms indicative of mesalamine-induced acute intolerance syndrome may closely resemble an exacerbation of ulcerative colitis. Therefore, it is crucial to monitor patients for any worsening of symptoms and to discontinue treatment if acute intolerance syndrome is suspected.

In cases where a hypersensitivity reaction is suspected, including but not limited to myocarditis and pericarditis, immediate evaluation of the patient is warranted, and treatment should be discontinued. Additionally, the risks and benefits of mesalamine should be assessed in patients with known liver impairment.

Healthcare providers should be vigilant for the first signs or symptoms of severe cutaneous adverse reactions or other hypersensitivity manifestations. In such instances, discontinuation of mesalamine is recommended, and further evaluation should be considered.

Patients with pre-existing skin conditions should be advised to minimize sun exposure, wear protective clothing, and utilize a broad-spectrum sunscreen when outdoors to mitigate the risk of skin reactions.

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 prevent stone formation.

General precautions include the potential for spuriously elevated test results when using liquid chromatography with electrochemical detection in patients receiving mesalamine. It is advisable to employ an alternative, selective assay for urinary normetanephrine to avoid inaccuracies in test results.

Regular monitoring of renal function is recommended for patients with known renal impairment or those on nephrotoxic drugs. Furthermore, due to the possibility of spurious results with standard testing methods, a selective assay for urinary normetanephrine should be utilized.

Side Effects

Patients receiving mesalamine suppositories may experience a range of adverse reactions, which can be categorized into common and serious reactions.

Common adverse reactions, occurring in 1% or more of patients, include dizziness, rectal pain, fever, rash, acne, and colitis.

Serious adverse reactions necessitate careful monitoring and evaluation. Renal impairment is a significant concern; patients with known renal impairment or those taking nephrotoxic drugs should have their renal function monitored closely. Mesalamine suppositories should be discontinued if renal function deteriorates. Additionally, mesalamine-induced acute intolerance syndrome may present symptoms that are difficult to distinguish from an exacerbation of ulcerative colitis; thus, treatment should be discontinued if acute intolerance syndrome is suspected.

Hypersensitivity reactions, which may include myocarditis and pericarditis, require immediate evaluation and discontinuation of the medication if such reactions are suspected. Hepatic failure is another serious risk, particularly in patients with pre-existing liver impairment, who should be carefully assessed for the risks and benefits of treatment. Severe cutaneous adverse reactions warrant discontinuation at the first signs or symptoms, along with further evaluation for hypersensitivity. Patients should also be advised about photosensitivity, particularly those with pre-existing skin conditions, to avoid sun exposure and use protective measures.

Nephrolithiasis is a potential risk, as mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Adequate hydration during treatment is essential to mitigate this risk.

Additional important notes include the potential for spuriously elevated test results for urinary normetanephrine in patients receiving mesalamine, necessitating the use of alternative, selective assays. 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 lead to electrolyte and blood pH imbalances, with possible involvement of other organs, including renal and hepatic systems.

In pediatric patients, adverse reactions such as abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea, and vomiting have been reported, mirroring those seen in adult patients. Furthermore, geriatric patients may experience a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia. It is recommended to monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine suppositories.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known 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

The safety and effectiveness of mesalamine in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. A 6-week, open-label, single-arm study evaluated mesalamine suppositories in 49 patients aged 5 to 17 years, of which only 14 had histologically-confirmed ulcerative proctitis. Efficacy was not demonstrated in this study.

Adverse reactions observed in pediatric patients included abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea, and vomiting. These reactions were similar to those reported in adult patients. Caution is advised when considering mesalamine for use in this population due to the lack of established efficacy and the potential for adverse effects.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, were not adequately represented in clinical trials of mesalamine, making it difficult to ascertain whether they respond differently compared to younger patients. However, reports from uncontrolled clinical studies and postmarketing surveillance indicate that there may be a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia, in geriatric patients receiving mesalamine-containing products, such as mesalamine suppositories, compared to their younger counterparts.

Due to these findings, it is essential to monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine suppositories. Additionally, when prescribing mesalamine to geriatric patients, healthcare providers should consider the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concurrent diseases or other drug therapies that may affect treatment outcomes. Careful assessment and monitoring are recommended to ensure the safety and efficacy of mesalamine in this population.

Pregnancy

Limited published data on mesalamine use in pregnant patients are insufficient to inform a drug-associated risk. Animal studies have shown no evidence of teratogenicity when mesalamine was administered orally to rats or rabbits during gestation at doses greater than the recommended human intra-rectal dose. Specifically, reproduction studies in rats at oral doses up to 320 mg/kg/day (approximately 1.7 times the recommended human intra-rectal dose based on body surface area) and in rabbits at doses up to 495 mg/kg/day (about 5.4 times the recommended human intra-rectal dose) during the period of organogenesis revealed no evidence of impaired fertility or harm to the fetus.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20%, respectively, in clinically recognized pregnancies. It is important to note that adverse outcomes in pregnancy can occur regardless of maternal health or medication use. Given the limited data and the unknown background risk of major birth defects and miscarriage for the indicated populations, healthcare professionals should carefully consider the potential benefits and risks of mesalamine use in pregnant patients.

Lactation

Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts. In published lactation studies, maternal mesalamine doses from various oral and rectal formulations ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L, while the concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid.

There are limited reports of diarrhea in breastfed infants, and lactating mothers should monitor their breastfed infants for this adverse effect. There is no information on the effects of mesalamine on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of mesalamine to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mesalamine and any potential adverse effects on the breastfed child from mesalamine or from the underlying maternal conditions.

Renal Impairment

Patients with renal impairment or those taking nephrotoxic drugs should have their risks and benefits evaluated prior to treatment. It is essential to monitor renal function closely in these individuals. If there is any deterioration in renal function, mesalamine suppositories should be discontinued to prevent further complications.

Hepatic Impairment

Patients with hepatic impairment should be carefully evaluated for the risks and benefits of treatment. It is essential to assess liver function prior to initiating therapy and to monitor liver parameters throughout the course of treatment. Adjustments to dosage may be necessary based on the severity of liver impairment, and close monitoring is recommended to ensure patient safety and therapeutic efficacy.

Overdosage

In cases of salicylate overdose, a range of symptoms may manifest, indicating the severity of toxicity. Common symptoms include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, headache, dizziness, confusion, and seizures. Healthcare professionals should be vigilant in monitoring these symptoms, as they can escalate quickly.

Severe salicylate intoxication can result in significant complications, including electrolyte and blood pH imbalances. Additionally, there is a risk of renal and liver involvement, which necessitates prompt medical intervention.

Management of mesalamine overdose is particularly challenging, as there is no specific antidote available. The primary focus should be on correcting fluid and electrolyte imbalances through appropriate intravenous therapy. It is crucial to maintain adequate renal function during the management of the overdose to prevent further complications. Continuous monitoring and supportive care are essential in the treatment of patients experiencing salicylate toxicity.

Nonclinical Toxicology

Mesalamine was evaluated for its potential carcinogenicity in a two-year study involving Wistar rats, where no increase in the incidence of neoplastic lesions was observed at doses up to 320 mg/kg/day, approximately 1.7 times the recommended human intra-rectal dose based on body surface area. Additionally, mesalamine demonstrated no mutagenic potential in several assays, including the Ames test, the mouse lymphoma cell (TK +/-) forward mutation test, and the mouse micronucleus test.

No adverse effects on fertility or reproductive performance were noted in male and female rats administered oral doses of mesalamine up to 320 mg/kg/day, which is about 1.7 times the recommended human intra-rectal dose based on body surface area.

Toxicology studies conducted in various animal models, including rats, mice, rabbits, and dogs, identified the kidney as the primary target organ for toxicity. In rats, adverse renal effects were observed following a single oral dose of 600 mg/kg, approximately 3.2 times the recommended human intra-rectal dose, and at intravenous doses exceeding 214 mg/kg, about 1.2 times the recommended human intra-rectal dose. A 13-week oral gavage toxicity study revealed papillary necrosis and/or multifocal tubular injury in male rats at a dose of 160 mg/kg, about 0.86 times the recommended human intra-rectal dose, and in both sexes at 640 mg/kg, approximately 3.5 times the recommended human intra-rectal dose.

In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were noted at oral doses of 100 mg/kg/day and above, which corresponds to about 0.54 times the recommended human intra-rectal dose. A 14-day rectal toxicity study in rabbits indicated that intra-rectal doses up to 800 mg/kg, approximately 8.6 times the recommended human intra-rectal dose, were not associated with any adverse effects.

In a six-month oral toxicity study in dogs, doses of 80 mg/kg, about 1.4 times the recommended human intra-rectal dose, and higher resulted in renal pathology similar to that observed in rats. Furthermore, a rectal toxicity study of mesalamine suppositories in dogs revealed that a dose of 166.6 mg/kg, approximately 3 times the recommended human intra-rectal dose, led to chronic nephritis and pyelitis. In a 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) was observed at oral doses of 40 mg/kg and above, which is about 0.72 times the recommended human intra-rectal dose.

Postmarketing Experience

Postmarketing experience with mesalamine suppositories has identified several serious side effects, which may occur in some patients. These include potential kidney problems, necessitating monitoring through specific tests before and during treatment. Acute intolerance syndrome and other allergic reactions have also been reported, with symptoms such as cramps, abdominal pain, bloody diarrhea, chest pain, decreased urine output, eye inflammation, fever, headache, rash, shortness of breath, and fatigue. Patients with a history of allergic reactions to sulfasalazine may be at increased risk for these reactions, which can also involve heart, liver, and lung complications.

Liver problems have been noted, particularly in individuals with a prior history of liver issues or those who have used other mesalamine-containing medications. Symptoms warranting immediate medical attention include yellowing of the eyes, itchy skin, extreme fatigue, flu-like symptoms, and gastrointestinal disturbances such as nausea or vomiting.

Severe skin reactions have been documented, with patients advised to discontinue use and seek medical attention if they experience blisters, peeling skin, mouth sores, or flu-like symptoms accompanied by a rash or enlarged lymph nodes. Additionally, mesalamine suppositories may increase sun sensitivity, particularly in individuals with atopic dermatitis or eczema, prompting recommendations for sun protection.

The formation of kidney stones has also been reported, with patients advised to maintain adequate hydration to mitigate this risk. Symptoms indicative of kidney stones include severe pain in the side or back and blood in the urine.

Common side effects associated with mesalamine suppositories include dizziness, acne, colitis, rectal pain, fever, and rash. Patients are encouraged to report any side effects to the FDA at 1-800-FDA-1088.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the proper use and potential risks associated with mesalamine suppositories. It is important to instruct patients not to cut or break the suppository and to retain it for one to three hours, or longer if possible, to ensure optimal effectiveness.

Patients should be encouraged to drink an adequate amount of fluids during treatment. In the event that a dose of mesalamine suppository is missed, patients should administer it as soon as possible, unless it is almost time for the next dose. They should be cautioned against using two mesalamine suppositories at the same time to compensate for a missed dose.

Healthcare providers should inform patients that their urine may become discolored reddish-brown while using mesalamine suppositories, particularly when it comes into contact with surfaces or water treated with hypochlorite-containing bleach. Patients should be advised to monitor their urine flow and to report any discoloration that occurs before contact with any surface or water.

It is essential to inform patients that mesalamine suppositories can stain direct contact surfaces, including fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Patients should be instructed to keep the suppositories away from these surfaces to prevent staining.

Patients should be made aware that mesalamine suppositories may decrease renal function, especially in those with known renal impairment or those taking nephrotoxic drugs, including NSAIDs. Periodic monitoring of renal function will be performed while they are on therapy, and patients should be advised to complete all blood tests ordered by their healthcare provider.

Healthcare providers should educate patients about the signs and symptoms of hypersensitivity reactions. Patients should be instructed to discontinue use of mesalamine suppositories and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome, such as cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis, or rash, as well as any other symptoms suggestive of mesalamine-induced hypersensitivity.

For patients with known liver disease, it is important to inform them of the signs and symptoms of worsening liver function and to advise them to report any such signs or symptoms to their healthcare provider.

Patients should also be informed about the signs and symptoms of severe cutaneous adverse reactions. They should be instructed to stop taking mesalamine suppositories and report to their healthcare provider at the first appearance of a severe cutaneous adverse reaction or any other sign of hypersensitivity.

For patients with pre-existing skin conditions, healthcare providers should recommend avoiding sun exposure, wearing protective clothing, and using a broad-spectrum sunscreen when outdoors.

Additionally, patients should be instructed to drink an adequate amount of fluids during treatment to minimize the risk of kidney stone formation. They should 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.

Finally, 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. Patients should be advised to complete all blood tests ordered by their healthcare provider.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It is essential to store the product below 25ºC (77ºF), although refrigeration is permissible. Care should be taken to keep the product away from direct heat, light, and humidity to maintain its integrity and efficacy. Proper handling and storage conditions are crucial to ensure the product remains effective throughout its shelf life.

Additional Clinical Information

Use of mesalamine may result in spuriously elevated urinary normetanephrine test results when measured by liquid chromatography with electrochemical detection. This occurs due to the similarity in chromatograms between normetanephrine and mesalamine’s primary metabolite, N-acetylaminosalicylic acid. Clinicians should consider utilizing an alternative, selective assay for accurate measurement of normetanephrine.

Patients should be counseled to avoid sun exposure, wear protective clothing, and apply a broad-spectrum sunscreen when outdoors to minimize the risk of sun-related adverse effects.

FDA Insert (PDF)

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

View full prescribing information (PDF)