Asacol (Mesalamine Delayed-Release Tablets)

ASACOL®

Procter & Gamble Pharmaceuticals

5-ASA

Lower Gastrointestinal Anti-inflammatory

Action And Clinical Pharmacology: The active ingredient in Asacol, mesalamine (5-aminosalicylic acid, also referred to as 5-ASA), is the major active component of sulfasalazine for the treatment of inflammatory bowel disease. The available evidence suggests that mesalamine has a topical anti-inflammatory effect on the colon, where it inhibits prostaglandin and leukotriene synthesis.

Asacol tablets have a special acrylic-based resin coating which delays release of mesalamine until the tablets reach the terminal ileum and colon. Once released in the colon, mesalamine is minimally absorbed and plasma levels are similar to those found following rectal administration of mesalamine. Approximately 20% of the administered dose released in the colon is absorbed, with about 80% being excreted in the feces. The absorbed mesalamine is rapidly acetylated through the gut mucosal wall and by the liver. It is mainly excreted by the kidney, as N-acetyl-5-aminosalicylic acid.

Pharmacokinetics: Mesalamine release from Asacol is delayed until the terminal ileum as reflected by tmax’s of about 7 hours for mesalamine and its metabolite, N-acetyl-5-ASA. The t 1/2elim.’s were about 3 hours for mesalamine and 10 hours for N-acetyl-5-ASA.

Human studies conducted using radiological and serum markers showed that the Asacol coating delayed release of mesalamine until the terminal ileum was reached. Other studies compared mesalamine absorption when administered as an enema (a readily available dosage form) and when released for absorption in the stomach, small intestine, and colon relative to an i.v. dose. Once released in the colon, mesalamine was minimally absorbed and plasma levels were similar to those found following rectal administration. Approximately 20% of the administered dose released was absorbed, with about 80% available for topical activity in the colon. The absorbed mesalamine was rapidly acetylated through the gut mucosal wall and by the liver. It was mainly excreted by the kidney as N-acetyl-5-ASA.

Serum levels and urinary excretion of mesalamine and N-acetyl-5-ASA following single and multiple equimolar Asacol and sulfasalazine doses to healthy subjects and to patients were compared. There was no consistent trend for greater serum mesalamine or metabolite levels following Asacol dosage. Based on urinary dose recoveries, the extent of mesalamine absorption for Asacol was no greater than that for sulfasalazine. Overall, there were no meaningful differences in the extents of mesalamine absorption following equimolar Asacol and sulfasalazine doses.

In another study, there was a dose response in serum mesalamine and metabolite levels at Asacol doses of 1.2 and 2.4 g/day. In other studies when Asacol was administered at higher or lower doses than 1.2 and 2.4 g/day, serum mesalamine and N-acetyl-5-ASA concentrations differed from those for the 1.2 and 2.4 g/day doses as would be expected following a linear dose response relationship. The effects of coadministration of Asacol with cimetidine, an antacid containing activated simethicone and aluminum hydroxide, and antacid with a high fat meal were addressed in another study. There were no significant in vivo effects on mesalamine release or the extent of drug absorption from Asacol by any of the three treatments.

Clinical Trials: In a randomized, double-blind, placebo controlled clinical trial it was shown that Asacol (4.8 g/day of mesalamine in divided doses) was highly effective in inducing remission in ulcerative colitis patients with active disease.

Additional double-blind clinical trials of 16-, 24-, and 52-weeks duration have shown Asacol, in doses ranging from 0.8 to 4.4 g/day to be as effective as sulfasalazine for maintenance of remission. It is particularly noteworthy that most patients intolerant or allergic to sulfasalazine can be effectively maintained in remission on Asacol, as demonstrated in open-labeled clinical trials. In addition, male infertility resulting from sulfasalazine therapy has been shown to be reversible upon treatment with Asacol.

Indications And Clinical Uses: The treatment of mild to moderate active ulcerative colitis. In the long-term management of ulcerative colitis patients, repeat dosing may be required. Abrupt discontinuation may result in relapse.

Contra-Indications: In patients with a history of sensitivity to salicylates; existing gastric or duodenal ulcer; urinary tract obstruction; and in infants under 2 years of age.

Manufacturers’ Warnings In Clinical States: If toxic or hypersensitivity reactions occur, the drug should be discontinued. In assessing liver and joint complications, it should be kept in mind that these are frequently associated with ulcerative colitis (see Precautions).

Precautions: Caution should be exercised in patients with impaired renal function and/or hepatic dysfunction.

Patients with pyloric stenosis may have prolonged gastric retention of Asacol tablets which could delay release of mesalamine in the colon.

Drug Interactions: There are no known drug interactions. The effects of coadministration of Asacol with cimetidine, with an antacid containing activated dimethicone and aluminum hydroxide, or with an antacid accompanied by a high fat meal were addressed in a clinical study. There were no significant in vivo effects on mesalamine release or the extent of drug absorption from Asacol by any of the 3 treatments. It has been reported that simultaneous administration of famotidine, a potent H2-antagonist, and Asacol does not influence the absorption and urinary excretion of mesalamine.

Asacol should not be administered with preparations which lower the stool pH, such as lactulose.

Interactions similar to ASA cannot be excluded.

Pregnancy: In reproduction studies, mesalamine was administered orally at a dosage of 480 mg/kg/day to pregnant rats and rabbits. No evidence of impaired female fertility or harm to the fetus due to therapy with 5-ASA was observed. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation: It has been reported in one case, that small amounts of 5-ASA and higher concentrations of acetyl-5-ASA are found in breast milk. Caution should be exercised when Asacol is administered to a nursing woman.

Children: Safety and effectiveness of 5-ASA therapy in children have not been established.

Information to be Provided to the Patient: 1. Swallow tablets whole, taking care not to break the outer coating. The outer coating is designed to remain intact, to protect the active ingredient until it reaches the terminal ileum, where the tablet coating dissolves and the contents of the tablet are released into the terminal ileum and colon.

2. Take Asacol tablets only as prescribed. Do not change the number or frequency of tablets ingested without first consulting your physician.

3. What appears to be intact or partially intact tablets may infrequently appear in the stool. If this occurs repeatedly, consult your physician.

Adverse Reactions: 5-ASA is generally well tolerated. Adverse events seen in clinical trials with 5-ASA have generally been mild and reversible, and have seldom resulted in discontinuation of treatment. Because Asacol does not contain a sulfa moiety, sulfa-related side effects are avoided. Many patients with a history of sulfasalazine intolerance are able to tolerate 5-ASA as demonstrated in open-label clinical trials.

The most frequently reported side effects (5% of the patients or greater) have been headache, rhinitis, fever, chills, weakness, dizziness, nausea, abdominal pain, dyspepsia, diarrhea, joint pain and rash. Other less frequently reported events (fewer than 5% of patients) include alopecia, pruritus, urticaria, acne, anxiety, insomnia, depression, tinnitus, vertigo, paresthesia, muscle cramps, anorexia, dyspnea and flatulence.

The relationship of the reported events to 5-ASA is unclear in many cases, particularly for reported events which could be considered part of the clinical presentation of ulcerative colitis.

Allergic: An acute hypersensitivity reaction characterized by cramping, abdominal pain, bloody diarrhea and occasionally by fever, headache, malaise, pruritus, rash and conjunctivitis has been infrequently reported to occur shortly after the initiation of mesalamine. If these symptoms occur, therapy should be discontinued. Symptoms usually abate promptly after discontinuation.

Hepatic: Asymptomatic elevations of liver function tests have occurred in patients taking 5-ASA. These elevations usually resolve during continued therapy or with the discontinuation of administration of 5-ASA. When any elevations in liver enzymes are assessed, it should be kept in mind that hepatic complications are frequently associated with inflammatory bowel disease.

Rare Events: The following events have been reported rarely during mesalamine use: pancreatitis, pericarditis, transverse myelitis, peripheral neuropathy, intestinal perforation, hepatitis, interstitial pneumonitis, leukopenia, agranulocytosis, minimal change nephropathy, and acute and chronic interstitial nephritis.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no experience with acute overdosage in humans. The drug is not metabolized to salicylate. If the amount ingested is considered dangerous or excessive, induce vomiting with ipecac syrup unless the patient is convulsing, comatose, or has lost the gag reflex, in which case perform gastric lavage using a large bore tube. If indicated, follow with activated charcoal and a saline cathartic. There is no specific antidote and treatment is symptomatic and supportive. tag_DosageDosage

Dosage: Usual daily adult dose is 2 to 8 Asacol 400 mg tablets, taken orally in divided doses. In patients with severe active disease, the dose may be increased to 12 tablets daily. Abrupt discontinuation is not recommended. Prolonged treatment may be required.

Availability And Storage: Each brown-red capsule-shaped, enteric coated, colon-targeted tablet contains: 5-ASA 400 mg (mesalamine), coated with a special acrylic-based resin, Eudragit S (methacrylic acid copolymer Type B), which delays release of the 5-ASA until the tablet reaches the terminal ileum. Nonmedicinal ingredients: dibutyl phthalate, iron oxide red, iron oxide yellow, lactose, magnesium stearate, Eudragit S (methacrylic acid copolymer Type B), polyethylene glycol, polyvinylpyrrolidone, sodium starch glycolate and talc. Bisulfite-, gluten-, paraben-, and tartrazine-free. Blister packs of 10, cartons of 10. Store at controlled room temperature (15 to 30°C).

ASACOL® Procter & Gamble Pharmaceuticals 5-ASA Lower Gastrointestinal Anti-inflammatory

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