Apriso Information
Apriso (Mesalamine) Indications And Usage
Apriso (Mesalamine) capsules are indicated for the maintenance of remission of
ulcerative colitis in patients 18 years of age and older.
Apriso (Mesalamine) Dosage And Administration
The recommended dose for maintenance of remission of ulcerative
colitis in adult patients is 1.5 g (four Apriso (Mesalamine) capsules) orally once
daily in the morning. Apriso (Mesalamine) may be taken without regard to
meals. Apriso (Mesalamine) should not be co-administered with antacids. An
evaluation of renal function is recommended before initiating therapy
with Apriso (Mesalamine) .
Apriso (Mesalamine) Dosage Forms And Strengths
Extended-release capsules containing 0.375 g
mesalamine.
Apriso (Mesalamine) Contraindications
Apriso (Mesalamine) is contraindicated in patients with hypersensitivity to
salicylates or aminosalicylates or to any of the components of Apriso (Mesalamine)
capsules.
Apriso (Mesalamine) Warnings And Precautions
Renal impairment, including minimal change nephropathy,
acute and chronic interstitial nephritis, and, rarely, renal
failure, has been reported in patients given products such as
Apriso (Mesalamine) that contain mesalamine or are converted to
mesalamine.
It is recommended that patients have an evaluation of
renal function prior to initiation of Apriso (Mesalamine) therapy and
periodically while on therapy. Exercise caution when using
Apriso (Mesalamine) in patients with known renal dysfunction or a history of
renal disease.
In animal studies, the kidney was the principal organ for
toxicity
Apriso (Mesalamine) Adverse Reactions
The data described below reflect exposure to Apriso (Mesalamine) in
557 patients, including 354 exposed for at least 6 months and
250 exposed for greater than one year. Apriso (Mesalamine) was studied in two
placebo-controlled trials (n = 367 treated
with Apriso (Mesalamine) ) and in one open-label, long-term study (n = 190
additional patients). The population consisted of
patients with ulcerative colitis; the mean age was 47 years,
54% were female, and 93% were white. Patients
received doses of Apriso (Mesalamine) 1.5 g administered orally once per day
for six months in the placebo-controlled trials and for up to 24
months in the open-label study.
Because clinical studies are conducted under widely
varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the
rates observed in practice.
In the two placebo-controlled trials, 59% of
Apriso (Mesalamine) -treated patients experienced an adverse reaction compared
with 64% of placebo patients. Most adverse
reactions with Apriso (Mesalamine) were mild or moderate in
severity. Severe adverse reactions occurred in
6% of Apriso (Mesalamine) -treated patients and 5% of
placebo-treated patients. Discontinuations due to
adverse reactions occurred in 11% of Apriso (Mesalamine) -treated
patients and 17% of placebo-treated patients; the most
common adverse reaction resulting in study discontinuation was
recurrence of ulcerative colitis (Apriso (Mesalamine) 6%, placebo
14%). The most common reactions reported with
Apriso (Mesalamine) (≥3%) are shown in Table 1 below.
The following adverse reactions, presented by body
system, were reported at a frequency less than 3% in
patients treated with Apriso (Mesalamine) for up to 24 months in controlled
and open-label trials.
Ear and Labyrinth
Disorders
Dermatological
Disorder
Gastrointestinal
Laboratory
Abnormalities
General Disorders and
Administration Site
Disorders
Hepatic
Renal
Disorders
Musculoskeletal
Respiratory
The following adverse reactions have been identified
during clinical trials of a product similar to Apriso (Mesalamine) and post
approval use of other mesalamine-containing products such as
Apriso (Mesalamine) . Because many of these reactions are reported
voluntarily from a population of unknown size, it is not always
possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Body as a
Whole
Cardiovascular
Gastrointestinal
Hepatic
Hematologic
Neurological/Psychiatric
Respiratory/Pulmonary
Skin
Renal/Urogenital
Apriso (Mesalamine) Drug Interactions
Based on in vitro studies, Apriso (Mesalamine) is not expected to inhibit the
metabolism of drugs that are substrates of CYP1A2, CYP2C9, CYP2C19,
CYP2D6, or CYP3A4.
Apriso (Mesalamine) Use In Specific Populations
Pregnancy Category B. Reproduction studies with
mesalamine have been performed in rats at oral doses up to 320
mg/kg/day (about 1.7 times the recommended human dose based on a
body surface area comparison) and rabbits at doses up to 495
mg/kg/day (about 5.4 times the recommended human dose based on a
body surface area comparison) and have revealed no evidence of
impaired fertility 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, this drug should be used during pregnancy only if
clearly needed.
Mesalamine is known to cross the placental
barrier.
Clinical studies of Apriso (Mesalamine) 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
responses between 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 Apriso (Mesalamine) .
Reports from uncontrolled clinical studies and
postmarketing reporting systems suggested a higher incidence of
blood dyscrasias, i.e., neutropenia, pancytopenia, in patients
who were 65 years or older who were taking mesalamine-containing
products such as Apriso (Mesalamine) . Caution should be taken to
closely monitor blood cell counts during mesalamine
therapy.
Mesalamine is known to be substantially excreted by the
kidney, and the risk of adverse reactions to this drug may be
greater in patients with impaired renal
function. Because elderly patients are more likely to
have decreased renal function, care should be taken when
prescribing this drug therapy. .
Apriso (Mesalamine) Overdosage
Apriso (Mesalamine) is an aminosalicylate, and symptoms of salicylate toxicity
include hematemesis, tachypnea, hyperpnea, tinnitus, deafness, lethargy,
seizures, confusion, or dyspnea. Severe intoxication may lead to
electrolyte and blood pH imbalance and potentially to other organ (e.g.,
renal and liver) involvement. There is no specific antidote
for mesalamine overdose; however, conventional therapy for salicylate
toxicity may be beneficial in the event of acute overdosage. This
includes prevention of further gastrointestinal tract absorption by
emesis and, if necessary, by gastric lavage. Fluid and electrolyte
imbalance should be corrected by the administration of appropriate
intravenous therapy. Adequate renal function should be
maintained. Apriso (Mesalamine) is a pH-dependent delayed-release product
and this factor should be considered when treating a suspected
overdose.
Apriso (Mesalamine) Description
Each Apriso (Mesalamine) capsule is a delayed- and extended-release dosage
form for oral administration. Each capsule contains 0.375 g of
mesalamine USP (5-aminosalicylic acid, 5-ASA), an anti-inflammatory
drug. The structural formula of mesalamine is:
Molecular Weight: 153.14
Molecular Formula:
CHNO
Each Apriso (Mesalamine) capsule contains granules composed of mesalamine in a
polymer matrix with an enteric coating that dissolves at pH 6 and
above.
The inactive ingredients of Apriso (Mesalamine) capsules are colloidal silicon
dioxide, magnesium stearate, microcrystalline cellulose, simethicone
emulsion, ethylacrylate/methylmethacrylate copolymer nonoxynol 100
dispersion, hypromellose, methacrylic acid copolymer, talc, titanium
dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone,
vanilla flavor, and edible black ink.
Apriso (Mesalamine) Clinical Pharmacology
Absorption
The pharmacokinetics of 5-ASA and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), were studied after a single and multiple oral doses of 1.5 g Apriso (Mesalamine) in a crossover study in healthy subjects under fasting conditions. In the multiple-dose period, each subject received Apriso (Mesalamine) 1.5 g (4 x 0.375 g capsules) every 24 hours (QD) for 7 consecutive days. Steady state was reached on Day 6 of QD dosing based on trough concentrations.
After single and multiple doses of Apriso (Mesalamine) , peak plasma concentrations were observed at about 4 hours post dose. At steady state, moderate increases (1.5-fold and 1.7-fold) in systemic exposure (AUC) to 5-ASA and N-Ac-5-ASA were observed when compared with a single-dose of Apriso (Mesalamine) .
Pharmacokinetic parameters after a single dose of 1.5 g Apriso (Mesalamine) and at steady state in healthy subjects under fasting condition are shown in Table 2.
In a separate study (n = 30), it was observed that under fasting conditions about 32% ± 11% (mean ± SD) of the administered dose was systemically absorbed based on the combined cumulative urinary excretion of 5-ASA and N-Ac-5-ASA over 96 hours post-dose.
The effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in Apriso (Mesalamine) capsules) was evaluated in 30 healthy subjects. Subjects received 1.6 g of mesalamine granules in sachet (2 x 0.8 g) following an overnight fast or a high fat meal in a crossover study. Under fed conditions, t for both 5-ASA and N-Ac-5-ASA was prolonged by 4 and 2 hours, respectively. A high fat meal did not affect C for 5-ASA, but a 27% increase in the cumulative urinary excretion of 5-ASA was observed with a high fat meal. The overall extent of absorption of N-Ac-5-ASA was not affected by a high fat meal. As Apriso (Mesalamine) and mesalamine granules in sachet were bioequivalent, Apriso (Mesalamine) can be taken without regard to food.
Distribution
In an study, at 2.5 μg/mL, mesalamine and N-Ac-5-ASA are 43 ± 6% and 78 ± 1% bound, respectively, to plasma proteins. Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at concentrations ranging from 1 to 10 μg/mL.
Metabolism
The major metabolite of mesalamine is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is formed by N-acetyltransferase activity in the liver and intestinal mucosa.
Elimination
Following single and multiple doses of Apriso (Mesalamine) , the mean half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours for N-Ac-5-ASA. Of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about 30% of the dose excreted as N-Ac-5-ASA.
In Vitro Drug-Drug Interaction Study
In an study using human liver microsomes, 5-ASA and its metabolite, N-Ac-5-ASA, were shown not to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Therefore, mesalamine and its metabolite are not expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
Apriso (Mesalamine) Nonclinical Toxicology
Renal Toxicity
Animal studies with mesalamine (13-week and 26-week oral
toxicity studies in rats, and 26-week and 52-week oral toxicity
studies in dogs) have shown the kidney to be the major target
organ of mesalamine toxicity. Oral doses of
40 mg/kg/day (about 0.20 times the human dose, on the
basis of body surface area) produced minimal to slight tubular
injury, and doses of 160 mg/kg/day (about 0.90 times the human
dose, on the basis of body surface area) or higher in rats
produced renal lesions including tubular degeneration, tubular
mineralization, and papillary necrosis. Oral doses of
60 mg/kg/day (about 1.1 times the human dose, on the
basis of body surface area) or higher in dogs also produced
renal lesions including tubular atrophy, interstitial cell
infiltration, chronic nephritis, and papillary
necrosis.
Overdosage
Single oral doses of 800 mg/kg (about 2.2 times the
recommended human dose, on the basis of body surface area) and
1800 mg/kg (about 9.7 times the recommended human dose, on the
basis of body surface area) of mesalamine were lethal to mice
and rats, respectively, and resulted in gastrointestinal and
renal toxicity.
Apriso (Mesalamine) How Supplied/storage And Handling
Apriso (Mesalamine) is available as light blue opaque hard gelatin capsules
containing 0.375 g mesalamine and with the letters
“G” and “M” on either side of a
black band imprinted on the capsule.
NDC 65649-103-02 Bottles of 120 capsules NDC 65649-103-01
Bottles of 4 capsules
Apriso (Mesalamine) Patient Counseling Information
Manufactured by Catalent Pharma Solutions
Manufactuered for:
Salix Pharmaceuticals, Inc.
Raleigh, NC 27615
* Apriso (Mesalamine) is a trademark of Salix Pharmaceuticals, Inc.
© 2008 Salix Pharmaceuticals, Inc.
Product protected by U.S. Patent No. 6,551,620 and U.S. Patent No. 7,547,451
VENART-113-1
Apriso (Mesalamine) Package Label - Principal Display Panel - Apriso Capsules, Bottle Label
Apriso (Mesalamine) Package Label - Principal Display Panel - Apriso Capsules, Carton Label
Apriso (Mesalamine) Package Label - Principal Display Panel - Apriso Capsules, Carton Label
Apriso (Mesalamine) Package Label - Principal Display Panel - Apriso Capsules, Bottle Label
