CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-301
`
`LABELING
`
`

`

`a
`
`'
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use APRISO
`safely and effectively. See full prescribing information for APRISO.
`.
`APR1501“ (mesalamine) extended-release capsules
`Initial U.S. Approval: 1987
`
`--—-----WARNINGS AND PRECAUTIONS~----
`- Renal impairment may occur. Assess renal fimction at the beginning
`of treatment and periodically during therapy (5.1)
`. Acute exacerbation of colitis symptoms can occur (5.2)
`- Use caution with pro-existing liver disease (5.4)
`------------ADVERSE REACTIONS---—-~--------—-
`
`"""‘""INDICAT10NS AND USAGE"""""
`0 APRISO is a locally-acting aminosalicylate indicated for the maintenance of
`remission of ulcerative colitis in adults (1)
`
`- The most common adverse reactions (incidence 23%) are headache,
`diarrhea, upper abdominal pain, nausea, nasopharyngitis, flu or flu—like
`illness, sinusitis (61)
`
`-------DOSAGE AND ADMINISTRATION-----
`- Four APRISO capsules once daily (15 We) in the morning with or
`without food. Do not co—administer with antacids (2)
`.
`
`To report SUSPECTED ADVERSE REACTIONS, contact Salix
`Pharmaceuticals, Inc. at 1-800-508-0024 or FDA at l-800-FDA-1088
`or www.fda.gov/medwateh.
`
`—--—DOSAGE FORMS AND STRENGTHS-—
`- Extended-release capsules: 0.375 g (3)
`
`'
`
`................DRUG INTERACTIONS---—-—-—-——
`‘
`- Do not co-administer with antacids (7. i)
`
`——-----CONTRAINDICATIONS-----------
`0 Hypersensitivity to salicylates, aminosalicylates, or any component of
`APRISO 6811811158 (4)
`'
`
`~run—USE IN SPECIFIC POPULATIONS—u—j—
`. Use with caution in patients with renal disease (5.1)
`0 Monitor blood cell counts in geriatric patients (8.5)
`- Advise patients with phenylketonuria that APRISO contains aspartame
`(17.1)
`
`Revised: 10/2008
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`FULL PRESCRIBING INFORMATION: CONTENTS"
`
`INDICATIONS AND USAGE
`1
`DOSAGE AND ADMINISTRATION
`2
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Renal Impairment
`5.2 Mesalamine-Induced Acute Intolerance Syndrome
`5.3 Hypersensitivity
`5.4 Hepatic Impairment
`ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`6.2 Adverse Reaction lnfonnation from Other Sources
`DRUG INTERACTIONS
`7.1 Antacids
`USE IN SPECIFIC POPULATIONS
`81 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism ofAction
`12.3 Phannacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 > Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Ulcerative Colitis
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`l7
`PATIENT COUNSELING INFORMATION
`17.1 Patients with Phenylketonuria
`17.2 General Counseling Information
`
`* Sections or subsections omitted from the full prescribing information
`are not listed
`
`.
`
`6
`
`7
`
`8
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`APRISO capsules are indicated for the maintenance of remission of ulcerative colitis in
`patients 18 years of age and older.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dose for maintenance of remission of ulcerative colitis in adult
`patients is 1.5 g (four APRISO capsules) orally once daily in the morning. APRISO
`may be taken without regard to meals. APRISO should not be co-administered with
`antacids. An evaluation of renal function is recommended before initiating therapy
`with APRISO.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Extended-release capsules containing 0.375 g mesalamine.
`
`4
`
`CONTRAINDICATIONS
`
`APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates
`or to any of the components of APRISO capsules.
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Renal Impairment
`
`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 that contain mesalamine or are converted to mesalamine.
`
`It is recommended that patients have an evaluation of renal function prior to initiation. of
`APRISO therapy and periodically while on therapy. Exercise caution when using APRISO
`in patients with known renal dysfunction or a history of renal disease.
`
`In animal studies, the kidney was the principal organ for toxicity [See Nonclinz'cal Toxicology
`(13.2)]
`
`5.2 Mesalamine-Induced Acute Intolerance Syndrome
`
`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 has not been determined, it has occurred in 3% of patients in controlled clinical
`trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain
`and bloody diarrhea, sometimesfever, headache, and rash. If acute intolerance syndrome is
`suspected, promptly discontinue treatment with APRISO.
`
`
`
`,....OKOOOQext/14>U)Ny—I
`
`'r—Iy—Ir—AWNH
`
`p... 4}.
`
`l—al—nGNU:
`,_. \)
`
`Ni—db-dOKOOO
`
`[\J _
`
`NN
`
`WWWWNNNNNNNWNi—‘OOOOQGNU’I-bw
`AgwwwwwHoxoooqoxu:
`
`U.)h
`
`

`

`42
`
`43
`44
`45
`46
`47
`48
`49
`50
`51
`
`52
`
`53
`
`54
`55
`56
`57
`58
`59
`6O
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`71
`72
`
`73
`74
`
`5.3
`
`Hypersensitivity
`
`Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a
`similar reaction to APRISO capsules or to other compounds that contain or are converted to
`mesalamine.
`
`Hepatic Impairment
`5.4
`There have been reports of hepatic failure in patients with pre—existing liver disease who have
`been administered mesalamine. Caution should be exercised when administering APRISO to
`patients with liver disease.
`'
`'
`
`6
`
`ADVERSE REACTIONS
`
`6.1
`
`Clinical Studies Experience
`
`The data described below reflect exposure to APRISO in 557 patients, including 354 exposed
`for at least 6 months and 250 exposed for greater than one year. APRISO was studied in two
`placebo-controlled trials (n = 367 treated with APRISO) 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 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-treated patients experienced an adverse
`reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were
`mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated
`patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions
`occurred in 11% of APRISO-treated patients and 17% of placebo—treated patients; the most
`common adverse reaction resulting in study discontinuation was recurrence of ulcerative
`colitis (APRISO 6%, placebo 14%). The most common reactions reported with APRISO
`(23%) are shown in Table 1 below.
`
`

`

`75
`76
`77
`
`Table 1: Treatment-Emergent Adverse Reactions during Clinical Trials
`Occurring in at Least 3% of APRISO—Treated Patients
`and at a Greater Rate than with Placebo
`
`APRISO 1.5 g/day
`N=367
`
`
`
`
`
`Placebo
`MedDRA Preferred Term
`N=185
`
`
`8%
`1 1%
`Headache
`7%
`8%
`Diarrhea
`
`
`3%
`5%
`Abdominal Pain U . 9 er
`
`
`%
`4%
`Nausea
`3%
`4%
`Naso ha n_itis
`
`
`
`Influenza & Influenza-like illness
`4%
`4%
`
`Sinusitis
`3%
`3%
`
`
`
`'
`
`78
`
`79
`80
`81
`
`82
`
`83
`84
`
`85
`86
`87
`88
`
`89
`90
`
`The following adverse reactions, presented by body system, were reported at a frequency less
`than 3% in patients treated With APRISO for up to 24 months in controlled and open—label
`trials.
`
`Bar and Labyrinth Disorders: tinnitus, vertigo
`
`.
`
`Dermatological Disorder: alopecia
`v
`.
`Gastrointestinal: abdominal'pain lower, rectal hemorrhage
`
`Laboratog Abnormalities: increased triglycerides, decreased hematocrit and hemoglobin
`
`91
`General Disorders and Administration Site Disorders: fatigue
`3% m: hepatitis cholestatic, transaminases increased
`3:
`Renal Disorders: creatinine clearance decreased, hematuria
`3'67 Musculoskeletal: pain, arthralgia
`33
`Respiratog: dyspnea
`
`l 00
`
`101
`
`102
`103
`104
`105
`106
`1 07
`
`108
`
`109
`
`6.2
`
`Adverse Reaction Information from Other Sources
`
`The following adverse reactions have been identified during clinical trials of a product
`similar to APRISO and post approval use of other mesalamine-containing products such as
`APRISO. 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: lupus-like syndrome, drug fever
`
`Cardiovascular: pericarditis, pericardial effusion, myocarditis
`
`

`

`110
`111
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`113
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`116
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`138
`139
`140
`141
`
`‘ 142
`
`143
`144
`145
`146
`147
`
`148
`
`149
`
`Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding,
`perforated peptic ulcer
`
`Hepatic: jaundice, cholestaticjaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like
`syndrome including changes in liver enzymes
`
`Hematologic: agranulocytosis, aplastic anemia
`
`Neurological/Psychiatric: peripheral neuropathy, Guillain-Barré syndrome, transverse
`myelitis
`
`Respiratog/Pulmonafl: eosinophilic pneumonia, interstitial pneumonitis
`
`Skin: psoriasis, pyoderma gangrenosum, erythema nodosum
`
`Renal/Urogenital: reversible oligospermia
`
`7
`
`DRUG INTERACTIONS
`
`Based on in vitro studies, APRISO is not expected to inhibit the metabolism of drugs that are
`substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
`
`7.1
`
`Antacids
`
`Because the dissolution of the coating of the granules in APRISO capsules depends on pH,
`APRISO capsules should not be co-administered with antacids.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`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.
`
`8.3
`
`Nursing Mothers
`
`Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have
`been detected in human breast milk. The clinical significance of this has not been
`determined and there is limited experience of nursing women using mesalamine. Caution
`should be exercised when APRISO is administered to a nursing woman.
`
`8.4
`
`Pediatric Use
`
`Safety and effectiveness of APRISO capsules in pediatric patients have not been established.
`
`

`

`150
`
`151
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`152
`153
`' 154
`155
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`8.5
`
`Geriatric Use
`
`Clinical studies of APRISO 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 fiinction, and of
`concomitant disease or other drug therapy in elderly patients should be considered when
`prescribing APRISO.
`
`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. 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. [see Warning and Precautions (5.7)].
`
`10
`
`OVERDOSAGE
`
`APRISO 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 is a pH—dependent delayed-release product and this factor should be
`considered when treating a suspected overdose.
`
`11
`
`DESCRIPTION
`
`Each APRISO capsule is a delayed- and extended-release dosage form for oral
`administration. Each capsule contains 0.375 g of mesalamine USP (S—aminosalicylic acid,
`5-ASA), an anti-inflammatory drug. The structural formula of mesalamine is:
`
`H N
`2
`
`o
`
`OH
`
`OH
`
`Molecular Weight: 153.14
`Molecular Formula: C7H7NO3
`
`

`

`l90
`191
`192
`193
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`195
`196
`197
`198
`
`Each APRISO 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 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.
`
`.199
`
`‘12
`
`CLINICAL PHARMACOLOGY
`
`200
`
`201
`202
`203
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`222
`223
`
`12.1 Mechanism of Action
`
`The mechanism of action of mesalamine (S-ASA) is unknown, but appears to be local to the
`intestinal mucosa rather than systemic. Mucosal production of arachidonic acid metabolites,
`both through the cyclooxygenase pathways, i.e., prostanoids, and through-the lipoxygenase
`pathways, i.e., leukotrienes and;hydroxyeicosatetraenoic acids, is increased in patientswith
`ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking
`production of arachidonic acid metabolites.
`‘
`
`12.3
`
`Pharmacokinetics
`
`Absorption
`
`Thelpharmacokinetics 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 in a crossover
`study in healthy subjects under fasting conditions. In the multiple-dose period, each subject
`received APRISO 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, peak plasma concentrations were observed at
`about 4 hours post dose. At steady state, moderate increases (1 .S-fold and 1.7-fold) in
`systemic exposure (AUC0-24) to 5-ASA and N—Ac-S-ASA were observed when compared
`with a single-dose of APRISO.
`
`Pharmacokinetic parameters after a single dose of 1.5 g APRISO and at steady state in
`healthy subjects under fasting condition are shown in Table 2.
`
`

`

`224
`225
`226
`
`Table 2: Single Dose and Multiple Dose Mean (iSD) Plasma Pharmacokinetic
`Parameters of Mesalamine (5-ASA) and N-Ac—S-ASA
`after 1.5 g APRISO Administration in Healthy Subjects
`
`Mesalamine 5-ASA
`
`AUCo_24 (ug*h/mL)
`AUCO-inf (ug*h/mL)
`Cmax(ug/mL)
`Tmax (h) a
`ty,(h)b
`-
`N—Ac—S—ASA
`
`AUCo-24 (ug*h/mL)
`AUCo_inf(ug*h/mL)
`Cmax (pg/mL)
`Tmax (bh)a
`ty,
`
`Single Dose
`n=24
`
`Multiple Dosec
`n=24
`
`'
`
`~
`
`11 :1: 5
`14 i 5
`2.1 :t 1.1
`4 (2, 16)
`947
`
`26 i 6
`51 a: 23
`2.8 :t 0.8
`4 (4, 12)
`12 :I: 1 1
`
`'
`
`17 i 6
`-
`2.7 :t1.1
`4 (2, 8)
`104:8
`
`37 i 9
`—
`3.4 i 0.9
`5 (2, 8)
`14 :1: 10
`
`227
`228
`
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`
`240 _
`241
`
`242
`243
`244
`
`245
`
`246
`247
`
`248
`
`249
`250
`251
`252
`
`a Median (range); b Harmonic mean (pseudo SD); ° after 7 days of treatment
`
`In a separate study (11 = 30), it was observed that under fasting conditions about 32% i 11%
`(mean i SD) of the administered dose was systemically absorbed based on the combined
`cumulative urinary excretion of S-ASA and N-Ac-S-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 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, tmax for both 5—ASA and N—Ac-S-ASA was
`prolonged by 4 and 2 hours, respectively. A high fat meal did not affect Cmax 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-S-ASA was not affected by a high fat meal.
`As APRISO and mesalamine granules in sachet were bioequivalent, APRISO can be taken
`without regard to food.
`
`Distribution
`
`In an in vitro study, at 2.5 ug/mL, mesalamine and N-Ac-5-ASA are 43 i 6% and 78 i 1%
`bound, respectively, to plasma proteins. Protein binding of N—Ac-S-ASA does not appear to
`be concentration dependent at concentrations ranging from 1 to 10 ug/mL.
`
`Metabolism
`
`The major metabolite of mesalamine is N—acetyl-S-aminosalicylic acid (N—Ac-S-ASA). It is
`formed by N—acetyltransferase activity in the liver and intestinal mucosa.
`
`Elimination
`
`Following single and multiple doses of APRISO, the mean half-lives were 9 to 10 hours for
`5-ASA, and 12 to 14 hours for N—Ac-S-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-S-ASA.
`
`

`

`253
`254
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`259
`260
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`261
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`292
`293
`
`. In Vitro Drug—Drug Interaction Study
`
`In an in vitro study using human liver microsomes, 5-ASA and its metabolite, N-Ac-S-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.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1 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 about 2. 6 and 5.4 times the recommended human
`dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight
`assumed or 1110 mg/m2), respectively, based on body surface area. Mesalamine was
`negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test,
`the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse
`bone marrow micronucleus test. Mesalamine at oral doses up to 320 mg/kg (about 1.7 times
`the recommended human dose based on body surface area) was found to have no effect on
`fertility or reproductive performance in rats. _
`
`13.2 Animal Toxicology and/or Pharmacology
`
`Renal Toxicily
`
`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
`resultedin gastrointestinal and renal toxicity.
`
`14
`
`CLINICAL STUDIES
`
`14.1 Ulcerative Colitis
`
`Two similar, randomized, double-blind, placebo-controlled, multi-center studies were
`conducted in a total of 5 62 adult patients in remission from ulcerative colitis. The study
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`populations had a mean age of 46 years (11% age 65 years or older), were 53% female, and
`were primarily white (92%).
`
`Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity
`Index1 (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding,
`mucosal appearance on endoscopy, and physician’s rating of disease activity. Each subscore
`can range from 0 to 3, for a total possible DAI score of 12.
`
`At baseline, approximately 80% of patients had a total DAI score of 0 or 1.0. Patients were
`randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six
`months. Patients were assessed at baseline, 1 month, 3 months, and 6 months in the clinic,
`with endoscopy performed at baseline, at end of study, or if clinical symptoms developed.
`Relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal
`appearance subscale score of 2 or more using the DA1. The analysis of the intent-to-treat
`population was a comparison of the proportions of patients who remained relapse-free at the
`end of six months of treatment. For the table below (Table 3) all patients who prematurely
`withdrew from the study for any reason were counted as relapses.
`
`In both studies, the proportion of patients who remained relapse-free at six months was
`greater for APRISO than for placebo.
`
`Table 3: Percentage of Patients Relapse-Free* through 6 Months
`in APRISO Maintenance Studies
`
`
`
`APRISO
`
`‘
`
`
`
`1.5 g/day
`% # no relase/N
`
`Placebo
`% # no relapse/N
`
`Difference
`95% CI.)
`
`P-value
`
`68% (143/209)
`
`51% (49/96)
`
`17% (5.5, 29.2)
`
`<0.oo1
`
`Study2
`
`71% (ll7/164)
`
`59% (55/93)
`
`12% (0, 24.5)
`
`0.046
`
`
`
`'* Relapse counted as rectal bleeding score 2 l and mucosal appearance score 2 2, or premature withdrawal
`from study.
`
`Examination of gender subgroups did not identify difference in response to APRISO among
`these subgroups. There were too few elderly and too few African-American patients to
`adequately assess difference in effects in those populations.
`
`The use of APRISO for treating ulcerative colitis beyond six months has not been evaluated
`in controlled clinical trials.
`
`15
`
`REFERENCES
`
`1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al.
`5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis,
`proctosigmoiditis, and proctitis. Gastroenterology 1987 ;92(6):l 894-1 898.
`
`

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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” 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
`
`.
`_
`Storage:
`Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and
`86°F). See USP Controlled Room Temperature.
`
`17
`
`17.1
`
`PATIENT COUNSELING INFORMATION
`
`Patients with Phenylketonuria
`
`Inform patients with phenylketonuria (PKU) or their caregivers that each APRISO
`capsule contains aspartame equivalent to 0.56 mg of phenylalanine, so that the
`recommended adult dosing provides an equivalent of 2.24 mg of phenylalanine per
`day.
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`17.2
`
`General Counseling Information
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`Instruct patients not to take APRISO capsules with antacids, because it could affect
`the way APRISO dissolves.
`
`Instruct patients to contact a health care provider if they experience a worsening of
`ulcerative colitis symptoms, because it could be due to a reaction to APRISO.
`
`Manufactured by Catalent Pharma Solutions for Salix Pharmaceuticals, Inc., Morrisville, NC
`27560
`* APRISOTM is a trademark of Salix Pharmaceuticals, Inc.
`© 2008 Salix Pharmaceuticals, Inc.
`
`Product protected by US Patent No. 6,551,620
`
`VENART—l 13-0
`
`

`

`This is a representation of an'electronic record thatwas signed electronically and
`this page is the manifestation of the electronic signature.
`
`Donna Griebel
`10/31/2008 02:57:51 PM
`
`