Mesalamine

Uses and Indications

Mesalamine is indicated for the treatment of ulcerative colitis in various formulations and patient populations.

Adult Indications

• Delayed-Release Tablets:

  • Indicated for the induction and maintenance of remission in adult patients with mildly to moderately active ulcerative colitis.

  • Indicated for the treatment of moderately active ulcerative colitis.

  • Limitation of Use: Safety and effectiveness of mesalamine delayed-release tablets beyond 6 weeks have not been established.

• Extended-Release Capsules:

  • Indicated for the maintenance of remission of ulcerative colitis in adults.

  • Indicated for the induction of remission and for the treatment of mildly to moderately active ulcerative colitis.

• Rectal Suspension Enema:

  • Indicated for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis, or proctitis in adults.

• Suppositories:

  • Indicated for the treatment of mildly to moderately active ulcerative proctitis in adults.

Pediatric Indications

• Delayed-Release Tablets:

  • Indicated for the treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg.

Limitations of Use

• The safety and effectiveness of mesalamine delayed-release tablets beyond 6 weeks have not been established.

Teratogenic and Nonteratogenic Effects

• No teratogenic effects are mentioned across the formulations.

• Nonteratogenic effects are not specifically detailed, but mesalamine is not expected to cause fetal harm.

Dosage and Administration

The recommended dosage and administration of mesalamine vary based on the formulation and the patient's age and weight.

Administration Instructions:Healthcare professionals should evaluate renal function prior to the initiation of mesalamine therapy and periodically during treatment. Mesalamine tablets and capsules should be swallowed whole; they must not be cut, broken, or chewed. Patients should be instructed to drink an adequate amount of fluids. Mesalamine delayed-release tablets should be taken on an empty stomach, at least 1 hour before and 2 hours after a meal, while mesalamine extended-release capsules can be taken without regard to meals. Co-administration with antacids should be avoided.

Recommended Dosage in Adults:

• For Induction of Remission: The dosage ranges from 2.4 g to 4.8 g (two to four 1.2 g tablets) once daily for 6 weeks.

• For Maintenance of Remission: The recommended dosage is 2.4 g (two 1.2 g tablets) once daily.

Recommended Dosage in Pediatric Patients:For the treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg who can swallow tablets whole:

• Weight 24 kg to 35 kg:

  • Week 0 to Week 8: 2.4 g (two 1.2 g tablets) once daily.

  • After Week 8: 1.2 g (one 1.2 g tablet) once daily.

• Weight greater than 35 kg to 50 kg:

  • Week 0 to Week 8: 3.6 g (three 1.2 g tablets) once daily.

  • After Week 8: 2.4 g (two 1.2 g tablets) once daily.

• Weight greater than 50 kg:

  • Week 0 to Week 8: 4.8 g (four 1.2 g tablets) once daily.

  • After Week 8: 2.4 g (two 1.2 g tablets) once daily.

Rectal Administration:For mesalamine rectal suspension enema, the recommended adult dosage is one rectal instillation (4 grams) once daily, preferably at bedtime, and retained for approximately eight hours for 3 to 6 weeks, depending on symptoms and sigmoidoscopic findings. Patients should be instructed to shake the bottle well before use and to follow proper positioning for administration.

Suppository Administration:The recommended adult dosage for mesalamine suppositories is 1000 mg administered rectally once daily at bedtime for 3 to 6 weeks. Patients should retain the suppository for one to three hours or longer, if possible, and should be cautioned about potential staining of surfaces.

Capsule Administration:For mesalamine extended-release capsules, the recommended dosage is 1.5 g (four 0.375 g capsules) once daily in the morning. Capsules should be swallowed whole, and the contents may be sprinkled onto applesauce or yogurt if necessary.

It is essential to adhere to these guidelines to ensure the safe and effective use of mesalamine in managing ulcerative colitis.

Contraindications

Known or suspected hypersensitivity to salicylates, aminosalicylates, or any components of mesalamine formulations is a contraindication for all forms of mesalamine, including delayed-release tablets, extended-release capsules, enemas, and suppositories. This includes hypersensitivity to sulfites in specific formulations such as mesalamine rectal suspension enema and other related products. Due to the risk of adverse reactions, mesalamine should not be used in patients with these hypersensitivities.

Warnings and Precautions

Renal Impairment Renal function should be assessed at the beginning of treatment and periodically during therapy. The risks and benefits of mesalamine should be evaluated in patients with known renal impairment or those taking nephrotoxic drugs. Mesalamine should be discontinued if renal function deteriorates during treatment.

Mesalamine-Induced Acute Intolerance Syndrome Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis. Patients should be monitored for worsening symptoms, and treatment should be discontinued if acute intolerance syndrome is suspected.

Hypersensitivity Reactions Patients should be evaluated immediately if a hypersensitivity reaction is suspected, including myocarditis and pericarditis. Mesalamine should be discontinued in such cases.

Hepatic Failure The risks and benefits of using mesalamine should be evaluated in patients with known liver impairment.

Severe Cutaneous Adverse Reactions Discontinue mesalamine at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity, and consider further evaluation.

Upper Gastrointestinal Tract Obstruction Mesalamine should be avoided in patients with pyloric stenosis or other organic or functional obstructions.

Photosensitivity Patients with pre-existing skin conditions should be advised to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.

Nephrolithiasis Cases of nephrolithiasis have been reported with the use of mesalamine. Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Adequate hydration should be ensured during treatment.

Interference with Laboratory Tests The use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. Alternative, selective assays for normetanephrine should be considered.

Laboratory Tests Renal function should be monitored at the beginning of treatment and periodically during therapy.

Emergency Medical Help Patients should seek immediate medical attention if a hypersensitivity reaction is suspected.

Stop Taking and Call Your Doctor Instructions Patients should discontinue mesalamine if renal function deteriorates, if acute intolerance syndrome is suspected, or at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity.

Side Effects

Patients receiving mesalamine may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common Adverse Reactions (≥2%)

• Adults:

  • Headache

  • Abdominal pain

  • Diarrhea

  • Flatulence

  • Nausea

  • Liver function test abnormal

  • Worsening of ulcerative colitis

• Pediatric Patients (≥5%):

  • Abdominal pain

  • Upper respiratory tract infection

  • Vomiting

  • Anemia

  • Headache

  • Viral infection

Serious Adverse Reactions

• Renal Impairment: Renal function should be assessed at the beginning of treatment and periodically thereafter. Mesalamine should be discontinued if renal function deteriorates.

• Mesalamine-Induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis. Patients should be monitored for worsening symptoms, and treatment should be discontinued if acute intolerance syndrome is suspected.

• Hypersensitivity Reactions: This includes myocarditis and pericarditis. Patients should be evaluated immediately, and mesalamine should be discontinued if a hypersensitivity reaction is suspected.

• Hepatic Failure: The risks and benefits of using mesalamine should be evaluated in patients with known liver impairment.

• Severe Cutaneous Adverse Reactions: Discontinue mesalamine at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

• Photosensitivity: Patients with pre-existing skin conditions should be advised to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.

• Nephrolithiasis: Cases of nephrolithiasis have been reported. Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Adequate hydration should be ensured during treatment.

• Upper Gastrointestinal Tract Obstruction: Mesalamine should be avoided in patients with pyloric stenosis or other organic or functional obstruction.

Additional Adverse Reactions or Important Notes

• Interference with Laboratory Tests: Mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection.

• Symptoms of Salicylate Toxicity: These may include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ involvement (e.g., renal and liver).

• Blood Dyscrasias in Elderly Patients: Reports suggest a higher incidence of blood dyscrasias (e.g., agranulocytosis, neutropenia, and pancytopenia) in patients aged 65 years and older receiving mesalamine-containing products. Monitoring of complete blood cell counts and platelet counts is recommended in elderly patients during treatment.

Drug Interactions

Nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs), may increase the risk of nephrotoxicity when used concurrently with mesalamine. It is recommended to monitor renal function and observe for any mesalamine-related adverse reactions.

Additionally, the use of azathioprine or 6-mercaptopurine in conjunction with mesalamine is associated with an increased risk of blood disorders, including blood dyscrasias. Regular monitoring of complete blood cell counts and platelet counts is advised to detect any potential hematological complications.

These interactions highlight the importance of careful patient management and monitoring when mesalamine is prescribed alongside these specific drug classes.

Pediatric Use

The safety and effectiveness of mesalamine delayed-release tablets have been established for the treatment of mildly to moderately active ulcerative colitis in pediatric patients weighing at least 24 kg. This indication is supported by evidence from adequate and well-controlled trials in adults, a multicenter, randomized, double-blind, parallel group trial involving 105 pediatric patients aged 5 to 17 years, and additional pharmacokinetic analyses. The safety profile in pediatric patients was found to be similar to that observed in adults.

However, the safety and effectiveness of mesalamine have not been established in pediatric patients weighing less than 24 kg. Additionally, the safety and effectiveness of mesalamine extended-release capsules, mesalamine enemas, and mesalamine suppositories in pediatric patients have not been established.

Mesalamine suppositories were evaluated in a 6-week, open-label, single-arm study involving 49 patients aged 5 to 17 years, but efficacy was not demonstrated. Adverse reactions observed in this study included abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea, and vomiting, which were similar to those seen in adult patients.

For mesalamine delayed-release capsules, the safety and effectiveness for the treatment of mildly to moderately active ulcerative colitis in pediatric patients aged 5 to 17 years have been established based on studies using mesalamine delayed-release 400 mg tablets. However, the safety and effectiveness of these capsules in patients below the age of 5 years have not been established, nor has their effectiveness in maintaining remission of ulcerative colitis in pediatric patients.

Geriatric Use

Clinical studies of mesalamine and its formulations (including delayed-release tablets, extended-release capsules, enemas, and suppositories) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and postmarketing data indicate a higher incidence of blood dyscrasias, such as agranulocytosis, neutropenia, and pancytopenia, in patients aged 65 years and older compared to younger patients receiving mesalamine-containing products.

Elderly patients may experience increased systemic exposures to mesalamine. Therefore, it is essential to monitor complete blood cell counts and platelet counts in elderly patients during treatment. Additionally, when prescribing mesalamine, healthcare providers should consider the greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this population.

For elderly patients, it is advisable to start treatment at the low end of the dosing range for induction to mitigate potential risks. Regular evaluation of renal function is also recommended, particularly for those with known renal impairment or those taking nephrotoxic drugs. If renal function deteriorates during therapy, mesalamine should be discontinued.

Pregnancy

Limited published data on the use of mesalamine in pregnant patients are insufficient to inform a drug-associated risk. Animal reproduction studies have shown no evidence of fetal harm when mesalamine was administered to pregnant rats and rabbits at doses up to 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose during organogenesis. However, 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.

Published data from meta-analyses, cohort studies, and case series have not reliably established an association between mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Increased disease activity in women with ulcerative colitis has been associated with adverse pregnancy outcomes, including preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g), and small for gestational age at birth. There is no clear evidence that mesalamine exposure in early pregnancy is linked to an increased risk of major congenital malformations, including cardiac malformations.

It is important to note that published epidemiologic studies have significant methodological limitations, which 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 incomplete information regarding the dose and duration of mesalamine treatment.

Given the potential risks associated with active inflammatory bowel disease during pregnancy, mesalamine should be used only if clearly needed, and healthcare providers should carefully consider the benefits and risks when prescribing this medication to pregnant patients.

Lactation

Data from published literature indicate that mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, are present in human milk in small amounts. The relative infant doses (RID) for mesalamine are reported to be 0.1% or less, while for N-acetyl-5-aminosalicylic acid, RIDs can be as high as 2%. Maternal doses of mesalamine from various formulations have ranged from 500 mg to 4.8 g daily.

The average concentration of mesalamine in breast milk has been found to range from non-detectable to 0.5 mg/L, and the concentration of N-acetyl-5-aminosalicylic acid has been reported between 0.2 mg/L and 18.1 mg/L. Based on these concentrations, estimated daily dosages for an exclusively breastfed infant are approximately 0 to 0.075 mg/kg/day for mesalamine and 0.03 to 2.72 mg/kg/day for N-acetyl-5-aminosalicylic acid.

There are case reports of diarrhea in breastfed infants exposed to mesalamine, and caregivers are advised to monitor for this side effect. However, there is no specific information available regarding the effects of mesalamine on milk production or the overall risk to breastfed infants. The lack of comprehensive clinical data during lactation necessitates careful consideration of the developmental and health benefits of breastfeeding against the mother's clinical need for mesalamine and any potential adverse effects on the breastfed child.

Caution should be exercised when administering mesalamine to nursing mothers, and it is recommended that healthcare providers discuss the risks and benefits with the mother, taking into account her health condition and the potential impact on the infant.

Renal Impairment

Patients with renal impairment require careful consideration when being treated with mesalamine, as the drug is substantially excreted by the kidneys. It is essential to assess renal function at the beginning of treatment and periodically throughout therapy. This monitoring is particularly important for patients with known renal impairment, a history of renal disease, or those taking nephrotoxic drugs.

The risks and benefits of mesalamine should be evaluated in these patients, and any deterioration in renal function necessitates the discontinuation of the medication. Adverse reactions related to mesalamine may be more pronounced in individuals with impaired renal function, including conditions such as minimal change disease, acute and chronic interstitial nephritis, and renal failure.

In addition to regular renal function assessments, it is advisable to ensure adequate hydration during treatment to prevent nephrolithiasis, as mesalamine-containing stones may not be detectable by standard imaging techniques. Overall, close monitoring and a thorough evaluation of the patient's renal status are critical to safely administering mesalamine in this population.

Hepatic Impairment

Patients with hepatic impairment should be evaluated for the risks and benefits of using mesalamine in all its formulations, including tablets (delayed-release), capsules (extended-release), enemas, and suppositories. There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered products containing mesalamine.

No specific dosage adjustments, special monitoring, or precautions are provided in the drug insert for patients with liver problems. Therefore, careful consideration and monitoring of liver function tests may be warranted in these patients to ensure safety and efficacy.

Overdosage

Symptoms of salicylate toxicity associated with mesalamine overdose may include nausea, vomiting, abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic manifestations such as headache, dizziness, confusion, and seizures. Severe intoxication can lead to significant electrolyte and blood pH imbalances, potentially resulting in renal and liver damage.

There is no specific antidote for mesalamine overdose. However, conventional therapy for salicylate toxicity may be beneficial in cases of acute overdosage. Management strategies should include gastrointestinal tract decontamination to prevent further absorption. It is crucial to correct any fluid and electrolyte imbalances through the administration of appropriate intravenous therapy and to maintain adequate renal function.

Given that mesalamine is a pH-dependent, delayed-release product, this characteristic should be taken into account when treating a suspected overdose. Continuous monitoring of the patient's clinical status and laboratory parameters is recommended to guide further management and interventions.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a series of nonclinical studies, mesalamine demonstrated no carcinogenic potential. Specifically, in a 104-week dietary carcinogenicity study involving CD-1 mice, mesalamine administered at doses up to 2,500 mg/kg/day was not tumorigenic, representing approximately 2.2 times the maximum recommended human dose based on body surface area. Similarly, in Wistar rats, doses up to 800 mg/kg/day also showed no tumorigenic effects, equating to about 1.4 times the recommended human dose. Furthermore, no evidence of mutagenicity was observed in various assays, including the Ames test and the mouse micronucleus test.

Regarding fertility, no adverse effects on reproductive performance were noted in male or female rats at oral doses of mesalamine up to 400 mg/kg/day, which is approximately 0.7 times the maximum recommended human dose based on body surface area.

Animal Toxicology

Animal studies have consistently identified the kidney as the primary target organ for mesalamine toxicity. In a 13-week oral toxicity study, renal lesions such as granular and hyaline casts, tubular degeneration, and papillary necrosis were observed in both mice and rats at doses of 2,400 mg/kg and 1,150 mg/kg, respectively. In cynomolgus monkeys, doses of 250 mg/kg or higher resulted in nephrosis and interstitial fibrosis.

Single oral doses of mesalamine at 800 mg/kg (approximately 2.2 times the recommended human dose) and 1,800 mg/kg (approximately 9.7 times the recommended human dose) were lethal to mice and rats, respectively, leading to gastrointestinal and renal toxicity. Chronic administration of mesalamine at doses of 80 mg/kg/day in dogs also resulted in significant renal pathology, including chronic nephritis and papillary necrosis.

In summary, while mesalamine has not shown teratogenic effects or significant mutagenic potential, it has demonstrated renal toxicity across various animal models, necessitating careful consideration of dosing and monitoring in clinical settings.

Storage and Handling

Mesalamine is supplied in various forms, including delayed-release tablets, extended-release capsules, enemas, and suppositories. The delayed-release tablets are available in HDPE bottles with child-resistant closures, containing either 120 or 500 tablets. The extended-release capsules are also supplied in bottles with child-resistant closures, typically containing 120 capsules.

All forms of Mesalamine should be stored at controlled room temperature, specifically between 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature. It is essential to protect the tablets from moisture; they can be dispensed without desiccant for up to 6 weeks.

For the enemas, once the foil-wrapped unit of seven bottles is opened, all enemas should be used promptly as directed by a physician. The contents of the enemas may darken over time, but slight darkening does not affect potency. However, enemas with dark brown contents should be discarded.

All forms should be stored in tight, light-resistant containers and kept out of reach of children. Suppositories should be stored below 25°C (77°F) and may be refrigerated, while also being kept away from direct heat, light, or humidity.