mesalamine 800 MG Delayed Release Oral Tablet

Generic Name: MESALAMINE
Brand Name: ASACOL HD
  • Substance Name(s):
  • MESALAMINE

DRUG INTERACTIONS

7 No formal drug interaction studies have been performed using Asacol HD with other drugs.

However, the following interactions between mesalamine-containing products and other drugs have been reported.

Nephrotoxic A g ents including NSAIDs: Renal reactions have been reported (7.1) Azathioprine or 6-mercaptopurine: Blood disorders have been reported (7.2) 7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti- inflammatory drugs (NSAIDs) may increase the risk of renal reactions [ see Warnings and Precautions ( 5.1 ) ] .

7.2 A z athioprine or 6-mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders.

OVERDOSAGE

10 There is no specific antidote for mesalamine overdose and treatment for suspected acute severe toxicity with Asacol HD should be symptomatic and supportive.

This may include prevention of further gastrointestinal tract absorption, correction of fluid electrolyte imbalance, and maintenance of adequate renal function.

Asacol HD is a pH dependent delayed-release product and this factor should be considered when treating a suspected overdose.

Single oral doses of 5000 mg/kg mesalamine suspension in mice (approximately 4.2 times the recommended human dose of Asacol HD based on body surface area), 4595 mg/kg in rats (approximately 7.8 times the recommended human dose of Asacol HD based on body surface area) and 3000 mg/kg in cynomolgus monkeys (approximately 10 times the recommended human dose of Asacol HD based on body surface area) were lethal.

DESCRIPTION

11 Each Asacol HD delayed-release tablet for oral administration contains 800 mg of mesalamine, an aminosalicylate.

Asacol HD delayed-release tablets have an outer protective coat consisting of a combination of acrylic based resins, Eudragit S (methacrylic acid copolymer B, NF) and Eudragit L (methacrylic acid copolymer A, NF).

The inner coat consists of an acrylic based resin, Eudragit S, which dissolves at pH 7 or greater, releasing mesalamine in the terminal ileum and beyond for topical anti- inflammatory action in the colon.

Mesalamine (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid; its structural formula is: Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl phthalate, edible black ink, ferric oxide red, ferric oxide yellow, lactose monohydrate, magnesium stearate, methacrylic acid copolymer B (Eudragit S), methacrylic acid copolymer A (Eudragit L), polyethylene glycol, povidone, sodium starch glycolate, and talc.

Mesalamine structural formula

CLINICAL STUDIES

14 14.1 Moderately Active Ulcerative Colitis The efficacy of Asacol HD at 4.8 g/day was studied in a six-week, randomized, double-blind, active- controlled study in 772 patients with moderately active ulcerative colitis (UC).

Moderately active UC was defined as a Physician’s Global Assessment (PGA) score of 2; the PGA is a four-point scale (0 to 3) that encompasses the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy findings.

Patients were randomized 1:1 to the Asacol HD 4.8 g/day group (two Asacol HD tablets three times a day) or the Asacol (mesalamine) 2.4 g/day group (two Asacol 400 mg tablets three times a day).

(One Asacol HD 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets [see Clinical Pharmacology ( 12.3 )].) Patients characteristically had a history of previous use of oral 5-ASAs (86 percent), steroids (41 percent), and rectal therapies (49 percent), and demonstrated clinical symptoms of three or more stools over normal per day (87 percent) and obvious blood in the stool most or all of the time (70 percent).

The study population was primarily Caucasian (97 percent), had a mean age of 43 years (8 percent aged 65 years or older), and included slightly more males (56 percent) than females (44 percent).

The primary endpoint was treatment success defined as improvement from baseline to Week 6 based on the PGA.

Treatment success rates were similar in the two groups: 70 percent in the Asacol HD group and 66 percent in the Asacol group (difference: 5 percent; 95 percent CI: [-1.9 percent, 11.2 percent]).

A second controlled study supported the efficacy of Asacol HD at 4.8 g/day.

Treatment success was 72 percent in patients with moderately active UC treated with Asacol HD.

HOW SUPPLIED

16 /STORAGE AND HANDLING Asacol® HD (mesalamine) delayed-release tablets are available as red-brown, capsule-shaped tablets containing 800 mg mesalamine and imprinted with “WC 800” in black.

N 0430-0783-27 Bottle of 180 tablets Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions are permitted 15° to 30° C (59° to 86° F).

[See USP Controlled Room Temperature]

GERIATRIC USE

8.5 Geriatric Use Clinical studies of Asacol HD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects.

Other reported clinical experience has not identified differences in response between the elderly and younger patients.

In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Asacol HD.

Reports from uncontrolled clinical studies and postmarketing reporting systems for Asacol (mesalamine) suggested a higher incidence of blood dyscrasias, that is, agranulocytosis, neutropenia, pancytopenia, in patients who were 65 years or older.

Caution should be taken to closely monitor blood cell counts during mesalamine therapy.

DOSAGE FORMS AND STRENGTHS

3 Asacol HD delayed-release tablets: 800 mg (red-brown, capsule-shaped and imprinted with “WC 800” in black).

Delayed-release tablets: 800 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic.

Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.

INDICATIONS AND USAGE

1 Asacol® HD is indicated for the treatment of moderately active ulcerative colitis in adults.

Safety and effectiveness of Asacol HD beyond 6 weeks have not been established.

Asacol HD is an aminosalicylate indicated for the treatment of moderately active ulcerative colitis in adults.

(1) Li m itation of Use: Safety and effectiveness of Asacol HD beyond 6 weeks have not been established (1)

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of Asacol HD in pediatric patients have not been established.

See the prescribing information for other approved mesalamine products for the safety and effectiveness of these products in pediatric patients.

PREGNANCY

8.1 Pregnancy Pregnancy Category C Risk summary There are no adequate well controlled studies of Asacol HD use in pregnant women.

Limited published human data on mesalamine show no increase in the overall rate of congenital malformations.

Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.

Furthermore, all pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

No evidence of fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.6 times (rat) and 3.2 times (rabbit) the recommended human dose.

However, dibutyl phthalate (DBP) is an inactive ingredient in Asacol HD’s enteric coating, and in animal studies in rats at doses higher than 80 times the human dose, maternal DBP was associated with external and skeletal malformations and adverse effects on the male reproductive system.

Asacol HD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human data Mesalamine crosses the placenta.

In prospective and retrospective studies of over 600 women exposed to mesalamine during pregnancy, the observed rate of congenital malformations was not increased above the background rate in the general population.

Some data show an increased rate of preterm birth, stillbirth, and low birth weight, but it is unclear whether this was due to underlying maternal disease, drug exposure, or both, as active inflammatory bowel disease is also associated with adverse pregnancy outcomes.

Animal data Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day.

There was no evidence of impaired fertility or harm to the fetus.

These mesalamine doses were about 1.6 times (rat) and 3.2 times (rabbit) the recommended human dose, based on body surface area.

Dibutyl phthalate (DBP) is an inactive ingredient in Asacol HD’s enteric coating.

The human daily intake of DBP from the maximum recommended dose of Asacol HD tablets is about 48 mg.

Published reports in rats show that male rat offspring exposed in utero to DBP (greater than or equal to 100 mg/kg/day, approximately 17 times the human dose based on body surface area), display reproductive system aberrations compatible with disruption of androgenic dependent development.

The clinical significance of this finding in rats is unknown.

At higher dosages (greater than or equal to 500 mg/kg/day, approximately 84 times the human dose based on body surface area), additional effects, including cryptorchidism, hypospadias, atrophy or agenesis of sex accessory organs, testicular injury, reduced daily sperm production, permanent retention of nipples, and decreased anogenital distance are noted.

Female offspring are unaffected.

High doses of DBP, administered to pregnant rats was associated with increased incidences of developmental abnormalities, such as cleft palate (greater than or equal to 630 mg/kg/day, about 106 times the human dose, based on body surface area) and skeletal abnormalities (greater than or equal to 750 mg/kg/day, about 127 times the human dose based on body surface area) in the offspring.

NUSRING MOTHERS

8.3 Nursing Mothers Mesalamine and its N-acetyl metabolite are present in human milk.

In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily.

The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L.

The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L.

Based on these concentrations, estimated infant daily doses for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid.

Dibutyl phthalate (DBP), an inactive ingredient in the enteric coating of Asacol HD tablets, and its primary metabolite mono-butyl phthalate (MBP) are excreted into human milk.

The clinical significance of this has not been determined.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Asacol HD and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Exercise caution when Asacol HD is administered to a nursing mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Development of Renal Impairment ( for example, minimal change nephropathy, acute and chronic interstitial nephritis renal failure): Assess renal function at beginning of treatment and periodically during therapy (5.1) Mesalamine-induced Acute I n tolerance Syndrome: Has been reported.

Observe patients closely for worsening of these symptoms while on treatment (5.2) Hypersensitivity Reactions: Use caution when treating patients who are hypersensitive to sulfasalazine.

Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported (5.3) Hepatic Failure: Has been reported in patients with pre-existing liver disease.

Use caution when treating patients with liver disease (5.4) Prolonged Gastric Retention in P a ti e nts with Upper Gastrointestinal Obstruction: May lead to a delay in onset of action (5.5) 5.1 Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients taking products such as Asacol HD that contain or are converted to mesalamine.

It is recommended that all patients have an evaluation of renal function prior to initiation of Asacol HD and periodically while on therapy.

Prescribers should carefully evaluate the risks and benefits when using Asacol HD in patients with known renal impairment or history of renal disease [ see Drug Interactions ( 7.1 ) and Nonclinical Toxicology ( 13.2 ) ].

5.

2 Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis.

Exacerbation of the symptoms of colitis has been reported in 2.3 percent of Asacol HD-treated patients in controlled clinical trials.

This acute reaction, characterized by cramping, abdominal pain, bloody diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has been reported after the initiation of Asacol HD tablets as well as other mesalamine products.

Symptoms usually abate when Asacol HD tablets are discontinued.

5.

3 Hypersensitivity Reactions Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to Asacol HD tablets or to other compounds that contain or are converted to mesalamine.

Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with Asacol HD and other mesalamine medications.

Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis.

5.

4 Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine.

Caution should be exercised when administering Asacol HD to patients with liver disease.

5.

5 Prolonged Gastric Retention in Patients w ith Upper Gastrointestinal Obstruction Organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of Asacol HD which would delay release of mesalamine in the colon.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Instruct patients to swallow the Asacol HD tablets whole, taking care not to break, cut, or chew the tablets, because the coating is an important part of the delayed-release formulation.

Inform patients that if they are switching from a previous oral mesalamine therapy to Asacol HD they should discontinue their previous oral mesalamine therapy and follow the dosing instructions for Asacol HD.

Inform patients that they should not substitute one Asacol HD tablet with two Asacol 400 mg tablets [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )].

Inform patients that intact, partially intact, and/or tablet shells have been reported in the stool.

Instruct patients to contact their physician if this occurs repeatedly.

Instruct patients to protect Asacol HD tablets from moisture.

Instruct patients to close the container tightly and to leave any desiccant pouches present in the bottle along with the tablets.

Advise women who are pregnant, breastfeeding, or of childbearing potential that Asacol HD contains dibutyl phthalate, which caused malformations and adverse effects on the male reproductive system in animal studies.

Dibutyl phthalate is excreted in human milk.

Manufactured by: Warner Chilcott Deutschland GmbH D-64331 Weiterstadt, Germany Marketed by: Warner Chilcott (US), LLC Rockaway, NJ 07866 Under license from Medeva Pharma Suisse AG (registered trademark owner).

U.S.

Patent No.

6,893,662.

0783G014 Warner Chilcott logo

DOSAGE AND ADMINISTRATION

2 Recommended dosage is two 800 mg tablets three times daily (4.8 grams/day) with or without food for 6 weeks (2.1) Instruct patients to swallow tablets whole without cutting, breaking, or chewing (2.2) One Asacol HD 800 mg tablet cannot be substituted for two Asacol® (mesalamine) delayed-release 400 mg tablets (2.2) Recommend that renal function be evaluated prior to initiation of Asacol HD (2.3, 5.1) 2.1 Dosage Information For the treatment of moderately active ulcerative colitis, the recommended dosage of Asacol HD in adults is two 800 mg tablets to be taken three times daily with or without food, for a total daily dose of 4.8 grams, for a duration of 6 weeks.

2.2 Important Administration Instructions Swallow Asacol HD tablets whole, do not cut, break or chew the tablets.

One Asacol HD 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets [ see Clinical Pharmacology ( 12.3 ) ] .

2.3 Testing Prior to Asacol HD Administration It is recommended that all patients have an evaluation of renal function prior to initiation of Asacol HD [see Warnings and Precautions ( 5.1 ) ] .