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
`
`
`-------------------------- RECENT MAJOR CHANGES --------------------------
`
`
`Warnings and Precautions, Phenylketonuria (5.5)
`03/2019
`
`
`
`
`--------------------------- 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)
`
`
`
`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
`
`5.5 Risks in Patients with Phenylketonuria
` 
`6 ADVERSE REACTIONS
` 
`6.1 Clinical Trials Experience
` 
`6.2 Adverse Reaction Information from Other Sources
`
` 
`7 DRUG INTERACTIONS
` 
`7.1 Antacids
` 
`8 USE IN SPECIFIC POPULATIONS
` 
`8.1 Pregnancy
`
`FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`Acute exacerbation of colitis symptoms can occur. (5.2)
`Use caution with pre-existing liver disease. (5.4)
`
`Contains phenylalanine (5.5)
`
`
`
`------------------------------ 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, a division of Valeant Pharmaceuticals North America
`LLC at 1-800-321-4576 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 (PKU) that APRISO contains
`
`
`aspartame. (17)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`Revised: 03/2019
`
`
`
` 
`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
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`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.
`
`Reference ID: 4402586
`
`

`

`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 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
`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.
`
`5.4 Hepatic Impairment
`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.
`
`5.5 Risks in Patients with Phenylketonuria
`Phenylalanine can be harmful to patients with phenylketonuria (PKU). APRISO contains phenylalanine, a component of
`aspartame. Each APRISO 0.375 g capsule contains 0.56 mg of phenylalanine. Before prescribing APRISO to a patient
`
`
`with PKU, consider the combined daily amount of phenylalanine from all sources, including APRISO.
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials 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.
`
`Reference ID: 4402586
`
`

`

`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 (≥3%) are shown in Table 1 below.
`
`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
`
`
`Headache
`Diarrhea
`Abdominal Pain Upper
`Nausea
`Nasopharyngitis
`Influenza and Influenza-like Illness
`Sinusitis
`
`
`
`APRISO 1.5 g/day
`
`N=367
`11%
`8%
`5%
`4%
`4%
`4%
`3%
`
`Placebo
`
`N=185
`8%
`7%
`3%
`3%
`3%
`4%
`3%
`
`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.
`
`Ear and Labyrinth Disorders: tinnitus, vertigo
`Dermatological Disorder: alopecia
`Gastrointestinal: abdominal pain lower, rectal hemorrhage
`Laboratory Abnormalities: increased triglycerides, decreased hematocrit and hemoglobin
`
`General Disorders and Administration Site Disorders: fatigue
`Hepatic: hepatitis cholestatic, transaminases increased
`
`Renal Disorders: creatinine clearance decreased, hematuria
`
`Musculoskeletal: pain, arthralgia
`Respiratory: dyspnea
`
`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
`Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer
`Hepatic: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like syndrome including changes
`in liver enzymes
`Hematologic: agranulocytosis, aplastic anemia
`Nervous System: intracranial hypertension
`
`Neurological/Psychiatric: peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis
`
`
`Reference ID: 4402586
`
`

`

` Renal and Urinary: nephrogenic diabetes insipidus
`
`Respiratory/Pulmonary: 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.
`
`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 function,
`
`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 Warnings and Precautions (5.1)].
`
`Reference ID: 4402586
`
`

`

`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 (5-aminosalicylic acid, 5-ASA), an anti-inflammatory drug. The structural formula of
`mesalamine is:
`
`Molecular Weight: 153.14
`Molecular Formula: C7H7NO3
`
`
`
`
`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 ethyl acrylate/methyl methacrylate copolymer nonoxynol 100 dispersion, hypromellose,
`methacrylic acid copolymer, talc, titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone, vanilla
`flavor, and edible black ink.
`
`
`Each APRISO 0.375 g capsule contains 0.56 mg of phenylalanine.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`The mechanism of action of mesalamine (5-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
`patients with ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of
`arachidonic acid metabolites.
`
`12.3 Pharmacokinetics
`Absorption
`
`
`Reference ID: 4402586
`
`

`

`The pharmacokinetics of 5-ASA and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), were studied after a
`single and multiple oral doses of 1.5 g APRISO 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 (1.5-fold and 1.7-fold) in systemic exposure (AUC0-24) to 5-ASA and N-Ac-5-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.
`
`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
`
`Single Dose
`(n=24)
`11±5
`14±5
`2.1±1.1
`4 (2, 16)
`9±7
`
`Mesalamine (5-ASA)
`
`AUC0-24 (mcg*h/mL)
`AUC0-inf (mcg*h/mL)
`Cmax (mcg/mL)
`
`Tmax (h) a
`
`
`t½ (h)b
`N-Ac-5-ASA
`
`26±6
`AUC0-24 (mcg*h/mL)
`AUC0-inf (mcg*h/mL)
`51±23
`2.8±0.8
`Cmax (mcg/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
`
`
`
`
`
`Multiple Dosec
`
`(n=24)
`17±6
`
`-
`2.7±1.1
`4 (2, 8)
`10±8
`
`37±9
`-
`3.4±0.9
`5 (2, 8)
`14±10
`
`In a separate study (n=30), it was observed that under fasting conditions about 32%±11% (mean±SD) of the administered
`dose was systemically absorbed based on the combined cumulative urinary excretion of 5-ASA and N-Ac-5-ASA over
`96 hours post-dose.
`
`The effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in APRISO
`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-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 in the cumulative urinary excretion of 5-ASA was observed with a high fat meal. The overall extent of absorption
`of N-Ac-5-ASA was not affected by a high fat meal. As APRISO and mesalamine granules in sachet were bioequivalent,
`APRISO can be taken without regard to food.
`
`
`Distribution
`
`In an in vitro study, at 2.5 mcg/mL, mesalamine and N-Ac-5-ASA are 43±6% and 78±1% bound, respectively, to plasma
`
`proteins. Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at concentrations ranging from 1
`to 10 mcg/mL.
`
`Metabolism
`
`The major metabolite of mesalamine is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is formed by N-acetyltransferase
`activity in the liver and intestinal mucosa.
`
`Elimination
`
`
`Reference ID: 4402586
`
`

`

`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-5-ASA. Of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the
`urine, compared with about 30% of the dose excreted as N-Ac-5-ASA.
`
`In Vitro Drug-Drug Interaction Study
`
`In an in vitro study using human liver microsomes, 5-ASA and its metabolite, N-Ac-5-ASA, were shown not to inhibit the
`
`major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Therefore, mesalamine and its
`metabolite are not expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9, CYP2C19,
`CYP2D6, or CYP3A4.
`
`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 Toxicity
`
`Animal studies with mesalamine (13-week and 26-week oral toxicity studies in rats, and 26-week and 52-week oral
`toxicity studies in dogs) have shown the kidney to be the major target organ of mesalamine toxicity. Oral doses of
`40 mg/kg/day (about 0.20 times the human dose, on the basis of body surface area) produced minimal to slight tubular
`injury, and doses of 160 mg/kg/day (about 0.90 times the human dose, on the basis of body surface area) or higher in rats
`produced renal lesions including tubular degeneration, tubular mineralization, and papillary necrosis. Oral doses of
`60 mg/kg/day (about 1.1 times the human dose, on the basis of body surface area) or higher in dogs also produced renal
`lesions including tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.
`
`
`
`
`Overdosage
`
`Single oral doses of 800 mg/kg (about 2.2 times the recommended human dose, on the basis of body surface area) and
`1800 mg/kg (about 9.7 times the recommended human dose, on the basis of body surface area) of mesalamine were lethal
`to mice and rats, respectively, and resulted in gastrointestinal and renal toxicity.
`
`
`
`
` 14 CLINICAL STUDIES
`
`14.1 Ulcerative Colitis
`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 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
`
`Reference ID: 4402586
`
`

`

`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 DAI. 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
`
`
`
`Placebo
`APRISO
`
`
`% (# no
`Difference
`1.5 g/day
`
`
`relapse/N)
`(95% C.I.)
`% (# no relapse/N)
`
`
`51% (49/96)
`17% (5.5, 29.2)
`68% (143/209)
`Study 1
`
`
`59% (55/93)
`12% (0, 24.5)
`71% (117/164)
`Study 2
`
`
`
` *Relapse counted as rectal bleeding score ≥1 and mucosal appearance score ≥2, or premature withdrawal from study.
`
`
`P-value
`<0.001
`0.046
`
`
`
` 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.
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`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
`
`
`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 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
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`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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`Instruct patients to contact a health care provider if they experience a worsening of ulcerative colitis symptoms,
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`because it could be due to a reaction to APRISO.
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`Manufactured for:
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`Salix Pharmaceuticals, a division of
`Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA
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`Reference ID: 4402586
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`By:
`Valeant Pharmaceuticals International, Inc.
`Steinbach, Manitoba R5G 1Z7 Canada
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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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`9602401
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`20001702
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`Reference ID: 4402586
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