Professional Information

Mesalamine (Oral-Local)

INN:
Mesalazine. ^{03} ^{06}

BAN:
Mesalazine. ^{06}

VA CLASSIFICATION
Primary: GA400

Commonly used brand name(s): Asacol; Mesasal; Pentasa; Salofalk.

Other commonly used names are
5-aminosalicylic acid and 5-ASA .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Bowel disease (inflammatory) suppressant—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Bowel disease, inflammatory (prophylaxis and treatment)—Mesalamine is indicated to treat ^{01} ^{02} ^{03} ^{04} ^{05} ^{07} ^{11} ^{12} ^{13} ^{14} ^{15} ^{18} ^{22} ^{34} and to maintain remission ^{02} ^{03} ^{04} ^{07} ^{08} ^{13} ^{15} ^{18} ^{19} ^{21} ^{22} ^{34} of mild to moderate ulcerative colitis or [Crohn's disease] . ^{04} ^{09} ^{13} ^{15} ^{16} ^{18}

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    153.14 ^{01} ^{02} ^{03} ^{04} ^{05} ^{06} ^{12} ^{33}

Mechanism of action/Effect:

Bowel disease (inflammatory) suppressant:

Uncertain. ^{01} ^{02} ^{04} ^{05} ^{11} ^{22} ^{33} Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with inflammatory bowel disease. ^{01} ^{02} ^{04} ^{05} ^{33} Mesalamine appears to diminish inflammation by inhibiting cyclooxygenase and lipoxygenase, thereby decreasing the production of prostaglandins, and leukotrienes and hydroxyeicosatetraenoic acids (HETEs), respectively. ^{01} ^{02} ^{03} ^{04} ^{05} ^{14} ^{22} ^{28} ^{33}

It is also believed that mesalamine acts as a scavenger of oxygen-derived free radicals ^{04} ^{05} ^{14} ^{28} ^{33}, which are produced in greater numbers in patients with inflammatory bowel disease. ^{33}

Absorption:

20 to 30% absorbed following oral administration. ^{01} ^{02} ^{03} ^{04} The site of mesalamine release and absorption within the gastrointestinal tract varies among the different formulations.

Asacol—Coated with an acrylic-based resin, Eudragit S, which dissolves at pH 7 or greater, releasing mesalamine into the distal ileum and the colon. ^{01} ^{03} ^{10} ^{11} ^{13} ^{16} ^{17} ^{19} ^{28} ^{33}

Mesasal and Salofalk—Coated with an acrylic-based resin, Eudragit L, which dissolves at pH 6 or greater, releasing mesalamine into the distal ileum and the colon. ^{05} ^{13} ^{28}

Pentasa—Microgranules of mesalamine individually coated with ethylcellulose, which allows continuous release of mesalamine into the small (jejunum and ileum) and large (colon) bowel, independent of luminal pH. ^{04} ^{13} ^{15} ^{18} ^{28} ^{33}

Biotransformation:

Absorbed mesalamine is rapidly acetylated ^{22} ^{33} to N-acetyl-5-aminosalicylic acid (Ac-5-ASA) ^{01} ^{03} ^{04} ^{33} in the intestinal mucosal wall ^{01} ^{03} ^{33} and the liver. ^{01} ^{03} ^{14} ^{33}

Half-life:

Elimination:

Asacol—

Mesalamine—3 hours. ^{03}

Ac-5-ASA—10 hours. ^{03}

Pentasa—

Because of the continuous release and absorption of mesalamine throughout the gastrointestinal tract, the true elimination half-life cannot be determined following oral administration. ^{02}

Salofalk—

Ac-5-ASA—

5 to 10 hours. ^{05}

Time to peak concentration:

Asacol—4 to 12 hours. ^{01} ^{03}

Mesasal—6.5 to 7 hours. ^{22}

Pentasa—3 hours. ^{02} ^{04}

Peak serum concentration:

Mesasal:

Mesalamine: 1.2 mcg per mL following a single 500-mg oral dose. ^{22}

Ac-5-ASA: 1.9 mcg per mL following a single 500-mg oral dose. ^{22}

Pentasa:

Mesalamine: 1 mcg per mL following a single 1-gram oral dose. ^{02} ^{04}

Ac-5-ASA: 1.8 mcg per mL following a single 1-gram oral dose. ^{02} ^{04}

Elimination:

Fecal—
        Asacol: Approximately 80% of an administered dose is recovered in the feces. ^{03}
        Pentasa: Approximately 13% of an administered dose is recovered in the feces. ^{02} ^{04}
        Salofalk: Partially recovered unchanged in the feces. ^{05}

Renal—
        Excreted in the urine as the Ac-5-ASA metabolite. ^{01} ^{02} ^{03} ^{04}

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to olsalazine ^{24}, sulfasalazine ^{04} ^{24}, or salicylates ^{14} may be sensitive to mesalamine also.

Carcinogenicity

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of mesalamine. ^{01}

Mutagenicity

No evidence of mutagenicity was observed in an in vitro Ames test ^{01} ^{02} or in an in vivo mouse micronucleus test. ^{02} ^{04}

Pregnancy/Reproduction
Fertility—
Oligospermia and infertility in men, which have been reported in association with sulfasalazine, have not been seen with mesalamine. ^{01} ^{02}

Mesalamine was found to have no effect on the fertility and reproductive performance of male and female rats when given orally at a dose corresponding to 7 times the maximum human dose. ^{01} ^{02} ^{03} ^{04}

Pregnancy—
Mesalamine crosses the placenta. ^{02} ^{04} Adequate and well-controlled studies have not been done in humans. ^{01} ^{02} ^{03}

Studies in pregnant rats and rabbits given doses of 1000 and 800 mg per kg of body weight (mg/kg) per day, respectively, have not shown that mesalamine causes adverse effects in the fetus. ^{02}

FDA Pregnancy Category B. ^{01} ^{02}

Breast-feeding

Mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, are distributed into breast milk. ^{01} ^{02} ^{03} ^{33} However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of mesalamine have not been performed in the pediatric population. Safety and efficacy have not been established. ^{01} ^{02} ^{03} ^{04} ^{22}

Geriatrics

No information is available on the relationship of age to the effects of mesalamine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving mesalamine.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Lactulose^{03}^{17}    (acidification of the colonic lumen by lactulose may impair release of mesalamine from delayed- or extended-release formulations)

Omeprazole    (omeprazole may increase gastrointestinal pH ^{32}; concurrent use may result in an increase in the absorption of mesalamine ^{31})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT])^{01}^{03}^{24} and
Alkaline phosphatase^{16}^{24}^{33} and
Aspartate aminotransferase (AST [SGOT])^{01}^{03}^{24}^{33}    (values may be increased, but return to normal with either continuation or discontinuation of therapy ^{01} ^{03} ^{16})

Bilirubin, serum^{01}^{24}    (concentration may be increased, but returns to normal with either continuation or discontinuation of therapy ^{01})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Risk-benefit should be considered when the following medical problems exist
Renal function impairment^{01}^{02}^{03}^{04}^{05}^{13}^{22}    (increased risk of interstitial nephritis and nephrotic syndrome ^{01} ^{02} ^{04} ^{29})

Sensitivity to mesalamine^{01}^{02}^{04} , olsalazine^{24} , sulfasalazine^{13}^{14} , or salicylates^{01}^{02}^{03}^{04}^{05}^{22}
Stenosis, pyloric^{01}^{02}^{03}^{05}    (prolonged gastric retention may delay release of mesalamine)

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood urea nitrogen (BUN) and
Creatinine, serum and
Urinalysis    (determinations recommended prior to, and periodically during, therapy ^{01} ^{02} ^{04} ^{19} ^{22})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent

Acute intolerance syndrome^{01}^{02}^{03}^{04}^{05} (abdominal or stomach cramps or pain, severe; bloody diarrhea; fever; headache, severe; skin rash and itching)
Note: Prompt withdrawal of mesalamine is recommended at the first signs of acute intolerance syndrome. ^{02} ^{03} ^{04}

Incidence rare

Hepatitis^{01}^{02}^{03}^{05} (yellow eyes or skin)

pancreatitis^{01}^{02}^{03}^{05}^{13}^{14}^{22}^{24}^{25}^{26} (back or stomach pain, severe; fast heartbeat; fever; nausea or vomiting; swelling of the stomach)

pericarditis^{01}^{02}^{03}^{05}^{13}^{22}^{23} (anxiety; blue or pale skin; chest pain, possibly moving to the left arm, neck, or shoulder; chills; shortness of breath; unusual tiredness or weakness)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Abdominal or stomach cramps or pain, mild^{01}^{02}^{03}^{04}^{05}^{10}^{15}^{16}^{18}^{20}^{22}^{28}^{33}

diarrhea, mild^{01}^{02}^{03}^{04}^{05}^{11}^{13}^{15}^{16}^{18}^{22}^{28}^{33}

dizziness^{01}^{03}^{18}

headache, mild^{01}^{02}^{03}^{04}^{05}^{08}^{11}^{13}^{15}^{18}^{20}^{22}^{28}^{33}

nausea^{01}^{02}^{03}^{04}^{05}^{11}^{13}^{15}^{18}^{20}^{22}^{28}^{33} or vomiting^{01}^{02}^{04}^{11}^{15}^{18}

rhinitis^{01}^{03}^{05}^{13} (runny or stuffy nose or sneezing)

unusual tiredness or weakness^{01}^{03}^{04}^{05}^{08}^{18}

Incidence less frequent or rare

Acne^{01}^{02}^{03}^{04}

alopecia^{01}^{02}^{03}^{04}^{05}^{13}^{15}^{18}^{24}^{27} (loss of hair)

anorexia^{01}^{02}^{03}^{18} (loss of appetite)

back^{01}^{04}^{05} or joint^{01}^{03}^{05} pain

dyspepsia^{01}^{02}^{03}^{04}^{11}^{13}^{15}^{28}^{33} (indigestion)

gas or flatulence^{01}^{03}^{05}^{11}^{15}

Overdose
For specific information on the agents used in the management of mesalamine overdose, see:

   • Charcoal, Activated (Oral-Local) monograph;
   • Ipecac (Oral-Local) monograph; and/or
   • Salicylates (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute effects ^{02} ^{04}

Confusion

diarrhea, severe or continuing

dizziness or lightheadedness

drowsiness, severe

fast or deep breathing

headache, severe or continuing

hearing loss or ringing or buzzing in ears, continuing

nausea or vomiting, continuing

Treatment of overdose
There has been no clinical experience with mesalamine overdosage. However, because mesalamine is an aminosalicylate, the symptoms of overdose may mimic the symptoms of salicylate overdose; therefore, measures used to treat salicylate overdose may be applied to mesalamine overdose. ^{02} ^{04}

To decrease absorption—The stomach may be emptied by induction of emesis with ipecac syrup (with care being taken to guard against aspiration) or by gastric lavage. Activated charcoal may also be administered. ^{02} ^{04}

Supportive care—Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Vital functions should be monitored and supported. ^{02} ^{04} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Mesalamine (Oral) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to mesalamine, olsalazine, sulfasalazine, or salicylates

Pregnancy—Crosses the placenta

Breast-feeding—Distributed into breast milk

Proper use of this medication
Swallowing capsules or tablets whole without breaking, crushing, or chewing

Taking medicine before meals and at bedtime with a full glass (8 ounces) of water

» Compliance with full course of therapy

» Not switching brands without consulting physician

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

Patient may notice small beads or empty tablet in stool left over after medication is absorbed

Side/adverse effects
Signs of potential side effects, especially acute intolerance syndrome, hepatitis, pancreatitis, and pericarditis

General Dosing Information
Mesalamine should be taken before meals and at bedtime with a full glass (8 ounces) of water. ^{04} ^{05} ^{22}

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

MESALAMINE EXTENDED-RELEASE CAPSULES

Usual adult dose
Ulcerative colitis ^{02} ^{04} ^{07} ^{33}; or
[Crohn's disease] ^{04} ^{13} ^{18}
1 gram four times a day for up to eight weeks.

Usual pediatric dose
Safety and efficacy have not been established. ^{02} ^{04}

Usual geriatric dose
See Usual adult dose. ^{30}

Strength(s) usually available
U.S.—

250 mg (Rx) [Pentasa (acetylated monoglyceride) (castor oil) (colloidal silicon dioxide ) (ethylcellulose) (hydroxypropyl methylcellulose) (starch) ( stearic acid) (sugar) ( talc) (white wax)]

Canada—

250 mg (Rx) [Pentasa]

Packaging and storage:
Store at controlled room temperature between 15 and 30 °C (59 and 86 °F). ^{02} ^{04}

Auxiliary labeling:
   • Take with a full glass (8 ounces) of water.

MESALAMINE DELAYED-RELEASE TABLETS

Note: There are differences in the rate and site of absorption among the various brands of mesalamine delayed-release tablets; therefore, these preparations are not bioequivalent, and one brand should not be substituted for another unless otherwise directed by the patient's physician.

Usual adult dose
Ulcerative colitis; or
[Crohn's disease]
Asacol: 800 mg three times a day for six weeks. ^{01} ^{03} ^{11} ^{34}

Mesasal: 1.5 to 3 grams daily in divided doses. ^{22}

Salofalk: 1 gram three or four times a day. ^{05}

Maintenance of remission of ulcerative colitis
Asacol: 1.6 grams daily in divided doses ^{34}.

Usual pediatric dose
Safety and efficacy have not been established. ^{01} ^{03}

Usual geriatric dose
See Usual adult dose. ^{30}

Strength(s) usually available
U.S.—

400 mg (Rx) [Asacol (Eudragit S)]

Canada—

250 mg (Rx) [Salofalk (Eudragit L)]

400 mg (Rx) [Asacol (Eudragit S)]

500 mg (Rx) [Mesasal (Eudragit L)] [Salofalk (Eudragit L)]

Packaging and storage:
Store at controlled room temperature between 15 and 30 °C (59 and 86 °F). ^{01} ^{03} ^{05}

Auxiliary labeling:
   • Take with a full glass (8 ounces) of water.

MESALAMINE EXTENDED-RELEASE TABLETS

Usual adult dose
See Mesalamine Extended-release Capsules.

Usual pediatric dose
Safety and efficacy have not been established. ^{02} ^{04}

Usual geriatric dose
See Mesalamine Extended-release Capsules.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—

250 mg (Rx) [Pentasa]

500 mg (Rx) [Pentasa]

Packaging and storage:
Store at controlled room temperature between 15 and 30 °C (59 and 86 °F). ^{04}

Auxiliary labeling:
   • Take with a full glass (8 ounces) of water.

Developed: 03/17/1995
Revised: 08/14/1998

References

Asacol package insert (Norwich Eaton—US), Rev 1/92, Rec 5/18/92.

Pentasa package insert (Marion Merrell Dow—US), Rev 5/93, Rec 7/6/93.

Asacol package insert (Proctor & Gamble—Canada), Rev 9/2/92, Rec 4/25/94.

Pentasa package insert (Nordic—Canada), Rev 4/21/93, Rec 8/8/94.

Salofalk package insert (Axcan—Canada), Rev 7/12/94, Rec 8/30/94.

Fleeger CA, editor. USP dictionary of USAN and international drug names. 1995 ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 416.

Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Am J Gastroenterol 1993; 88: 1188-97.

Faber SM, Korelitz BI. Experience with Eudragit-S–coated mesalamine (Asacol) in inflammatory bowel disease. An open study. J Clin Gastroenterol 1993; 17: 213-8.

Gendre J-P, Mary J-Y, Florent C, et al. Oral mesalamine (Pentasa) as maintenance treatment in Crohn's disease: a multicenter placebo-controlled study. Gastroenterology 1993; 104: 435-9.

Courtney MG, Nunes DP, Bergin CF, et al. Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis. Lancet 1992; 339: 1279-81.

Sninsky CA, Cort DH, Shanahan F, et al. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter study. Ann Intern Med 1991; 115: 350-5.

Bondesen S, Hegnhoj J, Larsen F, et al. Pharmacokinetics of 5-aminosalicylic acid in man following administration of intravenous bolus and per os slow-release formulation. Dig Dis Sci 1991; 36: 1735-40.

Thomson ABR. Review article: new developments in the use of 5-aminosalicylic acid in patients with inflammatory bowel disease. Aliment Pharmacol Ther 1991; 5: 449-70.

Peppercorn MA. Advances in drug therapy for inflammatory bowel disease. Ann Intern Med 1990; 112: 50-60.

Hanauer SB, Krawitt EL, Robinson M, et al. Long-term management of Crohn's disease with mesalamine capsules (Pentasa). Am J Gastroenterol 1993; 88: 1343-51.

Prantera C, Pallone F, Brunetti G, et al. Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn's disease. Gastroenterology 1992; 103: 363-8.

Riley SA, Tavares IA, Bishai PM, et al. Mesalazine release from coated tablets: efficacy of dietary fibre. Br J Clin Pharmacol 1991; 32: 248-50.

Singleton JW, Hanauer SB, Gitnick GL, et al. Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Gastroenterology 1993; 104: 1293-1301.

Riley SA, Mani V, Goodman MJ, et al. Comparison of delayed-release 5-aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis. Gastroenterology 1988; 94: 1383-9.

Donald IP, Wilkinson SP. The value of 5-aminosalicylic acid in inflammatory bowel disease for patients intolerant or allergic to sulphasalazine. Postgrad Med J 1985; 61: 1047-8.

Dew MJ, Harries AD, Evans N, et al. Maintenance of remission in ulcerative colitis with 5-aminosalicylic acid in high doses by mouth. Br Med J 1983; 287: 23-4.

Mesasal (SmithKline Beecham). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 763.

Lim AG, Hine KR. Fever, vasculitic rash, arthritis, pericarditis, and pericardial effusion after mesalazine. Br Med J 1994; 308: 113.

Hautekeete ML, Bourgeois N, Potvin P, et al. Hypersensitivity with hepatotoxicity to mesalazine after hypersensitivity to sulfasalazine. Gastroenterology 1992; 103: 1925-7.

Erdkamp F, Houben M, Ackerman E, et al. Pancreatitis induced by mesalamine. Neth J Med 1992; 41: 71-3.

Tran K, Froguel E, Jian R, et al. Acute pancreatitis induced by mesalazine [letter]. J Clin Gastroenterol 1991; 13: 715-6.

Hadjigogos H. Unusual side effects of mesalazine. Ital J Gastroenterol 1991; 23: 257.

Sutherland LR, May GR, Shaffer EA. Sulfasalazine revisited: a meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis. Ann Intern Med 1993; 118: 540-9.

Thuluvath PJ, Ninkovic M, Calam J, et al. Mesalazine induced interstitial nephritis. Gut 1994; 35: 1493-6.

Reviewers" consensus on monograph revision of 12/94.

Panel comment, 12/94.

Omeprazole package insert (Prilosec, Astra Merck—US), Rev 8/94, Rec 11/11/94.

Small RE, Schraa CC. Chemistry, pharmacology, pharmacokinetics, and clinical applications of mesalamine for the treatment of inflammatory bowel disease. Pharmacotherapy 1994; 14: 385-98.

Asacol package insert (Procter & Gamble—US), Rev 7/97, Rec 9/30/97.

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