Ulcerative Colitis: Achieving and Maintaining Remission

Hannah R. Howell, PharmD

Disclosures

US Pharmacist. 2008;33(12):30-38. 

In This Article

Aminosalicylates

5-aminosalicylic acid (5-ASA), also known as mesalamine, is effective for both induction and maintenance of remission in patients with UC.[8,9] Sulfasalazine, which is a sulfapyridine molecule linked to 5-ASA, was originally used to treat UC. It is associated with many intolerable and life-threatening adverse reactions (e.g., exanthema, fever, angioedema, liver damage). When studies found that the active portion of sulfasalazine was 5-ASA and that many of the adverse effects were a result of the sulfapyridine moiety, efforts became directed toward developing pure 5-ASA formulations, which have now become the mainstay of therapy.[10,11]

5-ASA exerts its therapeutic effects topically on the inflamed mucosa of the colon by interacting with damaged epithelium. The exact mechanism of action is unknown, but 5-ASA is a known scavenger of oxygen-free radicals, and it blocks production and chemotaxis of leukotrienes, in addition to many other actions aimed at modifying the immune response and inflammation.[12] When given orally, 5-ASA is readily absorbed prior to reaching the colon. Since the efficacy is dependent on 5-ASA reaching its site of action, delivery systems designed specifically to release 5-ASA in the colon have been developed, including both rectal and oral preparations (Table 3).

Rectal 5-ASA

For patients with distal UC (including proctosigmoiditis and proctitis), rectally administered 5-ASA is the preferred therapy for both mild to moderate active UC and maintenance of remission.[13] Advantages include direct delivery of the drug to the site of action, reduction of systemic adverse effects, and improved efficacy.[14] Suppositories deliver a large amount of 5-ASA that is confined to the rectum, while liquid enemas reliably reach as far as the splenic flexure.

Common complaints reported with rectally administered 5-ASA are related to patient discomfort and dislike of the drug instillation. These include abdominal bloating, discomfort during instillation, and difficulty retaining the drug.[15] There is some evidence that gels or foam preparations of 5-ASA are better tolerated due to higher retention, but these products are not currently available in the U.S.[16] A patient's willingness to comply and ability to retain a rectal treatment will ultimately determine the individual treatment regimen.

Randomized, controlled studies have demonstrated the superiority of rectally administered 5-ASA for active distal UC over placebo, rectally administered corticosteroids (CCSs), and oral 5-ASA.[2] There also seems to be a faster onset of relief than with oral 5-ASA.[17] No dose-response has consistently been documented with rectally administered 5-ASAs, and most data support between 1 and 4 g daily.[2] Increasing evidence indicates that combination therapy with either oral 5-ASA and rectal 5-ASA or rectal 5-ASA and rectal CCSs may achieve better remission rates than monotherapy in patients with distal disease.[18] For maintaining remission of distal UC, rectal 5-ASA is more effective than placebo and as effective as oral 5-ASA;[14] however, rectal therapies are generally not accepted by patients and are also underprescribed by physicians.[2]

Oral 5-ASA

For patients unwilling or unable to tolerate rectal 5-ASA or for those with more extensive disease, orally administered 5-ASA is effective for mild to moderate active disease and is the mainstay of therapy for maintaining remission.[3] Advantages include ease of use, wider patient acceptance, and enhanced compliance.

Different delivery systems are available that utilize physiochemical properties of the colon to release the active drug directly at the site of action. A novel multimatrix formulation of 5-ASA (MMX mesalamine [Lialda]) was recently approved; it has a pH-sensitive coating surrounding a matrix of hydrophilic polymer containing 5-ASA that is designed to slowly release the drug throughout the entire colon at relatively high concentrations.[19] Similar to sulfasalazine, the azo-bonded prodrugs balsalazide and olsalazine utilize a carrier molecule, which is cleaved from the active drug by colonic bacteria.[11] There does not appear to be a significant difference in efficacy between any of the currently available oral 5-ASA formulations.

A 2006 Cochrane meta-analysis reviewed the efficacy and safety of oral 5-ASA formulations compared to placebo or sulfasalazine for induction of remission in patients with active UC. The analysis included 21 studies and more than 2,000 patients. Oral 5-ASA was found to be superior to placebo, and there was a nonsignificant trend toward higher remission over sulfasalazine.[8]

Once remission has been achieved, it is very important to continue maintenance therapy in order to reduce the risk of relapse, proximal extension of disease, and the development of carcinoma.[4] A Cochrane review of oral 5-ASA for maintenance of remission evaluated almost 2,500 patients and concluded that oral 5-ASA formulations are effective in maintaining remission of UC.[9]

Since there are not enough data to conclusively determine that one particular oral formulation of 5-ASA is better than another, the choice should be based on the location of active disease, cost, and administration regimens. For example, patients who forget to take multiple doses should be given once-daily formulations, and those with more distal colitis may benefit from azo-bonded formulations combined with rectal therapy.

The optimal dosing regimen for both induction and maintenance of remission is a controversial topic. Higher doses of oral 5-ASA (≥4 g/day) are more effective for inducing remission.[3] There does not appear to be a dose-response relationship for maintenance therapy; thus, lower doses are recommended to minimize adverse effects (<2.4 g/day).[20] There is evidence that switching between different oral 5-ASA formulations may improve response rates in individual patients, so it is worth trying an alternative before considering oral 5-ASA a treatment failure.[21]

Oral formulations of 5-ASA are generally well tolerated. Mild, reversible adverse effects include nausea, diarrhea, headache, and rash. More severe reactions include pancreatitis, hepatitis, blood dyscrasias, and worsening of colitis. Interstitial nephritis is a rare, idiosyncratic reaction that has been reported; however, there is some evidence that IBD itself may increase the risk of renal impairment. Patients with preexisting renal dysfunction or on high doses of oral 5-ASA should be periodically monitored for changes in renal function.[10,11]

Both rectal and oral 5-ASA formulations are considered safe in pregnancy (Pregnancy Category B). Therapy should be continued because active disease has more potential for maternal/fetal harm than the use of these drugs.[22]

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