Mesalamine

Pronunciation

Class: Anti-inflammatory Agents
VA Class: GA900
Chemical Name: 5-Amino-2-hydroxybenzoic acid
Molecular Formula: C7H7NO3
CAS Number: 89-57-6
Brands: Asacol, Canasa, Lialda, Pentasa, Rowasa

Introduction

The 5-amino derivative of salicylic acid; a GI anti-inflammatory agent.1 3 4 6 15

Uses for Mesalamine

Ulcerative Colitis

Used for management of ulcerative colitis (as oral delayed-release tablets or extended-release capsules)228 229 231 232 233 236 and to induce (as extended-release capsules and as 1.2-g delayed-release tablets)229 236 448 and maintain (as 400-mg delayed-release tablets)228 234 235 clinical remission in adults with mildly to moderately active disease.

Management of mildly to moderately active distal ulcerative colitis (as rectal suspension) 1 2 3 7 71 72 74 78 93 94 104 154 175 176 177 203 204 205 including ulcerative proctosigmoiditis 1 2 7 15 97 99 100 102 120 122 153 154 173 175 and ulcerative proctitis.1 2 7 71 72 97 98 122 154

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Management of active ulcerative proctitis (as rectal suppositories).217 227 230 237

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.86 156

Crohn’s Disease

Has been used (as extended-release oral preparations) for the management of active Crohn’s disease106 261 339 341 342 343 344 345 and to induce300 339 341 and maintain clinical remission241 245 248 250 339 348 349 350 351 352 353 354 355 356 357 in adults with mildly to moderately active disease.

Has been used (as rectal preparations) in a limited number of patients for the management of active Crohn’s disease,70 but the role of such therapy in this condition is not as well defined as in the management of ulcerative colitis.88 199 200

Mesalamine Dosage and Administration

Administration

Administer orally66 73 80 81 83 85 90 91 96 136 156 164 172 174 228 229 231 233 234 235 236 448 or rectally.1 2 7 71 72 74 86 93 94 99 100 102 103 104 105 1 227

Oral Administration

Administer orally as delayed-release tablets (Asacol, Lialda)228 231 233 234 448 or extended-release capsules (Pentasa).229 235 236

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.228 448 Intact or partially intact tablets may be present in stools; if this occurs repeatedly, patients should notify their clinician.228

1.2-g delayed-release tablets (Lialda): Administer orally with food.448

Rectal Administration

Administer rectally as a suspension retention enema1 2 7 71 72 74 86 93 94 99 100 102 103 104 105 or suppositories.227 230

Administer rectal suspension preferably at bedtime and retain for about 8 hours.1 Best results are achieved if the bowel is emptied just prior to enema administration.2 Administer according to manufacturer’s instructions.1

Retain rectal suppositories for ≥1–3 hours, if possible, to achieve maximum benefit.70 217 227 230

Dosage

Pediatric Patients

Ulcerative Colitis or Crohn’s Disease
Oral

Delayed-release tablets have been given in an initial dosage of 20–30 mg/kg daily and then increased up to 60 mg/kg daily.333 335

Adults

Ulcerative Colitis
Management of Mildly to Moderately Active Ulcerative Colitis
Oral

Delayed-release tablets: Usually, 2.4 g daily (given as two 400-mg delayed-release tablets 3 times daily) for 6 weeks.228

Induction of Remission of Mildly to Moderately Active Ulcerative Colitis
Oral

Extended-release capsules: Usually, 4 g daily in equally divided doses (given as four 250-mg extended-release capsules or two 500-mg extended-release capsules 4 times daily) for up to 8 weeks.229 Lower dosages (e.g., 2–4 g daily [in divided doses]) have been used.250

Delayed-release tablets: 2.4 or 4.8 g once daily (given as two or four 1.2-g delayed-release tablets).448 Safety and efficacy beyond 8 weeks of treatment have not been established.448

Maintenance of Remission
Oral

Delayed-release tablets: Usually, 1.6 g daily (four 400-mg delayed-release tablets) given in divided doses for 6 months.228 Dosages of 800 mg to 4.8 g daily (in divided doses) also have been used.250

Extended-release capsules: Dosages of 1.5–3 g daily (in divided doses) have been used.250

Advise patients that ulcerative colitis rarely remits completely, and continued use of maintenance dosages of mesalamine may substantially decrease the risk of relapse.228

Distal Ulcerative Colitis
Rectal

Suppositories: 1 g (using 1-g suppositories) once daily at bedtime.227 230

Enema suspension: Usually, 4 g once daily (preferably at bedtime).1 2 72 78 86 93 94 205

Although clinical response may be apparent within 3–21 days, therapy with rectal mesalamine usually is continued for 3–6 weeks or until clinical and/or sigmoidoscopic remission is achieved.1 227 230

Efficacy of rectal therapy (in terms of modification of relapse rates) beyond 6 weeks has not been established,1 227 but mesalamine has been used rectally for prolonged periods (e.g., >1 year) in some patients.93

Lower dosages7 71 99 100 102 104 105 176 203 204 208 or less frequent administration93 204 of the rectal drug has been used in some patients, particularly after initial remission is achieved.

In some patients with distal ulcerative colitis in whom clinical remission occurred following daily administration of 4-g doses of the rectal suspension, dosage was reduced to 4 g every 2 or 3 nights or, occasionally, to less frequent administration.93 204 If clinical relapse occurred with such administration, dosage was increased to more frequent use.93 In some patients with distal ulcerative colitis or ulcerative proctosigmoiditis, the rectal suspension also has been used in dosages of 1–3 g daily.7 71 99 100 102 104 105 176 203 204 208

Crohn’s Disease
Management of Mildly to Moderately Active Crohn’s Disease
Oral

Adults have received dosages of 3.2–4.8 g daily (as delayed-release tablets)241 243 248 250 339 340 342 or 4 g daily (as extended-release capsules), generally in divided doses.300 339 Lower dosages do not appear to be effective.106 300 339 367 341

Prescribing Limits

Pediatric Patients

Ulcerative Colitis or Crohn’s Disease
Oral

Maximum 60 mg/kg daily.333 335

Adults

Ulcerative Colitis
Management of Mildly to Moderately Active Ulcerative Colitis
Oral

Delayed-release tablets (400 mg; Asacol): Maximum 4.8 g daily in divided doses.250

Extended-release capsules: Maximum 4 g daily in divided doses.229 250

Induction of Remission of Mildly to Moderately Active Ulcerative Colitis
Oral

Extended-release capsules: Maximum 4 g daily in divided doses.229

Delayed-release tablets (1.2 g; Lialda): Safety and efficacy beyond 8 weeks of therapy not established.448

Maintenance of Remission
Oral

Delayed-release tablets (400 mg; Asacol): Maximum 4.8 g daily, in divided doses.250

Extended-release capsules: Maximum 3 g daily in divided doses.250

Distal Ulcerative Colitis
Rectal

Enema suspension: Maximum 4 g once daily.1 2 72 78 86 93 94 205

The drug has been used rectally for >1 year.93

Crohn’s Disease
Management of Mildly to Moderately Active Crohn’s Disease
Oral

Delayed-release tablets (400 mg; Asacol): Maximum 4.8 g daily in divided doses.250

Extended-release capsules: Maximum 4 g daily in divided doses.250

Maintenance of Remission
Oral

Delayed-release tablets (400 mg; Asacol): Maximum 4.8 g daily in divided doses. 250

Extended-release capsules: Maximum 3 g daily in divided doses.250

Special Populations

Geriatric Patients

Careful dosage selection recommended due to possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.228 230 448

Cautions for Mesalamine

Contraindications

  • Extended-release capsules (Pentasa), delayed-release tablets (1.2-g; Lialda), rectal suppositories (Canasa): Known hypersensitivity to salicylates (including aspirin, mesalamine)229 230 448 or any ingredient in the respective formulation.1 227 228 229 230 448

Warnings/Precautions

Sensitivity Reactions

Possible acute intolerance (sensitivity reaction) syndrome (e.g., cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis, pruritus, rash); may require prompt discontinuance.1 2 78 112 114 121 156 180 198 213 227 228 229 230 448 A history of sulfasalazine intolerance, if any, should be reevaluated.1 2 198 227 228 230

Use with caution in patients with a history of hypersensitivity to sulfasalazine.1 227 228 230 448

Sulfite Sensitivity

Rectal suspension contains a sulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.1

General Precautions

Renal Impairment

Renal impairment (e.g., minimal change nephropathy, acute and chronic interstitial nephritis, renal failure) and increases in BUN and Scr reported.228 229

Use with caution and only if the benefits outweigh the risks448 in patients with renal impairment.1 228 229 230 448

Renal function should be evaluated prior to initiation of therapy and periodically thereafter.1 228 448

GI Effects

Pancolitis reported rarely in patients receiving rectal mesalamine.1 2 227 230

Possible worsening colitis or symptoms of inflammatory bowel disease (e.g., melena, hematochezia) in patients receiving rectal mesalamine.1

Potential for prolonged gastric retention of oral delayed-release tablets in patients with pyloric stenosis.228 448

The possibility of acute pancreatitis should be considered in any patient who develops new abdominal complaints while receiving mesalamine therapy.220

Cardiac Effects

Use with caution in patients with conditions predisposing them to the development of myocarditis or pericarditis.448 The possibility of pericarditis should be considered in any patient who develops chest pain or dyspnea during mesalamine therapy.1 Discontinuance may be needed.227

Specific Populations

Pregnancy

Category B.1 228 229 230 448

Lactation

Distributed into milk following oral administration.228 229 Use with caution.228 229 448

Not known whether the rectal drug is distributed into milk.1 227 230 Use of rectal mesalamine usually not recommended,1 227 although one manufacturer of rectal suppositories states the preparation may be used with caution.230

Pediatric Use

Safety and efficacy not established in children.1 228 229 230 448

Has been used (as oral delayed-release tablets) for the management of inflammatory bowel disease (i.e., mild ileal, ileocecal, ileocolonic, or colonic disease) and (as rectal mesalamine suspension) in those with left-sided colitis in a limited number of pediatric patients.59 199 200 333 335 (See Pediatric Patients under Dosage.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.228 230 448 Response does not appear to differ from that in younger adults; however, drug dosage should be selected cautiously.230 448

Possibility of increased incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, pancytopenia); CBCs should be monitored closely.228

Because mesalamine is substantially eliminated by kidneys, assess renal function prior to initiation of therapy and periodically thereafter since geriatric patients more likely to have decreased renal function.228

Hepatic Impairment

Use with caution in patients with hepatic impairment.229 448

Renal Impairment

Use with caution in patients with renal impairment.1 228 229 230

Common Adverse Effects

Oral therapy: Headache, rash, vomiting, diarrhea, flatulence, constipation, nausea, dyspepsia, abdominal pain, fever, arthralgia, flu syndrome.228 229 448

Rectal therapy: Headache, abdominal pain, nausea, diarrhea, gas/flatulence, fever, dizziness, rectal pain, rash, leg/joint pain, flu syndrome.1 227 230

Interactions for Mesalamine

No known drug interactions.228 229

Specific Drugs

Drug

Interaction

Azathioprine

Possible increased risk of hematologic toxicity448

Digoxin

Decreased GI absorption of digoxin with concomitant sulfasalazine or aminosalicylic acid;115 143 195 not known whether mesalamine alters digoxin absorption199 200

Mercaptopurine

Possible increased risk of hematologic toxicity448

Nephrotoxic drugs (e.g., NSAIAs)

Possible increased nephrotoxicity448

Mesalamine Pharmacokinetics

Absorption

Bioavailability

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.228

Following oral administration of extended-release capsules (Pentasa), about 20–30% of the drug is absorbed.229

Following oral administration of the 1.2-g delayed-release tablets (Lialda), about 21–22% of the drug is absorbed.448

Rectally administered suspension is poorly absorbed from the GI tract (about 15% [range: 5–35%]).1 2 15 43 47 49 65 68 210 227 The rectal suspension usually is retained for about 3.5–12 hours after administration as an enema;1 2 42 47 prolonged retention may increase absorption of the drug.199 200

Variably absorbed following rectal administration of the suppositories.230 Rectal suppositories usually are retained for 1–3 hours after administration.227

Food

Food does not appear to affect absorption of the 400-mg delayed-release tablets (Asacol).228

Food decreases rate of absorption and increases extent of absorption of the 1.2-g delayed-release tablets (Lialda).448

Distribution

Extent

Following oral or IV (IV preparation currently not available in the US) administration, the drug may be distributed into kidneys.1 199

Rectal suspension distributes from the rectum into the colon, generally reaching the splenic flexure7 42 95 207 and possibly the ascending colon.207 Rectal suppositories distribute to some extent in rectal tissues.230

Oral mesalamine crosses the placenta;3 47 108 229 448 serum concentrations of mesalamine in umbilical cord and amniotic fluid are very low.108

Not known whether rectal mesalamine crosses the placenta.3

Oral mesalamine is distributed into milk.228 229

Not known whether rectal mesalamine is distributed into milk.1 2 6

Plasma Protein Binding

Approximately 44–55% (as unchanged drug).3 54 60

Approximately 43% at a concentration of 2.5 mcg/mL.448

Elimination

Metabolism

Rapidly metabolized, principally in the liver to form N-acetyl-5-aminosalicylic acid.3 47 63 70 228 448

Elimination Route

Following oral administration, excreted in urine (about 20%) mainly as metabolites46 228 229 and in feces.229

Following rectal administration, principally excreted in feces (about 50%),47 71 as unchanged drug and metabolites,1 6 and in urine1 2 3 6 42 (about 10–35%).1 2 3 6 42 68 71

Half-life

400-mg delayed-release tablets (Asacol): 12 hours (range: 2–15 hours).228

1.2-g delayed-release tablets (Lialda): 7–9 hours (for mesalamine) and 8–12 hours (for N-acetyl-5-aminosalicylic acid metabolite).448

Rectal suspension: 0.5–1.5 hours (for mesalamine) and 5–10 hours (for N-acetyl-5-aminosalicylic acid metabolite).1 3 47 56 60 63

Rectal suppositories: 0.5–7 hours (for mesalamine) and 5–10 hours (for N-acetyl-5-aminosalicylic acid metabolite).227 230

Stability

Storage

Oral

Extended-release Capsules

25°C (may be exposed to 15–30°C).229

Delayed-release Tablets

400-mg tablets: 20–25°C.228

1.2-g tablets: 15–25°C (may be exposed to 30°C).448

Rectal

Suppositories

<25°C.230 Do not freeze; keep out of reach of children.230

Suspension

20–25°C (may be exposed to 15–30°C); keep out of reach of children.1 6 May darken with time once the container has been removed from the foil wrap;1 dark brown suspensions should be discarded.1 199

Actions

Advice to Patients

  • Importance of swallowing delayed-release tablets whole without breaking the outer coating.228 448

  • Importance of taking 1.2-g delayed-release tablets with food.448

  • Importance of informing patients that intact or partially intact tablets may be present in stools and if this occurs repeatedly, they should notify their clinician.228

  • Importance of informing patients that 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 enamel1 and therefore, they should carefully choose a suitable location for administration of the rectal suspension.1 230

  • Importance of informing patients with sulfasalazine sensitivity1 2 78 87 121 180 228 230 to discontinue mesalamine therapy and contact their clinician if signs of sensitivity (e.g., rash, fever) develop1 2 198 230 or increased diarrhea or rectal bleeding occurs.200

  • Importance of informing clinicians of existing pancreatitis.230

  • Importance informing patients that ulcerative colitis rarely remits completely and that continued use of maintenance dosages of mesalamine may substantially decrease the risk of relapse.228

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Mesalamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

250 mg

Pentasa

Shire

500 mg

Pentasa

Shire

Tablets, delayed-release

400 mg

Asacol

Procter & Gamble

1.2 g

Lialda

Shire

Rectal

Suppositories

1 g

Canasa

Axcan

Suspension

4 g/60 mL

Mesalamine Suspension Enema

Rowasa Suspension Enema

Alaven

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Apriso 0.375GM 24-hr Capsules (SALIX PHARMACEUTICALS): 120/$298.10 or 360/$860.11

Asacol 400MG Enteric-coated Tablets (WARNER CHILCOTT PROF PROD DIV): 30/$69.99 or 90/$189.96

Asacol HD 800MG Enteric-coated Tablets (WARNER CHILCOTT PROF PROD DIV): 90/$390.01 or 180/$760.00

Canasa 1000MG Suppositories (AXCAN PHARMA US): 30/$573.68 or 90/$1,677.10

Lialda 1.2GM Enteric-coated Tablets (SHIRE US INC.): 120/$766.97 or 360/$2,211.01

Mesalamine 4GM Enema (PERRIGO PHARMACEUTICALS): 60/$35.99 or 120/$59.98

Pentasa 250MG Controlled-release Capsules (SHIRE US INC.): 240/$332.01 or 720/$952.94

Pentasa 500MG Controlled-release Capsules (SHIRE US INC.): 30/$90.99 or 90/$247.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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