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mesalamine 4 gm/60 ml enema

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Uses

Ulcerative Colitis

Oral mesalamine (as delayed-release tablets or extended-release capsules) is used for the management of mildly to moderately active ulcerative colitis. In addition, mesalamine 400-mg delayed-release tablets (Asacol) are used to maintain clinical remission in patients with ulcerative colitis, while mesalamine extended-release capsules (Pentasa) and mesalamine 1.2-g delayed-release tablets (Lialda) are used to induce clinical remission in patients with mildly to moderately active ulcerative colitis. Mesalamine rectal suspension is used in the management of mildly to moderately active distal ulcerative colitis, including ulcerative proctosigmoiditis and ulcerative proctitis. Mesalamine rectal suppositories are used in the management of active ulcerative proctitis. The drug is used in the management of these conditions in conjunction with usual supportive and dietary measures. Oral preparations of the drug may be preferable to rectal preparations in patients with extensive inflammatory bowel disease, since efficacy of rectal preparations may be limited to disease distal to the splenic flexure.

Mildly to Moderately Active Ulcerative Colitis

Delayed- or extended-release oral preparations of mesalamine have been effective in patients with mildly to moderately active ulcerative colitis, including those with proctitis. When used in the management of mildly to moderately active ulcerative colitis, oral mesalamine has reduced disease activity, including improvement in sigmoidoscopic appearance of the bowel, rectal bleeding, abdominal/rectal pain, and stool consistency, frequency, and urgency.

Efficacy of mesalamine 400-mg delayed-release tablets (Asacol) for the management of mildly to moderately active ulcerative colitis has been established in 2 placebo-controlled studies. In one randomized, double-blind, multicenter, dose-ranging (1.6 or 2.4 g daily) study, reduction of disease activity (measured by improvement in sigmoidoscopic appearance) was reported in 49 or 27% of patients receiving mesalamine (2.4 g daily) or placebo, respectively, while no consistent evidence of efficacy was observed with the 1.6-g daily dosage. In addition, substantially more patients receiving mesalamine (2.4 g daily) showed improvement in rectal bleeding and stool frequency than those receiving placebo.

In the other randomized, double-blind, 6-week study, sigmoidoscopic improvement occurred in 74 or 26% of patients receiving mesalamine delayed-release tablets (4.8 g daily) or placebo, respectively. More patients receiving mesalamine have shown improvement in overall symptoms than those receiving placebo.

Efficacy of mesalamine extended-release capsules for the management of mildly to moderately active ulcerative colitis has been established in 2 randomized, double-blind, placebo-controlled, dose-ranging studies. Primary efficacy parameters in these studies were measured by clinical improvement assessed by clinician global assessment (proportion of patients with complete or marked improvement), sigmoidoscopic index (objective measure of disease activity rated by mucosal vascular pattern, erythema, friability, granularity/ulcerations, improvement from baseline in mucopus), and treatment failure (proportion of patients developing severe or fulminant ulcerative colitis requiring corticosteroid therapy, hospitalization, or worsening of the disease within 7 days of therapy or lack of substantial improvement by 14 days of therapy). Secondary efficacy parameters were assessed by clinical symptoms (e.g., stool consistency/frequency/urgency, rectal bleeding, abdominal/rectal pain). Patients received 2 g (1 g twice daily) or 4 g (1 g 4 times daily) of mesalamine extended-release capsules daily. In one of these studies, clinician global index of treatment success was reported in 59, 57, or 36% of patients receiving a daily 4-g dosage of mesalamine, 2-g dosage of mesalamine, or placebo, respectively, while reductions in sigmoidoscopic index (rated by a standard 15-point scale) were 5, 4.3, or 2.5, respectively. Treatment failure was reported in 9, 18, or 22% of patients receiving a daily 4-g dosage of mesalamine, 2-g dosage of mesalamine, or placebo, respectively. Similar efficacy was observed in the other placebo-controlled study; clinician global index of treatment success was reported in 55, 41, or 31% of patients receiving a daily 4-g dosage of mesalamine, 2-g dosage of mesalamine, or placebo, respectively, while reductions in sigmoidoscopic index were 3.8, 2.6, or 1.6, respectively, and treatment failure was reported in 9, 17, or 31% of patients, respectively. While the 4-g daily dosages of mesalamine produced consistent improvement in primary parameters in these studies, the 2-g daily dosage was associated with inconsistent results. Consistent improvement in secondary parameters and induction of remission (assessed by endoscopic and symptomatic endpoints) also were observed with the 4-g daily dosages.

Induction of Remission of Ulcerative Colitis

Safety and efficacy of oral mesalamine 1.2-g delayed-release tablets (Lialda) for induction of remission in patients with active, mild to moderate ulcerative colitis were evaluated in two 8-week randomized, double-blind, placebo-controlled trials that included 517 patients. Patients were randomized to receive a 2.4- or 4.8-g daily dosage of mesalamine or placebo. The primary efficacy end point at week 8 of treatment was the percentage of patients achieving remission (defined as an Ulcerative Colitis Disease Activity Index [UC-DAI] of 1 or less, with scores of zero for rectal bleeding and stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline). The incidence of remission at 8 weeks was about 34-41, 29-41, or 13-22% in patients receiving mesalamine 2.4 g daily, mesalamine 4.8 g daily, or placebo, respectively. Patients receiving mesalamine 2.4 or 4.8 g daily also experienced greater benefit in secondary efficacy parameters (e.g., clinical improvement, treatment failure, clinical remission, sigmoidoscopic appearance) compared with patients receiving placebo.

Maintenance of Remission of Ulcerative Colitis

Safety and efficacy of oral mesalamine 400-mg delayed-release tablets (Asacol) for maintenance therapy in patients with ulcerative colitis were evaluated in a 6-month randomized, double-blind, placebo-controlled study that included 264 patients. Patients were randomized to receive a daily 0.8-g dosage of mesalamine (90 patients), 1.6-g dosage of mesalamine (87 patients), or placebo (87 patients). Treatment success or failure was defined as maintenance of remission after 6 months or relapse during the study, respectively. Treatment success in patients receiving a daily 0.8-g mesalamine dosage was not statistically different from patients receiving placebo. Endoscopic remission of ulcerative colitis (based on intention-to-treat analysis) in all 174 patients receiving either 1.6 g of mesalamine daily or placebo, was reported in 61 out of 87 patients (70.1%) receiving mesalamine or 42 out of 87 patients (48.3%) in those receiving placebo. Pooled analysis of data from 4 comparator-drug (sulfasalazine) controlled maintenance trials indicate that treatment success occurred in 59 or 69% of patients receiving mesalamine extended-release capsules (0.8-2.8 g daily) or sulfasalazine (2-4 g daily), respectively; however, the difference in response was not statistically significant.

Mildly to Moderately Active Distal Ulcerative Colitis

When used in the management of active distal ulcerative colitis, including proctosigmoiditis or proctitis, mesalamine rectal suspension has reduced stool frequency, rectal bleeding, mucosal inflammation, and abdominal pain. When used in the management of active ulcerative proctitis, mesalamine rectal suppositories have reduced stool frequency, rectal bleeding, and mucosal inflammation. Patients most likely to respond to rectal mesalamine are those with disease confined to the distal 20-40 cm of the colon. Clinical remission has occurred in 30-90% of patients with these conditions receiving rectal mesalamine; however, relapse usually has occurred following discontinuance and, rarely, during continued use of the drug. In responsive disease, improvement usually is evident within 1 week to 3 months of initiation of therapy, and some patients may need prolonged periods of rectal mesalamine therapy to achieve improvement. However, some clinicians have suggested that if clinical remission is not achieved within 2-4 months of initiation of rectal mesalamine therapy, it is unlikely that further improvement would be achieved with more prolonged therapy. There is limited evidence that the efficacy of rectal mesalamine can be sustained during chronic therapy, but additional study and experience are needed.

The optimum role of rectal mesalamine in the management of active ulcerative colitis remains to be elucidated, particularly relative to other therapies (e.g., oral sulfasalazine) and in patients with severe and/or refractory disease. Clinical studies have shown that rectal mesalamine is more effective than placebo and at least as effective as oral sulfasalazine in reducing signs and symptoms (e.g., stool frequency, rectal bleeding, mucosal inflammation) of these conditions. However, many patients who were already receiving oral sulfasalazine therapy continued to receive the drug when rectal mesalamine was initiated, and combined therapy may be necessary for optimal response in many such patients. In addition, some clinicians state that sulfasalazine therapy should be continued to minimize the risk of an exacerbated flare developing secondary to withdrawal of the drug and the delayed onset of mesalamine. Rectal mesalamine also was at least as effective as rectal hydrocortisone in patients with sigmoidoscopically or radiographically confirmed mild to moderate distal ulcerative colitis.

In patients with ulcerative colitis whose symptoms progress despite a recommended regimen of oral sulfasalazine and/or rectal or oral corticosteroids, therapy with rectal mesalamine may be beneficial. Combined therapy with rectal mesalamine and oral sulfasalazine and/or rectal or oral corticosteroids may produce additive effects in reducing signs and symptoms of refractory ulcerative colitis, although combined rectal mesalamine and oral corticosteroid therapy may be no more effective than an oral corticosteroid alone in severe disease. In addition, although efficacy of rectal mesalamine may be limited in patients with severe ulcerative colitis, the drug has been effective in some patients refractory to, or intolerant of, oral sulfasalazine and/or rectal or oral corticosteroids.

Clinical studies have shown that mesalamine rectal suppositories are more effective than placebo in reducing signs and symptoms (e.g., stool frequency, rectal bleeding, mucosal inflammation) of active ulcerative proctitis. Efficacy of mesalamine rectal suppositories appears to be independent of patients' gender, duration and extent of disease, or duration of current episode.

Crohn's Disease

Mesalamine has been used for the management of active Crohn's disease.

Overview

Crohn's disease, a chronic inflammatory bowel disease, is characterized by focal, asymmetric, transmural, and occasionally, granulomatous inflammation affecting the GI tract (most frequently the ileum and colon) with a potential for systemic and extraintestinal complications and recurrent flare-ups.The etiology and pathogenesis of Crohn's disease have not been elucidated, but they appear to be multifactorial. Many clinicians have suggested that environmental (e.g., smoking, intestinal bacterial flora), immunologic (increased mucosal IgG), and genetic factors may contribute to the development of the disease. The disease can develop in any age group, although disease onset is more frequent in adolescents and young adults. Diagnosis of Crohn's disease is difficult because of the heterogenicity of manifestations, overlapping features with other inflammatory bowel diseases, and/or presentation without GI symptoms (i.e., extraintestinal symptoms). Symptoms of chronic or nocturnal diarrhea, abdominal pain, weight loss, fever, and rectal bleeding may be indicative of underlying inflammatory processes. Clinical manifestations of the disease include pallor, cachexia, abdominal mass or tenderness, and perianal fissures, fistulae, or abscesses. In children, growth arrest or loss of height may be one of the initial manifestations of Crohn's disease. Diagnosis and consequent treatment of Crohn's disease is based on clinical, laboratory, and diagnostic evaluations, including radiologic examinations and/or endoscopy.

Treatment

Crohn's disease is not medically or surgically curable and generally is managed by reducing inflammation, improving quality of life, and minimizing short- and long-term toxicity (associated with treatment) and complications. Choice of treatment depends on several factors, including the severity, location (stomach/duodenum, jejunum, ileum, colon, rectum, anus), extent (localized, diffused), and pattern/behavior (principally inflammatory, fistulizing, or fibrostenotic) of the disease. In addition, previous history of the disease (e.g., intestinal surgery, response to previous treatment), extraintestinal complications, certain patient characteristics (e.g., age, gender, lifestyle, nutrition, compliance, social and emotional status, resources, education, functional ability), and other factors (e.g., growth in children) should be considered when initiating therapy. Most currently available drugs for Crohn's disease including amino derivatives of salicylic acid (e.g., mesalamine, balsalazide, olsalazine, sulfasalazine), conventional corticosteroids (hydrocortisone, methylprednisolone, prednisolone, prednisone), more recently available corticosteroids (e.g., budesonide, having substantial topical anti-inflammatory activity and lower systemic availability than conventional corticosteroids), corticotropin, biologic response modifiers (e.g., adalimumab, infliximab, natalizumab), and immunosuppressive or immunomodulating agents (e.g., azathioprine, cyclosporine, mercaptopurine, methotrexate, mycophenolate mofetil, tacrolimus, thalidomide,) are used to manage chronic inflammation of the intestinal mucosa. In addition, since the intestinal bacterial flora may be associated with intestinal inflammation, anti-infective agents (metronidazole and/or ciprofloxacin) may be used in the management of mildly to moderately and moderately to severely active disease. Many clinicians currently state that therapy for inflammatory bowel disease (e.g., Crohn's disease) should be disease modifying rather than merely symptomatic whenever possible.

According to criteria established by the American College of Gastroenterology, severity of Crohn's disease may be classified as mildly to moderately active, moderately to severely active, or severely active to fulminant disease. Patients generally considered to be in remission are those who are asymptomatic, those without inflammatory sequelae, or those who have responded to acute medical intervention or have undergone surgical resection and have no gross evidence of residual disease.

Mildly to Moderately Active Crohn's Disease

Patients are considered to have mildly to moderately active Crohn's disease if they are ambulatory and can tolerate oral alimentation without experiencing more than 10% of body weight loss or presenting manifestations of dehydration, toxicity (e.g., high fever, rigor, prostration), or abdominal tenderness/painful mass/obstruction. For the initial management of ileal, ileocolonic, or colonic mildly to moderately active Crohn's disease, many clinicians recommend preparations containing or being metabolized to 5-aminosalicylic acid (e.g., mesalamine, sulfasalazine) or possibly, budesonide (a relatively new corticosteroid). In general, the choice of 5-aminosalicylic acid derivatives should be based on the location of the disease.

Oral formulations of mesalamine that are in a slow- or pH-dependent matrix can deliver therapeutic concentrations of the drug to the stomach, small bowel, or distal ileum and therefore are used in patients with gastroduodenal and/or ileal Crohn's disease. Results of placebo-controlled studies on the efficacy of oral mesalamine preparations in the management of mildly to moderately active Crohn's disease have been equivocal, since administration of the drug was not consistently more effective than placebo.(See Active Crohn's Disease under Crohn's Disease: Use of Mesalamine in Crohn's Disease, in Uses.)

Sulfasalazine has not been consistently effective in patients with ileal disease and it is recommended that the drug be used in ileocolonic or colonic disease, preferably with left-sided condition, restricted to the colon. Budesonide, which appears to be more effective than mesalamine in the treatment of mildly to moderately active disease, generally is used in patients with Crohn's disease involving the ileum and/or ascending colon. Therefore, some clinicians recommend that for initial management of Crohn's disease involving the ileum and/or ascending colon, patients should receive 8-16 weeks of therapy with budesonide delayed-release capsules and those with left-sided disease restricted to the colon should receive 16 weeks of therapy with sulfasalazine. Individuals who do not respond to therapy with sulfasalazine or budesonide or those who develop hypersensitivity to sulfasalazine should receive a conventional corticosteroid (e.g., prednisone, prednisolone). Therapy with metronidazole and/or ciprofloxacin also has been recommended in patients who do not respond to sulfasalazine. and

Currently, there are inadequate data regarding the management of upper GI (e.g., esophageal, gastroduodenal, jejunoileal) Crohn's disease. Results of uncontrolled studies in a limited number of patients indicate that symptoms of upper GI Crohn's disease may respond to proton-pump inhibitors (e.g., omeprazole), frequently given in conjunction with corticosteroids or other immunosuppressant agents. Jejunoileitis, which is often accompanied by overgrowth of bacteria in the small intestine, may be treated with anti-infective therapy.

Response to initial therapy should be evaluated within several weeks. Treatment of active disease should be continued until remission of symptoms or, alternatively, treatment failure (lack of continued improvement) occurs. Patients who achieve remission should be considered for maintenance therapy(see Maintenance of Remission of Crohn's Disease under Crohn's Disease: Treatment, in Uses), while alternative therapy (according to clinical status and possible reassessment of disease severity) should be instituted in those whose disease continues to be symptomatic.(See Moderately to Severely Active Crohn's Disease under Crohn's Disease: Treatment, in Uses.)

Moderately to Severely Active Crohn's Disease

Patients are considered to have moderately to severely active Crohn's disease if they have failed to respond to therapy for mildly to moderately active disease or have developed more severe symptoms (e.g., fever, substantial weight loss, abdominal pain/tenderness, intermittent nausea or vomiting, significant anemia) than those with mildly to moderately active disease, but no evidence of obstruction. Conventional corticosteroids (e.g., prednisone, prednisolone) or possibly, budesonide may be used for the management of moderately to severely active disease until resolution of symptoms and appropriate weight gain occurs (usually within 7-28 days). Most patients (greater than 50%), however, become corticosteroid dependent or resistant. Addition of 5-aminosalicylic acid derivatives to corticosteroids has not been associated with short- or long-term benefit, while adjunctive use of azathioprine or mercaptopurine with corticosteroids has been found to be beneficial. It should be considered, however, that up to 3-4 months of adjunctive therapy with these immunosuppressants may be needed before substantial benefits (including remission) become apparent, and, therefore, these drugs mainly are used for maintenance therapy. Parenteral methotrexate also has been shown to be effective in allowing corticosteroids to be tapered in corticosteroid-dependent patients. In addition, limited data indicate that mycophenolate mofetil may be beneficial in the management of moderately to severely active Crohn's disease.

Infliximab or, possibly, thalidomide may be used in patients who have had an inadequate response to conventional therapies (e.g., corticosteroids, mesalamine sulfasalazine, azathioprine, mercaptopurine, methotrexate) or in whom conventional therapies are contraindicated.

Anti-infective therapy (e.g., metronidazole, ciprofloxacin, other broad spectrum antibiotics) or drainage (percutaneous or surgical) may be necessary when infection or abscess is present in patients with moderately to severely active Crohn's disease.

Severely Active to Fulminant Crohn's Disease

Patients with severely active to fulminant Crohn's disease usually include those who have persisting symptoms despite oral corticosteroid or infliximab therapy or those who develop severe manifestations (e.g., high fever, persistent vomiting, rebound tenderness, evidence of GI obstruction or abscess) of the disease. Individuals without an abscess or those who have been receiving oral corticosteroids should be treated with parenteral corticosteroids, given as a continuous IV infusion or, possibly, by intermittent IV injections in divided doses. In patients with severe disease, IV corticotropin (ACTH) has been used rarely. Patients with an inflammatory abdominal mass should receive broad-spectrum anti-infectives in conjunction with parenteral corticosteroids; these individuals usually have intestinal perforation and surgery would be needed after an appropriate waiting period. In those unable to tolerate nutritional requirements, elemental feeding or parenteral hyperalimentation is indicated after 5-7 days of parenteral corticosteroid therapy.

Limited data indicate that patients who do not respond to parenteral corticosteroids may respond to other immunosuppressive agents (e.g., IV cyclosporine, tacrolimus). Although definitive data are lacking concerning the use of infliximab in patients with severe Crohn's disease, some clinicians state that the drug may be used in patients with severe disease who do not respond to parenteral corticosteroids. Individuals who have responded to parenteral therapy (e.g., corticosteroids, cyclosporine, tacrolimus) may be switched gradually to the equivalent oral therapy, while surgery is indicated in those who do not respond or whose symptoms worsen.

Perianal and Fistulizing Crohn's Disease

Patients with acute suppurative disease, including perianal and/or perirectal abscesses, often require surgical intervention. Although controlled studies regarding the use of anti-infective agents in the management of perianal and fistulizing Crohn's disease are lacking, limited data suggest that use of metronidazole or ciprofloxacin alone or, alternatively, combination therapy with the 2 anti-infectives may provide benefit in nonsuppurative fistulizing disease.

Metronidazole and/or ciprofloxacin mainly are used for short-term therapy, although relapse usually occurs upon discontinuance; however, safety and efficacy of long-term anti-infective therapy have not been established and further study and experience are needed to elucidate fully the long-term benefits of such therapy. In addition, there are no controlled studies with fistula closure, as the primary end point, demonstrating that immunosuppressive therapy with azathioprine or mercaptopurine is effective in fistulizing disease. Current clinical practice concerning use of these agents is based on a pooled analysis of 5 controlled trials in which fistula closure was considered a secondary end point and in several uncontrolled case studies. Data from these studies indicate that long-term (several years) therapy with azathioprine or mercaptopurine may be effective in the management of fistulizing Crohn's disease. Use of cyclosporine for fistulizing disease is based on results of uncontrolled case studies; short-term administration of cyclosporine has been beneficial in several patients. Results of one controlled and several uncontrolled case studies have shown that tacrolimus also may be beneficial in the management of fistulizing Crohn's disease.

Infliximab has been effective in the management of fistulizing Crohn's disease; the drug is used to reduce the number of draining enterocutaneous and rectovaginal fistulas and to maintain fistula closure. Further study is needed to determine the relative safety and efficacy of infliximab and other therapies used for the management of fistulizing Crohn's disease (e.g., azathioprine, ciprofloxacin and/or metronidazole, mercaptopurine, surgical intervention). Some clinicians suggest that, although data are not available to date to support use of infliximab as first-line therapy for fistulizing Crohn's disease, use of the drug should be considered when fistulas have not responded to appropriate anti-infective regimens (e.g., ciprofloxacin and/or metronidazole) and/or immunosuppressive therapy (e.g., azathioprine, mercaptopurine).

Maintenance of Remission of Crohn's Disease

The goals of maintenance therapy are to prolong periods of remission and improve quality of life. Once remission has been achieved, choice of maintenance therapy should be evaluated individually, based on the condition (e.g., length of remission, type of remission [medical or surgical]) and characteristics of each patient. Maintenance of remission remains problematic because of the difficulty in identifying subgroups of patients who undergo early clinical or subclinical flare-ups and who would benefit from appropriate and timely treatment.

There are no drug treatments available to prevent relapse of Crohn's disease; however, clinical relapse may be delayed by using anti-inflammatory or anti-infective agents, or to a greater extent by using immunomodulating drugs. Most patients who have received corticosteroid therapy for active Crohn's disease (including conventional corticosteroids or budesonide) usually develop relapse within a year, unless they receive maintenance therapy. Neither sulfasalazine nor mesalamine appears to be effective in maintaining remission of Crohn's disease after medically induced clinical remission. Some clinicians state that mesalamine may be the optimal therapy for maintenance of remission in patients with ileal or jejunoileal disease, although the drug is associated with substantially lower efficacy in those with colonic disease. Mesalamine has been used with equivocal results for maintenance therapy of Crohn's disease. In some, but not other, placebo-controlled studies in patients with medically induced remission, relapse rates were lower with mesalamine relative to placebo. In several placebo-controlled studies, budesonide was effective for maintenance therapy in patients with medically-induced remission for up to about 6 months of therapy; however, no substantial difference was observed at 1 year of therapy.

Both azathioprine and mercaptopurine are effective for maintenance therapy in patients with medically-induced remission of Crohn's disease. Response generally is apparent after 3-6 months of therapy. Although clinical benefits beyond 4 years of therapy remain to be established, limited data indicate that such benefits may persist longer than 4 years. Methotrexate also has been used effectively for maintenance of Crohn's disease. Infliximab may be used to maintain clinical remission in patients with moderately to severely active disease who have had an inadequate response to conventional therapies (e.g., azathioprine, corticosteroids, mercaptopurine, mesalamine, sulfasalazine).

Drug therapy for prevention of disease relapse following surgically induced remission has not been firmly established. Limited data indicate that mesalamine or, possibly, sulfasalazine may reduce the risk of postoperative recurrence for up to 3 years. However, equivocal results were reported in patients with surgically induced remission receiving mesalamine.(See Maintenance of Remission of Crohn's Disease under Crohn's Disease: Use of Mesalamine in Crohn's Disease, in Uses.) In patients with surgically induced remission of Crohn's disease, mercaptopurine appears to be more effective than placebo and efficacy of azathioprine appears to be similar to that of mesalamine. Limited data also indicate that high-dose (20 mg/kg) metronidazole therapy may reduce postoperative recurrence for up to 1 year; however, long-term studies are needed to elucidate further the efficacy of such therapy. Ornidazole (another nitroimidazole-derivative anti-infective agent; currently not commercially available in the US) has been shown to prevent early postoperative endoscopic recurrence and postpone symptomatic relapse.

Surgery in Patients with Crohn's Disease

Surgical resection is not a cure for Crohn's disease. However, surgical intervention is needed in greater than 60% of patients to treat intractable hemorrhage, perforation, persistent or recurrent obstruction, abscess, or unresponsive fulminant disease. Some clinicians state that since therapy to reduce the risk of postoperative recurrence is available (see Maintenance of Remission of Crohn's Disease under Crohn's Disease: Treatment, in Uses), there is little justification to prolong ineffective drug therapy and delay surgery in patients with complications of Crohn's disease whose quality of life would be improved by surgical intervention.

Crohn's Disease in Pediatric Patients

Crohn's disease in pediatric patients generally is managed by controlling disease activity and symptoms, providing nutritional intervention (to ensure adequate food intake and reverse impaired weight and growth velocities) and psychologic support, and monitoring for extraintestinal manifestations (e.g., arthralgias, arthritis). Similar to adults, choice of therapy depends on severity and location of the disease.

Sulfasalazine (initial dosage of 25-40 mg/kg daily increased to 50-75 mg/kg daily [up to 4 g daily], given with 1 mg of folic acid daily) or mesalamine (initial oral dosage of 20-30 mg/kg daily increased up to 60 mg/kg daily) has been used in pediatric patients with mild ileal, ileocecal, ileocolonic, or colonic Crohn's disease; topical mesalamine or corticosteroid enemas may be used in left-sided colitis. Systemic corticosteroids (e.g., prednisone 1-2 mg/kg daily up to 60 mg daily) usually have been used in those with mild esophageal or gastroduodenal disease. Children with mild perianal disease or those intolerant to sulfasalazine or mesalamine may receive metronidazole (10-20 mg/kg daily, up to a maximum of 1 g daily). Budesonide (as pH-dependent-release preparations administered in a dosage of 0.45 mg/kg daily up to a maximum dosage of 9 mg daily) has been used for the management of mildly to moderately active Crohn's disease in a limited number of children 9.5-18 years of age. Budesonide is more effective than mesalamine, but less effective than conventional corticosteroids (e.g., prednisone).

For the management of moderately to severely active disease, systemic corticosteroids (e.g., prednisone or methylprednisolone 1-2 mg/kg daily up to 60 mg daily) may be used; some clinicians suggest that an immunosuppressive agent (e.g., mercaptopurine) be used conjunctively with corticosteroids, once initial diagnosis is made. IV metronidazole or another anti-infective should be used with corticosteroids if infection or abscess is present.

In pediatric patients who become corticosteroid dependent or resistant, mercaptopurine or azathioprine may be used, while methotrexate therapy (10-15 mg/m) should be considered in those who had an inadequate response to or did not tolerate mercaptopurine or azathioprine. Infliximab has been used in a limited number of pediatric patients for the management of the signs and symptoms of active Crohn's disease. In children with refractory perianal fistulas, use of cyclosporine (4 mg/kg daily) may be considered.

Use of Mesalamine in Crohn's Disease

Active Crohn's Disease

Extended-release oral mesalamine preparations have been used in the management of Crohn's disease. It has been suggested that administration of extended-release oral mesalamine may be especially useful in the management of this condition since the drug is partially released from these preparations in the ileum, which may facilitate an anti-inflammatory effect in patients with ileitis.

Efficacy of oral mesalamine has been studied in several placebo-controlled studies in patients with mildly to moderately active Crohn's disease. In many of these studies, the Crohn's Disease Activity Index (CDAI) was used for clinical assessment. The CDAI score is based on subjective observations by the patient (e.g., the daily number of liquid or very soft stools, severity of abdominal pain, general well-being) and objective evidence (e.g., number of extraintestinal manifestations, presence of an abdominal mass, use or nonuse of antidiarrheal drugs, the hematocrit, body weight). Results of these studies have been equivocal.

In a 16-week multicenter, randomized, double-blind, dose-ranging, placebo-controlled study in 310 adults with mildly to moderately active ileal, ileocolonic, or colonic Crohn's disease, patients were randomized to receive placebo or oral mesalamine extended-release capsules (Pentasa) in a dosage of 1, 2, or 4 g daily. Remission (defined as a reduction from baseline CDAI of more than 50 points and a final CDAI score of less than 150 assessed at the final visit) was observed in 43 or 18% of patients receiving mesalamine 4 g daily or placebo, respectively, while a mean reduction of 72 or 21 points from baseline CDAI was observed, respectively. In addition, substantial improvements in time to remission and percentage of treatment failures (secondary parameters) also were observed in patients receiving the highest mesalamine dosage, when compared with placebo. CDAI reductions from baseline in patients receiving 1- or- 2 g daily dosages of mesalamine did not differ significantly from those receiving placebo. Location of the active disease was not associated with statistically different responses, although mean reductions of 93 points from baseline CDAI were observed in patients with ileitis receiving mesalamine 4 g daily compared with reductions of 2 points from baseline CDAI in those receiving placebo.

Investigators of this study conducted a second trial, very similar to the one described. In this 16-week randomized, double-blind, placebo-controlled study, patients with mildly to moderately active Crohn's disease were randomized to receive placebo or mesalamine (2 or 4 g daily) administered orally as extended-release capsules. Pooled analysis of the 2 trials in combination with data from another randomized, double-blind, placebo-controlled study in patients with mildly to moderately active Crohn's disease indicate that mesalamine, given in 4-g daily dosages, was associated with an 18-point greater reduction in CDAI than placebo, a difference that was not considered clinically important.

Results of several other placebo-controlled studies also failed to show an improved clinical response to oral mesalamine extended-release preparations when compared with placebo; however, in several of the studies, a lower dosage (e.g., 1 or 2 g daily) was used. Some clinicians state that high oral mesalamine dosages (exceeding 3 g daily) usually are needed for the treatment of Crohn's disease.

Substantial benefit of mesalamine versus placebo was observed in a small 16-week randomized, double-blind, placebo-controlled study in 38 adults with mildly to moderately active ileocolonic or colonic Crohn's disease (mean baseline CDAI of 231.7 or 204.8 in patients receiving mesalamine or placebo, respectively) who were randomized to receive oral mesalamine 400-mg delayed-release tablets (Asacol; 20 patients) in a dosage of 800 mg 4 times daily or placebo (18 patients). Individuals were permitted to continue oral corticosteroids if they were receiving fixed dosages of the drugs (not exceeding 20 mg of prednisone daily or equivalent). Complete clinical response (defined as a reduction from baseline CDAI of 70 points or more and a final CDAI score of less than 150, assessed after 4, 8, and 16 weeks of treatment) was observed in 60 or 22% of patients receiving mesalamine or placebo, respectively. Partial clinical response (defined as a reduction from baseline CDAI of 70 points or more, and a final CDAI score of 150 or more, assessed after 4, 8, and 16 weeks of treatment) was observed in 15 or 0% of patients receiving mesalamine or placebo, respectively.

Conventional or more recently available corticosteroids appear to be more effective than mesalamine in the management of active Crohn's disease. Results of a comparator-drug (mesalamine versus budesonide) controlled study (patients having a median baseline CDAI score of 272) have shown that clinical improvement was substantially lower in adults receiving 2-g twice daily dosages of oral mesalamine delayed-release tablets than in those receiving 9-mg daily dosages of oral budesonide delayed-release capsules (45% for mesalamine versus 69% for budesonide). In addition to a higher clinical improvement rate, quality-of-life scores (e.g., anxiety, depressed mood, sense of well-being, self-control, general health, vitality) also were improved to a greater extent in patients receiving budesonide than in those receiving mesalamine.

Rectal administration of mesalamine has been effective in a limited number of patients for the management of active Crohn's disease, but the role of such therapy in this condition is not as well defined as in the management of ulcerative colitis. In addition, rectal mesalamine appears to be less effective in reducing signs and symptoms of Crohn's disease than those of ulcerative colitis. Efficacy in patients with ileitis alone has not been established, but many clinicians suggest that the limited delivery of rectally administered drug to the ileum makes it unlikely that substantial clinical benefit would be achieved in such patients.

Maintenance of Remission Crohn's Disease

The relative efficacy of mesalamine as maintenance therapy for Crohn's disease is controversial, since the drug has been used with equivocal results. Some clinicians state that oral mesalamine may be the optimal treatment in patients with ileal or jejunoileal disease; however, the drug is associated with substantially lower efficacy in those with colonic disease. Several controlled studies indicate that use of oral mesalamine in the management of inactive ileitis is associated with a substantially lower frequency of relapse than placebo. In one double-blind placebo-controlled trial, oral mesalamine extended-release capsules (2 g daily) reduced frequency of relapse only in those patients who were in remission for less than 3 months at initiation of therapy; average remission rates at 2 years of therapy were 45 or 29% in patients receiving oral mesalamine or placebo, respectively. In addition, results of a double-blind, placebo-controlled trial in 125 patients in remission (CDAI score of less than 150) indicate that oral mesalamine delayed-release tablets (2.4 g daily) did not substantially reduce the frequency of relapse at 3 or 6 months; relapse (defined as CDAI score of greater than 150) rates at 3 months of therapy were 12 or 22%, respectively, in patients receiving oral mesalamine or placebo, while such rates at 6 months of therapy were 28 or 41%, respectively. However, relapse rates in patients receiving mesalamine (34%) or placebo (55%) were significantly different at 12 months of therapy.

Efficacy of controlled- or delayed-release oral mesalamine has been evaluated in several placebo-controlled trials in patients achieving remission following medical or surgical therapy. While in some of these studies in patients with medically or surgically induced remission, fewer relapses were reported with mesalamine than with placebo, in others, no statistically significant differences were found when the drug was compared with placebo. Results of a pooled analysis in patients receiving mesalamine to reduce postoperative recurrence of Crohn's disease have indicated that in 4 out of 7 studies, administration of oral mesalamine (compared with no therapy) was beneficial in reducing endoscopic or clinical recurrence, while in 2 other studies, a statistically non-significant trend in favor of therapy was shown. Results of another pooled analysis using oral mesalamine indicate that following surgically induced remission, clinical recurrence may be substantially reduced in patients with ileal disease or in those with prolonged disease duration. However, the overall effect usually was modest and further study is needed to evaluate the role of the drug in maintenance therapy of Crohn's disease.

Dosage and Administration

Administration

Mesalamine is administered orally as delayed-release tablets and as extended-release capsules. Mesalamine is administered rectally as a retention enema or suppositories.

Oral Administration

Mesalamine delayed-release tablets should be swallowed whole without breaking the outer coating, since the coating is designed to maintain the integrity of the tablets prior to entering the colon, where the drug is released. In clinical trials using mesalamine 400-mg delayed-release tablets (Asacol), about 2-3% of patients noticed intact or partially intact tablets in their stools; if this occurs repeatedly, patients should notify their clinician.

The manufacturer of mesalamine 1.2-g delayed-release tablets (Lialda) states that the tablets should be taken with food.

Rectal Administration

Mesalamine suppositories are administered rectally. A small amount of lubricating gel may be applied onto the tip of the suppository to assist insertion. The suppository should be inserted completely into the rectum with gentle pressure, pointed end first, and should be retained for 1-3 hours or longer, if possible, to achieve maximum benefit.

Mesalamine suspension is administered rectally as a retention enema, preferably at bedtime. Best results are achieved if the bowel is emptied just prior to enema administration. Mesalamine rectal suspension must be shaken well and the protective sheath removed from the applicator before administration. Lubrication of the applicator tip may facilitate insertion and minimize the risk of local trauma.

The patient should be given a copy of the mesalamine administration instructions provided by the manufacturer. To administer the enema, the patient should first lie on their left side with the lower leg extended and the upper right leg flexed forward for balance during and for 30 minutes after administration of the retention enema so that the drug will distribute throughout the sigmoid colon; the enema should be retained for approximately 8 hours, usually during sleeping. Alternatively, the patient may assume the ''knee-chest'' position, kneeling with their upper chest and one arm resting on a bed. The bottle should be held at its neck to avoid premature discharge of the suspension and the applicator tip inserted gently into the rectum, pointing the tip slightly toward the umbilicus. The bottle then should be grasped firmly and tilted slightly so that the nozzle is aimed toward the patient's back. A steady squeezing of the bottle will discharge most of the suspension. Following rectal instillation of the enema, the bottle should be withdrawn from the rectum and discarded. The rectal suspension and suppositories will cause staining of direct contact surfaces, including, but not limited to, fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Therefore, patients are advised to carefully choose a suitable location for administration of the rectal suspension.

Dosage

Oral Dosage

Ulcerative Colitis

For the management of mildly to moderately active ulcerative colitis, the usual adult oral dosage of mesalamine delayed-release tablets (Asacol) is 2.4 g daily (given as two 400-mg tablets 3 times daily) for 6 weeks. Mesalamine delayed-release tablets also have been administered in dosages up to 4.8 g daily (in divided doses). For the treatment and induction of remission of mildly to moderately active ulcerative colitis, the usual adult oral dosage of mesalamine extended-release capsules is 4 g daily, given in equally divided doses (as four 250-mg extended-release capsules or two 500-mg extended-release capsules) 4 times daily; treatment duration in controlled clinical trials was up to 8 weeks. Mesalamine extended-release capsules also have been administered in lower dosages (e.g., 2-4 g daily [in divided doses]).

For induction of remission in patients with mildly to moderately active ulcerative colitis, the recommended adult oral dosage of mesalamine 1.2-g delayed-release tablets (Lialda) is 2.4 or 4.8 g daily (given as two or four 1.2-g tablets once daily). Safety and efficacy beyond 8 weeks of treatment have not been established.

For maintenance of remission of ulcerative colitis, the recommended adult oral dosage of mesalamine delayed-release tablets (Asacol) is 1.6 g daily (four 400-mg delayed-release tablets) given in divided doses; treatment duration in the prospective, well-controlled trial was 6 months. For maintenance of remission, mesalamine delayed-release tablets also have been given in dosages of 800 mg to 4.8 g (in divided doses). In addition, mesalamine extended-release capsules (1.5-3 g) have been used for maintenance of remission. Patients should be advised that ulcerative colitis rarely remits completely, and that continued use of maintenance dosages of mesalamine may substantially decrease the risk of relapse.

Crohn's Disease

For the treatment of mildly to moderately active Crohn's disease in adults, oral mesalamine dosages of 3.2-4.8 g daily (as delayed-release tablets) or 4 g daily (as extended-release capsules) have been given, generally in divided doses. Lower dosages do not appear to be effective. For maintenance of remission of Crohn's disease in adults, oral mesalamine dosages of 800 mg to 4.8 g daily (as delayed-release tablets) or 1.5- 3 g daily (as extended-release capsules) in divided doses have been given.

Rectal Dosage

Distal Ulcerative Colitis

The usual adult rectal dosage of mesalamine as suppositories is 1 g once daily at bedtime (using 1-g suppositories) and as the enema suspension is 4 g once daily (preferably at bedtime). Although clinical response may be apparent within 3-21 days, therapy with the drug usually is continued for 3-6 weeks or until clinical and/or sigmoidoscopic remission is achieved. Efficacy of mesalamine therapy (in terms of modification of relapse rates) beyond 6 weeks has not been established, but the drug has been used rectally for prolonged periods (e.g., longer than 1 year) in some patients.

There is some evidence that lower dosages or less frequent administration of rectal mesalamine may be effective in some patients, particularly after initial remission is achieved. In a limited number of adults with distal ulcerative colitis in whom clinical remission occurred following daily administration of 4 g of mesalamine rectal suspension, dosage of mesalamine was reduced to 4 g every 2 or 3 nights or, occasionally, less frequently. If clinical relapse occurred with this less frequent administration, dosage was increased to more frequent administration. In a limited number of adults with distal ulcerative colitis or ulcerative proctosigmoiditis, mesalamine rectal suspension also has been used effectively in dosages of 1-3 g daily. Further long-term studies are needed to evaluate the optimal maintenance dosage of mesalamine rectal suspension.

Cautions

Frequency of some adverse effects associated with oral or rectal mesalamine generally appears to be less than that associated with oral sulfasalazine (a prodrug of mesalamine). Some adverse effects (e.g., hematologic effects, nervous system effects, hypersensitivity reactions, fever, male infertility) associated with sulfasalazine have been attributed to sulfapyridine, another metabolite of sulfasalazine, rather than to mesalamine.

Oral and rectal mesalamine preparations usually are well tolerated. The most common adverse effects of oral or rectal mesalamine are GI effects and headache. In clinical studies, most adverse effects associated with oral or rectal preparations were mild in severity and were transient or reversible. However, adverse effects have been severe enough to require discontinuance of the drug in less than 1% or in up to about 4-5% of patients receiving rectal or oral mesalamine, respectively, although in some studies, the rate of discontinuance of the drug was similar to or less than in those receiving placebo. Most of the adverse effects reported with the use of oral mesalamine 400-mg delayed-release tablets (Asacol) were similar in short- and long-term studies.

GI Effects

In controlled clinical trials in patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol), abdominal pain, eructation, nausea, diarrhea, dyspepsia, vomiting, constipation, flatulence, exacerbation of colitis, abdominal enlargement, gastroenteritis, GI hemorrhage, rectal disorder (e.g., hemorrhage, tenesmus), and stool abnormalities, were the most common adverse GI effects, occurring in about 2-18% of patients; dry mouth, indigestion, stomatitis, and cramping were reported rarely. Frequency of these GI effects did not seem to increase with increased dosages, although in uncontrolled studies, the incidence of abdominal pain, flatulence, and GI bleeding were dose related. In patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda), flatulence was reported in about 3-4% of patients. The most common adverse GI effects of oral mesalamine extended-released capsules were diarrhea (including melena), nausea, abdominal pain, dyspepsia, vomiting, anorexia, worsening of ulcerative colitis, and rectal urgency, occurring in greater than 0.4-3% of patients.

Exacerbation of colitis symptoms was reported in 3% of patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol). Exacerbation of colitis symptoms resulting in discontinuance of therapy was reported in 0.8% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda). Other adverse GI effects associated with oral mesalamine 1.2-g delayed-release tablets and occurring in less than 1% of patients include abdominal distention, diarrhea, pancreatitis, rectal polyp, and vomiting. Other adverse GI effects associated with oral mesalamine extended-release capsules and occurring in less than 1% of patients include abdominal distention, constipation, duodenal ulcer, dysphagia, eructation, esophageal or mouth ulcer, fecal incontinence, GI bleeding (e.g., rectal bleeding), stool abnormalities (e.g., change in color or texture), oral moniliasis, and thirst, although a causal relationship to the drug of many of these adverse effects has not been established.

Abdominal pain, cramps, and/or discomfort are the most common adverse GI effects of rectal mesalamine, occurring in about 4-8% of patients, and occasionally have occurred as components of an acute intolerance syndrome.(See Cautions: Sensitivity Reactions.) Flatulence and nausea occur in about 1-6% of patients receiving the drug rectally, and worsening or development of diarrhea, colitis, constipation, hemorrhoids, and rectal pain, burning, and/or soreness occur in about 1-3% of patients. Difficulty in retaining the enema occurs occasionally in patients receiving mesalamine rectal suspension, but retention time may increase during continued use of the drug. Pain on insertion of the enema applicator tip and anal irritation occur in about 1% of patients receiving mesalamine rectal suspension. Anal irritation may be severe enough to require topical analgesic or anti-inflammatory therapy. Anal fissures or lacerations following insertion of the enema applicator tip also have been reported rarely. Lubrication of the applicator tip may minimize these effects. In some patients receiving rectal mesalamine, inflammation has extended to the entire colon (pancolitis); however, extension of inflammation occurs in about 5-10% of patients as part of the natural progression of the disease, and a causal relationship to the drug has not been established. In addition, extension and/or acute exacerbations of inflammation reportedly occurred less frequently in patients receiving rectal mesalamine than placebo. Worsening of colitis or symptoms of inflammatory bowel disease (e.g., melena, hematochezia) may occur after initiation of mesalamine therapy.

Although previously it was suggested that sulfasalazine-induced pancreatitis resulted from the sulfonamide (sulfapyridine) component of the drug, current evidence suggests that 5-aminosalicylic acid (mesalamine) also may be responsible, at least in part, for the development of this adverse effect. The possibility of acute pancreatitis should be considered in any patient who develops new abdominal complaints while receiving mesalamine therapy. Acute pancreatitis has occurred rarely in patients receiving mesalamine or one of its prodrugs (e.g., olsalazine, sulfasalazine). Evidence of pancreatitis included severe upper abdominal pain (radiating to the back) and elevated serum amylase concentrations. In several of these patients, pancreatitis recurred upon rechallenge with mesalamine or one of its prodrugs. Increased serum lipase or amylase concentrations have been reported in less than 1% of patients, receiving mesalamine extended-release capsules; however, a causal relationship to the drug has not been established.

Other adverse GI effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include anorexia, taste perversion, gastritis, increased appetite, perforated peptic ulcer, and bloody diarrhea.

Nervous System Effects

Headache is the most common adverse nervous system effect of oral and rectal mesalamine, occurring in about 2-18 and 7% of patients, respectively. In controlled clinical trials in patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol), dizziness, asthenia, malaise, insomnia, anxiety, migraine, nervousness, paresthesia, and hypertonia were the most common adverse nervous system effects, occurring in about 2-8% of patients; lethargy, mild disorientation, and stuffy head were reported rarely. Frequency of these nervous system effects did not seem to increase with increased dosages, although in uncontrolled studies, the incidence of asthenia and fever were dose related. Adverse nervous system effects associated with oral mesalamine 1.2-g delayed-release tablets (Lialda) and occurring in less than 1% of patients include asthenia, fatigue, somnolence, and tremor. Adverse nervous system effects associated with oral mesalamine extended-release capsules and occurring in less than 1% of patients include depression, dizziness, insomnia, somnolence, malaise, asthenia, and paresthesia, although a causal relationship to the drug of many of these adverse effects has not been established.

Fatigue, asthenia, malaise, and weakness occur in about 3% and dizziness in about 2-3% of patients receiving mesalamine rectally. Mental depression and insomnia have been reported rarely in patients receiving rectal mesalamine.

Other adverse nervous system effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, and Guillain-Barre syndrome.

Sensitivity Reactions

An acute intolerance syndrome (sensitivity reaction), characterized by cramping, abdominal pain, bloody diarrhea, and, occasionally, fever, headache, malaise, conjunctivitis, pruritus, and rash, has occurred in a few patients receiving mesalamine and required prompt discontinuance of the drug. In patients manifesting such intolerance, a history of sulfasalazine intolerance, if any, should be reevaluated. In at least one sulfasalazine-sensitive patient, administration of mesalamine produced headache, fever, intense abdominal colic, and profuse diarrhea within 8-24 hours after administration of the drug; oral corticosteroid and rectal cromolyn therapy was ineffective, and colectomy was required 2 weeks after rechallenge with mesalamine. Intolerance to mesalamine, which occasionally required corticosteroid therapy, also has occurred in several other sulfasalazine-sensitive patients, although most sulfasalazine-sensitive patients reportedly tolerated mesalamine well. Nonetheless, mesalamine therapy should be initiated cautiously in patients with a history of sulfasalazine sensitivity, and patients should be advised to discontinue mesalamine and contact their clinician if signs of sensitivity (e.g., fever, rash) develop or increased diarrhea or rectal bleeding occurs during mesalamine therapy. In addition, some clinicians recommend challenge with 1 or 2 test enemas before a complete course of rectal mesalamine therapy is initiated in patients with sulfasalazine sensitivity. In patients with mesalamine sensitivity, rechallenge with the drug should be undertaken only if mesalamine therapy is clearly needed and under close supervision;reduced dosage should be considered for such rechallenge.

Photosensitivity has been reported in less than 1% of patients receiving oral mesalamine extended-release capsules; however, a causal relationship to the drug has not been definitely established. Stevens-Johnson syndrome, manifested by buccal ulceration and fever, has occurred rarely in patients receiving rectal mesalamine.

Dermatologic Effects

Rash, pruritus, and acne have been reported in less than 1 to about 6% of patients receiving mesalamine.(See Cautions: Sensitivity Reactions.) Alopecia has been reported in up to about 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda). Other dermatologic effects associated with oral mesalamine 1.2-g delayed-release tablets and occurring in less than 1% of patients include prurigo and urticaria. Other dermatologic effects associated with oral mesalamine extended-release capsules and occurring in less than 1% of patients include alopecia, dry skin, eczema, lichen planus, erythema nodosum, nail disorder, and urticaria, although a causal relationship to the drug of many of these adverse effects has not been established.

Alopecia has been reported in about 1% of patients receiving mesalamine rectal suspension. Alopecia usually is mild, being characterized as accelerated or excessive hair loss such as observably more hair in a comb, and usually is reversible following discontinuance of the drug. The manufacturer of rectal mesalamine preparations states that alopecia may not recur following reinstitution of mesalamine therapy and some clinicians have postulated that alopecia may result from flare-up of the disease rather than from the drug itself. Alopecia also has been reported in patients receiving sulfasalazine.

Other adverse dermatologic effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include psoriasis and pyoderma gangrenosum.

Renal and Genitourinary Effects

Mesalamine may adversely affect renal function.

In preclinical studies in animals, nephrotoxicity was the major adverse effect observed with oral or parenteral mesalamine and appeared to be dose related. Studies in rats, mice, and dogs receiving single oral mesalamine doses exceeding 900 mg/kg or single IV doses exceeding 214 mg/kg have revealed evidence of renal lesions (e.g., medullary and focal cortical lesions, papillary necrosis). In addition, renal lesions (e.g., granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, interstitial nephritis) have been reported in mice or rats receiving oral mesalamine dosages of 2400 or 1150 mg/kg daily, respectively. In cynomolgus monkeys receiving oral mesalamine dosages of 250 mg/kg daily, nephrosis, papillary edema, and interstitial fibrosis have been observed. It has been postulated that mesalamine-induced renal toxicity may be similar to analgesic nephropathy observed after chronic ingestion of large dosages of analgesics (e.g., aspirin), since these analgesics are structurally similar to mesalamine. Following single oral doses of 200 mg/kg in rats and dogs, no changes in urinary flow, specific gravity, or electrolyte excretion were observed; however, at higher doses (i.e., 600 mg/kg), increases in urinary sodium and protein excretion and in specific gravity were observed. Dose-related renal lesions were observed in male but not female rats and in dogs receiving oral mesalamine dosages of 160 mg/kg daily. Reversible, minimal tubular epithelial damage was observed in male rats receiving dosages of 40 mg/kg daily; however, no evidence of adverse renal effects was seen in dogs receiving such dosages for 6 months. Following oral mesalamine dosages of 640 mg/kg daily for 13 weeks in rats and dogs, death, probably secondary to renal failure, occurred; dose-related renal lesions (e.g., papillary necrosis and/or multifocal tubular injury) also were observed. In a combined 52-week toxicity and 127-week carcinogenicity study in rats receiving daily mesalamine dosages of 100-mg/kg and above, degeneration of kidneys was observed at 52 weeks, while at 127 weeks, increased incidence of kidney degeneration and hyalinization of basement membranes of Bowman's capsule was reported.

Renal impairment (e. g., minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure) and increases in blood urea nitrogen (BUN) and serum creatinine concentrations have been reported in patients receiving oral preparations containing or being metabolized to mesalamine. Nephrotoxicity also has occurred in patients receiving oral sulfasalazine. Adverse genitourinary effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include dysuria, albuminuria, urinary urgency, hematuria, epididymitis, decreased libido, amenorrhea, dysmenorrhea, menorrhagia, and hypomenorrhea.

Rectal mesalamine has not been associated with overt adverse renal effects in humans to date. Although the limited systemic absorption of rectally administered mesalamine suggests that the potential for inducing nephrotoxicity by this route of administration is low, the possibility that adverse renal effects may occur in patients receiving rectal mesalamine must be considered. Urinary tract infection and/or urinary burning have been reported in less than 1% of patients receiving mesalamine rectal suspension.

Cardiovascular Effects

In controlled clinical trials, chest pain and peripheral edema were reported in 3% of patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol). Tachycardia, hypertension, and hypotension were reported in less than 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda). Palpitations and vasodilation were reported in less than 1% of patients receiving oral mesalamine extended-release capsules; however, a causal relationship to the drug of these adverse effects has not been established. Myocarditis, pericarditis, and facial edema have been reported in patients receiving preparations containing or being metabolized to mesalamine.

Peripheral or generalized edema has been reported in about 1% of patients receiving the drug rectally. Pericarditis, manifested as chest pain, fever, and/or dyspnea, has occurred rarely in patients receiving rectal mesalamine. Evidence of pericarditis occurred within several days to weeks after initiation of rectal mesalamine therapy and resolved following discontinuance of the drug. In most patients, pericarditis recurred with mesalamine or olsalazine rechallenge. However, the risk of cross-sensitivity with sulfasalazine or other 5-aminosalicylic acid (mesalamine) prodrugs (e.g., olsalazine) currently is not known. Other evidence of pericarditis included pericardial friction rub, radiographic evidence of pleural effusion and/or cardiac enlargement with possible tamponade, echocardiographic evidence of pericardial effusion, and/or ECG abnormalities (e.g., ST- and T-wave changes and inferior Q waves suggestive of myocardial infarction, ST-segment depression). Although there appears to be an association between mesalamine use and the development of pericarditis in these patients, the mechanism is unknown and pericarditis also has been reported in patients with inflammatory bowel disease who were not receiving mesalamine. In some of these latter patients, pericarditis developed during sulfasalazine therapy and therefore, may have been secondary to the drug rather than to the underlying condition. The possibility of pericarditis should be considered in any patient who develops chest pain or dyspnea during mesalamine therapy. Discontinuance of therapy with the drug may be warranted in some such patients, while mesalamine rechallenge may be performed under careful clinical observation if there is a continued therapeutic need for the drug.

Because mesalamine prodrugs have been used safely (i.e., without exacerbating preexisting pericarditis) and effectively in patients with inflammatory bowel disease and preexisting pericarditis, use of mesalamine or its prodrugs in such patients in whom the development of pericarditis was not previously associated with the drugs is not contraindicated.

Hepatic Effects

Adverse hepatic effects associated with oral mesalamine extended-release capsules (and with other mesalamine-containing preparations) and occurring in less than 1% of patients include increased serum concentrations of AST (SGOT), ALT (SGPT), alkaline phosphatase, γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP), LDH, and amylase, although a causal relationship to the drug of many of these adverse effects has not been established. Increased serum bilirubin concentrations were reported in less than 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda). Other adverse hepatic effects, some of them fatal, associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include hepatotoxicity (e.g., jaundice [including cholestatic], hepatitis, cirrhosis, possible hepatocellular damage [liver necrosis, liver failure]), elevated serum bilirubin concentrations, cholecystitis, and (in at least one patient) Kawasaki-like disease (with changes in hepatic enzymes). Asymptomatic elevations of hepatic enzymes, which usually disappear with continued use or upon discontinuance of mesalamine, also have been reported.

Pulmonary and Respiratory Effects

In controlled clinical trials in patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol), pharyngitis, rhinitis, increased cough, sinusitis, and bronchitis were reported in about 2-18% of patients. The frequency of these pulmonary and respiratory effects did not seem to increase with increasing dosages, although in uncontrolled studies, the incidence of rhinitis was dose related. Pharyngolaryngeal pain was reported in less than 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda).

Upper respiratory infection has been reported in about 2% of patients receiving mesalamine rectally. Other adverse pulmonary and respiratory effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include eosinophilic pneumonia, interstitial pneumonitis, fibrosing alveolitis, dyspnea, exacerbation of asthma, pulmonary infiltrates, and pleuritis.

Hematologic Effects

Ecchymosis, thrombocythemia, and thrombocytopenia have been reported in less than 1% of patients receiving oral mesalamine extended-release capsules; however, a causal relationship to the drug of these adverse effects has not been established. Thrombocytopenia has been reported in less than 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda). Adverse hematologic effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include agranulocytosis, aplastic anemia, eosinophilia, leukopenia, anemia, and lymphadenopathy. In at least one patient receiving mesalamine rectal suppositories (500 mg every evening) for 7 months, leukopenia and thrombocytopenia occurred.

Musculoskeletal Effects

In controlled clinical studies in patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol), back pain/lower back discomfort, arthralgia, myalgia, arthritis, and joint pain/disorder were reported in 2-5% of patients; muscle cramps occurred rarely. The frequency of these musculoskeletal effects did not seem to increase with increasing dosages, although in the uncontrolled studies the incidence of back pain and arthralgia were dose related. Arthralgia and back pain were reported in less than 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda). Arthralgia, myalgia, and leg cramps were reported in less than 1% of patients receiving oral mesalamine extended-release capsules; however, a causal relationship to the drug of some of these adverse effects has not been established.

Leg or joint pain and/or stiffness has been reported in about 2% of patients receiving the drug rectally. Other musculoskeletal adverse effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include neck pain and gout.

Ocular and Otic Effects

In controlled clinical studies in patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol), otic disorder and otic pain were reported in 2% or more of patients; plugged ears were reported rarely. Otic pain was reported in less than 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda). Conjunctivitis was reported in less than 1% of patients receiving oral mesalamine extended-release capsules; however, a causal relationship to the drug has not been established.

Adverse ocular and otic effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include eye pain, blurred vision, and tinnitus. Keratoconjunctivitis sicca was reported in animals following oral administration of mesalamine; however, this ocular effect has not been reported in humans to date.

Other Adverse Effects

In controlled clinical trials in patients receiving oral mesalamine 400-mg delayed-release tablets (Asacol), pain/aching and fever were reported in 14 and 6% of patients, respectively; flu syndrome, chills, and sweating occurred in 3% of patients. The frequency of these adverse effects did not seem to increase with increasing dosages, although in uncontrolled studies, the incidence of flu syndrome, fever, and pain were dose related. Pyrexia was reported in less than 1% of patients receiving oral mesalamine 1.2-g delayed-release tablets (Lialda).

Fever has been reported in about 1-3% of patients receiving rectal mesalamine. Fever also has been reported as a component of an acute mesalamine intolerance syndrome.(See Cautions: Sensitivity Reactions.) At least one patient died after receiving mesalamine rectal suspension, but a causal relationship to the drug has not been established.

Precautions and Contraindications

Because mesalamine has been associated with adverse renal effects (see Cautions: Renal Effects),the drug should be used with caution in patients with renal impairment and only if the benefits outweigh the risks. Renal function should be evaluated in all patients prior to initiation of therapy with mesalamine and periodically thereafter. Although the potential for adverse mesalamine-induced renal effects appears to be low following rectal administration, the possibility of such effects occurring in patients receiving the drug should be considered, particularly when increased GI absorption or decreased renal elimination of the drug is possible or when a nonsteroidal anti-inflammatory agent or an oral preparation containing or metabolized to mesalamine is administered concomitantly. The manufacturers state that renal function should be monitored carefully during mesalamine therapy (especially during the initial phase of treatment, in patients with preexisting renal impairment, or in those receiving concomitant therapy with drugs that are a source of mesalamine [e.g., sulfasalazine]). Mesalamine-induced nephrotoxicity should be suspected in patients who develop renal dysfunction during treatment.

The possibility of extension and/or acute exacerbation of colitis occurring during mesalamine therapy should be considered.(See Cautions: GI Effects.)

Mesalamine therapy should be initiated with caution in patients with conditions predisposing them to the development of myocarditis or pericarditis. The possibility of pericarditis should be considered in any patient who develops chest pain or dyspnea during mesalamine therapy.(See Cautions: Cardiovascular Effects.)

Mesalamine therapy should be initiated with caution in patients with sulfasalazine sensitivity, although cross-sensitivity to mesalamine rectal suspension appears to be low. These patients should be instructed to discontinue mesalamine therapy and contact their clinician if signs of sensitivity (e.g., rash, fever) develop or increased diarrhea or rectal bleeding occur. The possibility that acute intolerance (sensitivity reaction) to mesalamine could occur in any patient receiving the drug should be considered.(See Cautions: Sensitivity Reactions.) Some clinicians also state that mesalamine, like other inhibitors of prostaglandin synthesis, should be used with caution in patients with aspirin sensitivity, although the risk of cross-sensitivity with mesalamine is not known.

Mesalamine should be used with caution in patients with hepatic impairment.

The possibility of acute pancreatitis should be considered in any patient who develops new abdominal complaints while receiving mesalamine therapy.(See Cautions: GI Effects.)

Patients with pyloric stenosis may experience prolonged gastric retention of oral mesalamine delayed-release tablets resulting in delayed release of the drug in the colon.

Mesalamine rectal suspension contains potassium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. If a severe hypersensitivity reaction occurs during therapy with mesalamine rectal suspension, the drug should be discontinued and the patient given appropriate treatment (e.g., epinephrine). The presence of sulfites in the parenteral epinephrine preparation and the possibility of allergic-type reactions should not deter use of epinephrine when indicated for the treatment of serious allergic reactions or for other emergency situations. Epinephrine is the preferred treatment for such conditions, and currently available alternatives to epinephrine may not be optimally effective. Preparations containing mesalamine are contraindicated in patients with known hypersensitivity to the drug or any ingredient in the respective formulation. The manufacturers of oral mesalamine extended-release capsules (Pentasa), oral mesalamine 1.2-g delayed-release tablets (Lialda), and mesalamine rectal suppositories (Canasa) state that the drug is contraindicated in patients with hypersensitivity to salicylates (including aspirin and mesalamine).

Pediatric Precautions

Safety and efficacy of oral delayed-release tablets, oral extended-release capsules, rectal suspensions, and rectal suppositories of mesalamine in pediatric patients have not been established.

Mesalamine (oral delayed-release tablets given as an initial dosage of 20-30 mg/kg daily and increased up to 60 mg/kg daily) has been used in a limited number of pediatric patients with inflammatory bowel disease (i.e., mild ileal, ileocecal, ileocolonic, or colonic disease) while rectal mesalamine suspension has been used in those with left-sided colitis. Limited data from a retrospective comparative study indicate that efficacy in maintaining remission of inflammatory bowel disease is similar in children receiving oral mesalamine delayed-release tablets compared with those receiving oral sulfasalazine. However, some patients may prefer mesalamine to sulfasalazine, because of ease and frequency of administration and better tolerance.

Geriatric Precautions

Clinical studies of oral mesalamine delayed-release tablets and rectal suppositories of the drug did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed differences in response, drug dosage should be selected cautiously in geriatric patients. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. Reports from uncontrolled studies suggest that a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, pancytopenia) may occur in patients 65 years of age or older receiving oral mesalamine delayed-release tablets; complete blood cell counts (CBCs) should be monitored closely in these patients during therapy with these oral preparations.

Mesalamine is substantially eliminated by the kidneys, and the risk of toxic reactions may be greater in patients with impaired renal function. Because of the greater frequency of decreased renal function observed in geriatric individuals, mesalamine should be used with caution in these patients and renal function monitored prior initiation of and during administration of oral mesalamine delayed-release tablets.

Mutagenicity and Carcinogenicity

Mesalamine did not produce mutagenic activity in the Ames mutagen test using Salmonella typhimurium, in mouse lymphoma cells, or in in vitro chromosomal aberrations in Chinese hamster ovary cells. In addition, there was no evidence of mutagenicity of forward mutation test or reverse mutations in an in vitro test system using an Escherichia coli strain, and there was no evidence of adverse chromosomal effects in an in vivo micronucleus test in mice receiving single oral doses of mesalamine up to 600 mg/kg or in an in vivo sister chromatid exchange test in mice receiving single oral doses up to 610 mg/kg.

When compared with controls, an increased incidence of neoplastic lesions was not observed in a 2-year carcinogenicity study in rats receiving oral mesalamine dosages of up to 320 mg/kg daily. In addition, no carcinogenic or tumorigenic potential was seen in mice or rats receiving mesalamine in dosages up to 2500 or up to 800 mg/kg daily, respectively, for up to 2 years.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral mesalamine dosages of up to 1000 mg/kg daily and up to 800 mg/kg daily, respectively, have not revealed evidence of teratogenic effects or harm to the fetus. In addition, reproduction studies in rats and rabbits using oral mesalamine daily doses up to 5 and 8 times the maximum recommended human rectal dose, respectively, have not revealed evidence of fetal malformation. Sulfasalazine (a prodrug of mesalamine) has been used for the treatment of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, during pregnancy. Although fetal abnormalities have been reported in infants born to women with inflammatory bowel disease who received sulfasalazine alone or combined with corticosteroids during pregnancy, most evidence indicates that sulfasalazine is not associated with a substantial risk of teratogenicity. The effect of sulfasalazine on subsequent growth, development, and functional maturation in children whose mothers received sulfasalazine during pregnancy has not been determined. Although the relevance to mesalamine of the experience with sulfasalazine in pregnant women currently is not known, placental transfer of mesalamine, but not sulfasalazine or sulfapyridine, has been reported to be negligible in pregnant women receiving oral sulfasalazine. Mesalamine crosses the placental barrier. Because there are no adequate and controlled studies to date using mesalamine or sulfasalazine in pregnant women, and animal studies are not always predictive of human response, the drugs should be used during pregnancy only when clearly needed.

Fertility

Reproduction studies in rats receiving oral mesalamine dosages up to 320-480 mg/kg daily have not revealed evidence of impaired fertility and/or reproductive performance. Oligospermia, abnormal sperm forms, impaired sperm motility, and infertility have occurred in men receiving sulfasalazine; however, these effects on sperm maturation appear to be caused by effects of sulfapyridine rather than mesalamine and appear to be reversible following discontinuance of sulfasalazine. Evidence of infertility has been reported very rarely following administration of rectal mesalamine, and sulfasalazine-induced infertility has resolved and not recurred in some males in whom mesalamine replaced sulfasalazine. In addition, there is evidence from comparative studies in animals that sulfapyridine rather than mesalamine is responsible for sulfasalazine-induced effects on male fertility.

Lactation

Following oral administration, low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. Although the clinical importance of this effect is not known, mesalamine should be used with caution and only if the benefits outweigh the risks in nursing women. The manufacturer of mesalamine extended-release capsules states that hypersensitivity reactions (e.g., diarrhea) in the infant of a breast-feeding woman receiving mesalamine cannot be excluded. The manufacturer of mesalamine rectal suspension recommends that the drug not be used in nursing women.

Drug Interactions

Azathioprine

Use of mesalamine in patients receiving azathioprine may increase the risk of hematologic toxicity.

Digoxin

Sulfasalazine and aminosalicylic acid (the 4-amino [para-amino] derivative of salicylic acid) may decrease GI absorption of digoxin, possibly by altering properties of the intestinal wall. In vitro, sulfasalazine did not appear to adsorb digoxin. After 2 weeks of concomitant oral administration of sulfasalazine or aminosalicylic acid with digoxin, absorption of digoxin was reduced 25 or 20%, respectively. It is not known whether concomitant administration of mesalamine (5-aminosalicylic acid) and digoxin results in similar alterations in absorption of the cardiac glycoside.

Mercaptopurine

Use of mesalamine in patients receiving mercaptopurine may increase the risk of hematologic toxicity.

Nephrotoxic Drugs

Use of mesalamine in patients receiving other nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]) may increase the risk of nephrotoxicity.

Pharmacokinetics

Absorption

Following oral administration of conventional capsules or uncoated tablets of mesalamine, the drug is absorbed extensively from the proximal part of the GI tract. Therefore, to achieve a local effect in lower portions of the GI tract, oral mesalamine is administered as delayed-release tablets or extended-release capsules.

Following oral administration of the 400-mg delayed-release tablets (Asacol), approximately 28% of mesalamine is absorbed and the remainder of the dose is available for topical activity and fecal excretion; absorption is similar in fed and fasting individuals. Peak plasma mesalamine concentrations usually occur within 4-12 hours following oral administration of the 400-mg delayed-release tablets; however, there is a relatively large interindividual variation in the plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid following administration of these tablets. Following oral administration of a single 2.4-g dose of delayed-release mesalamine in healthy adults, average peak serum mesalamine and N-acetyl-5-aminosalicylic acid concentrations of 1.27 and 2.3 mcg/mL, respectively, occurred within about 6 hours.

Mesalamine appears to be more extensively absorbed from the 400-mg delayed-release tablets than when released from sulfasalazine (a prodrug of mesalamine). Following multiple-dose administration of the 400-mg delayed-release tablets, peak plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid usually are achieved within 4-12 hours and are about 1.5-2 times higher than those following the equivalent mesalamine dose contained in sulfasalazine.

Following oral administration of 1.2-g delayed-release tablets (Lialda) to healthy individuals at a dosage of 2.4 or 4.8 g once daily for 14 days, approximately 21-22% of the mesalamine dose is absorbed. Following oral administration of a single 1.2-, 2.4-, or 4.8-g (as the 1.2-g delayed-release tablets) dose of mesalamine in fasting healthy adults, the drug is detectable in plasma after 2 hours, and peak plasma mesalamine concentrations occur at approximately 9-12 hours. Following oral administration of 1.2-g mesalamine delayed-release tablets, pharmacokinetics of the drug are highly variable. Peak plasma mesalamine concentrations of 857, 1595, and 2154 ng/mL were reported following oral administration of a single mesalamine dose of 1.2-, 2.4-, or 4.8-g (as 1.2-g delayed-release tablets), respectively, in healthy fasting individuals. When administered as 1.2-g delayed-release tablets, mesalamine exhibits slightly nonlinear pharmacokinetics over the dosage range of 1.2-4.8 g daily. Dose-proportional increases in peak plasma mesalamine concentrations were observed with oral administration of a single dose between 1.2 and 2.4 g of mesalamine and less-than-proportional increases reported with a single dose between 2.4 and 4.8 g, with the dose-normalized value at 4.8 g representing an average of 74% that at 2.4 g based on geometric mean calculations.

Following administration of a single 4.8-g dose of mesalamine (as the 1.2-g delayed-release tablets) with a high-fat meal, there is a delay in absorption compared with fasting administration, with detectable plasma concentrations occurring about 4 hours after administration. Administration of mesalamine 1.2-g delayed release tablets with a high-fat meal also results in increased systemic mesalamine exposure, with increases of 91 and 16% in peak plasma concentration and area under the concentration-time curve (AUC), respectively. Following administration of mesalamine in single or multiple doses of 2.4 or 4.8 g (as the 1.2-g delayed-release tablets) once daily with a meal to healthy individuals, plasma concentrations of mesalamine were detectable 4 hours after a single dose and reached a peak 8 hours after a single dose. Steady-state plasma concentrations generally were achieved within 2 days of multiple-dose administration. Mean AUC values at steady state following multiple-dose administration were about 1.1-1.4 times those predicted based on single-dose pharmacokinetics.

Following oral administration of extended-release capsules (Pentasa), about 20-30% of the drug is absorbed. Peak plasma mesalamine and N-acetyl-5-aminosalicylic acid concentrations of 1 and 1.8 mcg/mL, respectively, usually are attained in about 3 hours following oral administration of a 1-g dose of extended-release capsules. When administered as oral extended-release capsules, mesalamine exhibits nonlinear pharmacokinetics (unlike N-acetyl-5-aminosalicylic acid that exhibits linear kinetics) over the dosage range of 1-4 g daily, with plasma mesalamine concentrations at steady state being about 9 times higher (increasing from 0.14 to 1.21 mcg/mL) than those after a single oral dose of the drug, suggesting that mesalamine undergoes saturable first-pass elimination.

Rectal mesalamine suspension is poorly absorbed from the GI tract following rectal administration. Approximately 15% (range: 5-35%) of a rectally administered dose is absorbed. There is considerable interindividual variation in the extent of absorption of mesalamine rectal suspension. Absorption may depend on retention time of the enema, pH, and/or volume of mesalamine rectal suspension and also on the patient's underlying GI disease state. Rectal mesalamine suspension usually is retained for about 3.5-12 hours after administration as an enema; prolonged retention may increase absorption of the drug. Mesalamine is variably absorbed following rectal administration of the suppositories. Following rectal administration of a 500-mg suppository every 8 hours for 6 days in patients with ulcerative colitis, mean peak plasma mesalamine and N-acetyl-5-aminosalicylic acid plasma concentrations are about 353 and 467-1399 ng/mL, respectively, after the initial dose, while mean peak steady-state plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid are about 361 and 193-1304 ng/mL, respectively; the mean minimum steady-state plasma concentrations are of mesalamine 89 ng/mL. Following rectal administration, mesalamine does not appear to accumulate in plasma. Mesalamine rectal suppositories usually are retained for 1-3 hours after administration.

Absorption of mesalamine appears to be decreased and delayed at acidic compared with higher (e.g., neutral) pH. Absorption of the drug appears to be decreased substantially in patients with active inflammatory bowel disease, probably secondary to local inflammatory changes, and increased with increasing volumes of the rectal suspension in patients whose disease is in remission. Following rectal administration of a single 4-g dose of mesalamine suspension in adults with ulcerative colitis in remission or with active disease, peak total plasma mesalamine concentrations occur within 3-6 hours and average about 4 or 3 mcg/mL, respectively. Following rectal administration of a single 2- or 4-g dose of mesalamine in patients with ulcerative colitis, average peak plasma N-acetyl-5-aminosalicylic acid (the principal metabolite of mesalamine) concentrations of 2 or 2.5 mcg/mL, respectively, occur within 4-7 hours. When mesalamine is administered directly into the small intestine, systemic absorption is increased. Following jejunal administration of a single 150-mg dose of mesalamine in healthy adults, peak plasma mesalamine concentrations of 5.8 mcg/mL (range: 4.6-9.1 mcg/mL) occur within about 1 hour.

Steady-state plasma mesalamine and N-acetyl-5-aminosalicylic acid concentrations averaged 0.29 and 0.7 mcg/mL, respectively, in patients receiving rectal mesalamine dosages of 1 g daily for 10 days; appreciable accumulation of mesalamine or the acetylated metabolite does not appear to occur.

Distribution

Distribution of mesalamine into human body tissues and fluids has not been fully characterized. Following oral or IV administration of mesalamine in animals, the drug may be distributed into kidneys. Following rectal administration of mesalamine suspension in adults, the drug distributes from the rectum into the colon, generally reaching the splenic flexure and possibly the ascending colon. Following rectal administration of mesalamine suppositories, the drug distributes to some extent in rectal tissues. The apparent volume of distribution (Vd) of the drug in adults is approximately 0.2 L/kg.

In vitro, mesalamine and N-acetyl-5-aminosalicylic acid are approximately 44-55 and 80% bound, respectively, to plasma proteins. Mesalamine is approximately 43% bound to plasma proteins at a concentration of 2.5 mcg/mL. Protein binding of N-acetyl-5-aminosalicylic acid does not appear to be concentration dependent at concentrations ranging from 1-10 mcg/mL.

Mesalamine and N-acetyl-5-aminosalicylic acid cross the placenta following oral administration; however, serum concentrations of mesalamine in umbilical cord and amniotic fluid are very low. It is not known whether mesalamine crosses the placenta following rectal administration.

Following oral administration, low concentrations of mesalamine and higher concentrations of its metabolite, N-acetyl-5-aminosalicylic acid, have been detected in human breast milk. It is not known whether mesalamine or its metabolites are distributed into milk in humans following rectal administration.

Elimination

Serum mesalamine concentrations appear to decline in a biphasic manner following IV administration of the drug. Following IV infusion of 0.5 g of the drug in healthy adults, the half-life of mesalamine averaged about 17 minutes in the distribution phase (t½α) and about 42 minutes in the terminal elimination phase (t½β). Following oral administration of a single 1-g dose of mesalamine extended-release capsules (Pentasa), the drug may undergo biphasic elimination; however, because of the continuous release and absorption of mesalamine throughout the GI tract, the correct elimination half-life of the drug cannot be determined. There is a relatively large interindividual variation in the elimination half-lives of mesalamine and N-acetyl-5-aminosalicylic acid following oral administration of mesalamine delayed-release tablets (Asacol). Following oral administration of mesalamine 400-mg delayed-release tablets (Asacol), the elimination half-lives of mesalamine and N-acetyl-5-aminosalicylic acid are about 12 hours (range: 2-15 hours). Following oral administration of a single 2.4- or 4.8-g dose as the 1.2-g delayed-release tablets (Lialda) in healthy individuals, the elimination half-lives of mesalamine and N-acetyl-5-aminosalicylic acid are about 7-9 and 8-12 hours, respectively.

Following rectal administration of mesalamine suspension in healthy adults or those with inflammatory bowel disease, the elimination half-lives of mesalamine and N-acetyl-5-aminosalicylic acid are 0.5-1.5 hours and 5-10 hours, respectively. Following rectal administration of a 500-mg mesalamine suppository every 8 hours for 6 days in patients with ulcerative proctitis, the elimination half-lives of mesalamine and N-acetyl-5-aminosalicylic acid are 5 and 6 hours, respectively, after the initial dose, while the elimination half-lives of both the drug and its principal metabolite at steady-state are 7 hours.

The exact metabolic fate of mesalamine has not been clearly established. The drug undergoes rapidN-acetylation, probably in the liver and intestinal mucosa, to form N-acetyl-5-aminosalicylic acid; mesalamine and N-acetyl-5-aminosalicylic acid also may undergo conjugation with glucuronic acid. Several other, unidentified metabolites also may be formed. It has been suggested that N-acetylation also may occur (to a limited extent) in the intestinal wall and/or the lumen. The intestinal flora probably are involved in this acetylation, and extensive floral acetylation may adversely affect clinical efficacy of the drug. Correlation between acetylator phenotype of patients receiving mesalamine and the degree of N-acetylation does not appear to exist.

Although it has been suggested that N-acetyl-5-aminosalicylic acid may be pharmacologically active, therapeutic response has been poor in some patients treated rectally with this metabolite, and the relative contribution of this metabolite to the therapeutic effect of mesalamine remains questionable.N-acetyl-5-aminosalicylic acid did not inhibit lipoxygenase in vitro.

Following oral administration of mesalamine in healthy adults, approximately 20% of a dose is excreted in urine mainly as N-acetyl-5-aminosalicylic acid. Following oral administration of delayed- or extended-release mesalamine in patients with an ileorectal anastomosis or with colitis, amounts of mesalamine and N-acetyl-5-aminosalicylic acid excreted in urine appear to be similar to those excreted in healthy individuals; approximately 22% of a dose is excreted in urine (about 21% [i.e., about 4% of the dose] as N-acetyl-5-aminosalicylic acid). Of the approximately 21-22% of the dose absorbed following oral administration of mesalamine as the 1.2-g delayed-release tablets, less than 8% of the dose is excreted unchanged in the urine, compared with greater than 13% of the dose for N-acetyl-5-aminosalicylic acid. Following oral administration of delayed-release mesalamine, excretion of N-acetyl-5-aminosalicylic acid may be decreased in patients with Crohn's disease and in ileostomy patients. Following oral administration, mesalamine also is eliminated in feces. The amount of free mesalamine and salicylates excreted in feces in patients receiving mesalamine extended-release capsules, increase proportionally with the dose.

Following rectal administration of mesalamine suspension, unchanged drug and N-acetyl-5-aminosalicylic acid are excreted mainly in feces; small amounts of the drug and/or its metabolites are excreted in urine, mainly via tubular secretion. It is believed that the fraction of a rectal dose excreted in feces represents mainly unabsorbed drug. Biliary elimination of mesalamine appears to be negligible, although the drug may undergo some enterohepatic circulation. Following administration of a single rectal dose of mesalamine in patients with inflammatory bowel disease, about 50% of the dose is excreted in feces and about 10-35% (range: 6-79%) in urine within 24-48 hours. In patients with inflammatory bowel disease, about 44% of a single rectal dose is excreted in feces as unchanged drug, 3% as N-acetyl-5-aminosalicylic acid, and the remainder as unidentified metabolites. Following rectal administration, mesalamine is excreted in urine mainly as N-acetyl-5-aminosalicylic acid. It appears that urinary excretion characteristics may depend on the underlying disease state, dosage or volume of mesalamine suspension, and luminal pH. The presence of blood and mucus in the GI tract also may affect urinary excretion of the drug. The extent of urinary excretion of N-acetyl-5-aminosalicylic acid may be decreased at steady state, at low dosages, and in patients with active disease. Following rectal administration of mesalamine in patients with ulcerative colitis, approximately 10 (range: 2-18%) or 20% (range 10-37%) of the dose is excreted in urine of patients with active disease or those whose disease is in remission, respectively. Following rectal administration of a 4-g dose as a 100- or 200-mL suspension in patients with ulcerative colitis, approximately 16 or 25% of the dose was excreted in urine, respectively.

Following jejunal administration of mesalamine in healthy adults, approximately 54% (range: 47-70%) of the dose was excreted in urine and less than 2% in feces as N-acetyl-5-aminosalicylic acid within 24 hours.

Following oral administration of mesalamine in healthy individuals, the apparent renal clearance of N-acetyl-5-aminosalicylic acid is reported to average approximately 2.8-4.3 mL/minute per kg (range: 1-6.5 mL/minute per kg). The apparent renal clearance of this metabolite may be decreased in patients with ulcerative colitis or Crohn's disease.

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