Asacol 800: Indications, Dosage, Precautions, Adverse Effects
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Asacol 800 - Product Information

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

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Oral Mesalamine Delayed
Release Tablets, 800
mg
Lactose
For a complete listing see Dosage Forms,
Composition and Packaging Section

Indications and Clinical Use

ASACOL 800 (800 mg tablet; mesalamine or 5-aminosalicylic acid) is indicated for:

  • treatment of moderately active ulcerative colitis.

In the pivotal clinical trial with Asacol 800 (800 mg tablet), moderately active ulcerative olitis was determined by a Physician Global Assessment (PGA) which included clinical and endoscopic evaluations scored as a 2 on a 0 (normal) to 3 (severe) scale.

Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits completely. Abrupt discontinuation of mesalamine therapy is not recommended, and may result in relapse. It is important for patients to comply with the dosage prescribed by their doctors; by doing so, the risk of relapse can be substantially reduced.

Relevant clinical information:

Findings from the clinical studies for Asacol 800 (800 mg tablet), that a higher dose of mesalamine shows greater efficacy in patients with moderately active disease, is consistent with previous findings seen with Asacol (400 mg tablet). The demonstrated efficacy of Asacol 800 (800 mg tablet) administered at 4.8 g/day in patients with moderately active disease offers this patient population convenient dosing over Asacol (400 mg tablet) tablets by reducing the number of tablets by half. For information on the Clinical Efficacy and Safety of Asacol 800 (800 mg tablet) obtained from the Clinical Trials, please refer to the section “CLINICAL TRIALS” below. Interchangeability between Asacol (400 mg tablet) and Asacol 800 (800 mg tablet) has not been established. For information on the Asacol (400 mg tablet), please refer to the current Product Monograph for the Asacol (400 mg tablet) tablet.

Geriatrics

No data are available.

Pediatrics

Clinical trials of Asacol 800 (800 mg tablet) did not include pediatric patients. Asacol 800 (800 mg tablet) is contraindicated in patients unable to swallow an intact tablet and in patients less than 2 years of age.

Contraindications

ASACOL 800 (800 mg tablet) 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 the 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 tablet and
  • 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 and acute and chronic interstitial nephritis, and renal failure has been reported in patients taking mesalamine products. Asacol 800 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 800 (800 mg tablet) tablets and periodically while on Asacol 800 (800 mg tablet) therapy. For patients with moderate or mild renal impairment, see WARNING AND PRECAUTIONS.

General

Asacol 800 (800 mg tablet) 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.

Carcinogenesis and Mutagenesis

Preclinical animal data are provided in the Toxicology section.

Gastrointestinal

Acute exacerbation of the symptoms of colitis, characterized by cramping, abdominal pain, bloody diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has been reported in 3% of patients in controlled clinical trials of Asacol (400 mg tablet) versus sulfasalazine. This reaction has been reported after initiation of other mesalamine-containing products, and was reported by 2% of patients receiving Asacol 800 (800 mg tablet) in two controlled clinical trials. Symptoms usually abate when mesalamine therapy is discontinued.

Patients with pyloric stenosis may have prolonged gastric retention of Asacol 800 (800 mg tablet) tablets that 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 800 (800 mg tablet) (or other compounds that 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 pre-existing liver disease when treated with Mesalazine products. Therefore, Asacol 800 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 800 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 800 (800 mg tablet) tablets or to other compounds that contain, or are converted to, mesalamine. Asacol 800 (800 mg tablet) does not contain a sulfa moiety, thus sulfa-related side effects are avoided.

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 800 is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS). In patients with mild to moderate renal dysfunction, caution should be exercised and Asacol 800 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

Pregnant Women

There are no adequate and well controlled studies of Asacol 800 (800 mg tablet) 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 800 (800 mg tablet)’s enteric coating, and in animal studies at doses >80 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

Literature reports indicate that, following oral or rectal administration of mesalamine-containing products to lactating women, small amounts of 5-ASA and higher concentrations of the metabolite N-acetyl-5-ASA are found in breast milk. While the clinical significance of this has not been determined, caution should be exercised when Asacol 800 (800 mg tablet) tablets are administered to a nursing woman.

Dibutyl phthalate (DBP), an inactive ingredient in the enteric coating of Asacol 800 (800 mg tablet), and its primary metabolite mono-butyl phthalate (MBP) are excreted into human milk. The clinical significance of this has not been determined.

Pediatrics

Safety and effectiveness of Asacol 800 (800 mg tablet) therapy in patients younger than 18 years of age has not been established.

Geriatrics

Less than 10% of patients in the Asacol 800 (800 mg tablet) clinical trial were ≥ 65 years of age. Patients in this age range were not significantly different from the overall patient population with respect to safety and efficacy responses.

Monitoring and Laboratory Tests

It is recommended that all patients have an evaluation of renal function prior to initiation of Asacol 800 (800 mg tablet) tablets and periodically while on Asacol 800 (800 mg tablet) 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 approximate rates of occurrence.

In two double-blind, randomized 6 week, parallel-group design clinical trials in patients with mildly to moderately active ulcerative colitis, the safety and efficacy of Asacol 800 (800 mg tablet), dosed at 4.8 g/day, was compared to the safety and efficacy of Asacol (400 mg tablet), dosed at 2.4 g/day. In these trials, the overall incidence of adverse events was comparable between the two treatment groups, and similar to that observed previously with Asacol (400 mg tablet) therapy. Table 1 presents adverse events assessed as possibly or probably related to the study drug in 1% or more of patients in either treatment group.

Table 1 Adverse Events Assessed as Possibly or Probably Related to Study Drug Occurring in ≥1% in Either Treatment Group by MedDRA PT
MedDRA Preferred Term 2.4g/day Asacol
(400 mg Tablet)
(N=349)
n (%)
4.8g/day Asacol
(800 mg Tablet)
(N=338)
n (%)
Headache 13 (3.7%) 12 (3.6%)
Nausea 6 (1.7%) 8 (2.4%)
Vomiting 3 (0.9%) 4 (1.2%)
Abdominal pain 7 (2.0%) 3 (0.9%)
Ulcerative colitis 4 (1.1%) 3 (0.9%)
Abdominal distension 5 (1.4%) 1 (0.3%)

Post-Market Adverse Drug Reactions

In addition to the adverse events reported above in the two clinical trials involving Asacol 800 (800 mg tablet), the following adverse events have been reported in controlled clinical trials, open-label studies, literature reports, or foreign and domestic marketing experience with Asacol (400 mg tablet) or other products that contain or are metabolized to mesalamine. 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, and some may be part of the clinical presentation of ulcerative colitis.

Body as a Whole

Allergic reaction, facial edema, edema, peripheral edema, asthenia, drug fever (rare), chills, malaise, pain, neck pain, chest pain, back pain, abdominal enlargement, lupus-like syndrome, flu syndrome, infection.

Cardiovascular

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

Digestive

Dry mouth, stomatitis, oral ulcers, anorexia, increased appetite, dyspepsia, eructation, flatulence, pancreatitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer (rare), constipation, rectal hemorrhage, bloody diarrhea, tenesmus, rectal disorder, stool abnormality.

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.

Hematologic

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

Musculoskeletal

Gout, rheumatoid arthritis, arthritis, arthralgia, joint disorder, myalgia, hypertonia, leg cramps.

Nervous

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

Respiratory/Pulmonary

Epistaxis, rhinitis, sinusitis, pharyngitis, dyspnea, increased cough, asthma exacerbation, pleuritis, bronchitis, pneumonia, eosinophilic pneumonia, interstitial pneumonitis, lung disorder.

Skin

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

Special Senses

Ear pain, tinnitus, deafness, ear congestion, ear disorder, conjunctivitis, eye pain, amblyopia, blurred vision, vision abnormality, lacrimation disorder, taste perversion.

Urogenital

Interstitial nephritis (rare), minimal change nephropathy (rare), renal failure (rare) (See also WARNINGS AND PRECAUTIONS), cystitis, urinary tract infection, dysuria, urinary urgency, increased urination, hematuria, urine abnormality, epididymitis, prostate disorder, decreased libido, dysmenorrhea, menorrhagia, vaginitis, vaginal moniliasis.

Laboratory Abnormalities

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

Drug Interactions

Overview

There are no known drug interactions with Asacol (400 mg tablet). No drug interaction studies were performed with Asacol 800 (800 mg tablet). In clinical trials of Asacol 800 (800 mg tablet), there were no restrictions on the concomitant use of antacids, H2-receptor antagonists, proton-pump inhibitors, or other preparations affecting gastrointestinal pH. In subgroup analyses, patients receiving H2-receptor antagonists or proton-pump inhibitors were not significantly different from the overall patient population with respect to safety and efficacy response.

Drug-Food Interactions

Administration of the Asacol 800 (800 mg tablet) tablet immediately following a high fat meal had no significant effect on the extent of exposure to 5-ASA and N-acetyl-5-ASA based on AUC and percent of dose excreted in urine (Ae%). A reduction of approximately 50% was observed in Cmax, due to significantly delayed tmax when dosed following a high fat meal compared to dosing under fasting condition. However, no impact was observed on the safety profile or systemic exposure to 5-ASA and N-acetyl-5ASA in the clinical trials where doses were given without regards to meals. Therefore, Asacol 800 (800 mg tablet) can be taken in a fasted or fed state.

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. Abrupt discontinuation of Asacol 800 (800 mg tablet) is not recommended, and may result in relapse. It is important for patients to comply with the 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 moderately active ulcerative colitis

Usual daily adult dose is 6 Asacol 800 (800 mg tablet) tablets, taken orally in divided doses. Asacol 800 (800 mg tablet) may be given without regards to meals.

For alternate dosing for moderately active ulcerative colitis, see the Asacol (400 mg tablet) Product Monograph.

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. 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 800 (800 mg tablet) 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.

Overdosage

There is no clinical experience with overdose of Asacol 800 (800 mg tablet). Mesalamine is not metabolized to salicylate. There is no specific antidote for mesalamine overdose, and treatment is symptomatic and supportive.

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

Action and Clinical Pharmacology

Mechanism of Action

The active ingredient in Asacol 800 (800 mg tablet) is mesalamine (5-aminosalicylic acid, also referred to as 5-ASA). The available evidence suggests that mesalamine has a topical anti-inflammatory effect on the colon, where it inhibits prostaglandin and leukotriene synthesis.

Pharmacodynamics

Asacol 800 (800 mg tablet) 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. Asacol 800 (800 mg tablet) demonstrated expected enteric coating properties that were comparable to those of the Asacol (400 mg tablet) tablet, as indicated by in-vitro dissolution data as well as prolonged tmax and tlag following oral administration.

Pharmacokinetics

Once released in the colon, mesalamine is minimally absorbed and plasma levels are similar to those found in previous studies following oral administration of doses given as 400 mg tablets. The bioequivalence between Asacol 800 (800 mg tablet) and Asacol (400 mg tablet) tablets has not been established. Following oral administration of a single, 800 mg tablet under fasting conditions, the time to peak plasma concentration (tmax ) is approximately 10 hours while the terminal elimination half-life (t1/2 elm) is 12 to 19 hours for both mesalamine and its metabolite, N-acetyl-5-ASA.

Approximately 20% of the administered dose is absorbed systemically; the remainder is available for therapeutic activity in the colon and excretion in the feces. The extent of systemic exposure to 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-ASA.

Table 2 presents the mean pharmacokinetic parameters of 5-ASA and N-acetyl-5-ASA (N-Ac-5-ASA) following single and multiple dosing of Asacol 800 (800 mg tablet) in healthy subjects.

Table 2 Summary of mean pharmacokinetic parameters of 5-ASA and N-Ac-5-ASA following single and multiple dosing in healthy subjects
Mean Pharmacokinetic Parameters of 5-ASA
Parameter Single Dose (1 x 800 mg) Multiple Dose (4.8 g/day x 6 Days)
AUCtlast (ng•h/mL) 3449.2 -
AUC (ng•h/mL) 3548.2 20282.0a
Cmax (ng/mL) 354.03 4972.1
tmax (h) 9.61 2.63
tlag (h) 6.20 -
t1/2,Z (h) 13.41 11.89
%Ae (%) 0.21 9.28
Mean Pharmacokinetic Parameters of N-Ac-5-ASA
Parameter Single Dose (1 x 800 mg) Multiple Dose (4.8 g/day x 6 Days)
AUCtlast (ng•h/mL) 19900.8 -
AUC (ng•h/mL) 22034.2 24864.0a
Cmax (ng/mL) 1028.68 4614.78
tmax (h) 11.13 3.13
tlag (h) 5.39 -
t1/2,Z (h) 13.62 19.56
%Ae (%) 12.04 19.01
AUCtlast is the area under the plasma concentration-time curve from time zero to the last quantifiable concentration; AUC is the area under the plasma concentration-time curve from time zero to infinity; Cmax is the maximum plasma concentration; tmax is the time at which Cmax is observed; tlag is the lag time before the onset of drug absorption; t1/2,Z is the terminal exponential half-life; %Ae is the percentage of dose excreted in urine.
a AUCτ is the area under the plasma concentration-time curve over a dosing interval.

Storage and Stability

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

Dosage Forms, Composition and Packaging

Asacol 800 (800 mg tablet) tablets are available for oral administration as red-brown, capsule-shaped, enteric coated tablets, printed in black ink with “WC 800”.

Each red-brown capsule-shaped enteric coated tablet of Asacol 800 (800 mg tablet) contains 800 mg mesalamine. Asacol 800 (800 mg tablet) colon-targeted tablets are coated with a special acrylic-based resin, Eudragit-S {methacrylic acid copolymer Type B (USP)}, which dissolves at pH 7 or greater, that delays release of the mesalamine until the tablets reach the terminal ileum. A second enteric coating which begins to dissolve earlier in the gastrointestinal tract is added after the Eudragit-S. The outer coating consists of a combination of Eudragit-S and another acrylic-based resin, Eudragit-L {methacrylic acid copolymer Type A (USP)}.

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

Asacol 800 (800 mg tablet) colon-targeted tablets are supplied in bottles of 180 tablets each.