Pentasa Information
Pentasa (Mesalamine) Description
Pentasa (Mesalamine) for oral administration is a
controlled-release formulation of mesalamine, an aminosalicylate
anti-inflammatory agent for gastrointestinal use. Chemically, mesalamine is
5-amino-2-hydroxybenzoic acid. It has a molecular weight of 153.14.
The structural formula is:
Each 250 mg capsule contains 250 mg of mesalamine. It also contains the
following inactive ingredients: acetylated monoglyceride, castor oil, colloidal
silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic
acid, sugar, talc, and white wax. The capsule shell contains D&C Yellow #10,
FD&C Blue #1, FD&C Green #3, gelatin, titanium dioxide, and other
ingredients.
Each 500 mg capsule contains 500 mg of mesalamine. It also contains the
following inactive ingredients: acetylated monoglyceride, castor oil, colloidal
silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic
acid, sugar, talc, and white wax. The capsule shell contains FD&C Blue #1,
gelatin, titanium dioxide, and other ingredients.
Pentasa (Mesalamine) Clinical Pharmacology
Sulfasalazine is split by bacterial action in the colon into
sulfapyridine (SP) and mesalamine (5-ASA). It is thought that the mesalamine
component is therapeutically active in ulcerative colitis. The usual oral dose
of sulfasalazine for active ulcerative colitis in adults is 2 to 4 g per day in
divided doses. Four grams of sulfasalazine provide 1.6 g of free 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, ie,
prostanoids, and through the lipoxygenase pathways, ie, 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 prostagladin (PG)
production in the colon.
Plasma mesalamine concentration peaked at approximately 1 μg/mL 3 hours
following a 1-g Pentasa (Mesalamine) dose and declined in a biphasic manner. The literature
describes a mean terminal half-life of 42 minutes for mesalamine following
intravenous administration. Because of the continuous release and absorption of
mesalamine from Pentasa (Mesalamine) throughout the gastrointestinal tract, the true
elimination half-life cannot be determined after oral administration.
N-acetylmesalamine, the major metabolite of mesalamine, peaked at approximately
3 hours at 1.8 μg/mL, and its concentration followed a biphasic decline.
Pharmacological activities of N-acetylmesalamine are unknown, and other
metabolites have not been identified.
Oral mesalamine pharmacokinetics were nonlinear when Pentasa (Mesalamine) capsules were
dosed from 250 mg to 1 g four times daily, with steady-state mesalamine plasma
concentrations increasing about nine times, from 0.14 μg/mL to 1.21 μg/mL,
suggesting saturable first-pass metabolism. N-acetylmesalamine pharmacokinetics
were linear.
Pentasa (Mesalamine) Clinical Trials
In two randomized, double-blind, placebo-controlled,
dose-response trials (UC-1 and UC-2) of 625 patients with active mild to
moderate ulcerative colitis, Pentasa (Mesalamine) , at an oral dose of 4 g/day given 1 g four
times daily, produced consistent improvement in prospectively identified primary
efficacy parameters, PGA, Tx F, and SI as shown in the table below.
The 4-g dose of Pentasa (Mesalamine) also gave consistent improvement in secondary
efficacy parameters, namely the frequency of trips to the toilet, stool
consistency, rectal bleeding, abdominal/rectal pain, and urgency. The 4-g dose
of Pentasa (Mesalamine) induced remission as assessed by endoscopic and symptomatic
endpoints. In some patients, the 2-g dose of Pentasa (Mesalamine) was observed to improve
efficacy parameters measured. However, the 2-g dose gave inconsistent results in
primary efficacy parameters across the two adequate and well-controlled trials.
Pentasa (Mesalamine) Indications And Usage
Pentasa (Mesalamine) is indicated for the induction of remission and for the treatment of
patients with mildly to moderately active ulcerative colitis.
Pentasa (Mesalamine) Contraindications
Pentasa (Mesalamine) is contraindicated in patients who have demonstrated hypersensitivity to
mesalamine, any other components of this medication, or salicylates.
Pentasa (Mesalamine) Precautions
Caution should be exercised if Pentasa (Mesalamine) is administered to
patients with impaired hepatic function.
Mesalamine has been associated with an acute intolerance syndrome that may be
difficult to distinguish from a flare of inflammatory bowel disease. Although
the exact frequency of occurrence cannot be ascertained, it has occurred in 3%
of patients in controlled clinical trials of mesalamine or sulfasalazine.
Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes
fever, headache, and rash. If acute intolerance syndrome is suspected, prompt
withdrawal is required. If a rechallenge is performed later in order to validate
the hypersensitivity, it should be carried out under close medical supervision
at reduced dose and only if clearly needed.
Caution should be exercised if Pentasa (Mesalamine) is administered to
patients with impaired renal function. Single reports of nephrotic syndrome and
interstitial nephritis associated with mesalamine therapy have been described in
the foreign literature. There have been rare reports of interstitial nephritis
in patients receiving Pentasa (Mesalamine) . In animal studies, a 13-week oral toxicity study
in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus
monkeys have shown the kidney to be the major target organ of mesalamine
toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced
renal lesions including granular and hyaline casts, tubular degeneration,
tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and
interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or
higher produced nephrosis, papillary edema, and interstitial fibrosis. Patients
with preexisting renal disease, increased BUN or serum creatinine, or
proteinuria should be carefully monitored, especially during the initial phase
of treatment. Mesalamine-induced nephrotoxicity should be suspected in patients
developing renal dysfunction during treatment.
There are no data on interactions between Pentasa (Mesalamine) and other
drugs.
In a 104-week dietary carcinogenicity study of mesalamine, CD-1
mice were treated with doses up to 2500 mg/kg/day and it was not tumorigenic.
For a 50 kg person of average height (1.46 m body
surface area), this represents 2.5 times the recommended human dose on a body
surface area basis (2960 mg/m/day). In a 104-week
dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800
mg/kg/day was not tumorigenic. This dose represents 1.5 times the recommended
human dose on a body surface area basis.
No evidence of mutagenicity was observed in an in vitro Ames test and in an
in vivo mouse micronucleus test.
No effects on fertility or reproductive performance were observed in male or
female rats at oral doses of mesalamine up to 400 mg/kg/day (0.8 times the
recommended human dose based on body surface area).
Semen abnormalities and infertility in men, which have been reported in
association with sulfasalazine, have not been seen with Pentasa (Mesalamine) capsules during
controlled clinical trials.
Category B. Reproduction studies have been performed in rats at
doses up to 1000 mg/kg/day (5900 mg/M) and rabbits at
doses of 800 mg/kg/day (6856 mg/M) and have revealed no
evidence of teratogenic effects or harm to the fetus 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, Pentasa (Mesalamine)
should be used during pregnancy only if clearly needed.
Mesalamine is known to cross the placental barrier.
Minute quantities of mesalamine were distributed to breast milk
and amniotic fluid of pregnant women following sulfasalazine therapy. When
treated with sulfasalazine at a dose equivalent to 1.25 g/day of mesalamine,
0.02 μg/mL to 0.08 μg/mL and trace amounts of mesalamine were measured in
amniotic fluid and breast milk, respectively. N-acetylmesalamine, in quantities
of 0.07 μg/mL to 0.77 μg/mL and 1.13 μg/mL to 3.44 μg/mL, was identified in the
same fluids, respectively.
Caution should be exercised when Pentasa (Mesalamine) is administered to a nursing
woman.
No controlled studies with Pentasa (Mesalamine) during breast-feeding have been carried
out. Hypersensitivity reactions like diarrhea in the infant cannot be excluded.
Safety and efficacy of Pentasa (Mesalamine) in pediatric patients have not
been established.
Pentasa (Mesalamine) Adverse Reactions
In combined domestic and foreign clinical trials, more than 2100
patients with ulcerative colitis or Crohn's disease received Pentasa (Mesalamine) therapy.
Generally, Pentasa (Mesalamine) therapy was well tolerated. The most common events (ie,
greater than or equal to 1%) were diarrhea (3.4%), headache (2.0%), nausea
(1.8%), abdominal pain (1.7%), dyspepsia (1.6%), vomiting (1.5%), and rash
(1.0%).
In two domestic placebo-controlled trials involving over 600 ulcerative
colitis patients, adverse events were fewer in Pentasa (Mesalamine) -treated patients than in
the placebo group (Pentasa (Mesalamine) 14% vs placebo 18%) and were not dose-related. Events
occurring at 1% or more are shown in the table below. Of these, only nausea and
vomiting were more frequent in the Pentasa (Mesalamine) group. Withdrawal from therapy due to
adverse events was more common on placebo than Pentasa (Mesalamine) (7% vs 4%).
Clinical laboratory measurements showed no significant abnormal trends for
any test, including measurement of hematological, liver, and kidney
function.
The following adverse events, presented by body system, were reported
infrequently (ie, less than 1%) during domestic ulcerative colitis and Crohn's
disease trials. In many cases, the relationship to Pentasa (Mesalamine) has not been
established.
One week after completion of an 8-week ulcerative colitis study, a
72-year-old male, with no previous history of pulmonary problems, developed
dyspnea. The patient was subsequently diagnosed with interstitial pulmonary
fibrosis without eosinophilia by one physician and bronchiolitis obliterans with
organizing pneumonitis by a second physician. A causal relationship between this
event and mesalamine therapy has not been established.
Published case reports and/or spontaneous postmarketing surveillance have
described infrequent instances of pericarditis, fatal myocarditis, chest pain
and T-wave abnormalities, hypersensitivity pneumonitis, pancreatitis, nephrotic
syndrome, interstitial nephritis, hepatitis, aplastic anemia, pancytopenia,
leukopenia, agranulocytosis, or anemia while receiving mesalamine therapy.
Anemia can be a part of the clinical presentation of inflammatory bowel disease.
Allergic reactions, which could involve eosinophilia, can be seen in connection
with Pentasa (Mesalamine) therapy.
The following events have been identified during post-approval use of the
Pentasa (Mesalamine) brand of mesalamine in clinical practice. Because they are reported
voluntarily from a population of unknown size, estimates of frequency cannot be
made. These events have been chosen for inclusion due to a combination of
seriousness, frequency of reporting, or potential causal connection to
mesalamine:
Pentasa (Mesalamine) Overdosage
Single oral doses of mesalamine up to 5 g/kg in pigs or a single
intravenous dose of mesalamine at 920 mg/kg in rats were not lethal.
There is no clinical experience with Pentasa (Mesalamine) overdosage. Pentasa (Mesalamine) is an
aminosalicylate, and symptoms of salicylate toxicity may be possible, such as:
tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation,
vomiting, and diarrhea. Severe intoxication with salicylates can lead to
disruption of electrolyte balance and blood-pH, hyperthermia, and
dehydration.
Pentasa (Mesalamine) Dosage And Administration
The recommended dosage for the induction of remission and the symptomatic
treatment of mildly to moderately active ulcerative colitis is 1g (4 Pentasa (Mesalamine) 250
mg capsules or 2 Pentasa (Mesalamine) 500 mg capsules) 4 times a day for a total daily dosage
of 4g. Treatment duration in controlled trials was up to 8 weeks.
Pentasa (Mesalamine) How Supplied
Pentasa (Mesalamine) controlled-release 500 mg capsules are supplied in bottles of 120
capsules (), and in bottles of 180 capsules (). Each blue capsule contains 500 mg of mesalamine in
controlled-release beads. Pentasa (Mesalamine) controlled-release capsules are identified
with a pentagonal starburst logo and Pentasa (Mesalamine) 500 mg or S429 500 mg on the
capsules.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature].
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA
189 0107 008
Licensed from Ferring A/S, Denmark © 2007 Shire US Inc. Rev. 6/2008
Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146
Pentasa (Mesalamine) Principal Display Panel
Pentasa (Mesalamine) controlled-release 500 mg capsules
