Mesalamine

Description

The active ingredient in mesalamine 1,000 mg suppositories for rectal use is mesalamine, also referred to as mesalazine or 5-aminosalicylic acid (5-ASA). Mesalamine is chemically defined as 5-amino-2-hydroxybenzoic acid and is classified as an aminosalicylate. Each suppository contains 1,000 mg of mesalamine USP, formulated in a base of Hard Fat, NF. The molecular formula of mesalamine is C₇H₇NO₃, with a corresponding molecular weight of 153.14. The structural formula is as follows:

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, or to any components of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Patients with renal impairment or those taking nephrotoxic drugs require careful evaluation of the risks and benefits associated with mesalamine therapy. It is essential to monitor renal function regularly, and treatment should be discontinued if there is any deterioration in renal status.

Mesalamine-Induced Acute Intolerance Syndrome may present symptoms that are challenging to differentiate from an exacerbation of ulcerative colitis. Healthcare professionals should closely monitor patients for any worsening of symptoms and discontinue mesalamine if acute intolerance syndrome is suspected.

Hypersensitivity reactions, which may include serious conditions such as myocarditis and pericarditis, necessitate immediate evaluation. If a hypersensitivity reaction is suspected, mesalamine should be discontinued promptly.

In patients with known liver impairment, a thorough assessment of the risks and benefits of mesalamine therapy is warranted due to the potential for hepatic failure.

Severe cutaneous adverse reactions can occur, and it is critical to discontinue mesalamine at the first signs or symptoms of such reactions or any other indications of hypersensitivity. Further evaluation may be necessary in these cases.

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

Nephrolithiasis is a potential risk associated with mesalamine, as mesalamine-containing stones are not detectable by standard radiography or computed tomography (CT). Therefore, ensuring adequate hydration during treatment is crucial.

In terms of laboratory interactions, it is important to note that patients receiving mesalamine suppositories may experience spuriously elevated results in urinary normetanephrine tests when using liquid chromatography with electrochemical detection. An alternative, selective assay for normetanephrine should be utilized in these cases.

Regular monitoring of renal function is recommended for patients with known renal impairment or those on nephrotoxic medications to ensure safe use of mesalamine.

Side Effects

Common adverse reactions occurring in patients receiving mesalamine include dizziness, rectal pain, fever, rash, acne, and colitis, with an incidence of 1% or greater.

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

Hypersensitivity reactions, which may include myocarditis and pericarditis, necessitate immediate evaluation and discontinuation of mesalamine if such reactions are suspected. Hepatic failure is another serious risk, particularly in patients with known liver impairment, who should be carefully assessed for the risks and benefits of treatment. Severe cutaneous adverse reactions warrant discontinuation of the medication at the first signs or symptoms, along with further evaluation for hypersensitivity. Patients should also be advised about the risk of photosensitivity and encouraged to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors. Additionally, nephrolithiasis has been reported; mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT), making adequate hydration during treatment crucial.

In pediatric patients, adverse reactions observed in clinical trials included abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea, and vomiting, which were similar to those seen in adult patients.

In geriatric patients, uncontrolled clinical studies and postmarketing reports indicate a higher incidence of blood dyscrasias, such as agranulocytosis, neutropenia, and pancytopenia, in those aged 65 years or older compared to younger patients. Therefore, it is recommended to monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine suppositories.

It is also important to note that patients with known or suspected hypersensitivity to salicylates or aminosalicylates, or to any ingredients in the formulation, should not receive mesalamine. Furthermore, patients receiving mesalamine suppositories may experience spuriously elevated test results for urinary normetanephrine when using liquid chromatography with electrochemical detection; alternative, selective assays for normetanephrine should be utilized in these cases.

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 advisable to monitor renal function closely, as well as to observe for any mesalamine-related adverse reactions.

When administered alongside azathioprine or 6-mercaptopurine, there is an elevated risk of blood disorders. 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

The safety and effectiveness of mesalamine suppositories in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. In a 6-week, open-label, single-arm study involving 49 patients aged 5 to 17 years, mesalamine suppositories were evaluated for this indication. However, efficacy was not demonstrated in this study, which included only 14 patients with histologically confirmed cases of ulcerative proctitis.

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

Geriatric Use

Elderly patients, defined as those aged 65 years and older, were not adequately represented in clinical trials of mesalamine suppositories, making it difficult to ascertain whether they respond differently compared to younger patients. However, data from uncontrolled clinical studies and postmarketing reports indicate that this population may experience a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia, when treated with mesalamine-containing products.

Due to these findings, it is essential to monitor complete blood cell counts and platelet counts in geriatric patients receiving mesalamine suppositories. Additionally, 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, when prescribing mesalamine to elderly patients. These factors may necessitate dose adjustments or heightened vigilance during treatment.

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 and 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 for the indicated populations remains unknown. 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 important to note that adverse outcomes in pregnancy can occur regardless of maternal health or medication use. Therefore, healthcare professionals should consider these factors when counseling pregnant patients or women of childbearing potential regarding the use of mesalamine.

Lactation

Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts. The concentration of mesalamine in milk has been reported to range 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 infants for this adverse effect. However, there is no information available regarding 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 breastfeeding. Therefore, the developmental and health benefits of breastfeeding should be considered alongside the mother’s clinical need for mesalamine suppositories and any potential adverse effects on the breastfed child from the medication or from the underlying maternal conditions.

Renal Impairment

Patients with known 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 should be discontinued.

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 mesalamine overdose, it is important to recognize that while mesalamine absorption from the colon is limited, the use of mesalamine suppositories can still lead to significant toxicity. Symptoms of salicylate toxicity may manifest as nausea, vomiting, and abdominal pain. Additionally, patients may experience tachypnea, hyperpnea, tinnitus, and various neurologic symptoms, including headache, dizziness, confusion, and seizures.

Severe salicylate intoxication can result in serious complications, such as electrolyte and blood pH imbalances, which may further lead to involvement of other organs, including renal and hepatic systems.

Currently, there is no specific antidote available for mesalamine overdose. Therefore, management should focus on correcting fluid and electrolyte imbalances through the administration of appropriate intravenous therapy. It is also crucial to monitor and maintain adequate renal function throughout the treatment process. Healthcare professionals should remain vigilant for the development of any severe symptoms and manage them accordingly.

Nonclinical Toxicology

Toxicology studies of mesalamine were conducted in rats, mice, rabbits, and dogs, with the kidney identified as the primary target organ of toxicity.

Non-teratogenic effects were observed in various studies. In a two-year study involving Wistar rats fed up to 320 mg/kg/day of mesalamine, there was no increase in the incidence of neoplastic lesions compared to controls. Mesalamine was also found to be non-mutagenic in the Ames test, the mouse lymphoma cell (TK +/-) forward mutation test, and the mouse micronucleus test. Additionally, no effects on fertility or reproductive performance were noted in male and female rats at oral doses of mesalamine up to 320 mg/kg/day.

In terms of animal pharmacology and toxicology, adverse renal effects were noted in rats at a single oral dose of 600 mg/kg and at intravenous doses exceeding 214 mg/kg. A 13-week oral gavage toxicity study in rats revealed papillary necrosis and/or multifocal tubular injury in males receiving 160 mg/kg and in both sexes at 640 mg/kg. In a combined 52-week toxicity and 127-week carcinogenicity study, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were observed at oral doses of 100 mg/kg/day and above.

In a 14-day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg were not associated with any adverse effects. A six-month oral toxicity study in dogs indicated that doses of 80 mg/kg and higher caused renal pathology similar to that observed in rats. In a rectal toxicity study of mesalamine suppositories in dogs, a dose of 166.6 mg/kg resulted in chronic nephritis and pyelitis. Furthermore, in a 12-month eye toxicity study in dogs, keratoconjunctivitis sicca occurred at oral doses of 40 mg/kg and above.

Postmarketing Experience

Discoloration of urine to a reddish-brown hue has been reported in patients using mesalamine suppositories, particularly when urine comes into contact with surfaces or water treated with hypochlorite-containing bleach. Patients are advised to monitor their urine flow and to report any discoloration that occurs upon leaving the body, prior to contact with any surface or water.

Additionally, mesalamine suppositories have been associated with staining of surfaces that come into direct contact with the product. This includes, but is not limited to, fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. To prevent staining, it is recommended that mesalamine suppositories be kept away from these surfaces.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the proper use and potential effects of mesalamine suppositories. It is important to instruct patients not to cut or break the suppository, as this may affect its efficacy.

Patients should be informed to retain the suppository for one to three hours, or longer if possible, to ensure optimal absorption. Additionally, they should be encouraged to drink an adequate amount of fluids while using this medication.

In the event that a dose of mesalamine suppositories is missed, patients should be instructed to administer the missed dose as soon as possible, unless it is almost time for the next scheduled dose. They must be cautioned against using two mesalamine suppositories simultaneously to compensate for a missed dose.

Patients may experience discoloration of urine, which may appear reddish-brown when mesalamine comes into contact with surfaces or water treated with hypochlorite-containing bleach. Healthcare providers should advise patients to monitor their urine flow and report any discoloration that occurs upon leaving the body, prior to contact with any surface or water, to their healthcare provider.

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

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) and it may also be refrigerated if necessary. Care should be taken to keep the product away from direct heat, light, and humidity to maintain its integrity and efficacy. Proper storage conditions are crucial for ensuring the product's quality throughout its shelf life.

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 Camber Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)