Asacol 400: Indications, Dosage, Precautions, Adverse Effects
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Asacol 400 - Product Information

Manufacture: Warner Chilcott
Country: Canada
Condition: Ulcerative Colitis
Class: Gastrointestinal agents
Form: Tablets
Ingredients: 5-aminosalicylic aciddibutyl phthalate, edible black ink (ammonium hydroxide, n-butyl alcohol, shellac glaze [modified] in SD-45, synthetic black iron oxide and propylene glycol), iron oxide red, iron oxide yellow, lactose, magnesium stearate, Eudragit-S {methacrylic acid copolymer Type B (USP)}, polyethylene glycol, polyvinylpyrrolidone, sodium starch glycolate, colloidal silicon dioxide and talc

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
OralEnteric coated tablet
400 mg
Lactose
For a complete listing see Dosage Forms,
Composition and Packaging Section

Indications and Clinical Use

Asacol is indicated for:

  • the treatment of mild to moderate active ulcerative colitis
  • the maintenance of remission of mild to moderate ulcerative colitis. Asacol at the dosage tested of 1.6 g/day may not be effective for the maintenance of remission when the underlying disease is severe.

Abrupt discontinuation may result in relapse.

Pediatrics

Safety and effectiveness of Asacol therapy in children have not been established.

Contraindications

Asacol is contraindicated in:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of this product monograph.
  • Patients with a history of sensitivity to salicylates.
  • Patients with severe renal impairment (GFR<30ml/min/1.73m2) and/or severe hepatic impairment (see WARNINGS & PRECAUTIONS – Renal and Hepatic/Biliary/Pancreatic).
  • Patients with existing gastric or duodenal ulcer.
  • Patients with urinary tract obstruction.
  • Patients unable to swallow the intact tablets.
  • Infants under 2 years of age.

Warnings and Precautions

Serious Warnings and Precautions

Hypersensitivity

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.

Renal

Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and renal failure has been reported in patients taking Asacol tablets as well as in patients taking other mesalamine products. Asacol is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS). It is recommended that all patients have an evaluation of renal function prior to initiation of Asacol tablets and periodically while on Asacol therapy. For patients with moderate or mild renal impairment, see WARNINGS AND PRECAUTIONS.

General

Asacol and other mesalamine-containing products have differences in formulation and release characteristics that may lead to differences in concentrations of mesalamine delivered to the colon. If it is deemed necessary to switch from one mesalamine-containing product to another mesalamine-containing product, the prescriber should carefully assess the overall benefit-risk analysis based on the patient’s clinical conditions and on all available information for the various mesalamine-containing products.

Gastrointestinal

Exacerbation of the symptoms of colitis, thought to have been caused by mesalamine or sulfasalazine, has been reported in 3% of 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 tablets as well as other mesalamine products. Symptoms usually abate when Asacol tablets are discontinued.

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

What appears to be intact or partially intact tablets may be observed in the stool.

Hepatic / Biliary / Pancreatic

Caution should be exercised when using Asacol (or other compounds which contain or are converted to mesalamine or its metabolites) in patients with hepatic dysfunction.

In assessing liver complications, it should be kept in mind that these are frequently associated with ulcerative colitis.

There have been reports of hepatic failure and increased liver enzymes in patients with preexisting liver disease when treated with Mesalazine products. Therefore, Asacol is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS). In patients with mild to moderate liver function impairment, caution should be exercised and Asacol should only be used if the expected benefit clearly outweighs the risks to the patients. Appropriate assessment and monitoring of liver function should be performed.

Immune

Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to Asacol tablets or to other compounds that contain, or are converted to, mesalamine. Asacol does not contain a sulfa moiety, thus sulfa-related side effects are avoided. Many patients with a history of sulfasalazine intolerance are able to tolerate Asacol tablets as demonstrated in open-label clinical trials.

Renal

Reports of renal impairment, including minimal change nephropathy, and acute or chronic interstitial nephritis have been associated with mesalamine products and pro-drugs of mesalamine. Asacol is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS). In patients with mild to moderate renal dysfunction, caution should be exercised and Asacol should be used only if the benefits outweigh the risks. It is recommended that all patients have an evaluation of renal function prior to initiation of therapy and periodically while on treatment.

Special Populations

Pregnancy

There are no adequate and well controlled studies of Asacol use in pregnant women. Limited published data on the class of mesalamine products show an increased rate of preterm birth, stillbirth and low birth weight. These adverse pregnancy outcomes are also associated with active inflammatory bowel disease. Mesalamine crosses the placenta. Animal reproduction studies of mesalamine found no evidence of fetal harm.

Dibutyl phthalate (DBP) is an inactive ingredient in Asacol’s enteric coating, and in animal studies at doses >95 times the human dose based on body surface area, maternal DBP was associated with external and skeletal malformations and adverse effects on the male reproductive system. Asacol should be used during pregnancy only if the potential benefit justifies the potential risk.

Nursing Women

It has been reported that small amounts of 5-ASA and higher concentrations of acetyl-5-ASA are found in breast milk. While the clinical significance of this has not been determined, caution should be exercised when Asacol tablets are administered to a nursing woman.

Dibutyl phthalate (DBP), an inactive ingredient in the enteric coating of Asacol tablets, and its primary metabolite mono-butyl phthalate (MBP) are excreted into human milk. The clinical significance of this has not been determined.

Monitoring and Laboratory Tests

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

It is recommended that appropriate assessment and monitoring of liver function should be performed.

Adverse Reactions

Adverse Drug Reaction Overview

Asacol is generally well tolerated. The most commonly reported adverse reactions were nausea, diarrhea, abdominal pain and headache. Other common adverse reactions seen in clinical trials with Asacol were acute exacerbation of ulcerative colitis symptoms, abnormal hepatic functions tests and rash. Adverse events seen in clinical trials with Asacol tablets have generally been mild and reversible, and have seldom resulted in discontinuation of treatment.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates of occurrence.

In two short-term (6 weeks), double-blind, placebo-controlled clinical studies involving 245 patients, 155 of whom were randomized to Asacol tablets, five (3.2%) of the Asacol patients discontinued Asacol therapy because of adverse events as compared to two (2.2%) of the placebo patients. Adverse reactions leading to withdrawal from Asacol tablets included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache; rash, lethargy and constipation; dry mouth, malaise, lower back discomfort, mild disorientation, mild indigestion and cramping; headache, nausea, malaise, aching, vomiting, muscle cramps, a stuffy head, plugged ears, and fever.

Adverse events occurring at a frequency of greater than 2% in these clinical trials are listed below. Overall, the incidence of adverse events seen with Asacol tablets was similar to placebo.

Headache, abdominal pain, eructation, pain, nausea, pharyngitis, dizziness, asthenia, diarrhea, back pain, fever, rash, dyspepsia, rhinitis, arthralgia, vomiting, constipation, hypertonia, flatulence, flu syndrome, chills, colitis exacerbation, chest pain, peripheral edema, myalgia, pruritus, sweating, dysmenorrhea.

Of these adverse events, only rash showed a consistently higher frequency with increasing Asacol dose in these studies.

The following adverse reactions were seen in 2% of the patients in the controlled studies: malaise, arthritis, insomnia, increased cough, acne, and conjunctivitis.

In a 6 month placebo-controlled maintenance trial involving 264 patients, 177 of whom were randomized to Asacol tablets, six (3.4%) of the Asacol patients discontinued Asacol therapy because of adverse events, as compared to four (4.6%) of the placebo patients. Adverse reactions leading to withdrawal from Asacol tablets included (each in one patient): anxiety; headache; pruritus, decreased libido; rheumatoid arthritis; and stomatitis and asthenia.

In the 6 month placebo-controlled maintenance trial, the incidence of adverse events seen with Asacol tablets was similar to that seen with placebo. Adverse events occurring in Asacol 1.6 g/day group at a frequency of 2% or greater are listed in Table 1 below.

Table 1 Frequency (%) of Adverse Events Reported in the Long-Term (6 months) Double-Blind Controlled Study
EventPlacebo
(n=87)
Asacol 0.8 g/day
(n=90)
Asacol 1.6 g/day
(n=87)
Headache 495247
Rhinitis 364340
Diarrhea 493040
Abdominal Pain 443033
Flatulence 302128
Pain 111923
Pharyngitis 152221
Asthenia 162010
Nausea 151917
Fever 131214
Constipation 13413
Back Pain 112110
Flu Syndrome 201410
Colitis Flare 8810
Gastrointestinal Bleeding 8810
Stool Abnormality 8710
Infection 379
Dizziness 788
Chest Pain 688
Arthralgia 978
Myalgia 578
Increased Cough 16127
Sinusitis 677
Tenesmus 567
Rectal Disorder 217
Vomiting 766
Nervousness 266
Dyspepsia 995
Insomnia 545
Hypertonia 345
Gastroenteritis 125
Malaise315
Dysmenorrhea 215
Paresthesia 505
Pruritus 723
Joint Disorder 023
Increased Urination 023
Vision Abnormality 013
Hematuria 103
Lung Disorder 003
Rectal Bleeding 542
Anxiety 232
Bronchitis 232
Abdomen Enlargement 032
Arthritis 212
Dysuria 112
Monilia Vagina 112
Amblyopia 012
Dry Mouth 012
Epistaxis 012
Lacrimation Disorder 012
Prostate Disorder 012
Somnolence 302
Urticaria 102
Asthma 002
Cystitis 002
Deaf 002
Vaginitis 002

In addition, the following adverse reactions were seen in 1% of patients receiving Asacol 1.6 g/day in the maintenance study: migraine, ear disorder, rash, vasodilation, allergic reaction, dyspnea, chills, pneumonia, urine abnormality, peripheral edema, palpitations, anorexia, depression, urinary tract infection, leg cramps, alopecia and sweating.

In uncontrolled clinical studies, the following adverse events occurred at a frequency of 5% or greater and appeared to increase in frequency with increasing dose: Asthenia, flu syndrome, back pain, arthralgia, and rhinitis.

Abnormal Hematologic and Clinical Chemistry Findings

Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated serum creatinine and BUN.

Post-Market Adverse Drug Reactions

In addition to the adverse events listed above, the following adverse events have also been reported in controlled clinical trials, open-label studies, literature reports, or foreign and domestic marketing experience. Because many of these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The relationship of the reported events to Asacol is unclear in many cases, some, including anorexia, joint pain, pyoderma gangrenosum, oral ulcers, and anemia, are sometimes part of the clinical presentation of ulcerative colitis.

Body as a Whole

Neck pain, abdominal enlargement, facial edema, edema, lupus-like syndrome, drug fever (rare).

Cardiovascular

Pericarditis (rare), myocarditis (rare), vasodilation, migraine.

Digestive

Anorexia, pancreatitis, gastroenteritis, gastritis, increased appetite, dry mouth, oral ulcers, perforated peptic ulcer (rare), bloody diarrhea, tenesmus.

Hematologic

Agranulocytosis (rare), aplastic anemia (rare), thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy.

Musculoskeletal

Gout.

Nervous

Anxiety, depression, somnolence, emotional lability, hyperesthesia, vertigo, nervousness, confusion, paresthesia, tremor, peripheral neuropathy (rare), Guillain-Barré syndrome (rare), and transverse myelitis (rare).

Respiratory/Pulmonary

Sinusitis, eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleuritis.

Skin

Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), dry skin, erythema nodosum, urticaria.

Special Senses

Ear pain, eye pain, taste perversion, blurred vision, tinnitus.

Urogenital

Interstitial nephritis (rare), minimal change nephropathy (rare), renal failure (rare) (see WARNINGS AND PRECAUTIONS), dysuria, urinary urgency, hematuria, epididymitis, menorrhagia.

Hepatic

Hepatitis (rare), cholecystitis. Asymptomatic elevations of liver function tests have occurred in patients taking Asacol tablets. These elevations usually resolve during continued therapy or with discontinuation of Asacol. When any elevations in liver enzymes are assessed, it should be kept in mind that hepatic complications are frequently associated with inflammatory bowel disease.

Drug Interactions

Drug-Drug Interactions

There are no known drug interactions. The effects of co-administration of Asacol tablets 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 tablets by any of the three treatments. It has been reported that simultaneous administration of famotidine, a potent H2-antagonist, and Asacol tablets does not influence the absorption and urinary excretion of mesalamine.

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

Interactions similar to acetylsalicylic acid cannot be excluded.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.

Dosage and Administration

Dosing Considerations

Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits completely. Thus, it is important for patients to closely comply with the maintenance dosage prescribed by their doctors. By doing so, the risk of relapse can be substantially reduced.

Recommended Dose and Dosage Adjustment

For the treatment of mildly to moderately active ulcerative colitis

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.

For the maintenance of remission of ulcerative colitis

The recommended dosage in adults is 4 tablets, taken orally in divided doses. The treatment duration in a well-controlled clinical trial was 6 months.

Abrupt discontinuation is not recommended.

Ulcerative colitis rarely remits completely. Thus, it is important for patients to closely comply with the maintenance dosage prescribed by their doctors. By doing so, the risk of relapse can be substantially reduced.

Missed Dose

If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take double the dose.

Administration

  1. Tablets should be swallowed 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. Patients should be advised to take Asacol tablets only as prescribed. The number or frequency of tablets ingested should not be changed without first consulting their physician.
  3. Intact or partially intact tablets may infrequently appear in the stool. If this occurs repeatedly, the patient should be advised to consult their physician.

Overdosage

There are no documented reports of serious human toxicity following overdose with mesalamine. Based on the adverse effect profile, symptoms that might be observed following acute overdose include headache, abdominal pain, nausea, vomiting, and diarrhea. Mesalamine is not metabolized to salicylate. There is no specific antidote and treatment is symptomatic and supportive. In treatment of acute overdose, activated charcoal and/or gastric lavage may be indicated if implemented within sixty minutes from the time of ingestion.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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 does not allow the drug to be released below pH 7. The coating 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, the remainder is available for colon therapeutic activity and excretion in the feces. Absorption of mesalamine is similar in fasted and fed subjects. 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.

Stability and Storage Recommendations

Store at controlled room temperature (15°C – 30°C).

Dosage Forms, Composition and Packaging

Asacol tablets are available for oral administration as brown-red, capsule-shaped, enteric coated tablets printed in black ink with “0752 DR”.

Each brown-red capsule-shaped enteric coated tablet of Asacol contains 400 mg mesalamine. Asacol colon-targeted tablets are coated with a special acrylic-based resin, Eudragit-S {methacrylic acid copolymer Type B (USP)}, which delays release of the mesalamine until the tablets reach the terminal ileum.

Each tablet contains the following inactive ingredients: dibutyl phthalate, edible black ink (ammonium hydroxide, n-butyl alcohol, shellac glaze [modified] in SD-45, synthetic black iron oxide and propylene glycol), iron oxide red, iron oxide yellow, lactose, magnesium stearate, Eudragit-S {methacrylic acid copolymer Type B (USP)}, polyethylene glycol, polyvinylpyrrolidone, sodium starch glycolate, colloidal silicon dioxide and talc.

Asacol colon-targeted tablets are supplied in bottles of 180 tablets each.