APRISO

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 )] 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 )] 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. 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 Reported in at least 3% of APRISO-treated patients and at a greater rate than with placebo in Clinical Trials of Adults with Ulcerative Colitis APRISO 1.5 g once daily N=367 Placebo N=185 Headache 11% 8% Diarrhea 8% 7% Upper Abdominal Pain 5% 3% Nausea 4% 3% Nasopharyngitis 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 : 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 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 )] Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach. 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

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 )] . Known or suspected hypersensitivity to salicylates, aminosalicylates, or any component of APRISO capsules. ( 4 , 5.3 )

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: Molecular Weight: 153.14 Molecular Formula: C 7 H 7 NO 3 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, talc, titanium dioxide, triethyl citrate, vanilla flavor. Each APRISO 0.375 g capsule contains 0.56 mg of phenylalanine. Chemical Structure

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 ( 5.7 )]. Take APRISO without regard to meals [see Clinical Pharmacology ( 12.3 )]. 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 , 5.7 ) Take APRISO without regard to meals. ( 2 )

1 INDICATIONS AND USAGE APRISO ® is indicated for the maintenance of remission of ulcerative colitis in adults. APRISO is an aminosalicylate indicated for the maintenance of remission of ulcerative colitis in adults. ( 1 )

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.

7 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 ) 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.

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 (AUC 0-24 ) 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 Mesalamine (5-ASA) Single Dose (n=24) Multiple Dose c (n=24) a Median (range); b Harmonic mean (pseudo SD); c after 7 days of treatment AUC 0-24 (mcg*h/mL) 11±5 17±6 AUC 0-inf (mcg*h/mL) 14±5 - C max (mcg/mL) 2.1±1.1 2.7±1.1 T max (h) a 4 (2, 16) 4 (2, 8) t ½ (h) b 9±7 10±8 N-Ac-5-ASA AUC 0-24 (mcg*h/mL) 26±6 37±9 AUC 0-inf (mcg*h/mL) 51±23 - C max (mcg/mL) 2.8±0.8 3.4±0.9 T max (h) a 4 (4, 12) 5 (2, 8) t ½ (h) b 12±11 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, T max for both 5-ASA and N‑Ac‑5-ASA was prolonged by 4 and 2 hours, respectively. A high fat meal did not affect C max 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.

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 (AUC 0-24 ) 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 Mesalamine (5-ASA) Single Dose (n=24) Multiple Dose c (n=24) a Median (range); b Harmonic mean (pseudo SD); c after 7 days of treatment AUC 0-24 (mcg*h/mL) 11±5 17±6 AUC 0-inf (mcg*h/mL) 14±5 - C max (mcg/mL) 2.1±1.1 2.7±1.1 T max (h) a 4 (2, 16) 4 (2, 8) t ½ (h) b 9±7 10±8 N-Ac-5-ASA AUC 0-24 (mcg*h/mL) 26±6 37±9 AUC 0-inf (mcg*h/mL) 51±23 - C max (mcg/mL) 2.8±0.8 3.4±0.9 T max (h) a 4 (4, 12) 5 (2, 8) t ½ (h) b 12±11 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, T max for both 5-ASA and N‑Ac‑5-ASA was prolonged by 4 and 2 hours, respectively. A high fat meal did not affect C max 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.

20231027

33

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. Extended-release capsules: 0.375 g ( 3 )

APRISO mesalamine ANHYDROUS CITRIC ACID CROSPOVIDONE MESALAMINE MESALAMINE SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE HYPROMELLOSE, UNSPECIFIED METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) TALC TITANIUM DIOXIDE TRIETHYL CITRATE ASPARTAME Light Blue CAPSULE G;M VANILLA

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 1,800 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.

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 2,000 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 1,110 mg/m 2 ), 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 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 2,000 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 1,110 mg/m 2 ), 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 1,800 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.

NDA022301

APRISO

mesalamine

65649-103

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 65649-103-02 Rx only apriso ® (mesalamine) Extended-Release Capsules 0.375 g 120 Capsules Salix Pharmaceuticals 0.375GAPRISOLABEL

Warnings and Precautions Renal Impairment ( 5.1 ) 11/2022

17 PATIENT COUNSELING INFORMATION Administration Instruct patients: Swallow the capsules whole. Do not cut, break, crush or chew the capsules. Avoid co-administration of APRISO with antacids. Drink an adequate amount of fluids. APRISO capsules can be taken without regard to meals [ see Dosage and Administration (2) ] . Urine may become discolored reddish-brown while taking APRISO when it comes in contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, advise patients to observe their urine flow. Report to the healthcare provider only if urine is discolored on leaving the body, before contact with any surface or water (e.g., in the toilet). Renal Impairment Inform patients that APRISO may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, including NSAIDs, and periodic monitoring of renal function will be performed while they are on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [ see Warnings and Precautions (5.1) , Drug Interactions (7.2) ] . Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking APRISO and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [ see Warnings and Precautions (5.2, 5.3) ] . Hepatic Failure Inform patients with known liver disease of the signs and symptoms of worsening liver function and advise them to report to their healthcare provider if they experience such signs or symptoms [ see Warnings and Precautions (5.4) ] . Severe Cutaneous Adverse Reactions Inform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking APRISO and report to their healthcare provider at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity [ see Warnings and Precautions (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 [ see Warnings and Precautions (5.6) ] . Nephrolithiasis Instruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of a kidney stone (e.g., severe side or back pain, blood in the urine) [ see Warnings and Precautions (5.7) ] . 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 [ see Warnings and Precautions (5.8 )] . Blood Disorders Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood disorders and the need for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see Drug Interactions ( 7.3 ), Use in Specific Populations ( 8.5 )] . Distributed by: Salix Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Patented. See https://patents.salix.com/ for US patent information. APRISO is a trademark of Salix Pharmaceuticals, Inc. or its affiliates. © 2023 Salix Pharmaceuticals, Inc. or its affiliates 9602407

14 CLINICAL STUDIES 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 Index (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 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 Ulcerative Colitis Patients Relapse-Free Relapse counted as rectal bleeding score ≥1 and mucosal appearance score ≥2, or premature withdrawal from study. Through 6 Months in APRISO Maintenance Studies APRISO 1.5 g once daily % (# no relapse/N) Placebo % (# no relapse/N) Difference (95% C.I.) P-value Study 1 68% (143/209) 51% (49/96) 17% (5.5, 29.2) <0.001 Study 2 71% (117/164) 59% (55/93) 12% (0, 24.5) 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.

8.5 Geriatric Use Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 years and older 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 )].

8.4 Pediatric Use Safety and effectiveness of APRISO in pediatric patients have not been established.

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 USE IN SPECIFIC POPULATIONS Geriatric Patients : Increased risk of blood dyscrasias; monitor blood cell counts and platelet counts. ( 8.5 ) 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. 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 older 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. Discontinue APRISO if renal function deteriorates while on therapy [see Warnings and Precautions (5.1) , Adverse Reactions (6.2) , Drug Interactions (7.2)].

16 HOW SUPPLIED/STORAGE AND HANDLING APRISO ® extended-release capsules are available as light blue opaque hard gelatin capsules containing 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 and are available in bottles of 120 capsules (NDC 65649-103-02). 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].