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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` APRISO safely and effectively. See full prescribing information for
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` APRISO.
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`APRISO® (mesalamine) extended-release capsules
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`Initial U.S. Approval: 1987
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`--------------------------- INDICATIONS AND USAGE -------------------------­
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`APRISO is a locally-acting aminosalicylate indicated for the
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`maintenance of remission of ulcerative colitis in adults. (1)
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`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
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`Four APRISO capsules once daily (1.5 g/day) in the morning with or
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`without food. Do not co-administer with antacids. (2)
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`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
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`Extended-release capsules: 0.375 g (3)
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`•
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`------------------------------ CONTRAINDICATIONS ----------------------------­
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`Hypersensitivity to salicylates, aminosalicylates, or any component of
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`APRISO capsules (4)
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`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
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`Renal impairment may occur. Assess renal function at the beginning of
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`treatment and periodically during therapy. (5.1)
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`Acute exacerbation of colitis symptoms can occur. (5.2)
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`Use caution with pre-existing liver disease. (5.4)
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`------------------------------ ADVERSE REACTIONS ----------------------------­
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`The most common adverse reactions (incidence ≥3%) are headache,
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`diarrhea, upper abdominal pain, nausea, nasopharyngitis, flu or flu-like
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`illness, sinusitis. (6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact Valeant
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`Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800­
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`FDA-1088 or www.fda.gov/medwatch.
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`------------------------------ DRUG INTERACTIONS ----------------------------­
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`Do not co-administer with antacids (7.1)
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`----------------------- USE IN SPECIFIC POPULATIONS ---------------------­
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`Use with caution in patients with renal disease. (5.1)
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`• Monitor blood cell counts in geriatric patients. (8.5)
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`Advise patients with phenylketonuria that APRISO contains aspartame.
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`(17)
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`See 17 for PATIENT COUNSELING INFORMATION.
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`Revised: 07/2017
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`1 INDICATIONS AND USAGE
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`2 DOSAGE AND ADMINISTRATION
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`3 DOSAGE FORMS AND STRENGTHS
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`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Renal Impairment
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`5.2 Mesalamine-Induced Acute Intolerance Syndrome
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`5.3 Hypersensitivity
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`5.4 Hepatic Impairment
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`6 ADVERSE REACTIONS
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`6.1 Clinical Studies Experience
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`6.2 Adverse Reaction Information from Other Sources
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`7 DRUG INTERACTIONS
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`7.1 Antacids
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.3 Nursing Mothers
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`13.2 Animal Toxicology and/or Pharmacology
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`14 CLINICAL STUDIES
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`14.1 Ulcerative Colitis
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`15 REFERENCES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`Patients with Phenylketonuria
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`General Counseling Information
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`* Sections or subsections omitted from the full prescribing information are not listed.
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` FULL PRESCRIBING INFORMATION
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` 1 INDICATIONS AND USAGE
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` APRISO capsules are indicated for the maintenance of remission of ulcerative colitis in patients 18 years of age and older.
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` 2 DOSAGE AND ADMINISTRATION
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` The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO
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` capsules) orally once daily in the morning. APRISO may be taken without regard to meals. APRISO should not be co-
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` administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO.
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` 3 DOSAGE FORMS AND STRENGTHS
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` Extended-release capsules containing 0.375 g mesalamine.
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` 4 CONTRAINDICATIONS
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` APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components
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`Reference ID: 4130508
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` 5 WARNINGS AND PRECAUTIONS
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` 5.1 Renal Impairment
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` Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal
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` failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to
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` mesalamine.
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` It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and
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` periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history
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` of renal disease.
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` In animal studies, the kidney was the principal organ for toxicity [see Nonclinical Toxicology (13.2)].
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` 5.2 Mesalamine-Induced Acute Intolerance Syndrome
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` Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of
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` inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3%
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` of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain
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` and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly
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` discontinue treatment with APRISO.
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` 5.3 Hypersensitivity
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` Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO
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` capsules or to other compounds that contain or are converted to mesalamine.
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` 5.4 Hepatic Impairment
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` There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered
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` mesalamine. Caution should be exercised when administering APRISO to patients with liver disease.
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` 6 ADVERSE REACTIONS
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` 6.1 Clinical Studies Experience
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` The data described below reflect exposure to APRISO in 557 patients, including 354 exposed for at least 6 months and
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` 250 exposed for greater than one year. APRISO was studied in two placebo-controlled trials (n = 367 treated with
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` APRISO) and in one open-label, long-term study (n = 190 additional patients). The population consisted of patients with
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` ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO
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` 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-
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` label study.
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` Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical
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` trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
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` observed in practice.
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` In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64%
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` of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions
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` occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions
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` occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction
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` resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%). The most common
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` reactions reported with APRISO (≥3%) are shown in Table 1 below.
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`Reference ID: 4130508
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`

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` Table 1: Treatment-Emergent Adverse Reactions during Clinical Trials
` Occurring in at Least 3% of APRISO-Treated Patients and at a Greater
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` Rate than with Placebo
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` MedDRA Preferred Term
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` APRISO 1.5 g/day
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` N=367
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` 11%
` 8%
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` 5%
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` 4%
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` 4%
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` 4%
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` 3%
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` Placebo
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` N=185
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` 8%
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` 7%
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` 3%
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` 3%
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` 3%
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` 4%
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` 3%
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` Headache
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` Diarrhea
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` Abdominal Pain Upper
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` Nausea
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` Nasopharyngitis
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` Influenza & Influenza-like illness
` Sinusitis
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` The following adverse reactions, presented by body system, were reported at a frequency less than 3% in patients treated
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` Ear and Labyrinth Disorders: tinnitus, vertigo
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`Dermatological Disorder: alopecia
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`Gastrointestinal: abdominal pain lower, rectal hemorrhage
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`Laboratory Abnormalities: increased triglycerides, decreased hematocrit and hemoglobin
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`General Disorders and Administration Site Disorders: fatigue
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`Hepatic: hepatitis cholestatic, transaminases increased
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`Renal Disorders: creatinine clearance decreased, hematuria
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`Musculoskeletal: pain, arthralgia
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`Respiratory: dyspnea
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` 6.2 Adverse Reaction Information from Other Sources
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` The following adverse reactions have been identified during clinical trials of a product similar to APRISO and post
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` approval use of other mesalamine-containing products such as APRISO. Because many of these reactions are reported
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` voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a
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` causal relationship to drug exposure.
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` Body as a Whole: lupus-like syndrome, drug fever
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`Cardiovascular: pericarditis, pericardial effusion, myocarditis
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`Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer
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`Hepatic: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like syndrome including changes
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`in liver enzymes
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`Hematologic: agranulocytosis, aplastic anemia
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`Nervous System: intracranial hypertension
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`Neurological/Psychiatric: peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis
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`Renal and Urinary: nephrogenic diabetes insipidus
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`Respiratory/Pulmonary: eosinophilic pneumonia, interstitial pneumonitis
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`Skin: psoriasis, pyoderma gangrenosum, erythema nodosum
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`Renal/Urogenital: reversible oligospermia
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` 7 DRUG INTERACTIONS
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` Based on in vitro studies, APRISO is not expected to inhibit the metabolism of drugs that are substrates of CYP1A2,
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` CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
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`Reference ID: 4130508
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`

`

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` 7.1 Antacids
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` Because the dissolution of the coating of the granules in APRISO capsules depends on pH, APRISO capsules should not
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` 8 USE IN SPECIFIC POPULATIONS
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` 8.1 Pregnancy
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` Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to
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` 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at
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` doses up to 495 mg/kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and
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` have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate
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` and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human
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` response, this drug should be used during pregnancy only if clearly needed.
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` Mesalamine is known to cross the placental barrier.
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` 8.3 Nursing Mothers
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` Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human
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` using mesalamine. Caution should be exercised when APRISO is administered to a nursing woman.
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` 8.4 Pediatric Use
` Safety and effectiveness of APRISO capsules in pediatric patients have not been established.
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` 8.5 Geriatric Use
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` Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over to determine whether they
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` and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing APRISO.
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` Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood
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` containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine
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` Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be
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` care should be taken when prescribing this drug therapy [see Warnings and Precautions (5.1)].
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` 10 OVERDOSAGE
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` APRISO is an aminosalicylate, and symptoms of salicylate toxicity include hematemesis, tachypnea, hyperpnea, tinnitus,
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` and potentially to other organ (e.g., renal and liver) involvement. There is no specific antidote for mesalamine overdose;
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` however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. This includes
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` prevention of further gastrointestinal tract absorption by emesis and, if necessary, by gastric lavage. Fluid and electrolyte
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` imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should
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` be maintained. APRISO is a pH-dependent delayed-release product and this factor should be considered when treating a
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` suspected overdose.
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`Reference ID: 4130508
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`

`

`
`
` 11 DESCRIPTION
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` Each APRISO capsule is a delayed- and extended-release dosage form for oral administration. Each capsule contains
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` 0.375 g of mesalamine USP (5-aminosalicylic acid, 5-ASA), an anti-inflammatory drug. The structural formula of
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` mesalamine is:
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`Molecular Weight: 153.14
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`Molecular Formula: C7H7NO3
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`Each APRISO capsule contains granules composed of mesalamine in a polymer matrix with an enteric coating that
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`dissolves at pH 6 and above.
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`The inactive ingredients of APRISO capsules are colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose,
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`simethicone emulsion ethyl acrylate/methyl methacrylate copolymer nonoxynol 100 dispersion, hypromellose,
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`methacrylic acid copolymer, talc, titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone, vanilla
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`flavor, and edible black ink.
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` 12 CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` The mechanism of action of mesalamine (5-ASA) is unknown, but appears to be local to the intestinal mucosa rather than
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` systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e.,
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` prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in
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` patients with ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of
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` arachidonic acid metabolites.
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` 12.3 Pharmacokinetics
` Absorption
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` The pharmacokinetics of 5-ASA and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), were studied after a
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` single and multiple oral doses of 1.5 g APRISO in a crossover study in healthy subjects under fasting conditions. In the
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` multiple-dose period, each subject received APRISO 1.5 g (4 x 0.375 g capsules) every 24 hours (QD) for 7 consecutive
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` days. Steady state was reached on Day 6 of QD dosing based on trough concentrations.
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` After single and multiple doses of APRISO, peak plasma concentrations were observed at about 4 hours post dose. At
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` steady state, moderate increases (1.5-fold and 1.7-fold) in systemic exposure (AUC0-24) to 5-ASA and N-Ac-5-ASA were
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`observed when compared with a single-dose of APRISO.
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`Pharmacokinetic parameters after a single dose of 1.5 g APRISO and at steady state in healthy subjects under fasting
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`condition are shown in Table 2.
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`Reference ID: 4130508
`
`

`

`
` Table 2: Single Dose and Multiple Dose Mean (±SD) Plasma Pharmacokinetic
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` Parameters of Mesalamine (5-ASA) and N-Ac-5-ASA after 1.5 g
` APRISO Administration in Healthy Subjects
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` Single Dose
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` 11 ± 5
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` 14 ± 5
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` 2.1 ± 1.1
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` 4 (2, 16)
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` 9 ± 7
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` Mesalamine (5-ASA)
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` AUC0-24 (μg*h/mL)
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` AUC0-inf (μg*h/mL)
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` Cmax (μg/mL)
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`Tmax (h) a
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`t½ (h)b
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` N-Ac-5-ASA
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` AUC0-24 (μg*h/mL)
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` 26 ± 6
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` AUC0-inf (μg*h/mL)
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` 51 ± 23
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` 2.8 ± 0.8
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` Cmax (μg/mL)
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`Tmax (h)a
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` 4 (4, 12)
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`t½ (h)b
` 12 ± 11
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` a Median (range); b Harmonic mean (pseudo SD); c after 7 days of treatment
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` Multiple Dosec
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` 17 ± 6
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` 2.7 ± 1.1
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` 4 (2, 8)
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` 10 ± 8
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` 37 ± 9
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` 3.4 ± 0.9
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` 5 (2, 8)
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` 14 ± 10
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` In a separate study (n = 30), it was observed that under fasting conditions about 32% ± 11% (mean ± SD) of the
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` administered dose was systemically absorbed based on the combined cumulative urinary excretion of 5-ASA and N-Ac-5­
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` ASA over 96 hours post-dose.
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` The effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in APRISO
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` capsules) was evaluated in 30 healthy subjects. Subjects received 1.6 g of mesalamine granules in sachet (2 x 0.8 g)
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` following an overnight fast or a high fat meal in a crossover study. Under fed conditions, tmax for both 5-ASA and N-Ac-
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`5-ASA was prolonged by 4 and 2 hours, respectively. A high fat meal did not affect Cmax for 5-ASA, but a 27% increase
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`in the cumulative urinary excretion of 5-ASA was observed with a high fat meal. The overall extent of absorption of N­
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`Ac-5-ASA was not affected by a high fat meal. As APRISO and mesalamine granules in sachet were bioequivalent,
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`APRISO can be taken without regard to food.
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`Distribution
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`In an in vitro study, at 2.5 μg/mL, mesalamine and N-Ac-5-ASA are 43 ± 6% and 78 ± 1% bound, respectively, to plasma
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`proteins. Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at concentrations ranging from 1
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`Metabolism
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`The major metabolite of mesalamine is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is formed by N-acetyltransferase
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`activity in the liver and intestinal mucosa.
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`Elimination
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`Following single and multiple doses of APRISO, the mean half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours
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`for N-Ac-5-ASA. Of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the
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`urine, compared with about 30% of the dose excreted as N-Ac-5-ASA.
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`In Vitro Drug-Drug Interaction Study
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`In an in vitro study using human liver microsomes, 5-ASA and its metabolite, N-Ac-5-ASA, were shown not to inhibit the
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`major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Therefore, mesalamine and its
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`metabolite are not expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9, CYP2C19,
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`CYP2D6, or CYP3A4.
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`Reference ID: 4130508
`
`

`

`
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` 13 NONCLINICAL TOXICOLOGY
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` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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` 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
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` doses are about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day
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`(30 mg/kg if 50 kg body weight assumed or 1110 mg/m2), respectively, based on body surface area. Mesalamine was
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`negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid
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`exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test. Mesalamine at
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`oral doses up to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area) was found to have
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`no effect on fertility or reproductive performance in rats.
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` 13.2 Animal Toxicology and/or Pharmacology
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` Renal Toxicity
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` Animal studies with mesalamine (13-week and 26-week oral toxicity studies in rats, and 26-week and 52-week oral
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` toxicity studies in dogs) have shown the kidney to be the major target organ of mesalamine toxicity. Oral doses of
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` 40 mg/kg/day (about 0.20 times the human dose, on the basis of body surface area) produced minimal to slight tubular
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` 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
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` produced renal lesions including tubular degeneration, tubular mineralization, and papillary necrosis. Oral doses of
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` 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
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` lesions including tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.
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` Overdosage
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` Single oral doses of 800 mg/kg (about 2.2 times the recommended human dose, on the basis of body surface area) and
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` 1800 mg/kg (about 9.7 times the recommended human dose, on the basis of body surface area) of mesalamine were lethal
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` to mice and rats, respectively, and resulted in gastrointestinal and renal toxicity.
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` 14 CLINICAL STUDIES
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` 14.1 Ulcerative Colitis
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` Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult
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` patients in remission from ulcerative colitis. The study populations had a mean age of 46 years (11% age 65 years or
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` older), were 53% female, and were primarily white (92%).
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`Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index1 (DAI), which is a
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`sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s
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`rating of disease activity. Each subscore can range from 0 to 3, for a total possible DAI score of 12.
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`At baseline, approximately 80% of patients had a total DAI score of 0 or 1.0. Patients were randomized 2:1 to receive
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`either APRISO 1.5 g or placebo once daily in the morning for six months. Patients were assessed at baseline, 1 month,
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`3 months, and 6 months in the clinic, with endoscopy performed at baseline, at end of study, or if clinical symptoms
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`developed. Relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal appearance subscale score
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`of 2 or more using the DAI. The analysis of the intent-to-treat population was a comparison of the proportions of patients
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`who remained relapse-free at the end of six months of treatment. For the table below (Table 3) all patients who
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`prematurely withdrew from the study for any reason were counted as relapses.
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`In both studies, the proportion of patients who remained relapse-free at six months was greater for APRISO than for
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`placebo.
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`Reference ID: 4130508
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` Table 3: Percentage of Patients Relapse-Free* through 6 Months in APRISO
` Maintenance Studies
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` APRISO
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` Difference
` Placebo
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` 1.5 g/day
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` P-value
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` (95% C.I.)
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` % (# no relapse/N)
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` % (# no relapse/N)
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` <0.001
` 17% (5.5, 29.2)
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` 51% (49/96)
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` 68% (143/209)
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` Study 1
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` 0.046
` 12% (0, 24.5)
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` 59% (55/93)
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` 71% (117/164)
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` Study 2
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` ∗ Relapse counted as rectal bleeding score ≥ 1 and mucosal appearance score ≥ 2, or premature withdrawal from study.
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` Examination of gender subgroups did not identify difference in response to APRISO among these subgroups. There were
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` too few elderly and too few African-American patients to adequately assess difference in effects in those populations.
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` The use of APRISO for treating ulcerative colitis beyond six months has not been evaluated in controlled clinical trials.
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` 15 REFERENCES
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` 1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the
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` treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 1987;92(6):1894-1898.
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` 16 HOW SUPPLIED/STORAGE AND HANDLING
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` APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G”
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` and “M” on either side of a black band imprinted on the capsule.
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` NDC 65649-103-02 Bottles of 120 capsules
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` Storage:
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` Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled
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` Room Temperature].
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` 17 PATIENT COUNSELING INFORMATION
` Patients with Phenylketonuria
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` Inform patients with phenylketonuria (PKU) or their caregivers that each APRISO capsule contains aspartame
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`•
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` equivalent to 0.56 mg of phenylalanine, so that the recommended adult dosing provides an equivalent of 2.24 mg
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` of phenylalanine per day.
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` General Counseling Information
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` Instruct patients not to take APRISO capsules with antacids, because it could affect the way APRISO dissolves.
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`•
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` Instruct patients to contact a health care provider if they experience a worsening of ulcerative colitis symptoms,
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`•
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` because it could be due to a reaction to APRISO.
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`Reference ID: 4130508
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`Manufactured for:
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`Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC
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`Bridgewater, NJ 08807 USA
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`U.S. Patent Numbers: 6,551,620; 7,547,451; 8,337,886; 8,496,965; 8,865,688; 8,911,778; 8,940,328; and 8,956,647
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`Apriso is a trademark of Valeant Pharmaceuticals International, Inc., or its affiliates.
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`©Valeant Pharmaceuticals North America LLC
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`Please see www.salix.com for patent information.
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`Update p/n
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`Reference ID: 4130508
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