Continuing Education Activity

Mesalamine, also known as 5-aminosalicylic acid (5-ASA), is a medication used to treat ulcerative colitis. It is usually used to induce or maintain remission of mildly to moderately active ulcerative colitis. Clinicians may use mesalamine off-labeled in Crohn disease after surgical resection of the affected bowel. It is under the drug classification of aminosalicylates. This activity reviews the indications, mechanisms of action, contraindications, adverse effects, administration options, and other key factors of mesalamine. This activity will also highlight the relevant aspects for healthcare professionals in managing patients with ulcerative colitis and related conditions when administering mesalamine.

Objectives:

• Identify the mechanism of action of mesalamine.
• Describe the adverse effects of mesalamine.
• Review appropriate monitoring parameters for the administration of mesalamine.
• Summarize interprofessional team strategies for improving care coordination and communication to advance mesalamine and improve outcomes.

Indications

FDA-approved Indication: Mesalamine is useful in the induction or maintenance of remission in ulcerative colitis. It is usually used in mildly to moderately active ulcerative colitis.[1] 

Off-label indication: Clinicians may use mesalamine in Crohn disease after surgical resection of the affected bowel.[2][3][4]

The first-line treatment for mild to moderate ulcerative colitis is topical mesalamine.[5] A suppository formulation is an option for disease localized to the rectum, but mesalamine enemas are preferable for the disease that extends into the sigmoid colon. Overall, topical mesalamine formulations are preferred over oral forms and topical glucocorticoids unless the patient is unable to tolerate or is unwilling to use topical mesalamine.[6] If the patient does not feel any relief after four weeks of therapy, mesalamine can be supplemented with other drug options such as an addition of topical or oral glucocorticoid, oral 5-ASA, budesonide multi-matrix, or a TNFα inhibitor depending on the severity of the disease.[5]

Mesalamine is also used in maintenance therapy for patients with more than one episode or flare-up per year, patients with ulcerative proctosigmoiditis, or ulcerative colitis extending into the sigmoid colon. The use of topical mesalamine significantly decreases the risk of relapse.[7][8]

Mechanism of Action

The exact mechanism of mesalamine is unknown. However, the hypothesis is that it modulates the inflammatory response derived from the cyclooxygenase and lipooxygenase pathways, thus decreasing the synthesis of prostaglandins and leukotrienes. Other potential mechanisms include interference with the production of inflammatory cytokines via reducing the activity of nuclear factor­ κB (NF-κB) and inhibition of tumor necrosis factor (TNF), cellular functions of mucosal lymphocytes, macrophages, and natural killer cells. Mesalamine has also been postulated as a free radical scavenger and an antioxidant.[3][9]

Administration

Mesalamine can be taken orally as a capsule or a tablet with or without food. Depending on the formulation, mesalamine can get released at different sites along the GI tract. For example, the 5-ASA delayed-release capsules can be released anywhere from the jejunum to the rectum, the 5-ASA pH-dependent release can be released anywhere from the ileum to the rectum, Sulfasalazine (prodrug) can be released anywhere from the proximal colon to the rectum, 5-ASA enemas get released in the distal colon and rectum, and 5-ASA suppositories are released only in the rectum.[6][10] The effectiveness of mesalamine depends on the concentration at the site of active disease and is thought to work topically.[4]

Mesalamine can also be administered rectally as an enema, foam, or suppository. Topical formulations such as the suppository and the enema are preferable for treating ulcerative colitis.[3] Mesalamine is metabolized in the liver and the GI tract to N-acetyl-5-aminosalicylic acid via N-acetylation (NAT). The half-life elimination of mesalamine is about 25 hours on average. Excretion of mesalamine is by urine and feces, depending on the formulation of the drug.[11][10]

Dosage Formulation

• The oral formulation of mesalamine is available as delayed-release capsules (400 mg), extended-release capsules (250 mg, 375 mg, 500 mg),  and delayed-release tablets (800 mg, 1200 mg). Mesalamine delayed-release capsules and delayed-release tablets are not therapeutically equivalent (not AB-rated); hence clinicians should carefully consider the dosage formulation and dose for mesalamine. In addition, it is recommended not to cut, chew or crush mesalamine extended-release products.
• The rectal formulation of mesalamine is available as an enema (4 gm) and a suppository (1000 mg).

Mild/Moderate Active Ulcerative Colitis 

Adult Patients: The recommended daily dosage of delayed-release mesalamine capsules is 800 mg three times daily to administer a total daily dosage of 2.4 grams for six weeks. 

Pediatric Population: For patients five years or older, the recommended daily dosage of mesalamine delayed-release capsules is based on body weight to the maximum of 2.4 grams per day which can be divided into two daily doses for six weeks. 

Maintenance of Remission of Ulcerative Colitis

The recommended daily dosage of delayed-release mesalamine capsules in adults is 1.6 grams (four 400 mg capsules) in two to four divided doses.

Special Patient Population

Patients with Renal Impairment: No information is available in product labeling for patients with renal impairment. Evaluate the benefits and risks of administering mesalamine in patients with a history of renal disease or known renal impairment and/or taking concomitant nephrotoxic drugs.

Patients with liver impairment: Mesalamine should be prescribed with caution. There are reports of hepatic failure in patients with pre-existing hepatic diseases treated with mesalamine. Evaluate the benefits and risks of using mesalamine in patients with known liver impairment.

Pregnancy Considerations: Mesalamine is considered pregnancy category B medicine. There are inadequate well-controlled studies of its use in pregnant women. Limited published human data on mesalamine show no increase in the overall rate of congenital malformations. It should be used during pregnancy only if clearly needed. Mesalamine crosses the placenta. In retrospective and prospective clinical studies of more than 600 women exposed to mesalamine during pregnancy, the rate of congenital malformations was not higher than the background rate in the general population.

Breastfeeding Women: Mesalamine and its N-acetyl metabolite are present in human milk. Breastfeeding is not contraindicated using mesalamine, but the infant should be monitored for diarrhea or other side effects.[2] The developmental benefits of breastfeeding should be considered along with the women’s clinical need for treatment and any potential adverse drug reactions on the breastfed infant from the mesalamine or the mother’s underlying medical condition. Caution should be exercised when administering mesalamine to a nursing woman.

Adverse Effects

Patients tolerate most mesalamine (5-ASA) formulations well. However, adverse effects may include nausea, GI upset, abdominal pain, headaches, nasopharyngitis, rash, arthralgias, agranulocytosis, aplastic anemia, myalgias, bone marrow suppression, oligospermia, hematuria, and cholestatic hepatitis. Renal impairment, including interstitial nephritis, nephrotic syndrome, and renal failure, can be seen and must be carefully monitored before initiating treatment and during treatment for these reasons.[4][12]

Hypersensitivity reactions are also common, and there have been reports of pericarditis, myocarditis, hepatitis, nephritis, pneumonitis, and hematology-associated reactions. Patients may also be intolerant to mesalamine, which causes symptoms such as cramping, headache, fever, malaise, pruritis, rash, and abdominal pain. Treatment must discontinue if such issues occur.[13][14]

Drug Interactions

• Antacids: May disrupt the pH-dependent formulations of mesalamine. This condition can result in the premature release and a decrease in the therapeutic effect of mesalamine.[15]
• Heparin: 5-ASA can enhance the pharmacologic effects of heparin and can subsequently increase the risk of bleeding or bruising.[16]
• Cardiac glycosides: 5-ASA may decrease the concentration of cardiac glycosides in the blood.[17]
• Myelosuppressive agents (e.g., mercaptopurine): Increase bone marrow suppression risk.[18]
• H2 receptor blocker: May increase gastrointestinal pH and cause premature release of mesalamine, and decrease its therapeutic effect.
• NSAIDs: Increases the risk of nephrotoxicity.
• Thiopurine analogs (e.g., mercaptopurine): Interaction with 5-ASA may decrease the metabolism of thiopurine analogs.[18]
• Proton pump inhibitors: May increase gastrointestinal pH and cause premature release of mesalamine, and decrease the therapeutic effect.
• Varicella vaccine: Increases risk of Reye syndrome and may enhance the toxic effects of these vaccines.[4]

Contraindications

Contraindications for mesalamine include hypersensitivity to mesalamine, salicylates, or aminosalicylates. Contraindications also include patients with severe renal or hepatic impairment due to the toxic nature of mesalamine in the kidneys and the liver. Other contraindications for using mesalamine are urinary tract obstruction and use in infants and patients with existing gastric or duodenal ulcers.[4] 

Warning/Precautions

Mesalamine-Induced Acute Intolerance Syndrome

Mesalamine administration is associated with an acute intolerance syndrome which may be difficult to differentiate from an exacerbation of ulcerative colitis. It has occurred in approximately 3% of the controlled clinical study populations of mesalamine or sulfasalazine. Symptoms reported include abdominal pain, cramping, headache, malaise, pruritis, conjunctivitis, rash, bloody diarrhea, and sometimes fever. Clinicians should monitor patients closely for worsening of mentioned symptoms while using mesalamine. If acute intolerance syndrome is suspected, it is recommended to discontinue treatment with mesalamine promptly.

Photosensitivity

Patients with pre-existing atopic dermatitis or atopic eczema treated with mesalamine have reported severe photosensitivity reactions. It is advised to avoid sun exposure, wear protective gear, and use broad-spectrum sunscreen when sun exposure occurs.

Nephrolithiasis 

There are cases of nephrolithiasis reported with the administration of mesalamine (including stones made of 100% mesalamine content). These stones are radiotransparent and not detectable by radiography or computed tomography (CT). Ensure adequate fluid intake by patients during treatment with mesalamine.

Interference with Laboratory Tests

Normetanephrine is a metabolite of norepinephrine. This laboratory test is ordered to detect possible pheochromocytoma or paraganglioma. Administration of mesalamine may lead to spuriously elevated laboratory test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of its similarity in the chromatograms of normetanephrine and the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

Monitoring

Due to mesalamine's toxic nature to the kidneys, the healthcare team should monitor the patient's renal function before and during the use of this drug. CBC should also be checked to look out for bone marrow suppression, especially in elderly patients. The hepatic function requires monitoring due to the possible risk of hepatic failure, cholestatic hepatitis, hepatic insufficiency, and other signs and symptoms of hepatotoxicity.[3][8]

Toxicity

An adult patient overdosed using 14.5 g of mesalamine suppository is reported in the literature. The patient experienced hyperemia, edema of the anal channel, and a 1.5 cm ulcer. The ulcer was recovered after 15 days of overdose, and no other adverse events were identified during the follow-up.[19]

Enhancing Healthcare Team Outcomes

The goal for patients with ulcerative colitis is to improve mucosal healing and achieve remission. Symptoms may improve within a week, but remission may take four to six weeks or even longer. A proper understanding of mesalamine and the use of adjuvant therapy is essential for people contributing to the management of this disease. After achieving remission, healthcare professionals need to monitor the patient blood work and colonoscopies. A colonoscopy should be done six to twelve months following remission. Laboratory monitoring of inflammatory markers such as CRP, liver function, renal function, anemia, and stool marker (calprotectin) will be helpful in the health maintenance of ulcerative colitis.[9] Routine health maintenance, including nutrition or dietary therapy managed by dieticians, screening, and prevention of other diseases, such as colon cancer, must be appropriately addressed by healthcare professionals.[20]

Primary care physicians must ensure patients with inflammatory bowel disease (IBD) receive the required and recommended vaccinations. Due to the use of immunosuppressive therapy in patients with IBD, patients need to be informed about the risk of infection, osteoporosis, and certain cancers, including colon, cervical, and skin cancer. As a result of the complexity of this disease, shared decision-making, interprofessional communication, and collaboration between healthcare team members are critical, and doing so will provide the best possible outcome for the patient.[7][8] [Level 1]

When using mesalamine, an interprofessional team approach is the most beneficial methodology. When the clinician prescribes the drug, a pharmacist should check for drug interactions, verify dosing, and counsel the patient on potential adverse events. Nursing should counsel the patient, monitor and follow up on subsequent visits, and report any issues to the prescriber. This interprofessional coordination will improve patient outcomes with mesalamine. [Level 5]