Mesalamine

Description

The active ingredient in mesalamine 1000 mg suppositories 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 contains 1000 mg of mesalamine, USP in a base of hard fat. The molecular 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 1000 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 during treatment.

When administering the suppository, it is important to ensure that it is not cut or broken. Patients should be advised to drink an adequate amount of fluids to facilitate the treatment. After insertion, the suppository should be retained for one to three hours, or longer if possible, to maximize its therapeutic effect.

Healthcare professionals should also inform patients that mesalamine suppositories may cause staining of surfaces that come into direct contact with the medication. This includes, but is not limited to, fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. It is advisable to keep mesalamine suppositories away from these surfaces to prevent staining.

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 contraindication is due to the potential for severe allergic reactions in these individuals.

Warnings and Precautions

Patients with renal impairment should be carefully evaluated for the risks and benefits of treatment with mesalamine. It is essential to monitor renal function regularly, and mesalamine suppositories 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 monitor patients for any worsening of symptoms and discontinue treatment if acute intolerance syndrome is suspected.

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

In patients with known liver impairment, a thorough assessment of the risks and benefits of mesalamine therapy is necessary 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 should be considered 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 vital to minimize this risk.

It is important to note that mesalamine can interfere with laboratory tests for urinary normetanephrine. Specifically, spuriously elevated results may occur with liquid chromatography using electrochemical detection. Healthcare professionals should consider using an alternative, selective assay for normetanephrine in patients receiving mesalamine to avoid misinterpretation of test results.

Side Effects

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

Common adverse reactions, occurring in 1% or more of patients, include dizziness, rectal pain, fever, rash, acne, and colitis. These reactions are generally mild and may not require discontinuation of therapy.

Serious adverse reactions necessitate careful monitoring and management. Renal impairment is a significant concern; patients with known renal impairment or those taking nephrotoxic drugs should have their renal function evaluated regularly. 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. 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, require immediate evaluation and discontinuation of mesalamine if suspected. Hepatic failure is another serious risk, particularly in patients with known liver impairment, necessitating a careful assessment of risks and benefits. Severe cutaneous adverse reactions should prompt immediate discontinuation of the medication at the first signs or symptoms, along with further evaluation for hypersensitivity. Patients are also advised to avoid sun exposure and use protective measures due to the risk of photosensitivity.

Nephrolithiasis has been reported, with mesalamine-containing stones being undetectable by standard radiography or computed tomography (CT). Adequate hydration during treatment is crucial to mitigate this risk.

Additional important notes include the potential for spuriously elevated results in laboratory tests for urinary normetanephrine when using liquid chromatography with electrochemical detection in patients receiving mesalamine; alternative assays should be considered. Symptoms of salicylate toxicity, which may occur in cases of overdosage, include 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, as well as 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 observed, mirroring those seen in adults. Furthermore, elderly patients (aged 65 years and older) 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 this population during treatment.

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, which were consistent with those reported in adult patients.

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, 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, such as mesalamine suppositories.

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 careful dose adjustments and heightened vigilance during treatment.

Pregnancy

Limited published data on mesalamine use in pregnant women 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 is unknown. However, 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 important to note that adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. Therefore, healthcare professionals should consider these factors when prescribing mesalamine to pregnant patients or women of childbearing potential.

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 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.

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 function throughout the course of treatment. Adjustments to dosage may be necessary based on the severity of liver impairment. Close monitoring of liver-related laboratory values is recommended to ensure patient safety and to mitigate potential adverse effects associated with compromised liver function.

Overdosage

In cases of mesalamine overdose, healthcare professionals should be vigilant for a range of symptoms indicative of salicylate toxicity. These symptoms may include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, headache, dizziness, confusion, and seizures.

Severe salicylate intoxication can result in significant complications, including electrolyte and blood pH imbalances, which may lead to renal and liver involvement. Therefore, prompt recognition and management of these symptoms are critical.

Management of mesalamine overdose does not involve a specific antidote. Instead, the focus should be on correcting fluid and electrolyte imbalances through appropriate intravenous therapy. Additionally, it is essential to monitor and maintain adequate renal function throughout the management process to mitigate the risk of further complications.

Nonclinical Toxicology

Mesalamine was evaluated for its potential carcinogenic effects in a two-year study involving Wistar rats. The results indicated no increase in the incidence of neoplastic lesions compared to controls at doses of up to 320 mg/kg/day, which is approximately 1.7 times the recommended human intra-rectal dose based on body surface area. Furthermore, 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.

In terms of reproductive toxicity, no adverse effects on fertility or reproductive performance were observed in male and female rats administered oral doses of mesalamine up to 320 mg/kg/day, again approximately 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 associated with mesalamine. In rats, adverse renal effects were noted following a single oral dose of 600 mg/kg, which is about 3.2 times the recommended human intra-rectal dose, and at intravenous doses exceeding 214 mg/kg, approximately 1.2 times the recommended 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 dose, and in both sexes at 640 mg/kg, approximately 3.5 times the recommended 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 observed at oral doses of 100 mg/kg/day, around 0.54 times the recommended human intra-rectal dose and higher. A 14-day rectal toxicity study in rabbits indicated that intra-rectal doses up to 800 mg/kg, approximately 8.6 times the recommended dose, were not associated with any adverse effects.

In dogs, a six-month oral toxicity study showed that 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. Additionally, a rectal toxicity study of mesalamine suppositories in dogs revealed that a dose of 166.6 mg/kg, approximately 3 times the recommended dose, led to chronic nephritis and pyelitis. In a 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) was noted at oral doses of 40 mg/kg, about 0.72 times the recommended human intra-rectal dose, and above.

Postmarketing Experience

Postmarketing experience with mesalamine suppositories has identified several serious side effects reported voluntarily or through surveillance programs.

Kidney problems have been noted, with healthcare providers advised to conduct specific tests prior to and during treatment. Acute intolerance syndrome and other allergic reactions have also been reported, particularly in individuals with a history of allergic reactions to sulfasalazine. Symptoms associated with these reactions may include cramps, fever, abdominal pain, headache, bloody diarrhea, rash, chest pain, shortness of breath, decreased urine output, fatigue, and eye inflammation.

Liver problems have been observed, especially in patients with a prior history of liver issues or those who have used other mesalamine-containing medications. Symptoms indicative of liver problems include yellowing of the eyes, flu-like symptoms, itchy skin, nausea or vomiting, and extreme fatigue.

Severe skin reactions have been documented, with patients advised to discontinue use and consult a physician if they experience blisters or peeling skin, high fever, mouth sores, enlarged lymph nodes, or rashes.

Sun sensitivity has been reported, particularly in individuals with pre-existing skin conditions such as atopic dermatitis and atopic eczema. Patients are encouraged to limit sun exposure and utilize protective measures such as sunscreen and appropriate clothing.

Additionally, there have been reports of kidney stones associated with the use of mesalamine suppositories. Patients are advised to maintain adequate hydration to reduce the risk of kidney stones and to seek medical attention if they experience severe side pain, blood in urine, or severe back pain.

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.

Patients may notice that their urine becomes discolored reddish-brown while using mesalamine suppositories, particularly when it comes into contact with surfaces or water treated with hypochlorite-containing bleach. They should be advised to monitor their urine flow and report to their healthcare provider only if the discoloration occurs upon leaving the body, prior to 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.

Healthcare providers should inform patients that mesalamine may decrease renal function, particularly in those with known renal impairment or those taking nephrotoxic drugs, including NSAIDs. Periodic monitoring of renal function will be necessary during therapy, and patients should be advised to complete all blood tests ordered by their healthcare provider.

Patients should be made aware of the signs and symptoms of hypersensitivity reactions. They should be instructed to discontinue use of mesalamine 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, malaise, conjunctivitis, and rash, or 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.

Healthcare providers should also inform patients about the signs and symptoms of severe cutaneous adverse reactions. Patients 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.

Patients with pre-existing skin conditions should be advised to avoid sun exposure, wear protective clothing, and use 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 encouraged to complete all blood tests as directed 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 25°C (77°F), 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

The use of mesalamine may result in spuriously elevated urinary normetanephrine test results due to the similarity in chromatographic profiles between normetanephrine and mesalamine's primary metabolite, N-acetylaminosalicylic acid. Clinicians are advised to consider alternative, selective assays for accurate measurement of normetanephrine.

Patients should be counseled to avoid excessive sun exposure, wear protective clothing, and apply a broad-spectrum sunscreen when outdoors to mitigate potential adverse effects.

FDA Insert (PDF)

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

View full prescribing information (PDF)