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
