`
` 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
`
`Severe Cutaneous Adverse Reactions (5.5)
`
`
`
`11/2021
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE -------------------------­
`
`
`
`APRISO is an aminosalicylate indicated for the maintenance of remission of
`ulcerative colitis in adults. (1)
`
`
`
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`Dosage
`The recommended dosage is 1.5 g (four 0.375 g capsules) once daily in the
`
`
`
`
`
`
`morning. (2)
`
`
`Administration Instructions
`
`Evaluate renal function before initiating therapy with APRISO. (2)
`
`
`
`
`•
`Swallow the capsules whole. Do not cut, break, crush or chew the
`
`
`
`
`
`•
`capsules. (2)
`
`Avoid co-administration with antacids. (2, 7.1)
`
`Drink an adequate amount of fluids. (2, 5.6)
`
`
`
`Take APRISO without regard to meals. (2)
`
`
`
`
`•
`
`•
`
`•
`
`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`
`
`Extended-release capsules: 0.375 g (3)
`
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`
`
`
`
`Known or suspected hypersensitivity to salicylates, aminosalicylates, or any
`
`
`
`
`
`component of APRISO capsules. (4, 5.3)
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
`
`
`
`
`Renal Impairment: Assess renal function at the beginning of treatment
`
`
`
`
`
`
`•
`and periodically during treatment. Evaluate the risks and benefits in
`
`
`
`
`patients with known renal impairment or taking nephrotoxic drugs;
`
`
`monitor renal function. (5.1, 7.2, 8.6)
`
`• Mesalamine-Induced Acute Intolerance Syndrome: Symptoms may be
`
`
`
`
`difficult to distinguish from an exacerbation of ulcerative colitis;
`
`
`
`monitor for worsening symptoms; discontinue treatment if acute
`
`
`
`intolerance syndrome is suspected. (5.2)
`
`
`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 Reactions
`
`5.4 Hepatic Failure
`
`5.5 Severe Cutaneous Adverse Reactions
`
`
`5.6 Photosensitivity
`
`5.7 Nephrolithiasis
`
`5.8 Risks in Patients with Phenylketonuria
`
`
`
`5.9 Interference with Laboratory Tests
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`7.1 Antacids
`7.2 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory
`
`
`Drugs
`
`Reference ID: 4881178
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`Hypersensitivity Reactions, including Myocarditis and Pericarditis:
`
`
`Evaluate patients immediately and discontinue if a hypersensitivity
`
`
`reaction is suspected. (5.3)
`
`
`Hepatic Failure: Evaluate the risks and benefits in patients with known
`
`
`
`
`
`liver impairment. (5.4)
`
`Severe Cutaneous Adverse Reactions: Discontinue at the first signs or
`
`
`
`symptoms of severe cutaneous adverse reactions or other signs of
`
`
`
`
`hypersensitivity and consider further evaluation. (5.5)
`
`
`
`Photosensitivity: Advise patients with pre-existing skin conditions to
`
`
`avoid sun exposure, wear protective clothing, and use a broad-spectrum
`
`
`
`sunscreen when outdoors. (5.6)
`
`
`Nephrolithiasis: Mesalamine-containing stones are undetectable by
`
`
`
`standard radiography or computed tomography (CT). Ensure adequate
`
`
`
`fluid intake during treatment. (5.7)
`
`
`Risks in Patients with Phenylketonuria: Contains phenylalanine. Before
`
`
`prescribing APRISO to a patient with PKU, consider the combined daily
`
`
`
`
`amount of phenylalanine from all sources, including APRISO. (5.8)
`
`
`
`
`
`Interference with Laboratory Tests: Use of mesalamine may lead to
`
`
`
`
`spuriously elevated test results when measuring urinary normetanephrine
`
`
`
`by liquid chromatography with electrochemical detection. (5.9)
`
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`Most common adverse reactions (≥3%) are: headache, diarrhea, upper
`
`
`
`
`abdominal pain, nausea, and nasopharyngitis. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Salix
`
`Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or
`
`
`
`www.fda.gov/medwatch.
`
`
`------------------------------ DRUG INTERACTIONS ----------------------------­
`
`
`
`
`Nephrotoxic Agents including NSAIDs: Increased risk of
`
`
`
`
`•
`nephrotoxicity; monitor for changes in renal function and mesalamine­
`
`
`related adverse reactions. (7.2)
`
`Azathioprine or 6-Mercaptopurine: Increased risk of blood disorders;
`
`
`
`monitor complete blood cell counts and platelet counts. (7.3)
`
`
`
`
`
`•
`
`----------------------- USE IN SPECIFIC POPULATIONS ---------------------­
`
`
`
`
`Geriatric Patients: Increased risk of blood dyscrasias; monitor blood cell
`
`
`
`
`
`counts and platelet counts. (8.5)
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`Revised: 11/2021
`
`
`
`
`7.3 Azathioprine or 6-Mercaptopurine
`
`
`7.4 Interference with Urinary Normetanephrine Measurements
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`
`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
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`
`
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
` APRISO is indicated for the maintenance of remission of ulcerative colitis in adults.
`
`
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
` Dosage
`
`
`The recommended dosage in adults is 1.5 g (four 0.375 g capsules) orally once daily in the morning.
`
`
`
`
`
`
`
`Administration Instructions
`
`
`• Evaluate renal function before initiating therapy with APRISO [see Warnings and Precautions (5.1)].
`
`
`
`
`• Swallow APRISO capsules whole. Do not cut, break, crush or chew the capsules.
`
`
`• Avoid co-administration of APRISO with antacids [see Drug Interactions (7.1)].
`
`
`
`
`• Drink an adequate amount of fluids [see Warnings and Precautions (5.6)].
`
`
`
`
`
`• Take APRISO without regard to meals [see Clinical Pharmacology (12.3)].
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
` Extended-release capsules: 0.375 g mesalamine in a light blue opaque gelatin capsule with the letters “G” and “M”
`
`
`
` imprinted on either side of a black band.
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
`
` APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components
`
` of APRISO capsules [see Warnings and Precautions (5.3), Adverse Reactions (6.2), Description (11)].
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Renal Impairment
` Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been
`
`
`
`
`
`
`
` reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. In animal
` studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions (6.2), Nonclinical Toxicology
`
`
`
`
` (13.2)].
`
` Evaluate renal function prior to initiation of APRISO therapy and periodically while on therapy. Evaluate the risks and
`
`
`
`
`
`
` benefits of using APRISO in patients with known renal impairment or a history of renal disease or taking concomitant
` nephrotoxic drugs [see Drug Interactions (7.2), Use in Specific Populations (8.6)].
`
`
`
`
`
` 5.2 Mesalamine-Induced Acute Intolerance Syndrome
`
` Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an
`
`
`
`
`
`
`
`
`
` exacerbation of ulcerative colitis. 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. Monitor patients for worsening of these symptoms while
` on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO.
`
`
`
`
`
`Reference ID: 4881178
`
`

`

` 5.3 Hypersensitivity Reactions
`
` Some patients have experienced a hypersensitivity reaction to sulfasalazine. Some patients may have a similar reaction to
`
`
`
`
`
` APRISO or to other compounds that contain or are converted to mesalamine.
`
`
`
` As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement,
`
`
`
` including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients
` immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue APRISO if an alternative
`
`
`
`
`
`
` etiology for the signs and symptoms cannot be established.
`
`
`
` 5.4 Hepatic Failure
`
` There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered
`
`
`
`
`
` mesalamine. Evaluate the risks and benefits of using APRISO in patients with known liver impairment.
`
`5.5 Severe Cutaneous Adverse Reactions
`
`Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN),
`drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis
`
`
`
`(AGEP) have been reported with the use of mesalamine [see Adverse Reactions (6.2)]. Discontinue APRISO at the first
`
`
`signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further
`
`
`
`
`
`evaluation.
`
` 5.6 Photosensitivity
`
`
`Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe
`
`
`
`
`photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum
`
`sunscreen when outdoors.
`
` 5.7 Nephrolithiasis
`
`
` Cases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content.
`
`
`
`
`
` Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography
` (CT). Ensure adequate fluid intake during treatment with APRISO.
`
`
`
`
`
`
` 5.8 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.
`
`
`
` 5.9 Interference with Laboratory Tests
`
`
`Use of APRISO may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid
`chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and
`
`
`
` the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective
`
`
`
`
`
`assay for normetanephrine.
`
`
` 6 ADVERSE REACTIONS
`
` The following clinically significant adverse reactions are described elsewhere in labeling:
`
`
`
`
`
`
`
`
`
` • Renal Impairment [see Warnings and Precautions (5.1)]
`
`
`
` • Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)]
`
`
`
` • Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`
`Reference ID: 4881178
`
`

`

` • Hepatic Failure [see Warnings and Precautions (5.4)]
`
`
`
`
` • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]
`
`
`
` • Photosensitivity [see Warnings and Precautions (5.6)]
`
`
`
`
` • Nephrolithiasis [see Warnings and Precautions (5.7)]
`
`
`
`
`
` • Risks in Patients with Phenylketonuria [see Warnings and Precautions (5.8)]
`
`
`
`
`
`
`
`
`
`
` 6.1 Clinical Trials Experience
`
`
` 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.
`
`
`
` 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.
`
`
`
`
`
` In the two placebo-controlled trials, the most common reactions reported in at least 3% of APRISO-treated patients and at
`
`
`
`
`
` a greater rate than placebo are shown in Table 1 below.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 1:
`
`
`
`
`
` Common Adverse Reactions* in Clinical Trials of Adults with Ulcerative Colitis
` APRISO
`
`Placebo
`
`1.5 g once daily
`N=185
`
`
`N=367
`
`
` Headache
`
` 11%
`
` Diarrhea
` 8%
`
` Upper Abdominal Pain
`
` 5%
`
` Nausea
`
` 4%
` Nasopharyngitis
`
` 4%
`
`
` * Reported in at least 3% of APRISO-treated patients and at a greater rate than with placebo
`
`
`
` 8%
`
` 7%
`
` 3%
`
` 3%
`
` 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: lower abdominal pain, 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
`
`
`Reference ID: 4881178
`
`

`

` 6.2 Postmarketing Experience
`
`
`
`
` The following adverse reactions have been identified during post approval use of APRISO or other mesalamine­
` containing products. 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 [see Warnings and Precautions (5.3)]
`
`
`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
`
`
`
`Renal and Urinary: nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease,
`
`
`
`
`nephrolithiasis [see Warnings and Precautions (5.1, 5.7)]
`
`
`
`
`Respiratory/Pulmonary: eosinophilic pneumonia, interstitial pneumonitis, pleurisy/pleuritis
`
`
`Skin: psoriasis, pyoderma gangrenosum, erythema nodosum, SJS/TEN, DRESS, and AGEP [see Warnings and
`
`
`
`
`Precautions (5.5)]
`
`Renal/Urogenital: reversible oligospermia
`
`
`
`
` 7 DRUG INTERACTIONS
` 7.1 Antacids
`
` Because the dissolution of the coating of the granules in APRISO capsules depends on pH, avoid co-administration of
`
`
`
` APRISO capsules with antacids [see Dosage and Administration (2)].
`
`
`
` 7.2 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs
`
`
`
` The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs
` (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal
`
`
`
`
`
`
`
`
`
` function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1)].
`
`
`
`7.3 Azathioprine or 6-Mercaptopurine
`
`
`
`
`
`
` The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause
` myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If
`
`
`
`
` concomitant use of APRISO and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including
`
`
` complete blood cell counts and platelet counts.
`
` 7.4 Interference with Urinary Normetanephrine Measurements
`
`
` Use of APRISO may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid
` chromatography with electrochemical detection [see Warnings and Precautions (5.9)]. Consider an alternative, selective
`
`
` assay for normetanephrine.
`
`Reference ID: 4881178
`
`

`

`
`
` 8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
` Risk Summary
`Published data from meta-analyses, cohort studies and case series on the use of mesalamine during pregnancy have not
`
`
`
`
`
`reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal
`
`
`outcomes (see Data).
`
`
`
`In animal reproduction studies, there were no adverse developmental outcomes with administration of oral mesalamine
`
`
`
`
`during organogenesis to pregnant rats and rabbits at doses 1.7 and 5.4 times, respectively, the maximum recommended
`
`
`
`
`
`human dose (see Data).
`
`
`
`The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse
`
`
`
`
`outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general
`
`
`
`population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
`
`
`
`to 4% and 15 to 20%, respectively.
`
`
`Clinical Considerations
`
`
`Disease-associated maternal and embryo/fetal risk
`
`Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy
`
`
`
`
`
`outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of
`
`gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
`
`
`
`
`
`
`Data
`
`
`Human Data
`Published data from meta-analyses, cohort studies and case series on the use of mesalamine during early pregnancy (first
`
`
`
`
`
`trimester) and throughout pregnancy have not reliably informed an association of mesalamine and major birth defects,
`
`
`
`
`
`miscarriage, or adverse maternal or fetal outcomes. There is no clear evidence that mesalamine exposure in early
`
`
`
`pregnancy is associated with an increased risk in major congenital malformations, including cardiac malformations.
`
`
`
`
`
`
`
`Published epidemiologic studies have important methodological limitations which hinder interpretation of the data,
`
`
`including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant
`
`
`medications, and missing information on the dose and duration of use for mesalamine products.
`
`
`
`
`
`
`Animal Data
`Reproduction studies with mesalamine during organogenesis 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 harm to the fetus due to mesalamine.
`
`
`
`
`
`
`
`
` 8.2 Lactation
`
` Risk Summary
`Data from published literature report the presence of mesalamine and its metabolite, N-acetyl 5-aminosalicylic acid in
`
`
`
`
`
`human milk in small amounts with relative infant doses (RID) of 2% or less (see Data). There are case reports of diarrhea
`
`
`
`
`
`in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of the
`
`
`
`
`drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of APRISO
`
`
`to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along
`
`with the mother’s clinical need for APRISO and any potential adverse effects on the breastfed child from APRISO or
`
`
`
`
`from the underlying maternal condition.
`
`
`
`Clinical Considerations
`
`
`
`
`
`
`Advise the caregiver to monitor the breastfed infant for diarrhea.
`
`
`Reference ID: 4881178
`
`

`

` Data
`
`In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged
`
`
`
`
`
`from 500 mg to 4.8 g daily. The average concentration of mesalamine in milk ranged from non-detectable to 0.5 mg/L.
`
`
`
`The average concentration of the N-acetyl-5-aminosalicylic acid in milk ranged from 0.2 to 9.3 mg/L. Based on these
`
`
`concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day (RID 0 to
`
`
`0.1%) of mesalamine and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid.
`
`
`
`8.4 Pediatric Use
`
` Safety and effectiveness of APRISO in pediatric patients have not been established.
`
`
`
`
`
`8.5 Geriatric Use
`
`
` Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 years and over to determine whether
` they respond differently than younger subjects. Reports from uncontrolled clinical studies and postmarketing reporting
`
`
`
`
` systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients
`
` who were 65 years or older compared to younger patients taking mesalamine-containing products such as APRISO.
`
`
` Monitor complete blood cell counts and platelet counts in elderly patients during treatment with APRISO. In general,
`
`
`
` consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
`
`
`
` therapy in elderly patients when prescribing APRISO [see Use in Specific Populations (8.6)].
`
`
`
`
`
`
`
`
`
` 8.6 Renal Impairment
`
`
`
`
`
`
` 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. Evaluate renal function in all patients prior to initiation and periodically
`
`
`
`
`
`
`
`
` while on APRISO therapy. Monitor patients with known renal impairment or history of renal disease or taking
` nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions [see Warnings and Precautions
`
`
`
` (5.1), Adverse Reactions (6.2), Drug Interactions (7.2)].
`
`
` 10 OVERDOSAGE
`
`APRISO is an aminosalicylate, and symptoms of salicylate toxicity include nausea, vomiting and abdominal pain,
`
`
`
`tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate
`
`
`
`
`intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) damage.
`
`
`There is no specific antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be
`
`
`
`beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent further
`
`
`
`absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain
`
`
`
`
`
`adequate renal function. 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 aminosalicylate. The structural formula of mesalamine is:
`
`
`
`Reference ID: 4881178
`
`

`

`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: anhydrous citric acid, aspartame, colloidal silicon dioxide, edible black
`
`
`
`
`ink, hypromellose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone, simethicone
`
`
`emulsion ethyl acrylate/methyl methacrylate copolymer nonoxynol 100 dispersion, talc, titanium dioxide, triethyl citrate,
`
`vanilla flavor.
`
`
`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 not fully understood, but appears to be a local anti-inflammatory
`
`
`
`
`
`
`
`
`
` effect on colonic epithelial cells. 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
`
`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 (four 0.375 g capsules) once daily for 7 consecutive days.
`
`
`
`Steady state was reached on Day 6 of once daily 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.
`
`Reference ID: 4881178
`
`

`

`
`
` 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
`Mesalamine (5-ASA)
`
`
`Single Dose
`
`(n=24)
`
`
` 11±5
`
` 14±5
`
` 2.1±1.1
`
` 4 (2, 16)
`
` 9±7
`
`
`
`
` AUC0-24 (mcg*h/mL)
`
` AUC0-inf (mcg*h/mL)
`
` Cmax (mcg/mL)
`
`
` Tmax (h) a
`
`
` t½ (h)b
`N-Ac-5-ASA
`
`
` AUC0-24 (mcg*h/mL)
`
` 26±6
`
` AUC0-inf (mcg*h/mL)
` 51±23
`
`
` Cmax (mcg/mL)
`
` 2.8±0.8
`
`
`
` 4 (4, 12)
` Tmax (h)a
`
`
`
` 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.
`
` Food Effects
`
`
`
`
`
` 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 [see Dosage and Administration (2)].
`
`
`
`
`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.
`
`
`Elimination
`
`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.
`
`
`Excretion
`
`
`
`
`
`
`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.
`
`
`Drug Interaction Studies
`
`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.
`
`Reference ID: 4881178
`
`

`

` 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.
`
`
`
`
`
`
`No effects on fertility or reproductive performance in male and female rats were observed with oral mesalamine doses up
`
`
`
`to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area).
`
`
`
`
` 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. 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. 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.
`
`
`
`
` 14 CLINICAL STUDIES
`
`
` Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult
`
`
`
`
`
`
` patients in rem