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.
`
`APRISO™ (mesalamine) extended-release capsules
`Initial U.S. Approval: 1987
`
`
`-----------INDICATIONS AND USAGE----------
`• APRISO is a locally-acting aminosalicylate indicated for the maintenance of
`remission of ulcerative colitis in adults (1)
`
`-------DOSAGE AND ADMINISTRATION----­
`• Four APRISO capsules once daily (1.5 g/day) in the morning with or
`
`without food. Do not co-administer with antacids (2)
`
`
`----DOSAGE FORMS AND STRENGTHS----
`• Extended-release capsules: 0.375 g (3)
`
`
`------------CONTRAINDICATIONS------------
`
`• Hypersensitivity to salicylates, aminosalicylates, or any component of
`
`APRISO capsules (4)
`
`
`
`
`
`
`
`
`--------WARNINGS AND PRECAUTIONS------
`• Renal impairment may occur. Assess renal function at the beginning
`of treatment and periodically during therapy (5.1)
`• Acute exacerbation of colitis symptoms can occur (5.2)
`• Use caution with pre-existing liver disease (5.4)
`
`---------------ADVERSE REACTIONS----------------
`• The most common adverse reactions (incidence ≥3%) are headache,
`diarrhea, upper abdominal pain, nausea, nasopharyngitis, flu or flu-like
`illness, sinusitis (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Salix
`
`Pharmaceuticals, Inc. at 1-800-508-0024 or FDA at 1-800-FDA-1088
`
`or www.fda.gov/medwatch.
`
`
`
`-----------------DRUG INTERACTIONS---------------­
`• Do not co-administer with antacids (7.1)
`
`
`
`
`
`--------USE IN SPECIFIC POPULATIONS---------
`• Use with caution in patients with renal disease (5.1)
`• 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*
`
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Renal Impairment
`
`5.2 Mesalamine-Induced Acute Intolerance Syndrome
`
`5.3 Hypersensitivity
`
`5.4 Hepatic Impairment
`6
`ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`6.2 Adverse Reaction Information from Other Sources
`7
`DRUG INTERACTIONS
`
`7.1 Antacids
`8
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`
`
`
`
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`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
`17 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
`
`
`
`

`

`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`APRISO capsules are indicated for the maintenance of remission of ulcerative colitis in
`patients 18 years of age and older.
`
`
`DOSAGE AND ADMINISTRATION
`2
`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.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Extended-release capsules containing 0.375 g mesalamine.
`
`
`CONTRAINDICATIONS
`4
`APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates
`or to any of the components of APRISO capsules.
`
`WARNINGS AND PRECAUTIONS
`5
`Renal Impairment
`5.1
`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 Nonclinical 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, sometimes fever, headache, and rash. If acute intolerance syndrome is
`suspected, promptly discontinue treatment with APRISO.
`
`
`

`

`5.3 Hypersensitivity
`42
`43
`Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a
`44
`similar reaction to APRISO capsules or to other compounds that contain or are converted to
`45 mesalamine.
`
`46
`
`5.4 Hepatic Impairment
`47
`48
`There have been reports of hepatic failure in patients with pre-existing liver disease who have
`49
`been administered mesalamine. Caution should be exercised when administering APRISO to
`
`patients with liver disease.
`50
`51
`
`ADVERSE REACTIONS
`6
`
`52
`Clinical Studies Experience
`6.1
`53
`54
`The data described below reflect exposure to APRISO in 557 patients, including 354 exposed
`55
`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
`56
`
`57
`study (n = 190 additional patients). The population consisted of patients with ulcerative
`58
`colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received
`59
`doses of APRISO 1.5 g administered orally once per day for six months in the placebo­
`60
`controlled trials and for up to 24 months in the open-label study.
`61
`
`62 Because clinical studies are conducted under widely varying conditions, adverse reaction
`63
`rates observed in the clinical trials of a drug cannot be directly compared to rates in the
`64
`clinical trials of another drug and may not reflect the rates observed in practice.
`65
`
`In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse
`66
`67
`reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were
`68 mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated
`69
`patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions
`70
`occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most
`71
`common adverse reaction resulting in study discontinuation was recurrence of ulcerative
`72
`colitis (APRISO 6%, placebo 14%). The most common reactions reported with APRISO
`(≥3%) are shown in Table 1 below.
`73
`74
`
`
`

`

`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
`
`MedDRA Preferred Term
`APRISO 1.5 g/day
`
`N=367
`11%
`8%
`5%
`4%
`4%
`4%
`3%
`
`
`Headache
`Diarrhea
`Abdominal Pain Upper
`Nausea
`Nasopharyngitis
`
`Influenza & Influenza-like illness
`Sinusitis
`
`Placebo
`N=185
`8%
`7%
`3%
`3%
`3%
`4%
`3%
`
`78
`
`79
`The following adverse reactions, presented by body system, were reported at a frequency less
`80
`than 3% in patients treated with APRISO for up to 24 months in controlled and open-label
`81
`trials.
`82
`
`83
`Ear and Labyrinth Disorders: tinnitus, vertigo
`84
`
`85 Dermatological Disorder: alopecia
`86
`
`87 Gastrointestinal: abdominal pain lower, rectal hemorrhage
`88
`
`Laboratory Abnormalities: increased triglycerides, decreased hematocrit and hemoglobin
`89
`90
`
`91 General Disorders and Administration Site Disorders: fatigue
`
`92
`
`93 Hepatic: hepatitis cholestatic, transaminases increased
`94
`
`95 Renal Disorders: creatinine clearance decreased, hematuria
`96
`
`97 Musculoskeletal: pain, arthralgia
`
`98
`99 Respiratory: dyspnea
`
`100
`Adverse Reaction Information from Other Sources
`6.2
`101
`102
`The following adverse reactions have been identified during clinical trials of a product
`103
`similar to APRISO and post approval use of other mesalamine-containing products such as
`104 APRISO. Because many of these reactions are reported voluntarily from a population of
`105
`unknown size, it is not always possible to reliably estimate their frequency or establish a
`106
`causal relationship to drug exposure.
`
`107
`108 Body as a Whole: lupus-like syndrome, drug fever
`
`109 Cardiovascular: pericarditis, pericardial effusion, myocarditis
`
`

`

`110 Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding,
`111
`perforated peptic ulcer
`112 Hepatic: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like
`113
`syndrome including changes in liver enzymes
`114 Hematologic: agranulocytosis, aplastic anemia
`115 Neurological/Psychiatric: peripheral neuropathy, Guillain-Barré syndrome, transverse
`116 myelitis
`117 Respiratory/Pulmonary: eosinophilic pneumonia, interstitial pneumonitis
`
`Skin: psoriasis, pyoderma gangrenosum, erythema nodosum
`118
`119 Renal/Urogenital: reversible oligospermia
`120
`
`DRUG INTERACTIONS
`7
`121
`122 Based on in vitro studies, APRISO is not expected to inhibit the metabolism of drugs that are
`123
`substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
`124
`
`Antacids
`7.1
`125
`126 Because the dissolution of the coating of the granules in APRISO capsules depends on pH,
`127 APRISO capsules should not be co-administered with antacids.
`128
`
`USE IN SPECIFIC POPULATIONS
`8
`129
`Pregnancy
`8.1
`130
`131
`Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats
`132
`at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a
`133
`body surface area comparison) and rabbits at doses up to 495 mg/kg/day (about 5.4 times the
`134
`recommended human dose based on a body surface area comparison) and have revealed no
`135
`evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however,
`136
`no adequate and well-controlled studies in pregnant women. Because animal reproduction
`137
`studies are not always predictive of human response, this drug should be used during
`138
`pregnancy only if clearly needed.
`139
`
`140 Mesalamine is known to cross the placental barrier.
`141
`
`Nursing Mothers
`8.3
`142
`143
`Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have
`144
`been detected in human breast milk. The clinical significance of this has not been
`145
`determined and there is limited experience of nursing women using mesalamine. Caution
`146
`should be exercised when APRISO is administered to a nursing woman.
`147
`
`Pediatric Use
`8.4
`148
`149
`Safety and effectiveness of APRISO capsules in pediatric patients have not been established.
`
`

`

`
`150
`8.5 Geriatric Use
`151
`152 Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over
`153
`to determine whether they respond differently than younger subjects. Other reported clinical
`154
`experience has not identified differences in responses between elderly and younger patients.
`155
`In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of
`156
`concomitant disease or other drug therapy in elderly patients should be considered when
`157
`prescribing APRISO.
`158
`
`159 Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a
`160
`higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65
`161
`years or older who were taking mesalamine-containing products such as APRISO. Caution
`162
`should be taken to closely monitor blood cell counts during mesalamine therapy.
`163
`
`164 Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse
`165
`reactions to this drug may be greater in patients with impaired renal function. Because
`166
`elderly patients are more likely to have decreased renal function, care should be taken when
`prescribing this drug therapy. [see Warning and Precautions (5.1)].
`167
`168
`
`OVERDOSAGE
`10
`169
`170 APRISO is an aminosalicylate, and symptoms of salicylate toxicity include hematemesis,
`171
`tachypnea, hyperpnea, tinnitus, deafness, lethargy, seizures, confusion, or dyspnea. Severe
`172
`intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ
`173
`(e.g., renal and liver) involvement. There is no specific antidote for mesalamine overdose;
`174
`however, conventional therapy for salicylate toxicity may be beneficial in the event of acute
`175
`overdosage. This includes prevention of further gastrointestinal tract absorption by emesis
`176
`and, if necessary, by gastric lavage. Fluid and electrolyte imbalance should be corrected by
`177
`the administration of appropriate intravenous therapy. Adequate renal function should be
`178 maintained. APRISO is a pH-dependent delayed-release product and this factor should be
`179
`considered when treating a suspected overdose.
`180
`
`181
`182
`183
`184
`185
`
`DESCRIPTION
`11
`Each APRISO 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:
`
`
`NH2
`
`O
`
`OH
`
`OH
`
`
`186
`187 Molecular Weight: 153.14
`
`188 Molecular Formula: C7H7NO3
`
`189
`
`

`

`Each APRISO capsule contains granules composed of mesalamine in a polymer matrix with
`190
`an enteric coating that dissolves at pH 6 and above.
`191
`192
`
`The inactive ingredients of APRISO capsules are colloidal silicon dioxide, magnesium
`193
`
`stearate, microcrystalline cellulose, simethicone emulsion, ethylacrylate/methylmethacrylate
`194
`copolymer nonoxynol 100 dispersion, hypromellose, methacrylic acid copolymer, talc,
`195
`titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone, vanilla flavor,
`196
`and edible black ink.
`197
`198
`
`12
`CLINICAL PHARMACOLOGY
`
`199
`12.1 Mechanism of Action
`200
`The mechanism of action of mesalamine (5-ASA) is unknown, but appears to be local to the
`201
`intestinal mucosa rather than systemic. Mucosal production of arachidonic acid metabolites,
`202
`both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase
`203
`pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with
`204
`ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking
`205
`production of arachidonic acid metabolites.
`206
`207
`
`12.3 Pharmacokinetics
`208
`Absorption
`209
`
`The pharmacokinetics of 5-ASA and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5­
`210
`211 ASA), were studied after a single and multiple oral doses of 1.5 g APRISO in a crossover
`212
`study in healthy subjects under fasting conditions. In the multiple-dose period, each subject
`213
`received APRISO 1.5 g (4 x 0.375 g capsules) every 24 hours (QD) for 7 consecutive days.
`214
`Steady state was reached on Day 6 of QD dosing based on trough concentrations.
`215
`
`216 After single and multiple doses of APRISO, peak plasma concentrations were observed at
`217
`about 4 hours post dose. At 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 observed when compared
`218
`219 with a single-dose of APRISO.
`220
`
`Pharmacokinetic parameters after a single dose of 1.5 g APRISO and at steady state in
`221
`222
`healthy subjects under fasting condition are shown in Table 2.
`223
`
`
`

`

`224
`225
`226
`
`
`
`
`
`37 ± 9
`-
`3.4 ± 0.9
`5 (2, 8)
`14 ± 10
`
`Table 2: Single Dose and Multiple Dose Mean (±SD) Plasma Pharmacokinetic
`Parameters of Mesalamine (5-ASA) and N-Ac-5-ASA
`after 1.5 g APRISO Administration in Healthy Subjects
`Multiple Dosec
`Single Dose
`
`(n=24)
`(n=24)
`17 ± 6
`11 ± 5
`-
`14 ± 5
`2.7 ± 1.1
`2.1 ± 1.1
`4 (2, 8)
`4 (2, 16)
`9 ± 7
`10 ± 8
`
`
`Mesalamine (5-ASA)
`
`AUC0-24 (µg*h/mL)
`AUC0-inf (µg*h/mL)
`Cmax (µg/mL)
`
`Tmax (h) a
`
`
`t½ (h)b
`
` N-Ac-5-ASA
`
`AUC0-24 (µg*h/mL)
`26 ± 6
`51 ± 23
`AUC0-inf (µg*h/mL)
`2.8 ± 0.8
`Cmax (µg/mL)
`
`Tmax (h)a
`4 (4, 12)
`
`
`t½ (h)b
`12 ± 11
`
` a Median (range); b Harmonic mean (pseudo SD); c after 7 days of treatment
`
`
`
`
`
`
`227
`In a separate study (n = 30), it was observed that under fasting conditions about 32% ± 11%
`228
`(mean ± SD) of the administered dose was systemically absorbed based on the combined
`229
`cumulative urinary excretion of 5-ASA and N-Ac-5-ASA over 96 hours post-dose.
`230
`
`231
`The effect of a high fat meal intake on absorption of mesalamine granules (the same granules
`232
`contained in APRISO capsules) was evaluated in 30 healthy subjects. Subjects received
`233
`1.6 g of mesalamine granules in sachet (2 x 0.8 g) following an overnight fast or a high-fat
`234
`235 meal in a crossover study. Under fed conditions, tmax for both 5-ASA and N-Ac-5-ASA was
`236
`prolonged by 4 and 2 hours, respectively. A high fat meal did not affect Cmax for 5-ASA, but
`237
`a 27% increase in the cumulative urinary excretion of 5-ASA was observed with a high fat
`238 meal. The overall extent of absorption of N-Ac-5-ASA was not affected by a high fat meal.
`239 As APRISO and mesalamine granules in sachet were bioequivalent, APRISO can be taken
`240 without regard to food.
`
`241 Distribution
`In an in vitro study, at 2.5 μg/mL, mesalamine and N-Ac-5-ASA are 43 ± 6% and 78 ± 1%
`242
`243
`bound, respectively, to plasma proteins. Protein binding of N-Ac-5-ASA does not appear to
`244
`be concentration dependent at concentrations ranging from 1 to 10 μg/mL.
`
`245 Metabolism
`The major metabolite of mesalamine is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is
`246
`247
`formed by N-acetyltransferase activity in the liver and intestinal mucosa.
`Elimination
`
`248
`Following single and multiple doses of APRISO, the mean half-lives were 9 to 10 hours for
`249
`250
`5-ASA, and 12 to 14 hours for N-Ac-5-ASA. Of the approximately 32% of the dose
`251
`absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about
`252
`30% of the dose excreted as N-Ac-5-ASA.
`
`

`

`
`253
`In Vitro Drug-Drug Interaction Study
`254
`In an in vitro study using human liver microsomes, 5-ASA and its metabolite, N-Ac-5-ASA,
`255
`256 were shown not to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9,
`257 CYP2C19, CYP2D6, and CYP3A4). Therefore, mesalamine and its metabolite are not
`258
`expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9,
`259 CYP2C19, CYP2D6, or CYP3A4.
`260
`
`NONCLINICAL TOXICOLOGY
`13
`261
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`262
`263 Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in
`264 mice at 2000 mg/kg/day. These doses are about 2.6 and 5.4 times the recommended human
`265
`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
`266
`267
`negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test,
`268
`the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse
`269
`bone marrow micronucleus test. Mesalamine at oral doses up to 320 mg/kg (about 1.7 times
`270
`the recommended human dose based on body surface area) was found to have no effect on
`271
`fertility or reproductive performance in rats.
`
`272
`
`13.2 Animal Toxicology and/or Pharmacology
`273
`Renal Toxicity
`274
`275 Animal studies with mesalamine (13-week and 26-week oral toxicity studies in rats, and 26­
`276 week and 52-week oral toxicity studies in dogs) have shown the kidney to be the major target
`277
`organ of mesalamine toxicity. Oral doses of 40 mg/kg/day (about 0.20 times the human
`278
`dose, on the basis of body surface area) produced minimal to slight tubular injury, and doses
`279
`of 160 mg/kg/day (about 0.90 times the human dose, on the basis of body surface area) or
`280
`higher in rats produced renal lesions including tubular degeneration, tubular mineralization,
`281
`and papillary necrosis. Oral doses of 60 mg/kg/day (about 1.1 times the human dose, on the
`282
`basis of body surface area) or higher in dogs also produced renal lesions including tubular
`
`atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.
`283
`284 Overdosage
`285
`Single oral doses of 800 mg/kg (about 2.2 times the recommended human dose, on the basis
`286
`of body surface area) and 1800 mg/kg (about 9.7 times the recommended human dose, on the
`287
`basis of body surface area) of mesalamine were lethal to mice and rats, respectively, and
`288
`resulted in gastrointestinal and renal toxicity.
`
`289
`
`14
`CLINICAL STUDIES
`290
`14.1 Ulcerative Colitis
`291
`292
`Two similar, randomized, double-blind, placebo-controlled, multi-center studies were
`
`conducted in a total of 562 adult patients in remission from ulcerative colitis. The study
`293
`
`

`

`populations had a mean age of 46 years (11% age 65 years or older), were 53% female, and
`294
`295 were primarily white (92%).
`296
`
`297 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,
`298
`299 mucosal appearance on endoscopy, and physician’s rating of disease activity. Each subscore
`300
`can range from 0 to 3, for a total possible DAI score of 12.
`301
`
`302 At baseline, approximately 80% of patients had a total DAI score of 0 or 1.0. Patients were
`303
`randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six
`304 months. Patients were assessed at baseline, 1 month, 3 months, and 6 months in the clinic,
`305 with endoscopy performed at baseline, at end of study, or if clinical symptoms developed.
`306 Relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal
`307
`appearance subscale score of 2 or more using the DAI. The analysis of the intent-to-treat
`308
`population was a comparison of the proportions of patients who remained relapse-free at the
`309
`end of six months of treatment. For the table below (Table 3) all patients who prematurely
`310 withdrew from the study for any reason were counted as relapses.
`311
`
`In both studies, the proportion of patients who remained relapse-free at six months was
`312
`313
`greater for APRISO than for placebo.
`314
`
`315
`316
`317
`
`Table 3: Percentage of Patients Relapse-Free* through 6 Months
`in APRISO Maintenance Studies
`
`
`
`
`
`
`
`318
`319
`320
`
`321
`322
`323
`324
`
`325
`326
`327
`
`328
`329
`330
`331
`332
`
`
`APRISO
`
`
`
`Difference
`Placebo
`1.5 g/day
`
`P-value
`(95% C.I.)
`% (# no relapse/N)
`% (# no relapse/N)
`<0.001
`17% (5.5, 29.2)
`51% (49/96)
`68% (143/209)
`Study 1
`0.046
`12% (0, 24.5)
`59% (55/93)
`71% (117/164)
`Study 2
`
`
` * Relapse counted as rectal bleeding score ≥ 1 and mucosal appearance score ≥ 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):1894-1898.
`
`
`
`
`
`
`

`

`HOW SUPPLIED/STORAGE AND HANDLING
`16
`333
`334 APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g
`335 mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the
`336
`capsule.
`337
`
`338 NDC 65649-103-02 Bottles of 120 capsules
`339 NDC 65649-103-01 Bottles of 4 capsules
`
`340
`Storage:
`341
`342
`Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and
`343
`86°F). See USP Controlled Room Temperature.
`344
`
`345
`346
`
`17
`PATIENT COUNSELING INFORMATION
`17.1 Patients with Phenylketonuria
`
`
`347
`348
`349
`350
`
`351
`
`352
`353
`
`354
`355
`
`•
`
`
`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.
`
`17.2 General Counseling Information
`
`
`•
`
`
`•
`
`
`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.
`
`356
`
`357 Manufactured by Catalent Pharma Solutions for Salix Pharmaceuticals, Inc., Morrisville, NC
`358
`27560
`* APRISOTM is a trademark of Salix Pharmaceuticals, Inc.
`359
`360 © 2008 Salix Pharmaceuticals, Inc.
`361
`
`Product protected by U.S. Patent No. 6,551,620
`362
`363
`
`364 VENART-113-0
`
`