Asacol®
(mesalamine)
Delayed-Release Tablets
DESCRIPTION: Each Asacol delayed-release tablet for oral
administration contains 400 mg of mesalamine, an anti-inflammatory drug. The Asacol
delayed-release tablets are coated with acrylic based resin, Eudragit S
(methacrylic acid copolymer B, NF), which dissolves at pH 7 or greater,
releasing mesalamine in the terminal ileum and beyond for topical
anti-inflammatory action in the colon. Mesalamine has the chemical name
5-amino-2-hydroxybenzoic acid; its structural formula is:
Molecular
Weight: 153.1
Molecular Formula: C7H7NO3
Inactive
Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl
phthalate, edible black ink, iron oxide red, iron oxide yellow, lactose,
magnesium stearate, methacrylic acid copolymer B (Eudragit S),
polyethylene glycol, povidone, sodium starch glycolate, and talc.
CLINICAL
PHARMACOLOGY: Mesalamine is thought to be the major therapeutically
active part of the sulfasalazine molecule in the treatment of ulcerative
colitis. Sulfasalazine is converted to equimolar amounts of sulfapyridine and
mesalamine by bacterial action in the colon. The usual oral dose of
sulfasalazine for active ulcerative colitis is 3 to 4 grams daily in divided
doses, which provides 1.2 to 1.6 grams of mesalamine to the colon. The
mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears
to be topical rather than systemic. Mucosal production of arachidonic acid (AA)
metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and
through the lipoxygenase pathways, i.e., 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.
Pharmacokinetics: Asacol
tablets are coated with an acrylic-based resin that delays release of
mesalamine until it reaches the terminal ileum and beyond. This has been
demonstrated in human studies conducted with radiological and serum markers.
Approximately 28% of the mesalamine in Asacol tablets is absorbed after
oral ingestion, leaving the remainder available for topical action and
excretion in the feces. Absorption of mesalamine is similar in fasted and fed
subjects. The absorbed mesalamine is rapidly acetylated in the gut mucosal wall
and by the liver. It is excreted mainly by the kidney as
N-acetyl-5-aminosalicylic acid. Mesalamine from orally administered Asacol
tablets appears to be more extensively absorbed than the mesalamine released
from sulfasalazine. Maximum plasma levels of mesalamine and
N-acetyl-5-aminosalicylic acid following multiple Asacol doses are about
1.5 to 2 times higher than those following an equivalent dose of mesalamine in
the form of sulfasalazine. Combined mesalamine and N-acetyl-5-aminosalicylic
acid AUC's and urine drug dose recoveries following multiple doses of Asacol
tablets are about 1.3 to 1.5 times higher than those following an equivalent
dose of mesalamine in the form of sulfasalazine. The tmax for mesalamine and
its metabolite, N-acetyl-5-aminosalicylic acid, is usually delayed, reflecting
the delayed release, and ranges from 4 to 12 hours. The half-lives of
elimination (t1/2elm) for mesalamine and N-acetyl-5-aminosalicylic acid are
usually about 12 hours, but are variable, ranging from 2 to 15 hours. There is
a large intersubject variability in the plasma concentrations of mesalamine and
N-acetyl-5-aminosalicylic acid and in their elimination half-lives following
administration of Asacol tablets.
Clinical
Studies: Mildly to moderately active ulcerative colitis: Two
placebo-controlled studies have demonstrated the efficacy of Asacol
tablets in patients with mildly to moderately active ulcerative colitis. In one
randomized, double-blind, multi-center trial of 158 patients, Asacol
doses of 1.6 g/day and 2.4 g/day were compared to placebo. At the dose of 2.4
g/day, Asacol tablets reduced the disease activity, with 21 of 43 (49%) Asacol
patients showing improvement in sigmoidoscopic appearance of the bowel compared
to 12 of 44 (27%) placebo patients (p = 0.048). In addition, significantly more
patients in the Asacol 2.4 g/day group showed improvement in rectal
bleeding and stool frequency. The 1.6 g/day dose did not produce consistent
evidence of effectiveness. In a second randomized, double-blind,
placebo-controlled clinical trial of 6 weeks duration in 87 ulcerative colitis
patients, Asacol tablets, at a dose of 4.8 g/day, gave sigmoidoscopic
improvement in 28 of 38 (74%) patients compared to 10 of 38 (26%) placebo
patients (p <0.001). Also, more patients in the Asacol 4.8 g/day
group showed improvement in overall symptoms.
Maintenance of remission of ulcerative colitis: A 6-month, randomized,
double-blind, placebo-controlled, multi-center study involved 264 patients
treated with Asacol 0.8 g/day (n=90), 1.6 g/day (n=87), or placebo
(n=87). The proportion of patients treated with 0.8 g/day who maintained
endoscopic remission was not statistically significant compared to placebo. In
the intention to treat (ITT) analysis of all 174 patients treated with Asacol
1.6 g/day or placebo, Asacol maintained endoscopic remission of ulcerative
colitis in 61 of 87 (70.1%) of patients, compared to 42 of 87 (48.3%) of
placebo recipients (p=0.005). A pooled efficacy analysis of 4 maintenance
trials compared Asacol, at doses of 0.8 g/day to 2.8 g/day, with
sulfasalazine, at doses of 2 g/day to 4 g/day (n=200). Treatment success was 59
of 98 (59%) for Asacol and 70 of 102 (69%) for sulfasalazine, a
non-significant difference.
Study to assess the effect on male fertility: The effect of Asacol
(mesalamine) on sulfasalazine-induced impairment of male fertility was examined
in an open-label study. Nine patients (age < 40 years) with chronic
ulcerative colitis in clinical remission on sulfasalazine 2 g/day to
3 g/day were crossed over to an equivalent Asacol dose (0.8 g/day
to 1.2 g/day) for 3 months. Improvement in sperm count (p < 0.02) and
morphology (p < 0.02) occurred in all cases. Improvement in sperm motility
(p < 0.001) occurred in 8 of the 9 patients.
INDICATIONS
AND USAGE: Asacol tablets are indicated for the treatment of
mildly to moderately active ulcerative colitis and for the maintenance of
remission of ulcerative colitis.
CONTRAINDICATIONS: Asacol
tablets are contraindicated in patients with hypersensitivity to salicylates or
to any of the components of the Asacol tablet.
PRECAUTIONS: General: Patients with
pyloric stenosis may have prolonged gastric retention of Asacol tablets
which could delay release of mesalamine in the colon. Exacerbation of the
symptoms of colitis has been reported in 3% of Asacol-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
tablets as well as other mesalamine products. Symptoms usually abate when Asacol
tablets are discontinued. Some patients who have experienced a hypersensitivity
reaction to sulfasalazine may have a similar reaction to Asacol tablets
or to other compounds which contain or are converted to mesalamine.
Renal: Renal
impairment, including minimal change nephropathy, and acute and chronic
interstitial nephritis, has been reported in patients taking Asacol
tablets as well as other compounds which contain or are converted to
mesalamine. In animal studies (rats, dogs), the kidney is the principal target
organ for toxicity. At doses of approximately 750 mg/kg to 1000 mg/kg [15
to 20 times the administered recommended human dose (based on a 50 kg
person) on a mg/kg basis and 3 to 4 times on a mg/m2 basis], mesalamine causes
renal papillary necrosis. Therefore, caution should be exercised when using
Asacol (or other compounds which contain or are converted to mesalamine or its
metabolites) in patients with known renal dysfunction or history of renal
disease. It is recommended that all patients have an evaluation of renal
function prior to initiation of Asacol tablets and periodically while on Asacol
therapy.
Information for Patients: Patients should be instructed to swallow the Asacol
tablets whole, taking care not to break the outer coating. The outer coating is
designed to remain intact to protect the active ingredient and thus ensure
mesalamine availability for action in the colon. In 2% to 3% of patients in
clinical studies, intact or partially intact tablets have been reported in the
stool. If this occurs repeatedly, patients should contact their physician.
Patients with ulcerative colitis should be made aware that ulcerative colitis
rarely remits completely, and that the risk of relapse can be substantially
reduced by continued administration of Asacol at a maintenance dosage.
Drug
Interactions: There are no known drug interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Dietary mesalamine
was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at
2000 mg/kg/day. These doses are 2.4 and 5.1 times the maximum recommended human
maintenance dose of Asacol of 1.6 g/day (32 mg/kg/day if 50 kg body
weight assumed or 1184 mg/m2), respectively, based on body surface area.
Mesalamine was negative in the Ames assay for mutagenesis, negative for
induction of sister chromatid exchanges (SCE) and chromosomal aberrations in
Chinese hamster ovary cells in vitro, and negative for induction of micronuclei
(MN) in mouse bone marrow polychromatic erythrocytes. Mesalamine, at oral doses
up to 480 mg/kg/day, had no adverse effect on fertility or reproductive
performance of male and female rats.
Pregnancy: Teratogenic
Effects: Pregnancy Category B: Reproduction studies in rats and rabbits at
oral doses up to 480 mg/kg/day have revealed no evidence of teratogenic
effects or fetal toxicity due to mesalamine. 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.
Nursing
Mothers: Low concentrations of mesalamine and higher concentrations
of its N-acetyl metabolite have been detected in human breast milk. While the
clinical significance of this has not been determined, caution should be
exercised when mesalamine is administered to a nursing woman.
Pediatric
Use: Safety and effectiveness of Asacol tablets in
pediatric patients have not been established.
ADVERSE
REACTIONS: Asacol tablets have been evaluated in 3685
inflammatory bowel disease patients (most patients with ulcerative colitis) in
controlled and open-label studies. Adverse events seen in clinical trials with Asacol
tablets have generally been mild and reversible. Adverse events presented in
the following sections may occur regardless of length of therapy and similar
events have been reported in short- and long-term studies and in the
post-marketing setting. In two short-term (6 weeks) 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 in Asacol-treated
patients at a frequency of 2% or greater in the two short-term, double-blind,
placebo-controlled trials mentioned above are listed in Table 1 below.
Overall, the incidence of adverse events seen with Asacol tablets was
similar to placebo.
TABLE 1
Frequency (%) of Common Adverse Events Reported in Ulcerative Colitis Patients
Treated with Asacol Tablets or Placebo in Short-Term (6-Week)
Double-Blind Controlled Studies
Percent of Patients with Adverse Events
|
Event |
Placebo
|
Asacol
tablets |
|
Headache |
36 |
35 |
|
Abdominal Pain |
14 |
18 |
|
Eructation |
15 |
16 |
|
Pain |
8 |
14 |
|
Nausea |
15 |
13 |
|
Pharyngitis |
9 |
11 |
|
Dizziness |
8 |
8 |
|
Asthenia |
15 |
7 |
|
Diarrhea |
9 |
7 |
|
Back Pain |
5 |
7 |
|
Fever |
8 |
6 |
|
Rash |
3 |
6 |
|
Dyspepsia |
1 |
6 |
|
Rhinitis |
5 |
5 |
|
Arthralgia |
3 |
5 |
|
Hypertonia |
3 |
5 |
|
Vomiting |
2 |
5 |
|
Constipation |
1 |
5 |
|
Flatulence |
7 |
3 |
|
Dysmenorrhea |
3 |
3 |
|
Chest Pain |
2 |
3 |
|
Chills |
2 |
3 |
|
Flu Syndrome |
2 |
3 |
|
Peripheral Edema |
2 |
3 |
|
Myalgia |
1 |
3 |
|
Sweating |
1 |
3 |
|
Colitis Exacerbation |
0 |
3 |
|
Pruritus |
0 |
3 |
|
Acne |
1 |
2 |
|
Increased Cough |
1 |
2 |
|
Malaise |
1 |
2 |
|
Arthritis |
0 |
2 |
|
Conjunctivitis |
0 |
2 |
|
Insomnia |
0 |
2 |
Of
these adverse events, only rash showed a consistently higher frequency with
increasing Asacol dose in these studies.
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.
In addition to events listed in Table 1, the following adverse events occurred
in Asacol- treated patients at a frequency of 2% or greater in this
study: abdominal enlargement, anxiety, bronchitis, ear disorder, ear pain,
gastroenteritis, gastrointestinal hemorrhage, infection, joint disorder,
migraine, nervousness, paresthesia, rectal disorder, rectal hemorrhage,
sinusitis, stool abnormalities, tenesmus, urinary frequency, vasodilation, and
vision abnormalities.
In
3342 patients 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, fever, flu syndrome, pain, abdominal pain, back
pain, flatulence, gastrointestinal bleeding, arthralgia, and rhinitis.
In
addition to the adverse events listed above, the following events have been
reported with Asacol use:
Body
as a Whole: Neck pain, facial edema, edema.
Cardiovascular:
Pericarditis (rare), myocarditis (rare).
Digestive:
Anorexia, hepatitis (rare), pancreatitis, gastritis, increased appetite,
cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer (rare), bloody
diarrhea.
Hematologic:
Agranulocytosis (rare), aplastic anemia (rare), thrombocytopenia, eosinophilia,
leukopenia, anemia, lymphadenopathy.
Musculoskeletal: Gout.
Nervous:
Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion,
tremor, peripheral neuropathy (rare), transverse myelitis (rare),
Guillain-Barré syndrome (rare).
Respiratory/Pulmonary:
Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation.
Skin:
Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), dry skin, erythema
nodosum, urticaria.
Special
Senses: Eye pain, taste perversion, blurred vision, tinnitus.
Urogenital:
Interstitial nephritis (See also Renal subsection in PRECAUTIONS), minimal
change nephropathy (See also Renal subsection in PRECAUTIONS), dysuria, urinary
urgency, hematuria, epididymitis, menorrhagia.
Laboratory
Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline
phosphatase, elevated serum creatinine and BUN.
Hepatitis has been reported to occur rarely with Asacol tablets. More
commonly, asymptomatic elevations of liver enzymes have occurred which usually
resolve during continued use or with discontinuation of the drug.
DRUG
ABUSE AND DEPENDENCY:
Abuse: None reported.
Dependency: Drug
dependence has not been reported with chronic administration of mesalamine.
OVERDOSAGE: Two
cases of pediatric overdosage have been reported. A 3-year-old male who
ingested 2 grams of Asacol tablets was treated with ipecac and activated
charcoal; no adverse events occurred. Another 3-year-old male, approximately 16
kg, ingested an unknown amount of a maximum of 24 grams of Asacol
crushed in solution (i.e., uncoated mesalamine); he was treated with orange
juice and activated charcoal, and experienced no adverse events. In dogs,
single doses of 6 grams of delayed-release Asacol tablets resulted in
renal papillary necrosis but were not fatal. This was approximately 12.5 times
the recommended human dose (based on a dose of 2.4 g/day in a 50 kg person).
Single oral doses of uncoated mesalamine in mice and rats of 5000 mg/kg and
4595 mg/kg, respectively, or of 3000 mg/kg in cynomolgus monkeys, caused
significant lethality.
DOSAGE
AND ADMINISTRATION:
For the treatment of mildly to moderately active ulcerative colitis: The
usual dosage in adults is two 400-mg tablets to be taken three times a day for
a total daily dose of 2.4 grams for a duration of 6 weeks. For the
maintenance of remission of ulcerative colitis: The recommended dosage in
adults is 1.6 grams daily, in divided doses. Treatment duration in the
prospective, well-controlled trial was 6 months.
HOW
SUPPLIED: Asacol tablets are available as red-brown, capsule-shaped
tablets containing 400 mg mesalamine and imprinted "Asacol NE" in
black.
NDC 0149-0752-02 Bottle of 100
Store at controlled room temperature 20°- 25°C (68°- 77°F) [See USP].
CAUTION: Federal law prohibits dispensing without prescription.
Procter & Gamble Pharmaceuticals
Cincinnati, Ohio 45202, under license from
Tillotts Pharma AG and Medeva PLC,
the registered trademark owners.
Made in Germany, D-64331 Weiterstadt
U.S. Patent Nos. 5,541,170 and 5,541,171
REVISED OCTOBER 1997