Mesalamine

Description

Each Mesalamine Extended-Release Capsule, USP is a delayed- and extended-release dosage form for oral administration. Each capsule contains 0.375 g of mesalamine USP (5-aminosalicylic acid, 5-ASA), an aminosalicylate. The structural formula of mesalamine is represented by the molecular formula C7H7NO3, with a molecular weight of 153.14 g/mol. The capsules contain granules composed of mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above. The inactive ingredients include ethylcellulose, FD&C Blue No. 1, gelatin, hypromellose, methacrylic acid and methyl methacrylate copolymer, silicon dioxide, sodium lauryl sulfate, sugar spheres (corn starch and sucrose), talc, titanium dioxide, and triethyl citrate. The imprinting ink consists of ferrosoferric oxide, potassium hydroxide, and shellac.

Uses and Indications

Mesalamine extended-release capsules are indicated for the maintenance of remission of ulcerative colitis in adults.

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

Dosage and Administration

The recommended dosage of mesalamine extended-release capsules is 1.5 g, which corresponds to four 0.375 g capsules, administered once daily in the morning.

Prior to initiating therapy, healthcare professionals should evaluate the patient's renal function to ensure safety and efficacy. The capsules must be swallowed whole; they should not be cut, broken, crushed, or chewed, as this may affect the release mechanism of the medication.

Co-administration with antacids is not advised, as it may interfere with the therapeutic effects of mesalamine. Patients should be encouraged to drink an adequate amount of fluids while on this medication. Mesalamine extended-release capsules can be taken without regard to meals, allowing for flexibility in administration.

Contraindications

Use of mesalamine extended-release capsules is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or any component of the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Renal function should be assessed at the initiation of treatment and monitored periodically throughout the course of therapy. In patients with known renal impairment or those taking nephrotoxic medications, a careful evaluation of the risks and benefits is essential. If there is any deterioration in renal function, treatment must be discontinued.

Healthcare professionals should be vigilant for symptoms of Mesalamine-Induced Acute Intolerance Syndrome, which may mimic an exacerbation of ulcerative colitis. Close monitoring for worsening symptoms is advised, and treatment should be halted if acute intolerance syndrome is suspected.

Hypersensitivity reactions, including myocarditis and pericarditis, require immediate evaluation. If a hypersensitivity reaction is suspected, treatment should be discontinued without delay. Additionally, in patients with known liver impairment, a thorough assessment of the risks and benefits of continuing treatment is necessary due to the potential for hepatic failure.

Severe cutaneous adverse reactions can occur; therefore, treatment should be stopped at the first indication of such reactions or any other signs of hypersensitivity, and further evaluation should be considered. Patients should also be informed about the risk of photosensitivity. Those with pre-existing skin conditions are advised to avoid sun exposure, wear protective clothing, and apply a broad-spectrum sunscreen when outdoors.

The risk of nephrolithiasis should be communicated to patients, as mesalamine-containing stones are not detectable by standard radiography or computed tomography (CT). It is crucial to ensure adequate fluid intake during treatment to mitigate this risk.

In terms of laboratory considerations, the use of mesalamine may interfere with certain laboratory tests, specifically leading to spuriously elevated results when measuring urinary normetanephrine via liquid chromatography with electrochemical detection.

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

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. The most common adverse reactions, occurring in 3% or more of participants, include headache (11%), diarrhea (8%), upper abdominal pain (5%), nausea (4%), and nasopharyngitis (4%).

Less common adverse reactions, occurring in less than 3% of patients, encompass a variety of systems. Ear and labyrinth disorders may present as tinnitus and vertigo. Dermatological disorders may include alopecia. Gastrointestinal issues can manifest as lower abdominal pain and rectal hemorrhage. Laboratory abnormalities may be observed, such as increased triglycerides and decreased hematocrit and hemoglobin. General disorders may include fatigue, while hepatic reactions can involve cholestatic hepatitis and increased transaminases. Renal disorders may present as decreased creatinine clearance and hematuria. Musculoskeletal complaints can include pain and arthralgia, and respiratory issues may manifest as dyspnea.

Postmarketing experience has revealed additional adverse reactions. Body as a whole reactions include lupus-like syndrome and drug fever. Cardiovascular events may involve pericarditis, pericardial effusion, and myocarditis. Gastrointestinal complications can include pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, and perforated peptic ulcer. Hepatic reactions may present as jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, and Kawasaki-like syndrome with changes in liver enzymes. Hematologic reactions can include agranulocytosis and aplastic anemia. Neurological and psychiatric reactions may involve peripheral neuropathy, Guillain-Barré syndrome, and transverse myelitis. Renal and urinary complications may include nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease, and nephrolithiasis. Respiratory and pulmonary reactions may present as eosinophilic pneumonia, interstitial pneumonitis, and pleurisy/pleuritis. Skin reactions can include psoriasis, pyoderma gangrenosum, erythema nodosum, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Additionally, renal/urogenital reactions may include reversible oligospermia.

It is important to note that urine discoloration may occur ex vivo due to contact of mesalamine, including its inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.

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 of mesalamine extended-release capsules in pediatric patients have not been established. Therefore, caution should be exercised when considering the use of this medication in children and adolescents. Further studies are needed to determine appropriate dosing and outcomes in this population.

Geriatric Use

Clinical studies of mesalamine extended-release capsules did not include a sufficient number of subjects aged 65 years and older to determine whether these elderly patients respond differently than younger subjects. However, reports from uncontrolled clinical studies and postmarketing surveillance have indicated a higher incidence of blood dyscrasias, including agranulocytosis, neutropenia, and pancytopenia, in patients aged 65 years and older compared to their younger counterparts using mesalamine-containing products.

Given these findings, it is essential to monitor complete blood cell counts and platelet counts in geriatric patients during treatment with mesalamine extended-release capsules. Additionally, when prescribing this medication to elderly patients, healthcare providers should consider the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may affect treatment outcomes.

Pregnancy

Published data from meta-analyses, cohort studies, and case series regarding the use of mesalamine during pregnancy have not consistently demonstrated an association with major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, administration of oral mesalamine during organogenesis to pregnant rats and rabbits at doses 1.7 and 5.4 times, respectively, the maximum recommended human dose did not result in adverse developmental outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated populations remains unknown. It is important to note that adverse outcomes in pregnancy can occur regardless of maternal health or medication use. 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.

In women with ulcerative colitis, published data suggest that increased disease activity is associated with a higher risk of adverse pregnancy outcomes, which may include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g), and small for gestational age infants at birth. Furthermore, while there is no clear evidence that mesalamine exposure in early pregnancy is linked to an increased risk of major congenital malformations, including cardiac malformations, the methodological limitations of existing epidemiologic studies must be acknowledged. These limitations include the inability to control for confounding factors such as underlying maternal disease and concomitant medication use, as well as gaps in information regarding the dose and duration of mesalamine use.

Overall, healthcare professionals should consider these factors when prescribing mesalamine to pregnant patients and remain vigilant regarding the potential risks associated with increased disease activity in this population.

Lactation

Data from published literature indicate that mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, are present in human milk in small amounts, with relative infant doses (RID) of 2% or less. The average concentration of mesalamine in milk has been reported to range 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. Based on these concentrations, estimated daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day (RID 0% to 0.1%) for mesalamine 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 limits the ability to clearly determine the risk of mesalamine extended-release capsules to an infant during breastfeeding. Therefore, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for mesalamine extended-release capsules 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

Mesalamine is substantially excreted by the kidneys, which may increase the risk of adverse reactions in patients with impaired renal function. It is essential to evaluate renal function in all patients prior to the initiation of mesalamine extended-release capsules therapy and to conduct periodic assessments throughout the treatment course.

Patients with known renal impairment, a history of renal disease, or those taking nephrotoxic drugs should be closely monitored for any signs of decreased renal function and mesalamine-related adverse reactions. If there is any deterioration in renal function during therapy, mesalamine extended-release capsules should be discontinued.

Healthcare professionals should carefully assess the risks and benefits of treatment in patients with known renal impairment or those on nephrotoxic medications, ensuring that renal function is monitored regularly.

Hepatic Impairment

Patients with hepatic impairment should be carefully evaluated for the risks and benefits associated with 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 overdosage, healthcare professionals should be vigilant for symptoms indicative of salicylate toxicity. These symptoms may include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, headache, dizziness, confusion, and seizures.

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

There is currently no specific antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may provide some benefit. In cases of acute overdosage, gastrointestinal tract decontamination may be necessary to prevent further absorption of the drug.

Management should also focus on correcting fluid and electrolyte imbalances through appropriate intravenous therapy, ensuring adequate renal function is maintained throughout the treatment process. It is important to note that mesalamine extended-release capsules are a pH-dependent delayed-release formulation, which should be taken into account when treating a suspected overdose.

Nonclinical Toxicology

Dietary mesalamine was evaluated for carcinogenic potential in both rats and mice. The results indicated that mesalamine was not carcinogenic at doses of up to 480 mg/kg/day in rats and 2,000 mg/kg/day in mice. These doses correspond to approximately 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules, which is 1.5 g/day (equivalent to 30 mg/kg for a 50 kg individual or 1,110 mg/m²), based on body surface area.

In terms of mutagenicity, mesalamine demonstrated negative results in several assays, including the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.

Regarding 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, which is approximately 1.7 times the recommended human dose based on body surface area.

Animal studies assessing the pharmacology and toxicology of mesalamine, including 13-week and 26-week oral toxicity studies in rats, as well as 26-week and 52-week oral toxicity studies in dogs, identified the kidney as the primary target organ for mesalamine toxicity. Lethal doses of mesalamine were determined to be 800 mg/kg (approximately 2.2 times the recommended human dose based on body surface area) for mice and 1,800 mg/kg (approximately 9.7 times the recommended human dose based on body surface area) for rats, both of which resulted in gastrointestinal and renal toxicity.

At lower oral doses of 40 mg/kg/day (about 0.20 times the human dose based on body surface area), minimal to slight tubular injury was noted. Doses of 160 mg/kg/day (approximately 0.90 times the human dose based on body surface area) or higher in rats led to renal lesions, including tubular degeneration, tubular mineralization, and papillary necrosis. Similarly, oral doses of 60 mg/kg/day (about 1.1 times the human dose based on body surface area) or higher in dogs resulted in renal lesions characterized by tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.

Postmarketing Experience

During postmarketing surveillance of mesalamine extended-release capsules and other mesalamine-containing products, various adverse reactions have been reported. These reactions are derived from voluntary reports and surveillance programs, and due to the nature of the reporting population, it is not always feasible to accurately estimate their frequency or establish a causal relationship with drug exposure.

Body as a Whole: Reports include lupus-like syndrome and drug fever.

Cardiovascular: Adverse events such as pericarditis, pericardial effusion, and myocarditis have been documented.

Gastrointestinal: Cases of pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, and perforated peptic ulcer have been identified.

Hepatic: Adverse reactions include jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, and Kawasaki-like syndrome, which may involve changes in liver enzymes.

Hematologic: Instances of agranulocytosis and aplastic anemia have been reported.

Nervous System: There have been reports of intracranial hypertension.

Neurological/Psychiatric: Peripheral neuropathy, Guillain-Barré syndrome, and transverse myelitis have been noted.

Renal and Urinary: Adverse events include nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease, and nephrolithiasis.

Additionally, urine discoloration has been observed ex-vivo due to contact of mesalamine, including its inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.

Respiratory/Pulmonary: Reports of eosinophilic pneumonia, interstitial pneumonitis, and pleurisy/pleuritis have been documented.

Skin: Adverse skin reactions include psoriasis, pyoderma gangrenosum, erythema nodosum, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).

Renal/Urogenital: Reversible oligospermia has also been reported.

Patient Counseling

Healthcare providers should advise patients to swallow mesalamine extended-release capsules whole and to avoid cutting, breaking, crushing, or chewing the capsules. It is important to inform patients to refrain from co-administering these capsules with antacids and to ensure they drink an adequate amount of fluids during treatment.

Patients may take mesalamine extended-release capsules without regard to meals. They should be made aware that their urine may become discolored reddish-brown when it comes into contact with surfaces or water treated with hypochlorite-containing bleach. If patients observe discolored urine, they should monitor their urine flow and report to their healthcare provider only if the urine is discolored upon leaving the body, prior to contact with any surface or water.

Healthcare providers should inform patients that mesalamine extended-release capsules 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 conducted during therapy, and patients should be advised to complete all blood tests ordered by their healthcare provider.

Patients should be educated about the signs and symptoms of hypersensitivity reactions. They must be instructed to discontinue the use of mesalamine extended-release capsules 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.

For patients with known liver disease, healthcare providers should inform them of the signs and symptoms of worsening liver function and advise them to report any such signs or symptoms to their healthcare provider. Additionally, patients should be made aware of the signs and symptoms of severe cutaneous adverse reactions. They should be instructed to stop taking mesalamine extended-release capsules 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. Furthermore, healthcare providers should instruct patients to drink an adequate amount of fluids during treatment to minimize the risk of kidney stone formation and 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.

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 ordered by their healthcare provider.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F) as outlined by USP Controlled Room Temperature guidelines. Additionally, it is crucial to keep the product out of reach of children to ensure safety.

Additional Clinical Information

Postmarketing experience has revealed a range of adverse effects associated with the medication. Clinicians should be aware of potential systemic reactions such as lupus-like syndrome and drug fever. Cardiovascular events may include pericarditis, pericardial effusion, and myocarditis. Gastrointestinal complications can manifest as pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, and perforated peptic ulcer.

Hepatic issues reported include jaundice, cholestatic jaundice, hepatitis, liver necrosis, and liver failure, along with Kawasaki-like syndrome characterized by changes in liver enzymes. Hematologic concerns involve agranulocytosis and aplastic anemia, while neurological effects may present as intracranial hypertension, peripheral neuropathy, Guillain-Barré syndrome, and transverse myelitis. Renal and urinary complications include nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease, and nephrolithiasis.

Additionally, urine discoloration may occur ex-vivo due to contact with surfaces or water treated with hypochlorite-containing bleach. Respiratory and pulmonary adverse effects include eosinophilic pneumonia, interstitial pneumonitis, and pleurisy/pleuritis. Dermatological reactions can involve psoriasis, pyoderma gangrenosum, erythema nodosum, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Lastly, reversible oligospermia has been noted in the renal/urogenital category.

FDA Insert (PDF)

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

View full prescribing information (PDF)