Continuing Education Activity

Mesalamine (USAN), also known as 5-aminosalicylic acid (5-ASA), is primarily indicated to treat inflammatory bowel disease and is effective in inducing or maintaining remission in mild-to-moderate cases of ulcerative colitis. Topical mesalamine stands as the first-line treatment for this condition. Clinicians may use 5-ASA off-label in Crohn disease following surgical resection of the affected bowel. Although patients with ulcerative colitis typically receive 5-ASA prescriptions from their managing gastroenterologist or primary care clinician, a surgeon may become involved in off-label uses. This activity provides healthcare professionals with a comprehensive understanding of mesalamine, covering FDA-approved indications, mechanisms of action, administration strategies, contraindications, and adverse effects profile. This activity also highlights the crucial role of the interprofessional healthcare team in effectively treating patients with ulcerative colitis, inflammatory bowel disease, and related conditions by enhancing their understanding of mesalamine's indications.

Objectives:

• Identify appropriate indications for mesalamine therapy in inflammatory bowel disease, including ulcerative colitis and potential off-label uses in Crohn disease after surgery.

• Implement evidence-based dosing strategies for mesalamine based on disease severity and patient-specific factors.

• Select appropriate adjunctive therapies or alternative treatment options when mesalamine monotherapy is inadequate or contraindicated.

• Coordinate follow-up care and monitoring for patients on long-term mesalamine therapy, emphasizing the importance of medication adherence and regular disease assessment.

Indications

Mesalamine (USAN), also known as 5-aminosalicylic acid (5-ASA), is approved by the US Food and Drug Administration (FDA) and is primarily indicated to treat inflammatory bowel disease.[1] Mesalamine is effective in inducing or maintaining remission in mild-to-moderate cases of ulcerative colitis. 

FDA-Approved Indications

Mesalamine or 5-ASA is useful in the induction or maintenance of remission in ulcerative colitis for mild-to-moderate ulcerative colitis. Topical mesalamine stands as the first-line treatment for this condition.[2] A suppository formulation is an option for disease localized to the rectum, but 5-ASA enemas are preferable for inflammation that extends into the sigmoid colon. Overall, topical 5-ASA formulations are preferred over oral forms and topical glucocorticoids unless the patient cannot tolerate or is unwilling to use topical mesalamine.[3][4] The American Gastroenterological Association guidelines recommend 5-ASA enemas or suppositories in patients with mild-to-moderate ulcerative proctosigmoiditis or proctitis.

Additionally, a combination of rectal 5-ASA with oral 5-ASA is recommended for extensive mild-to-moderate ulcerative colitis. Combining oral and rectal 5-ASA achieves higher rates of induction and maintenance of remission, avoiding escalation to corticosteroids or immunosuppression.[5] After 4 weeks of therapy, 5-ASA can be supplemented with other drug options, such as an addition of topical or oral glucocorticoid, oral 5-ASA, budesonide multi-matrix, or a TNF-α inhibitor, depending on the severity of the disease.[2] 5-ASA is also used in maintenance therapy for patients with more than 1 episode or flare-up per year, patients with ulcerative proctosigmoiditis, or ulcerative colitis extending into the sigmoid colon. The use of topical 5-ASA significantly decreases the risk of relapse.[6][7]

Off-Label Uses

Clinicians may use 5-ASA in Crohn disease after surgical resection of the affected bowel.[8][9][10] The American College of Physicians guidelines do not recommend 5-ASA to prevent recurrent diverticulitis.[11] As per the American Society of Colon and Rectal Surgeons guidelines, 5-ASA does not significantly reduce the recurrence rate of diverticulitis. However, it may aid in alleviating symptoms in individuals diagnosed with symptomatic uncomplicated diverticular disease.[12] A recent meta-analysis suggests that 5-ASA might demonstrate modest effectiveness in relieving global symptoms of irritable bowel syndrome with diarrhea. However, the quality of evidence supporting this is considered low. Further, randomized controlled trials are required in this context.[13]

Mechanism of Action

The exact mechanism of 5-ASA is unknown. However, the hypothesis is that it modulates the inflammatory response derived from the cyclooxygenase and lipooxygenase pathways, 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. 5-ASA has also been postulated as a free radical scavenger and an antioxidant.[9][14]

Pharmacokinetics

Absorption: 5-ASA can be ingested orally as a capsule or a tablet with or without food. Depending on the formulation, 5-ASA can be 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.[3] The effectiveness of 5-ASA depends on the concentration at the site of active disease and is thought to work topically.[10] 

Conventional oral formulations are mainly absorbed in the upper gastrointestinal tract; delayed-release tablets are used for targeted release in the distal gastrointestinal tract, including the terminal ileum and colon. Approximately 28% of mesalazine is absorbed following an oral administration of 400 mg delayed-release tablets.[15] 5-ASA can also be administered rectally as an enema, foam, or suppository. Topical formulations such as the suppository and the enema are preferred for treating ulcerative colitis.[9]

Distribution: The plasma protein binding of 5-ASA is approximately 43±6%, while the plasma protein binding of N-acetyl-5-ASA is approximately 78±1%. 5-ASA rectal suppository distributes within local tissue but does not demonstrate plasma accumulation.

Metabolism: 5-ASA is metabolized in the liver and the gastrointestinal tract to N-acetyl-5-ASA via N-acetylation (NAT).[16]

Elimination: The half-life elimination of 5-ASA is about 25 hours on average. Excretion of 5-ASA is by urine and feces, depending on the formulation of the drug.[17][18]

Administration

Available Dosage Forms and Strengths

• The oral formulation of 5-ASA is available as delayed-release capsules (400 mg), extended-release capsules (250 mg, 375 mg, and 500 mg), and delayed-release tablets (800 mg and 1200 mg). 5-ASA delayed-release capsules and tablets are not therapeutically equivalent (not AB-rated); hence, clinicians should consider the formulation and dose for 5-ASA. In addition, it is recommended not to cut, chew, or crush 5-ASA extended-release products. 5-ASA can be taken orally as a capsule or a tablet with or without food.

• The rectal formulation of 5-ASA is available as an enema (4 g) and a suppository (1000 mg)

Adult Dosage

• Mild-to-moderately active ulcerative colitis: The recommended daily dosage of delayed-release 5-ASA capsules is 800 mg 3 times daily, which amounts to 2.4 g for 6 weeks.

• Maintenance of remission of ulcerative colitis: The recommended daily dosage of delayed-release 5-ASA capsules in adults is 1.6 g (4 400 mg capsules) in 2 to 4 divided doses. The dosage of the extended-release capsule is 1.5 g (4 375 mg capsules) once daily in the morning.

• Mild-to-moderately active ulcerative proctitis: The recommended daily dosage of 5-ASA rectal suppository is 1000 mg at bedtime for 3 to 6 weeks. 

• Mild-to-moderate distal ulcerative colitis, proctitis, or proctosigmoiditis: The recommended adult dose of 5-ASA rectal suspension enema is one instillation (4 g) daily, preferably at bedtime, retained for around 8 hours. The therapeutic response is observed within 3 to 21 days; the typical treatment duration ranges from 3 to 6 weeks.

Specific Patient Populations

Hepatic impairment: 5-ASA should be prescribed with caution. There are reports of hepatic failure in patients with pre-existing hepatic diseases treated with 5-ASA. Evaluate the benefits and risks of using 5-ASA in patients with known liver impairment.[16]

Renal impairment: The updated 5-ASA FDA label highlights the necessity to assess and monitor renal function in all patients before and during treatment due to the predominant excretion via the kidneys. Patients with impaired renal function, a history of kidney disease, or concomitant nephrotoxic drugs are at increased risk of adverse reactions. Regular monitoring is essential, and if renal function deteriorates during therapy, discontinuation is recommended to prevent further complications. Mesalamine-induced acute interstitial nephritis has been reported.[19]

Pregnancy considerations: 5-ASA is considered pregnancy category B medicine. There are inadequate, well-controlled studies of its use in pregnant women. Limited published human data on 5-ASA show no increase in the overall rate of congenital malformations. The medication should be used during pregnancy only if needed. 5-ASA crosses the placenta. In retrospective and prospective clinical studies of more than 600 women exposed to 5-ASA during pregnancy, the rate of congenital malformations was not higher than the background rate in the general population.

Breastfeeding considerations: 5-ASA and its N-acetyl metabolite are present in human milk. Breastfeeding is not contraindicated using 5-ASA, but the infant should be monitored for diarrhea or other adverse effects.[8] 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 5-ASA or the mother’s underlying medical condition. Caution should be exercised when administering 5-ASA to a nursing woman.

Pediatric patients: The recommended daily dosage of 5-ASA delayed-release capsules is based on body weight for patients 5 years or older. The dosage can be increased to a maximum of 2.4 g/d, divided into 2 daily doses for 6 weeks.

Delayed-release tablets are FDA-approved for mild-to-moderately active ulcerative colitis in pediatric patients ≥24 kg.

Older patients: Daily administration of oral 5-ASA might enhance adherence in older patients. Difficulties related to the self-application of topical treatments, such as suppositories and enemas, should be considered.[20]

Adverse Effects

Patients tolerate most 5-ASA formulations. However, adverse effects may include nausea, gastrointestinal 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.[10][21]

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 4-ASA, which causes symptoms such as cramping, headache, fever, malaise, pruritis, rash, and abdominal pain. Treatment must be discontinued if such issues occur.[22][23] Mesalaine-induced myocarditis has been reported, which may require discontinuation of 4-ASA.[24][25]

Drug-Drug Interactions

• Antacids: Antacids may disrupt the pH-dependent formulations of 5-ASA. This condition can result in premature release and a decrease in the therapeutic effect of 5-ASA.[26]

• Heparin: 5-ASA can enhance the pharmacologic effects of heparin and subsequently increase the risk of bleeding or bruising.[27]

• Cardiac glycosides: 5-ASA may decrease the concentration of cardiac glycosides in the blood.[28]

• Myelosuppressive agents (eg, mercaptopurine): Increase bone marrow suppression risk.[29]

• H2 receptor blocker: H2 receptor blockers may increase gastrointestinal pH, cause premature release of 5-ASA, and decrease the therapeutic effect.

• NSAIDs: Concomitant use of NSAIDs with 5-ASA increases the risk of nephrotoxicity.

• Thiopurine analogs (eg, mercaptopurine): Interaction with 5-ASA may decrease the metabolism of thiopurine analogs.[29]

• Proton pump inhibitors: Proton pump inhibitors may increase gastrointestinal pH, induce premature release of 5-ASA, and decrease the therapeutic effect.

• Varicella vaccine: Increases risk of Reye syndrome and may enhance the toxic effects of these vaccines.[10]

Contraindications

Box Warnings

Contraindications for 5-ASA include hypersensitivity to 5-ASA, salicylates, or aminosalicylates. Contraindications also include patients with severe renal or hepatic impairment. Other contraindications for using 5-ASA are urinary tract obstruction and use in infants and patients with existing gastric or duodenal ulcers.[10]

Warning and Precautions

Mesalamine-induced acute intolerance syndrome: 5-ASA 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 5-ASA 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 5-ASA. If acute intolerance syndrome is suspected, it is recommended that treatment with 5-ASA be discontinued promptly.[30] The drug-induced lymphocyte stimulation test can be utilized for identifying 5-ASA intolerance syndrome. The positive drug-induced lymphocyte stimulation test can aid in confirming the diagnosis, but a negative result does not entirely rule out acute 5-ASA intolerance.[31][32]

Photosensitivity: Patients with pre-existing atopic dermatitis or atopic eczema treated with 5-ASA have reported severe photosensitivity reactions. It is advised to avoid sun exposure, wear protective gear, and use broad-spectrum sunscreen when sun exposure occurs.[33]

Nephrolithiasis: There are cases of nephrolithiasis reported with the administration of 5-ASA (including stones made of 100% 5-ASA content). These stones are radiotransparent and undetectable by radiography or computed tomography.[34][35] Ensure adequate fluid intake by patients during treatment.

Interference with laboratory tests: Normetanephrine is a metabolite of norepinephrine. This laboratory test is ordered to detect possible pheochromocytoma or paraganglioma. Administration of 5-ASA may lead to 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 5-ASA, N-acetyl-5-ASA acid (N-Ac-5-ASA).[36] Consider an alternative, selective assay for normetanephrine.

Monitoring

Due to 5-ASA's toxicity to the kidneys, the healthcare team should monitor the patient's renal function before and during the use of this drug. Complete blood count (CBC) should also be checked for bone marrow suppression, especially in older 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.[9][7]

Toxicity

Signs and Symptoms of Overdose

5-ASA, an aminosalicylate, can lead to symptoms of salicylate toxicity. The classic triad of mild toxicity includes nausea, vomiting, and tinnitus. Severe salicylate intoxication can induce respiratory alkalosis by stimulating the respiratory centers, followed by metabolic acidosis due to the uncoupling of oxidative phosphorylation. Some reported symptoms of overdose include hyperemia, edema of the anal channel, and ulceration.[37]

Management of Overdose

There is no antidote for 5-ASA overdose. Management typically involves urinary alkalization and, if needed, hemodialysis.[38][39] Gastrointestinal decontamination is recommended to prevent further absorption. Initial steps include fluid and electrolyte repletion through intravenous therapy and maintenance of optimal renal function.

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 4 to 6 weeks or longer. Properly understanding 5-ASA and the use of adjuvant therapy is essential for people managing this disease. After achieving remission, healthcare professionals should monitor the patient blood work and colonoscopies. A colonoscopy is indicated 6 to 12 months following remission. Laboratory monitoring of inflammatory markers such as CRP, liver function, renal function, anemia, and stool marker (calprotectin) helps monitor ulcerative colitis.[14] Collaboration with a gastroenterologist is beneficial for accurate diagnosis, optimal treatment strategies, and long-term patient care. 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.[40] 

Primary care clinicians must ensure patients with inflammatory bowel disease receive the required and recommended vaccinations. Due to the use of immunosuppressive therapy, 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.[6][7]