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1 INDICATIONS AND USAGE Mesalamine delayed-release capsules are an aminosalicylate indicated for: Treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. ( 1.1 ) Maintenance of remission of ulcerative colitis in adults. ( 1.2 ) 1.1 Treatment of Mildly to Moderately Active Ulcerative Colitis Mesalamine delayed-release capsules are indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. 1.2 Maintenance of Remission of Ulcerative Colitis Mesalamine delayed-release capsules are indicated for the maintenance of remission of ulcerative colitis in adults.

2 DOSAGE AND ADMINISTRATION Important Administration Instructions : Do not substitute two mesalamine delayed-release 400 mg capsules with one mesalamine delayed-release 800 mg tablet. ( 2.1 ) Evaluate renal function prior to initiation of mesalamine delayed-release capsules. ( 2.1 , 5.1 ) Take with or without food. ( 2.1 ) Swallow the capsules whole; do not cut, break, crush or chew. ( 2.1 ) For patients who are unable to swallow the capsules, the capsules can be opened and the inner tablets swallowed. ( 2.1 ) Drink an adequate amount of fluids. ( 2.1 , 5.7 ) Treatment of Mildly to Moderately Active Ulcerative Colitis: Adults: 800 mg (two 400 mg capsules) three times daily for 6 weeks. Pediatric Patients 5 years or older: See weight-based dosing table in the full prescribing information; twice daily dosing for 6 weeks. ( 2.2 ) Maintenance of Remission of Ulcerative Colitis: Adults: 1.6 grams (four 400 mg capsules) daily, in two to four divided doses. ( 2.3 ) 2.1 Important Administration Instructions Do not substitute two mesalamine delayed-release 400 mg capsules with one mesalamine delayed-release 800 mg tablet. Evaluate renal function prior to initiation of mesalamine delayed-release capsules. Take mesalamine delayed-release capsules with or without food. Swallow the capsules whole; do not cut, break, crush or chew the capsules. For patients who are unable to swallow the capsules whole, carefully open the capsule(s) and swallow the contents (four 100 mg tablets). Open the number of capsules required to make up a complete dose [see Dosage and Administration ( 2.2 , 2.3 )] . There are 4 tablets per capsule. Ensure all tablets per capsule are swallowed and no tablets are retained in the mouth. Swallow the tablets whole; do not cut, break, crush or chew the tablets. Drink an adequate amount of fluids [see Warnings and Precautions ( 5.7 )] . Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly. Protect mesalamine delayed-release capsules from moisture. Close the container tightly and leave any desiccant pouches present in the bottle along with the capsules. 2.2 Dosage for Treatment of Mildly to Moderately Active Ulcerative Colitis Adults For adults, the recommended dosage of mesalamine delayed-release capsules is 800 mg (two 400 mg capsules) three times daily (total daily dosage of 2.4 grams) for a duration of 6 weeks [see Clinical Studies ( 14.1 )] . Pediatrics For pediatric patients 5 years of age and older, the recommended total daily dosage of mesalamine delayed-release capsules is weight-based (up to maximum of 2.4 grams per day) divided into two daily doses for a duration of 6 weeks (see Table 1). Table 1. Pediatric Dosage by Weight Weight Group (kg) Daily Dosage (mg/kg/day) Maximum Daily Dosage (grams per day) Morning Dosage Afternoon Dosage 17 to 32 36 to 71 1.2 two 400 mg capsules one 400 mg capsules 33 to 53 37 to 61 2 three 400 mg capsules two 400 mg capsules 54 to 90 27 to 44 2.4 three 400 mg capsules three 400 mg capsules 2.3 Dosage for Maintenance of Remission of Ulcerative Colitis The recommended dosage of mesalamine delayed-release capsules in adults is 1.6 grams (four 400 mg capsules) daily in two to four divided doses.

3 DOSAGE FORMS AND STRENGTHS Mesalamine delayed-release capsules are clear capsules imprinted with “TEVA” and “5907” on both the cap and the body in black ink. Each capsule contains four reddish-brown, film-coated round 100 mg mesalamine tablets. Delayed-release capsules (containing four 100 mg tablets): 400 mg ( 3 )

4 CONTRAINDICATIONS Mesalamine delayed-release capsules are contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release capsules [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.2 ), Description ( 11 )] . Known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release capsules. ( 4 , 5.3 )

5 WARNINGS AND PRECAUTIONS Renal Impairment: Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits of using mesalamine delayed-release capsules in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. Discontinue mesalamine delayed-release capsules if renal function deteriorates. ( 5.1 , 7.1 , 8.6 , 13.2 ) Mesalamine-induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an ulcerative colitis exacerbation; monitor for worsening symptoms while on treatment; discontinue treatment, if acute intolerance syndrome is suspected. ( 5.2 ) Hypersensitivity Reactions, including myocarditis and pericarditis: Evaluate patients immediately and discontinue mesalamine delayed-release capsules, if a hypersensitivity reaction is suspected. ( 5.3 ) Hepatic Failure: Evaluate the risks and benefits of using mesalamine delayed-release capsules 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 undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment. ( 5.7 ) Iron Content of Mesalamine Delayed-Release Capsules: Consider the iron content of mesalamine delayed-release capsules in patients taking iron supplementation and those at risk of iron overload. ( 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 ) 5.1 Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients taking products such as mesalamine delayed-release capsules 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 mesalamine delayed-release capsules and periodically while on therapy. Discontinue mesalamine delayed-release capsules if renal function deteriorates while on therapy. Evaluate the risks and benefits of using mesalamine delayed-release capsules in patients with known renal impairment or history of renal disease or taking concomitant nephrotoxic drugs [see Drug Interactions ( 7.1 ), 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 controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, abdominal pain, bloody diarrhea, and sometimes fever, headache, malaise, pruritus, conjunctivitis and rash. Monitor patients closely for worsening of these symptoms while on treatment.

has not been determined, it has occurred in 3% of controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, abdominal pain, bloody diarrhea, and sometimes fever, headache, malaise, pruritus, conjunctivitis and rash. Monitor patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine delayed-release capsules. 5.3 Hypersensitivity Reactions Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine 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 mesalamine delayed-release capsules if an alternative etiology for the signs or 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 risk and benefits of using mesalamine delayed-release capsules 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 mesalamine delayed-release capsules at the first appearance of signs or symptoms of severe cutaneous adverse reactions, or other signs of hypersensitivity and consider further evaluation. 5.6 Photosensitivity Patients treated with mesalamine or sulfasalazine who have 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 of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with mesalamine delayed-release capsules. 5.8 Iron Content of Mesalamine Delayed-Release Capsules Mesalamine delayed-release capsules contains iron oxide as a colorant in the coating of the delayed-release capsules. Each 400 mg delayed-release capsule contains 0.589 mg of iron. The total content of iron is 3.54 mg at the maximum recommended daily dosage in adults [see Dosage and Administration ( 2.2 )] . Before prescribing mesalamine delayed-release capsules to patients receiving iron supplementation or those at risk of developing iron overload, consider the combined daily amount of iron from all sources, including mesalamine delayed-release capsules. 5.9 Interference with Laboratory Tests Use of mesalamine delayed-release capsules 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 most serious adverse reactions seen in mesalamine clinical trials or with other products that contain or are metabolized to mesalamine are: 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 )] The most common adverse reactions (≥5%) are: Adults: eructation, abdominal pain, constipation, dizziness, rhinitis, back pain, and rash. ( 6.1 ) Pediatrics: nasopharyngitis, headache, abdominal pain, dizziness, sinusitis, rash, cough and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials 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 safety of mesalamine has been established based on adequate and well-controlled studies of mesalamine delayed-release tablets. In total, mesalamine delayed-release 400 mg tablets have been evaluated in 2690 patients with ulcerative colitis in controlled and open-label trials. Below is a description of the adverse reactions of mesalamine delayed-release tablets in these adequate and well-controlled studies. Clinical studies supporting mesalamine delayed-release tablets use for the treatment of mildly to moderately active ulcerative colitis included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study of 2 dosage levels in children with mildly to moderately active ulcerative colitis (Study 3). Clinical studies supporting the use of mesalamine delayed-release tablets in the maintenance of remission of ulcerative colitis included a 6-month, randomized, double-blind, placebo-controlled, multi-center study (Study 4) and four active-controlled maintenance trials comparing mesalamine delayed-release with sulfasalazine. Mesalamine delayed-release tablets have been evaluated in 427 adults and 107 children with ulcerative colitis in these controlled studies. Treatment of Mildly to Moderately Active Ulcerative Colitis Adults In a 6-week placebo-controlled clinical study (Study 1) involving 105 patients, 53 of whom were randomized to mesalamine delayed-release tablets 2.4 grams per day [see Clinical Studies ( 14.1 )], 4% of the mesalamine delayed release tablets-treated patients in 2.4 grams per day group discontinued therapy because of adverse reactions as compared to 0% of the placebo-treated patients. The average age of patients was 41 years and 49% of patients were male. Adverse reactions leading to withdrawal from mesalamine delayed-release tablets included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache. The most common adverse reactions in patients treated with mesalamine delayed release tablets 2.4 grams per day in Study 1 are listed in Table 2 below. Table 2.

to withdrawal from mesalamine delayed-release tablets included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache. The most common adverse reactions in patients treated with mesalamine delayed release tablets 2.4 grams per day in Study 1 are listed in Table 2 below. Table 2. Most Common Adverse Reactions Reported in Study 1 for the Treatment of Mild to Moderate Ulcerative Colitis in Adults* Adverse Reaction % of Patients with Adverse Reactions Mesalamine Delayed-Release 2.4 grams per day Placebo (n = 53) (n = 52) Eructation 26 19 Abdominal pain 21 12 Constipation 11 0 Dizziness 9 8 Rhinitis 8 6 Back pain 6 4 Rash 6 4 Dyspepsia 4 0 Flu syndrome 4 2 * At Least 2% of Patients in the Mesalamine Delayed-Release Tablets Group and at a Rate Greater than Placebo Pediatric Patients 5 to 17 Years Old A randomized, double-blind, 6-week study of 2 dosage levels of mesalamine delayed-release 400 mg tablets (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dosage (1.2, 2, and 2.4 grams per day for the respective body weight category) or a high dosage (2.0, 3.6, and 4.8 grams per day). The high dosage regimen is not recommended because it was not found to be more effective than the recommended low dosage regimen [see Dosage and Administration ( 2.2 ), Clinical Studies ( 14.1 )] . Duration of exposure to mesalamine among the 82 patients in the study ranged from 12 to 50 days (mean of 40 days in each dosage group). The majority (88%) of patients in each group were treated for more than 5 weeks. Table 3 provides a summary of the specific reported adverse reactions. Table 3. Adverse Reactions ≥ 5% Reported in Study 3 for the Treatment of Mild to Moderate Ulcerative Colitis in Pediatric Patients* Adverse Reaction % of Patients with Adverse Reactions Low Dosage High Dosage (n=41) (n=41) Nasopharyngitis 15 12 Headache 10 5 Abdominal pain 10 2 Dizziness 7 2 Sinusitis 7 0 Rash 5 5 Cough 5 0 Diarrhea 5 0 Fatigue 2 10 Pyrexia 0 7 Increased Lipase 0 5 Low Dosage = mesalamine 400 mg delayed-release tablet 1.2 to 2.4 grams/day; High Dosage = mesalamine 400 mg delayed-release tablet 2.0 to 4.8 grams/day. Dosage was dependent on body weight. Adverse Reactions reported at the 1-week telephone follow-up visit are included. * At Least 5% of Patients in the low dosage or high dosage group Twelve percent of the patients in the low dosage group (5 patients) and 2% of the patients in the high dosage group (1 patient) had serious adverse reactions. The serious adverse reactions consisted of sinusitis, adenovirus infection, and pancreatitis in one patient each in the low dosage group. Abdominal pain and decreased body mass index occurred in one patient and bloody diarrhea and sclerosing cholangitis also occurred in one patient in the low dosage group. Anemia and syncope occurred in one patient in the high dosage group. Five patients were withdrawn from the study due to adverse reactions: 3 (7%) in the low dosage group (1 patient each with adenovirus infection, sclerosing cholangitis, and pancreatitis) and 2 patients (5%) in the high dosage group (1 patient with increased amylase and increased lipase, and 1 patient with upper abdominal pain). In general, the nature and severity of reactions in the pediatric population was similar to those reported in adult populations of patients with ulcerative colitis.

ancreatitis) and 2 patients (5%) in the high dosage group (1 patient with increased amylase and increased lipase, and 1 patient with upper abdominal pain). In general, the nature and severity of reactions in the pediatric population was similar to those reported in adult populations of patients with ulcerative colitis. Maintenance of Remission of Ulcerative Colitis Clinical studies supporting the use of mesalamine delayed release tablets in the maintenance of remission of ulcerative colitis in adults included a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration in 264 patients (Study 4) [see Clinical Studies ( 14.2 )] . In Study 4, a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration, 87 patients were randomized to receive mesalamine delayed release tablets 1.6 grams per /day compared to 87 patients randomized to placebo. The average age of patients in Study 4 was 42 years and 55% of patients were male. Adverse reactions leading to study withdrawal in patients using mesalamine delayed release tablets included (each in one patient): anxiety, stomatitis and asthenia. In addition to the adverse reactions listed in Table 2, the following occurred at a frequency of 2% or greater in patients who received mesalamine delayed-release tablets in Study 4: abdominal enlargement, gastroenteritis, gastrointestinal hemorrhage, infection, joint disorder, nervousness, paresthesia, hemorrhoids, tenesmus, urinary frequency and vision abnormalities. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mesalamine delayed-release capsules or other mesalamine-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Neck pain, facial edema, edema, lupus-like syndrome, drug fever. Cardiovascular: Pericarditis, myocarditis [see Warnings and Precautions ( 5.3 )] . Endocrine: Nephrogenic diabetes insipidus. Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer, bloody diarrhea. Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy. Musculoskeletal: Gout. Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome, intracranial hypertension. Renal: Renal failure, interstitial nephritis, minimal change disease, nephrolithiasis [see Warnings and Precautions ( 5.1 , 5.7 )] . Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleurisy/pleuritis. Skin: Alopecia, psoriasis, pyoderma gangrenosum, dry skin, erythema nodosum, urticaria, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions ( 5.5 )] . Special Senses: Eye pain, taste perversion, blurred vision, tinnitus. Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia. Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite containing bleach Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.

<table width="800px" cellpadding="5"><caption>Table 2. Most Common Adverse Reactions Reported in Study 1 for the Treatment of Mild to Moderate Ulcerative Colitis in Adults*</caption><col/><col/><col/><tbody><tr><td valign="top" rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Adverse Reaction</paragraph></td><td align="center" valign="top" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>% of Patients with Adverse Reactions</paragraph></td></tr><tr><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Mesalamine Delayed-Release 2.4 grams per day</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Placebo</paragraph></td></tr><tr><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>(n = 53)</paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>(n = 52)</paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Eructation </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>26 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>19 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Abdominal pain </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>21 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>12 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Constipation </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>11 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Dizziness </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>9 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>8 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Rhinitis </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>8 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>6 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Back pain </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>6 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>4 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Rash </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>6 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>4 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Dyspepsia </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>4 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule"

Rrule"> <paragraph>Dyspepsia </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>4 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td></tr><tr><td valign="top" styleCode=" Botrule Toprule Lrule Rrule" > <paragraph>Flu syndrome </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>4 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>2 </paragraph></td></tr><tr><td valign="top" colspan="3" styleCode=" Botrule Toprule Lrule Rrule"> * At Least 2% of Patients in the Mesalamine Delayed-Release Tablets Group and at a Rate Greater than Placebo</td></tr></tbody></table> <table width="800px" cellpadding="5"><caption>Table 3.

> <paragraph>Flu syndrome </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>4 </paragraph></td><td align="center" valign="top" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>2 </paragraph></td></tr><tr><td valign="top" colspan="3" styleCode=" Botrule Toprule Lrule Rrule"> * At Least 2% of Patients in the Mesalamine Delayed-Release Tablets Group and at a Rate Greater than Placebo</td></tr></tbody></table> <table width="800px" cellpadding="5"><caption>Table 3. Adverse Reactions &#x2265; 5% Reported in Study 3 for the Treatment of Mild to Moderate Ulcerative Colitis in Pediatric Patients*</caption><col/><col/><col/><tbody><tr><td rowspan="3" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Adverse Reaction </paragraph></td><td align="center" colspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>% of Patients with Adverse Reactions</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Low Dosage</paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>High Dosage</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>(n=41) </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>(n=41) </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Nasopharyngitis </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>15 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>12 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Headache </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>10 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>5 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Abdominal pain </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>10 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>2 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Dizziness </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>7 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>2 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Sinusitis </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>7 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Rash </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>5 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>5 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Cough </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>5 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Diarrhea </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>5 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Fatigue </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>2 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>10 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Pyrexia </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td><td align="center" styl

aph>2 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>10 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Pyrexia </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td><td align="center" styl eCode=" Botrule Toprule Lrule Rrule"> <paragraph>7 </paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>Increased Lipase </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>0 </paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"> <paragraph>5 </paragraph></td></tr><tr><td colspan="3" styleCode=" Lrule Rrule"> Low Dosage = mesalamine 400 mg delayed-release tablet 1.2 to 2.4 grams/day; High Dosage = mesalamine 400 mg delayed-release tablet 2.0 to 4.8 grams/day. Dosage was dependent on body weight. Adverse Reactions reported at the 1-week telephone follow-up visit are included.</td></tr><tr><td valign="top" colspan="3" styleCode=" Botrule Lrule Rrule"> * At Least 5% of Patients in the low dosage or high dosage group</td></tr></tbody></table>

7 DRUG INTERACTIONS Nephrotoxic Agents including NSAIDs: Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. ( 7.1 ) Azathioprine or 6-Mercaptopurine: Increased risk of blood disorders; monitor complete blood cell counts and platelet counts. ( 7.2 ) 7.1 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 )] . 7.2 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 mesalamine delayed-release capsules and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. 7.3 Interference With Urinary Normetanephrine Measurements Use of mesalamine delayed-release capsules 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.

8 USE IN SPECIFIC POPULATIONS Geriatric Patients: Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. ( 8.5 ) 8.1 Pregnancy Risk Summary There are no adequate and well controlled studies of mesalamine use in pregnant women. Limited published human data on mesalamine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease. Furthermore, all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No evidence of fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose. Mesalamine should be used during pregnancy only if clearly needed. Human Data Mesalamine crosses the placenta. In prospective and retrospective studies of over 600 women exposed to mesalamine during pregnancy, the observed rate of congenital malformations was not increased above the background rate in the general population. Some data show an increased rate of preterm birth, stillbirth, and low birth weight, but it is unclear whether this was due to underlying maternal disease, drug exposure, or both, as active inflammatory bowel disease is also associated with adverse pregnancy outcomes. Animal data Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the fetus. These mesalamine doses were about 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose, based on body surface area. 8.2 Lactation Mesalamine and its N-acetyl metabolite are present in human milk. In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 mg/L to 18.1 mg/L. Based on these concentrations, estimated infant daily doses for an exclusively breastfed infant are 0 mg/kg/day to 0.017 mg/kg/day of mesalamine and 0.75 mg/kg/day to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mesalamine and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Caution should be exercised when mesalamine delayed-release capsules are administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of mesalamine delayed-release capsules for the treatment of mildly to moderately active ulcerative colitis in pediatric patients 5 to 17 years of age has been established based on adequate and well-controlled studies using mesalamine delayed-release 400 mg tablets. Use of mesalamine delayed-release capsules in these pediatric age groups is supported by evidence from adequate and well controlled studies of mesalamine delayed-release 400 mg tablets in adults and a single 6-week study in 82 pediatric patients 5 to 17 years of age [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 )] .

les in these pediatric age groups is supported by evidence from adequate and well controlled studies of mesalamine delayed-release 400 mg tablets in adults and a single 6-week study in 82 pediatric patients 5 to 17 years of age [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 )] . The safety and effectiveness of mesalamine delayed-release capsules for the treatment of mildly to moderately active ulcerative colitis in pediatric patients below the age of 5 years have not been established. The safety and effectiveness of mesalamine delayed-release capsules in the maintenance of remission of ulcerative colitis in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of mesalamine delayed-release tablets did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and postmarketing experience suggest a higher incidence of blood dyscrasias (agranulocytosis, neutropenia, pancytopenia) in subjects receiving mesalamine delayed-release tablets who are 65 years or older compared to younger patients taking mesalamine-containing products such as mesalamine delayed-release capsules. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine delayed-release capsules. 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 mesalamine delayed-release capsules [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 toxic reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine delayed-release capsules 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 mesalamine delayed-release capsules if renal function deteriorates while on therapy [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.2 ), Drug Interactions ( 7.1 )] .

8.1 Pregnancy Risk Summary There are no adequate and well controlled studies of mesalamine use in pregnant women. Limited published human data on mesalamine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease. Furthermore, all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No evidence of fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose. Mesalamine should be used during pregnancy only if clearly needed. Human Data Mesalamine crosses the placenta. In prospective and retrospective studies of over 600 women exposed to mesalamine during pregnancy, the observed rate of congenital malformations was not increased above the background rate in the general population. Some data show an increased rate of preterm birth, stillbirth, and low birth weight, but it is unclear whether this was due to underlying maternal disease, drug exposure, or both, as active inflammatory bowel disease is also associated with adverse pregnancy outcomes. Animal data Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the fetus. These mesalamine doses were about 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose, based on body surface area.

8.4 Pediatric Use The safety and effectiveness of mesalamine delayed-release capsules for the treatment of mildly to moderately active ulcerative colitis in pediatric patients 5 to 17 years of age has been established based on adequate and well-controlled studies using mesalamine delayed-release 400 mg tablets. Use of mesalamine delayed-release capsules in these pediatric age groups is supported by evidence from adequate and well controlled studies of mesalamine delayed-release 400 mg tablets in adults and a single 6-week study in 82 pediatric patients 5 to 17 years of age [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 )] . The safety and effectiveness of mesalamine delayed-release capsules for the treatment of mildly to moderately active ulcerative colitis in pediatric patients below the age of 5 years have not been established. The safety and effectiveness of mesalamine delayed-release capsules in the maintenance of remission of ulcerative colitis in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of mesalamine delayed-release tablets did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and postmarketing experience suggest a higher incidence of blood dyscrasias (agranulocytosis, neutropenia, pancytopenia) in subjects receiving mesalamine delayed-release tablets who are 65 years or older compared to younger patients taking mesalamine-containing products such as mesalamine delayed-release capsules. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine delayed-release capsules. 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 mesalamine delayed-release capsules [see Use in Specific Populations ( 8.6 )] .

10 OVERDOSAGE Mesalamine delayed-release capsules 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) involvement. 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 of further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function. Mesalamine delayed-release capsules is a pH dependent delayed-release product and this factor should be considered when treating a suspected overdose.

11 DESCRIPTION Each Mesalamine delayed-release capsule for oral administration contains four 100 mg tablets of mesalamine, USP an aminosalicylate. Mesalamine delayed-release capsules contain acrylic based resin, methacrylic acid copolymer (Eudragit S), which dissolves at pH 7 or greater and releases mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colon. Mesalamine, USP (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid. Its structural formula is: C 7 H 7 NO 3 M.W. 153.14 Inactive Ingredients: Each capsule contains colloidal silicon dioxide, dibutyl sebacate, hypromellose, iron oxide black, iron oxide red, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol, potassium hydroxide, povidone, propylene glycol, shellac, sodium starch glycolate (potato), strong ammonia solution and talc. 1

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of mesalamine is not fully understood, but appears to be a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. 12.3 Pharmacokinetics Absorption Approximately 28% of mesalamine in mesalamine delayed-release formulation is absorbed after oral ingestion. Following replicate single dose oral administration of mesalamine delayed-release 400 mg capsules containing four 100 mg tablets in healthy subjects (N = 146) under fasted conditions, the mean C max , AUC 8-48 and AUC tldc values were 150 ± 235 ng/mL, 640 ± 521 ng.h/mL, and 909 ± 777 ng.h/mL, respectively. The median [range] T max for mesalamine following mesalamine delayed-release 400 mg capsules containing four 100 mg tablets was approximately 10 hours [5.5 to 48 hours], reflecting the delayed-release characteristics of the formulation. A high fat meal increased systemic exposure of mesalamine (geometric mean C max : ↑ 32%; AUC 8-48 h: ↑ 46%; AUC: ↑ 29%) and delayed the median t max by approximately 4 hours compared to results in the fasted state. The observed differences in mesalamine exposure due to concomitant food intake are not considered to be clinically relevant at the total daily dosage of 2.4 grams per day. Elimination Metabolism The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5-aminosalicylic acid. Excretion Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces. After intravenous administration, the elimination half-life of mesalamine is reported to be approximately 40 minutes. After oral dosing, the median terminal t 1/2 values for mesalamine are usually about 25 hours, but are variable, ranging from 1.5 to 296 hours. There is a large inter-subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid and in their terminal half-lives following administration of mesalamine. Specific Populations Pediatric Patients In a dose-ranging pharmacokinetic study evaluating 30 mg/kg, 60 mg/kg and 90 mg/kg per day doses of mesalamine delayed-release 400 mg tablets administered twice daily for four weeks, the mean C avg values of mesalamine in pediatric ulcerative colitis patients ranged from approximately 400 ng/mL to 2100 ng/mL based on data from all dose levels. In a study evaluating mesalamine delayed-release tablets in pediatric ulcerative colitis patients (Study 3), mean plasma concentrations of mesalamine (based on sparse sampling) were 820 to 988 ng/mL at the low dose level (that is, 1.2, 2 or 2.4 grams/day based on body weight strata of 17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg, respectively).

12.1 Mechanism of Action The mechanism of action of mesalamine is not fully understood, but appears to be a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

12.3 Pharmacokinetics Absorption Approximately 28% of mesalamine in mesalamine delayed-release formulation is absorbed after oral ingestion. Following replicate single dose oral administration of mesalamine delayed-release 400 mg capsules containing four 100 mg tablets in healthy subjects (N = 146) under fasted conditions, the mean C max , AUC 8-48 and AUC tldc values were 150 ± 235 ng/mL, 640 ± 521 ng.h/mL, and 909 ± 777 ng.h/mL, respectively. The median [range] T max for mesalamine following mesalamine delayed-release 400 mg capsules containing four 100 mg tablets was approximately 10 hours [5.5 to 48 hours], reflecting the delayed-release characteristics of the formulation. A high fat meal increased systemic exposure of mesalamine (geometric mean C max : ↑ 32%; AUC 8-48 h: ↑ 46%; AUC: ↑ 29%) and delayed the median t max by approximately 4 hours compared to results in the fasted state. The observed differences in mesalamine exposure due to concomitant food intake are not considered to be clinically relevant at the total daily dosage of 2.4 grams per day. Elimination Metabolism The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5-aminosalicylic acid. Excretion Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces. After intravenous administration, the elimination half-life of mesalamine is reported to be approximately 40 minutes. After oral dosing, the median terminal t 1/2 values for mesalamine are usually about 25 hours, but are variable, ranging from 1.5 to 296 hours. There is a large inter-subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid and in their terminal half-lives following administration of mesalamine. Specific Populations Pediatric Patients In a dose-ranging pharmacokinetic study evaluating 30 mg/kg, 60 mg/kg and 90 mg/kg per day doses of mesalamine delayed-release 400 mg tablets administered twice daily for four weeks, the mean C avg values of mesalamine in pediatric ulcerative colitis patients ranged from approximately 400 ng/mL to 2100 ng/mL based on data from all dose levels. In a study evaluating mesalamine delayed-release tablets in pediatric ulcerative colitis patients (Study 3), mean plasma concentrations of mesalamine (based on sparse sampling) were 820 to 988 ng/mL at the low dose level (that is, 1.2, 2 or 2.4 grams/day based on body weight strata of 17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg, respectively).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Mesalamine was not carcinogenic at dietary doses of up to 480 mg/kg/day in rats and 2000 mg/kg/day in mice, which are about 2.9 and 6.1 times the maximum recommended maintenance dose of mesalamine of 1.6 grams per day or 26.7 mg/kg/day, based on 60 kg body weight, respectively, based on body surface area. Mutagenesis Mesalamine was negative in the Ames assay for mutagenesis, negative for induction of sister chromatid exchanges (SCE) and chromosomal aberrations in Chinese hamster ovary cells in vitro , and negative for induction of micronuclei (MN) in mouse bone marrow polychromatic erythrocytes. Impairment of Fertility Mesalamine, at oral doses up to 480 mg/kg/day (about 1.9 times the recommended human treatment dose on a body surface area basis), was found to have no effect on fertility or reproductive performance of male and female rats. 13.2 Animal Toxicology and/or Pharmacology In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 2.4 grams per day dose for a 60 kg person.) Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (approximately 3 to 4 times the recommended human dose based on body surface area). Doses of 170 and 360 mg/kg/day (about 0.7 and 1.5 times the recommended human dose based on body surface area) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia. In mice, oral doses of 4000 mg/kg/day mesalamine (approximately 8 times the recommended human dose based on body surface area) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis. In dogs, single doses of 6000 mg (approximately 8 times the recommended human dose based on body surface area) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (1.1 times the recommended human dose based on body surface area).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Mesalamine was not carcinogenic at dietary doses of up to 480 mg/kg/day in rats and 2000 mg/kg/day in mice, which are about 2.9 and 6.1 times the maximum recommended maintenance dose of mesalamine of 1.6 grams per day or 26.7 mg/kg/day, based on 60 kg body weight, respectively, based on body surface area. Mutagenesis Mesalamine was negative in the Ames assay for mutagenesis, negative for induction of sister chromatid exchanges (SCE) and chromosomal aberrations in Chinese hamster ovary cells in vitro , and negative for induction of micronuclei (MN) in mouse bone marrow polychromatic erythrocytes. Impairment of Fertility Mesalamine, at oral doses up to 480 mg/kg/day (about 1.9 times the recommended human treatment dose on a body surface area basis), was found to have no effect on fertility or reproductive performance of male and female rats.

13.2 Animal Toxicology and/or Pharmacology In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 2.4 grams per day dose for a 60 kg person.) Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (approximately 3 to 4 times the recommended human dose based on body surface area). Doses of 170 and 360 mg/kg/day (about 0.7 and 1.5 times the recommended human dose based on body surface area) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia. In mice, oral doses of 4000 mg/kg/day mesalamine (approximately 8 times the recommended human dose based on body surface area) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis. In dogs, single doses of 6000 mg (approximately 8 times the recommended human dose based on body surface area) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (1.1 times the recommended human dose based on body surface area).

14 CLINICAL STUDIES The safety and efficacy of mesalamine has been established based on adequate and well-controlled studies of mesalamine delayed-release tablets. Below is a description of the results of the adequate and well-controlled studies of mesalamine delayed-release tablets for the treatment of mildly to moderately active ulcerative colitis in adults and pediatric patients 5 to 17 years of age and the maintenance of remission of ulcerative colitis in adults. 14.1 Treatment of Mildly to Moderately Active Ulcerative Colitis Adults Two placebo-controlled studies (Studies 1 and 2) have demonstrated the efficacy of mesalamine delayed-release tablets in patients with mildly to moderately active ulcerative colitis. In one randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 weeks’ duration in 158 patients (Study 1), patients received mesalamine delayed release dosages of 1.6 grams per day (800 mg twice a day; n=53) and 2.4 grams per day (800 mg three times a day; n=53), compared to placebo (n=52). The scoring system for determination of treatment efficacy included assessment of stool frequency, rectal bleeding, sigmoidoscopic findings, patient’s functional assessment, and physician global assessment. At the dosage of 2.4 grams per day, 21 of 43 (49%) patients using mesalamine delayed release tablets showed an improvement in sigmoidoscopic appearance of the bowel compared to 12 of 44 (27%) patients using placebo (p = 0.048). In addition, significantly more patients in the mesalamine delayed release tablets 2.4 grams per day group showed improvement in rectal bleeding and stool frequency. The 1.6 grams per day dosage regimen is not recommended because it did not produce consistent evidence of effectiveness [see Dosage and Administration ( 2.2 )] . In a second randomized, double-blind, placebo-controlled clinical trial of 6 weeks’ duration in 87 patients (Study 2), patients received mesalamine delayed release tablets of 1.6 grams per day (400 mg four times a day; n=11) and 4.8 grams per day (1.2 grams four times a day; n=38), compared to placebo four times a day (n=38). Mesalamine delayed release tablets 4.8 grams per day for 6 weeks resulted in sigmoidoscopic improvement in 28 of 38 (74%) patients compared to 10 of 38 (26%) placebo patients (p less than 0.001). Also, more patients in the mesalamine delayed release tablets 4.8 grams per day group than the placebo group showed improvement in overall symptoms. The 4.8 grams per day dosage regimen is not recommended because greater efficacy was not demonstrated with this dosage compared to the 2.4 grams per day dosage [see Dosage and Administration ( 2.2 )] . Pediatrics The safety and effectiveness of mesalamine delayed release in pediatric patients 5 to 17 years of age for treatment of mildly to moderately active ulcerative colitis are supported by evidence from adequate and well controlled studies of mesalamine delayed release in adults and a single study in pediatric patients.

rics The safety and effectiveness of mesalamine delayed release in pediatric patients 5 to 17 years of age for treatment of mildly to moderately active ulcerative colitis are supported by evidence from adequate and well controlled studies of mesalamine delayed release in adults and a single study in pediatric patients. A randomized, double-blind, 6-week study of two dosage levels of mesalamine delayed release tablets (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly or moderately active ulcerative colitis defined as a score of 10 to 55 on the Pediatric Ulcerative Colitis Activity Index (PUCAI) (which includes assessment of abdominal pain, rectal bleeding, stool consistency, number of stools per 24 hours, presence of nocturnal bowel movement and activity level, and has a total maximum score of 85; each of the subscales are scored from 0 to 10 except rectal bleeding which is scored from 0 to 30, and number of stools per 24 hours which is scored from 0 to 15) and rectal bleeding and stool frequency Mayo subscale scores of ≥1 (each of these subscales are scored from zero (normal) to three (most severe). All patients were divided by weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dosage (1.2, 2, and 2.4 grams per day for the respective weight category) or a high dosage (2, 3.6, and 4.8 grams per day). Doses were administered every 12 hours. The proportion of patients who achieved success based on the Truncated Mayo Score (TM-Mayo) (based on the stool frequency and rectal bleeding subscores of the Mayo Score) and based on the PUCAI was measured after 6 weeks of treatment. Success based on TM-Mayo was defined as either partial response (improvement from baseline in stool frequency or rectal bleeding subscores with no worsening in the other) or complete response (both stool frequency and rectal bleeding subscores equal 0). Success based on PUCAI was defined as either partial response (PUCAI reduction of greater than or equal to 20 points from Baseline to Week 6 with Week 6 score greater than or equal to 10) or complete response (PUCAI less than 10 at Week 6). There were 41 patients in the low dosage group and 41 patients in the high dosage group who received at least one dose of mesalamine delayed-release 400 mg tablets; 36 patients in each dosage group completed the study. Patients were considered treatment failures if they did not achieve success or dropped out due to adverse reaction or lack of efficacy. At Week 6, 73% of the patients in the low dosage group, and 70% of the patients in the high dosage group achieved success based on the TM-Mayo; 34% of the patients in the low dosage group and 43% of the patients in the high dosage group achieved complete response. At Week 6, 56% of the patients in the low dosage group, and 55% of the patients in the high dosage group achieved success based on the PUCAI; 46% of the patients in the low dosage group and 43% of the patients in the high dosage group achieved complete response. The high dosage regimen is not recommended because it was not more effective than the low dosage regimen [see Dosage and Administration ( 2.2 )] . 14.2 Maintenance of Remission of Ulcerative Colitis Adults In a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration in 264 patients (Study 4), patients received mesalamine delayed-release tablets of 0.8 grams per day (400 mg twice a day; n = 90) and 1.6 grams per day (400 mg four times a day; n = 87), compared to placebo four times a day (n = 87).

d, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration in 264 patients (Study 4), patients received mesalamine delayed-release tablets of 0.8 grams per day (400 mg twice a day; n = 90) and 1.6 grams per day (400 mg four times a day; n = 87), compared to placebo four times a day (n = 87). The proportion of patients treated with 0.8 grams per day who maintained endoscopic remission was not statistically significant compared to placebo; the 0.8 grams per day dosage regimen is not recommended [see Dosage and Administration ( 2.3 )] . The number of patients using mesalamine delayed-release tablets 1.6 grams per day who maintained endoscopic remission of ulcerative colitis was 61 of 87 (70%) compared with 42 of 87 (48%) of placebo patients (p = 0.005). A pooled efficacy analysis of 4 maintenance trials compared mesalamine delayed release tablets at dosages of 0.8 to 2.8 grams per day, in divided doses ranging from twice daily to four times per day, with sulfasalazine, at dosages of 2 to 4 grams per day. Treatment success was seen in 59 of 98 (59%) patients using mesalamine delayed release tablets and 70 of 102 (69%) patients using sulfasalazine, a non-significant difference.

16 HOW SUPPLIED/STORAGE AND HANDLING Mesalamine delayed-release capsules are available as clear capsules imprinted with “TEVA” and “5907” on both the cap and the body in black ink. Each capsule contains four reddish-brown, film-coated round 100 mg mesalamine tablets. NDC 0093-5907-86 Bottle of 180 capsules Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION Administration Inform patients that if they are switching from a previous oral mesalamine therapy to mesalamine delayed-release capsules to discontinue their previous oral mesalamine therapy and follow the dosing instructions for mesalamine delayed-release capsules. Inform patients that two mesalamine delayed-release 400 mg capsules cannot be substituted for one mesalamine delayed-release 800 mg tablet. Inform patients that mesalamine delayed-release capsules can be taken with or without food. Instruct patients to swallow the mesalamine delayed-release capsules whole. Do not cut, break, crush or chew the capsules. For patients who are unable to swallow the capsules whole, carefully open the capsules and swallow the contents (four 100 mg tablets). Open the number of capsules required to make up a complete dose. There are 4 tablets per capsule. Ensure all tablets per capsule are swallowed and no tablets are retained in the mouth. Swallow the tablets whole; do not cut, break, crush or chew the tablets. Drink an adequate amount of fluids. Inform patients that intact, partially intact, and/or tablet shells have been reported in the stool. Instruct patients to contact their healthcare provider if this occurs repeatedly. Inform patients that urine may become discolored reddish-brown while taking mesalamine delayed-release capsules 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). Instruct patients to protect mesalamine delayed-release capsules from moisture. Instruct patients to close the container tightly and to leave any desiccant pouches present in the bottle along with the capsules. Renal Impairment Inform patients that mesalamine delayed-release capsules 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 ( 7.1) ] . Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking mesalamine delayed-release capsules and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis 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.

iver 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 mesalamine delayed-release capsules 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 maintain an adequate fluid intake 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 )] . Iron Content of Mesalamine Delayed-Release Capsules Advise patients to inform their healthcare provider if they take iron-containing supplements [see Warnings and Precaution ( 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 ( 7.2 ), Use in Specific Populations ( 8.5 )] . Manufactured In Israel By: Teva Pharmaceutical Ind. Ltd. Kfar Saba, 4410202, Israel Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. H 5/2025

1 INDICATIONS AND USAGE sfROWASA is indicated for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis in adults. sfROWASA is an aminosalicylate indicated for treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Evaluate renal function before initiating therapy with sfROWASA [see Warnings and Precautions (5.1) ] . Recommended Dosage The recommended dosage is one rectal instillation (4 grams) once a day, preferably at bedtime, and retained for approximately eight hours for 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. Administration Instructions • Shake the bottle to ensure the suspension is homogeneous. • Remove the protective sheath from the applicator tip. • Assume the correct body position: o Lie on the left side with the lower leg extended and the upper right leg flexed forward for balance. o Alternatively, sit in the knee to chest position. • Gently insert the applicator tip in the rectum pointing toward the umbilicus. • Steadily squeeze the bottle to discharge the medication. • Remain in the position for at least 30 minutes. Administer at bedtime with the objective of retaining it all night. • Drink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7) ] . • Evaluate renal function prior to initiation of sfROWASA and periodically while on therapy. ( 2 , 5.1 ) • The recommended dosage is one rectal instillation (4 grams) once a day, preferably at bedtime, and retained for approximately eight hours for 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. ( 2 ) • Drink an adequate amount of fluids. ( 2 . 5.7 )

4 CONTRAINDICATIONS sfROWASA is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates or any other component of this medication [see Warnings and Precautions (5.3) ] . Known or suspected hypersensitivity to salicylates, aminosalicylates or any other of the ingredients in sfROWASA. ( 4 , 5.1 )

5 WARNINGS AND PRECAUTIONS • Renal Impairment : Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits of sfROWASA in patients with known renal impairment or taking nephrotoxic drug. Discontinue sfROWASA if renal function deteriorates while on therapy. ( 7.1 ) • Mesalamine-Induced Acute Intolerance Syndrome : Discontinue treatment if acute intolerance syndrome (cramping, acute abdominal pain, bloody diarrhea, sometimes fever, headache and rash) is suspected. ( 5.2 ) • Hepatic Failure : Evaluate the risks and benefits of using sfROWASA in patients with known liver impairment. ( 5.3 ) • Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other sings of hypersensitivity and consider further evaluation. ( 5.4 ) • Photosensitivity : Avoid sun exposure if pre-existing skin conditions. ( 5.5 ) • Nephrolithiasis : Cases of nephrolithiasis have been reported with the use of mesalamine. Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. ( 5.6 ) • Interference with Laboratory Tests : Mesalamine may lead to elevated urinary normetanephrine test results. ( 5.7 ) 5.1 Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given sfROWASA or other products that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Nonclinical Toxicology (13.2) ] . Evaluate the risks and benefits of using sfROWASA in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Evaluate renal function in all patients prior to initiation and periodically while on sfROWASA therapy. Discontinue sfROWASA if renal function deteriorates while on therapy [see Drug Interactions (7.1) , 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 a flare of inflammatory bowel disease. Although the exact frequency of occurrence cannot be ascertained, 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 sfROWASA. 5.3 Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. Evaluate the risks and benefits of using sfROWASA in patients with known liver impairment. 5.4 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) ] . Discontinue sfROWASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine [see Adverse Reactions (6) ] . Discontinue sfROWASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.5 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. 5.6 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. 5.7 Interference with Laboratory Tests Use of mesalamine 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 the labeling: • Renal impairment [see Warnings and Precautions (5.1) ] • Mesalamine-induced acute intolerance syndrome [see Warnings and Precautions (5.2) ] • Hepatic failure [see Warnings and Precautions (5.3) ] • Severe cutaneous adverse reactions [see Warnings and Precautions (5.4) ] • Photosensitivity [see Warnings and Precautions (5.5) ] • Nephrolithiasis [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥1%) are: gas/flatulence, flu, fever, leg/joint pain, hemorrhoids, rectal pain and hair loss. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc at 1-866-210-5949 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials 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. Table 1: Adverse Reactions reported in 1% or more of sfROWASA-treated patients and greater than placebo in Clinical Trials of sfROWASA in Adult Patients with Ulcerative Colitis, Proctosigmoiditis or Proctitis Adverse Reaction sfROWASA (N=815) % Placebo (N=128) % Gas/Flatulence 6 4 Flu 5 1 Fever 3 0 Leg/Joint pain 2 1 Hemorrhoids 1 1 Rectal pain 1 0 Hair loss 1 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mesalamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: pancreatitis Hematologic Disorders: agranulocytosis, aplastic anemia, eosinophilia, leukopenia, neutropenia, pancytopenia, thrombocytopenia Hepatic Disorders: elevated liver enzymes, hepatic failure [see Warnings and Precautions (5.3) ] Nervous System: intracranial hypertension Renal and Urinary Disorders: acute renal failure, chronic renal failure, interstitial nephritis, nephrogenic diabetes insipidus, nephrolithiasis, nephrotoxicity [see Warnings and Precautions (5.1) , (5.6) ] • Urine discoloration occurring ex-vivo caused by contact of mesalamine including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach Reproductive System and Breast Disorders: reversible oligospermia Respiratory, Thoracic, and Mediastinal Disorders: fibrosing alveolitis, pleurisy/pleuritis Skin and Subcutaneous Tissue Disorders: AGEP, DRESS, SJS/TEN [see Warnings and Precautions (5.4) ]

<table styleCode="Noautorules" width="100%"><caption>Table 1: Adverse Reactions<footnote ID="_Ref174678302">reported in 1% or more of sfROWASA-treated patients and greater than placebo</footnote> in Clinical Trials of sfROWASA in Adult Patients with Ulcerative Colitis, Proctosigmoiditis or Proctitis</caption><col width="34%"/><col width="33%"/><col width="32%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">sfROWASA</content></paragraph><paragraph><content styleCode="bold">(N=815)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N=128)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gas/Flatulence</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Flu</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Leg/Joint pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hemorrhoids</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rectal pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Hair loss</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • Nephrotoxic Agents including Non-Steroidal Anti-inflammatory Drugs (NSAIDs) : Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. ( 7.1 ) • Azathioprine or 6-Mercaptopurine : Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. ( 7.2 ) 7.1 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 (5.2) ] . 7.2 Azathioprine or 6-Mercaptopurine The concurrent use of mesalamine with azathioprine or 6‑mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of sfROWASA and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. 7.3 Interference with Urinary Normetanephrine Measurements Use of sfROWASA may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions (5.7) ] . Consider an alternative, selective assay for normetanephrine.

8 USE IN SPECIFIC POPULATIONS Geriatric Patients : Increased risk of blood dyscrasias; monitor complete 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 ) . There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations ) . In animal reproduction studies, rats and rabbits administered mesalamine during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, did not reveal any evidence of harm to the embryo or the fetus (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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, the active moiety of sfROWASA, 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 increase 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 have been performed with mesalamine in rats and rabbits during organogenesis at oral doses up to 5 and 8 times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus. 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 0.1% or less for mesalamine (see Data ) . There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations ) . There is no information on the effects of mesalamine on milk production.

minosalicylic acid in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine (see Data ) . There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations ) . There is no information on the effects of mesalamine on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of sfROWASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sfROWASA and any potential adverse effects on the breastfed child from sfROWASA 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 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 of mesalamine (RID 0% to 0.1%) and 0.03 to 1.4 mg/kg/day of N‑acetyl‑5‑aminosalicylic acid. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical trials of sfROWASA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as sfROWASA who were 65 years or older compared to younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function. Consider monitoring complete blood cell counts and platelet counts in patients 65 years and over during treatment with sfROWASA. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in patients 65 years and over when prescribing sfROWASA. 8.6 Renal Impairment Mesalamine is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on sfROWASA 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 sfROWASA if renal function deteriorates while on therapy [see Warnings and Precautions (5.2) ] .

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 ) . There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations ) . In animal reproduction studies, rats and rabbits administered mesalamine during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, did not reveal any evidence of harm to the embryo or the fetus (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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, the active moiety of sfROWASA, 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 increase 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 have been performed with mesalamine in rats and rabbits during organogenesis at oral doses up to 5 and 8 times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus.

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 ) . There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations ) . In animal reproduction studies, rats and rabbits administered mesalamine during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, did not reveal any evidence of harm to the embryo or the fetus (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. 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 0.1% or less for mesalamine (see Data ) . There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations ) . There is no information on the effects of mesalamine on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of sfROWASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sfROWASA and any potential adverse effects on the breastfed child from sfROWASA or from the underlying maternal condition.

8.5 Geriatric Use Clinical trials of sfROWASA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as sfROWASA who were 65 years or older compared to younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function. Consider monitoring complete blood cell counts and platelet counts in patients 65 years and over during treatment with sfROWASA. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in patients 65 years and over when prescribing sfROWASA.

10 OVERDOSAGE sfROWASA 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) involvement. 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.

11 DESCRIPTION The active ingredient in sfROWASA ® (mesalamine) Rectal Suspension, a disposable (60 mL) unit, is mesalamine, also known as 5-aminosalicylic acid (5-ASA). Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid. The empirical formula is C 7 H 7 NO 3 , representing a molecular weight of 153.14. The structural formula is: sfROWASA is supplied as a suspension for rectal administration. Each rectal suspension unit contains 4 grams of mesalamine. The inactive ingredients are carbomer 934P, edetate disodium, potassium acetate, purified water, sodium benzoate and xanthan gum. Sodium benzoate is added as a preservative. The disposable unit consists of an applicator tip protected by a polyethylene cover and lubricated with USP white petrolatum. The unit has a one-way valve to prevent back flow of the dispensed product. mesalamine structural formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of 5-ASA (mesalamine) is not fully understood, but appears to be a topical 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 mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of mesalamine have not been fully characterized. 12.3 Pharmacokinetics Absorption Mesalamine administered rectally as sfROWASA is poorly absorbed from the colon and is excreted principally in the feces during subsequent bowel movements. The extent of absorption is dependent upon the retention time of the drug product, and there is considerable individual variation. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of 2 mcg/mL, about two-thirds of which was the N-acetyl metabolite. In addition, steady state plasma levels demonstrated a lack of accumulation of either parent drug or N-acetyl metabolite during repeated daily rectal administrations. Distribution Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. The poor colonic absorption of rectally administered mesalamine is substantiated by the low serum concentration of 5-ASA and N-acetyl-5-ASA seen in ulcerative colitis patients after dosage with mesalamine. Elimination Metabolism It is known that the compound undergoes acetylation but whether this process takes place at colonic or systemic sites has not been elucidated. Excretion Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N-acetyl-5-ASA metabolite. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. While the elimination half-life of mesalamine is short (0.5 to 1.5 hours), the acetylated metabolite exhibits a half-life of 5 to 10 hours.

12.1 Mechanism of Action The mechanism of action of 5-ASA (mesalamine) is not fully understood, but appears to be a topical 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 mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

12.3 Pharmacokinetics Absorption Mesalamine administered rectally as sfROWASA is poorly absorbed from the colon and is excreted principally in the feces during subsequent bowel movements. The extent of absorption is dependent upon the retention time of the drug product, and there is considerable individual variation. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of 2 mcg/mL, about two-thirds of which was the N-acetyl metabolite. In addition, steady state plasma levels demonstrated a lack of accumulation of either parent drug or N-acetyl metabolite during repeated daily rectal administrations. Distribution Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. The poor colonic absorption of rectally administered mesalamine is substantiated by the low serum concentration of 5-ASA and N-acetyl-5-ASA seen in ulcerative colitis patients after dosage with mesalamine. Elimination Metabolism It is known that the compound undergoes acetylation but whether this process takes place at colonic or systemic sites has not been elucidated. Excretion Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N-acetyl-5-ASA metabolite. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. While the elimination half-life of mesalamine is short (0.5 to 1.5 hours), the acetylated metabolite exhibits a half-life of 5 to 10 hours.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study in Wistar rats fed up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison). of mesalamine admixed with diet, mesalamine did not cause an increase in the incidence of neoplastic lesions over controls. Mutagenesis Mesalamine is not mutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, TA1538. There were no reverse mutations in an assay using E. coli strain WP2UVRA. There were no evidence of genotoxicity in an in vivo mouse micronucleus assay at 600 mg/kg and in an in vivo sister chromatid exchange assay at doses up to 610 mg/kg. Impairment of Fertility Mesalamine had no effects on fertility in rats at doses up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison). 13.2 Animal Toxicology and/or Pharmacology Preclinical studies have shown the kidney to be the major target organ for mesalamine toxicity. Adverse renal function changes were observed in rats after a single 600 mg/kg oral dose, but not after a 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after a single oral >900 mg/kg dose, and after I.V. doses of >214 mg/kg. Mice responded similarly. In a 13-week oral (gavage) dose study in rats, the high dose of 640 mg/kg/day mesalamine caused deaths, probably due to renal failure, and dose-related renal lesions (papillary necrosis and/or multifocal tubular injury) were seen in most rats given the high dose (males and females) as well as in males receiving lower doses 160 mg/kg/day. Renal lesions were not observed in the 160 mg/kg/day female rats. Minimal tubular epithelial damage was seen in the 40 mg/kg/day males and was reversible. In a six-month oral study in dogs, the no-observable dose level of mesalamine was 40 mg/kg/day and doses of 80 mg/kg/day and higher caused renal pathology similar to that described for the rat. In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration in kidneys was observed at doses of 100 mg/kg/day and above admixed with diet for 52 weeks, and at 127 weeks increased incidence of kidney degeneration and hyalinization of basement membranes and Bowman's capsule were seen at 100 mg/kg/day and above. In the 12-month eye toxicity study in dogs, Keratoconjunctivitis Sicca (KCS) occurred at oral doses of 40 mg/kg/day and above. The oral preclinical studies were done with a highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study in Wistar rats fed up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison). of mesalamine admixed with diet, mesalamine did not cause an increase in the incidence of neoplastic lesions over controls. Mutagenesis Mesalamine is not mutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, TA1538. There were no reverse mutations in an assay using E. coli strain WP2UVRA. There were no evidence of genotoxicity in an in vivo mouse micronucleus assay at 600 mg/kg and in an in vivo sister chromatid exchange assay at doses up to 610 mg/kg. Impairment of Fertility Mesalamine had no effects on fertility in rats at doses up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison).

13.2 Animal Toxicology and/or Pharmacology Preclinical studies have shown the kidney to be the major target organ for mesalamine toxicity. Adverse renal function changes were observed in rats after a single 600 mg/kg oral dose, but not after a 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after a single oral >900 mg/kg dose, and after I.V. doses of >214 mg/kg. Mice responded similarly. In a 13-week oral (gavage) dose study in rats, the high dose of 640 mg/kg/day mesalamine caused deaths, probably due to renal failure, and dose-related renal lesions (papillary necrosis and/or multifocal tubular injury) were seen in most rats given the high dose (males and females) as well as in males receiving lower doses 160 mg/kg/day. Renal lesions were not observed in the 160 mg/kg/day female rats. Minimal tubular epithelial damage was seen in the 40 mg/kg/day males and was reversible. In a six-month oral study in dogs, the no-observable dose level of mesalamine was 40 mg/kg/day and doses of 80 mg/kg/day and higher caused renal pathology similar to that described for the rat. In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration in kidneys was observed at doses of 100 mg/kg/day and above admixed with diet for 52 weeks, and at 127 weeks increased incidence of kidney degeneration and hyalinization of basement membranes and Bowman's capsule were seen at 100 mg/kg/day and above. In the 12-month eye toxicity study in dogs, Keratoconjunctivitis Sicca (KCS) occurred at oral doses of 40 mg/kg/day and above. The oral preclinical studies were done with a highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred.

14 CLINICAL STUDIES In a 6-week placebo-controlled trial, international, multicenter trial of 153 patients with active distal ulcerative colitis, proctosigmoiditis or proctitis, sfROWASA ® (mesalamine) rectal suspension reduced the overall disease activity index (DAI) and individual components as follows: EFFECT OF TREATMENT ON SEVERITY OF DISEASE DATA FROM U.S.-CANADA TRIAL COMBINED RESULTS OF EIGHT CENTERS Each parameter has a 4-point scale with a numerical rating: 0 = normal, 1 = mild, 2 = moderate, 3 = severe. The four parameters are added together to produce a maximum overall DAI of 12. Activity Indices, mean N Baseline Day 22 End Point Change Baseline to End Point * Percent change for overall DAI only (calculated by taking the average of the change for each individual patient). Overall DAI sfROWASA ® Placebo 76 77 7.42 7.40 4.05 † Significant sfROWASA®/placebo difference. p < 0.01 6.03 3.37 ‡ Significant sfROWASA®/placebo difference. p < 0.001 5.83 -55.07% -21.58% Stool Frequency sfROWASA ® Placebo 1.58 1.92 1.11 § Significant sfROWASA®/placebo difference. p < 0.05 1.47 1.01 1.50 -0.57 -0.41 Rectal Bleeding sfROWASA ® Placebo 1.82 1.73 0.59 1.21 0.51 1.11 -1.30 -0.61 Mucosal Inflammation sfROWASA ® Placebo 2.17 2.18 1.22 1.74 0.96 1.61 -1.21 -0.56 Physician’s Assessment of Disease Severity sfROWASA ® Placebo 1.86 1.87 1.13 1.62 0.88 1.55 -0.97 -0.30 Differences between sfROWASA ® (mesalamine) Rectal Suspension and placebo were also statistically different in subgroups of patients on concurrent sulfasalazine and in those having an upper disease boundary between 5 and 20 or 20 and 40 cm. Significant differences between sfROWASA ® (mesalamine) Rectal Suspension and placebo were not achieved in those subgroups of patients on concurrent prednisone or with an upper disease boundary between 40 and 50 cm.

<table width="100%"><caption>EFFECT OF TREATMENT ON SEVERITY OF DISEASE DATA FROM U.S.-CANADA TRIAL COMBINED RESULTS OF EIGHT CENTERS</caption><col width="17%"/><col width="16%"/><col width="13%"/><col width="14%"/><col width="13%"/><col width="13%"/><col width="14%"/><tfoot><tr><td align="left" colspan="7" valign="top">Each parameter has a 4-point scale with a numerical rating:</td></tr><tr><td align="left" colspan="7" valign="top">0 = normal, 1 = mild, 2 = moderate, 3 = severe. The four parameters are added together to produce a maximum overall DAI of 12.</td></tr></tfoot><tbody><tr styleCode="Toprule"><td colspan="2" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Activity Indices, mean</content></paragraph></td><td styleCode="Botrule " valign="bottom"/><td styleCode="Botrule " valign="bottom"/><td styleCode="Botrule " valign="bottom"/><td styleCode="Botrule " valign="bottom"/><td styleCode="Botrule " valign="bottom"/></tr><tr><td styleCode="Botrule " valign="top"/><td styleCode="Toprule Botrule " valign="bottom"/><td styleCode="Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">N</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Baseline</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Day 22</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">End Point</content></paragraph></td><td styleCode="Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Change Baseline to End Point<footnote ID="_Ref174681769">* Percent change for overall DAI only (calculated by taking the average of the change for each individual patient).</footnote></content></paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Overall DAI</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>sfROWASA^&#xAE;</paragraph><paragraph>Placebo</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>76</paragraph><paragraph>77</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>7.42</paragraph><paragraph>7.40</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>4.05<footnote ID="_Ref174681814">&#x2020; Significant sfROWASA&#xAE;/placebo difference. p &lt; 0.01</footnote></paragraph><paragraph>6.03</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>3.37<footnote ID="_Ref174681808">&#x2021; Significant sfROWASA&#xAE;/placebo difference. p &lt; 0.001</footnote></paragraph><paragraph>5.83</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>-55.07%<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>-21.58%</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Stool Frequency</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>sfROWASA^&#xAE;</paragraph><paragraph>Placebo</paragraph></td><td styleCode="Toprule Botrule " valign="top"/><td styleCode="Toprule Botrule " valign="top"><paragraph>1.58</paragraph><paragraph>1.92</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>1.11<footnote ID="_Ref174681826">&#xA7; Significant sfROWASA&#xAE;/placebo difference.

>Placebo</paragraph></td><td styleCode="Toprule Botrule " valign="top"/><td styleCode="Toprule Botrule " valign="top"><paragraph>1.58</paragraph><paragraph>1.92</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>1.11<footnote ID="_Ref174681826">&#xA7; Significant sfROWASA&#xAE;/placebo difference. p &lt; 0.05</footnote></paragraph><paragraph>1.47</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>1.01<footnoteRef IDREF="_Ref174681814"/></paragraph><paragraph>1.50</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>-0.57<footnoteRef IDREF="_Ref174681826"/></paragraph><paragraph>-0.41</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Rectal Bleeding</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>sfROWASA^&#xAE;</paragraph><paragraph>Placebo</paragraph></td><td styleCode="Toprule Botrule " valign="top"/><td styleCode="Toprule Botrule " valign="top"><paragraph>1.82</paragraph><paragraph>1.73</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>0.59<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>1.21</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>0.51<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>1.11</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>-1.30<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>-0.61</paragraph></td></tr><tr><td styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Mucosal Inflammation</content></paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>sfROWASA^&#xAE;</paragraph><paragraph>Placebo</paragraph></td><td styleCode="Toprule Botrule " valign="top"/><td styleCode="Toprule Botrule " valign="top"><paragraph>2.17</paragraph><paragraph>2.18</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>1.22<footnoteRef IDREF="_Ref174681814"/></paragraph><paragraph>1.74</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>0.96<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>1.61</paragraph></td><td styleCode="Toprule Botrule " valign="top"><paragraph>-1.21<footnoteRef IDREF="_Ref174681814"/></paragraph><paragraph>-0.56</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Physician&#x2019;s Assessment of Disease Severity</content></paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph>sfROWASA^&#xAE;</paragraph><paragraph>Placebo</paragraph></td><td styleCode="Botrule Toprule " valign="top"/><td styleCode="Botrule Toprule " valign="top"><paragraph>1.86</paragraph><paragraph>1.87</paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph>1.13<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>1.62</paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph>0.88<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>1.55</paragraph></td><td styleCode="Botrule Toprule " valign="top"><paragraph>-0.97<footnoteRef IDREF="_Ref174681808"/></paragraph><paragraph>-0.30</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING sfROWASA ® (mesalamine) rectal suspension is an off-white to tan colored suspension. Each disposable suspension bottle contains 4 grams of mesalamine in 60 mL aqueous suspension. Suspension bottles are supplied in boxed, foil-wrapped trays as follows: NDC 0037-0022-60 .................. Sample – 1 Bottle NDC 0037-0022-07 .................. Carton of 7 Bottles NDC 0037-0022-14 .................. Carton of 14 Bottles NDC 0037-0022-28 .................. Carton of 28 Bottles sfROWASA ® (mesalamine) rectal suspension is for rectal use only. Storage Store at controlled room temperature 20°C to 25°C (68°F to 77°F); Excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Once the foil wrapped unit of seven bottles is opened, all suspensions should be used promptly as directed by your physician. Contents of suspensions removed from the foil pouch may darken with time. Slight darkening will not affect potency, however, suspensions with dark brown contents should be discarded.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Instructions for Use ). Renal Impairment Inform patients that sfROWASA may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, 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) ] . Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions Instruct patients to stop taking sfROWASA 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 Advise patients with known liver disease to contact their healthcare provider if they experience signs or symptoms of worsening liver function [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 sfROWASA 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 (5.7) ] . 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) ] . 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 (7.2) , Use in Specific Populations (8.5) ] . Administration Advise patients that sfROWASA will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Administer the product in a suitable location. Instruct patients: • Shake the bottle to ensure the suspension is homogeneous. • Remove the protective sheath from the applicator tip. • Lie on the left side with the lower leg extended and the upper right leg flexed forward for balance. Alternatively, alternative is the knee-chest position. • Gently insert the applicator tip in the rectum pointing toward the umbilicus. • Steadily squeeze the bottle to discharge the medication. • Administer at bedtime with the objective of retaining it all night. • Drink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7) ] . • Advise patients that urine may become discolored reddish-brown while taking sfROWASA 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.

luids during treatment [see Warnings and Precautions (5.7) ] . • Advise patients that urine may become discolored reddish-brown while taking sfROWASA 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). IN-003260-08 Distributed by: Meda Pharmaceuticals Canonsburg, PA 15317 U.S.A. © 2024 Viatris Inc. sfROWASA is a registered trademark of Alaven Pharmaceutical LLC, a Viatris Company. For Medical Inquiries, Call Toll Free: 1-866-210-5949

INSTRUCTIONS FOR USE sfROWASA ® [s f ro wa sa] (mesalamine) rectal suspension sulfite-free formulation This Instructions for Use contains information on how to use sfROWASA ® (mesalamine) rectal suspension. Read these Instructions for Use that come with your sfROWASA (mesalamine) rectal suspension before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. How should I Store sfROWASA? • Store sfROWASA at room temperature between 68°F to 77°F (20°C to 25°C). • sfROWASA is an off-white to tan colored suspension. The medicine removed from the foil pouch may darken with time. Slight darkening will not affect how well sfROWASA works. • Throw away sfROWASA (mesalamine) rectal suspensions with dark brown medicine. • Keep sfROWASA and all medicines out of the reach of children. Important Information You Need to Know Before Using sfROWASA • sfROWASA is for rectal use only. • Do not share sfROWASA with other people, it may harm them. • If a caregiver is giving sfROWASA make sure they read and understand these Instructions for Use. • Use sfROWASA exactly as your healthcare provider tells you to use it. • It is recommended to use 1 sfROWASA bottle each day. • After the foil wrapped unit of 7 bottles is opened, use each bottle of sfROWASA (mesalamine) rectal suspension right away. • Empty bowels right before the medicine is given. • Give at bedtime. • sfROWASA will stain some surfaces including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing the right place for giving the sfROWASA (mesalamine) rectal suspension. Preparing to use sfROWASA Step 1. Remove the bottles. • Remove all the bottles from the protective foil pouch by grasping at the seam and tearing downward or by using scissors at the top of the foil pouch (See Figure A). • Be careful not to squeeze or puncture bottles. Figure A Step 2. Prepare to give the medicine. • Shake the first bottle well to make sure that the medicine is mixed well. • Remove the protective sheath from the applicator tip. Hold the bottle at the neck so as not to cause any of the medicine to be released (See Figure B) . Figure B Step 3. Get in position. • Lay on your left side with your left leg extended and your right leg flexed forward for balance (See Figure C) . Figure C or • Get in the knee-chest position as shown here (See Figure D) . Figure D Step 4. Giving the medicine. • Lubricate the applicator tip. • Gently insert the lubricated applicator tip into the rectum pointing slightly toward the belly button (navel) to prevent damage to the rectal wall. • Grasp the bottle firmly, then tilt slightly so that the nozzle is aimed toward the back. • Squeeze the bottle slowly to release the medicine into the rectum (See Figure E) . • Steady hand pressure will release most of the medicine. Figure E • After giving the medicine, withdraw the applicator tip. • Remain in position for at least 30 minutes to allow the medicine to spread inside the body. • Throw away (discard) the bottle. • Try to keep the medicine inside your body all night, if possible. Distributed by: Meda Pharmaceuticals Canonsburg, PA 15317 U.S.A. © 2024 Viatris Inc. U.S. Patent No. 7,645,801 sfROWASA is a registered trademark of Alaven Pharmaceutical LLC, a Viatris Company. IN-003260-08 Rev.

ody. • Throw away (discard) the bottle. • Try to keep the medicine inside your body all night, if possible. Distributed by: Meda Pharmaceuticals Canonsburg, PA 15317 U.S.A. © 2024 Viatris Inc. U.S. Patent No. 7,645,801 sfROWASA is a registered trademark of Alaven Pharmaceutical LLC, a Viatris Company. IN-003260-08 Rev. 7/2024 For Medical Inquiries, Call Toll Free: 1-866-210-5949 Figure A Figure B Figure C Figure D Figure E

<table styleCode="Noautorules" width="100%"><col width="100%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">SHAKE WELL BEFORE USING</content></paragraph></td></tr></tbody></table>

1 INDICATIONS AND USAGE Mesalamine Rectal Suspension is indicated for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis in adults. MESALAMINE rectal suspension is an aminosalicylate indicated for treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Evaluate renal function before initiating therapy with Mesalamine Rectal Suspension [see Warnings and Precautions (5.1) ]. Recommended Dosage The recommended dosage is one rectal instillation (4 grams) once a day, preferably at bedtime, and retained for approximately eight hours for 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. Administration Instructions Shake the bottle to ensure the suspension is homogeneous. Remove the protective sheath from the applicator tip. Assume the correct body position: Alternatively, sit in the knee to chest position. Lie on the left side with the lower leg extended and the upper right leg flexed forward for balance. Gently insert the applicator tip in the rectum pointing toward the umbilicus. Steadily squeeze the bottle to discharge the medication. Remain in the position for at least 30 minutes. Administer at bedtime with the objective of retaining it all night. Drink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7) ]. Evaluate renal function prior to initiation of MESALAMINE rectal suspension and periodically while on therapy. ( 2 , 5.1 ) The recommended dosage is one rectal instillation (4 grams) once a day, preferably at bedtime, and retained for approximately eight hours for 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. ( 2 ) Drink an adequate amount of fluids. ( 2 . 5.7 )

4 CONTRAINDICATIONS Mesalamine Rectal Suspension is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, sulfites or any other component of this medication [see Warnings and Precautions (5.3) ]. Known or suspected hypersensitivity to salicylates, aminosalicylates, sulfites or any other of the ingredients in MESALAMINE rectal suspension. ( 4 , 5.1 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Sulfite-related reactions (MESALAMINE rectal suspension contains potassium metabisulfite) and sulfasalazine-associated reactions (myocarditis and pericarditis) can occur; evaluate patients immediately and discontinue MESALAMINE rectal suspension if a hypersensitivity reaction is suspected. ( 5.3 ) Renal Impairment : Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits of MESALAMINE rectal suspension in patients with known renal impairment or taking nephrotoxic drug. Discontinue MESALAMINE rectal suspension if renal function deteriorates while on therapy. ( 5.1 , 7.1 ) Mesalamine-Induced Acute Intolerance Syndrome : Discontinue treatment if acute intolerance syndrome (cramping, acute abdominal pain, bloody diarrhea, sometimes fever, headache and rash) is suspected. ( 5.2 ) Hepatic Failure : Evaluate the risks and benefits of using MESALAMINE rectal suspension 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 sings of hypersensitivity and consider further evaluation. ( 5.5 ) Photosensitivity : Avoid sun exposure if pre-existing skin conditions. ( 5.6 ) Nephrolithiasis : Cases of nephrolithiasis have been reported with the use of mesalamine. Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. ( 5.7 ) Interference with Laboratory Tests : Mesalamine may lead to elevated urinary normetanephrine test results. ( 5.8 ) 5.1 Hypersensitivity Reactions Sulfite-Related Reactions Mesalamine Rectal Suspension contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low. Sulfite sensitivity is seen more frequently in asthmatic or in atopic nonasthmatic persons. Epinephrine is the preferred treatment for serious allergic or emergency situations even though epinephrine injection contains sodium or potassium metabisulfite with the above-mentioned potential liabilities. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in epinephrine injection should not deter the administration of the drug for treatment of serious allergic or other emergency situations. S ulfasalazine-Associated Reactions Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to Mesalamine Rectal Suspension 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 Mesalamine Rectal Suspension if an alternative etiology for the signs and symptoms cannot be established.

ment, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue Mesalamine Rectal Suspension if an alternative etiology for the signs and symptoms cannot be established. 5.2 Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given Mesalamine Rectal Suspension or other products that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Nonclinical Toxicology (13.2) ]. Evaluate the risks and benefits of using Mesalamine Rectal Suspension in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Evaluate renal function in all patients prior to initiation and periodically while on Mesalamine Rectal Suspension therapy. Discontinue Mesalamine Rectal Suspension if renal function deteriorates while on therapy [see Drug Interactions (7.1) , Use in Specific Populations (8.6) ]. 5.3 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 cannot be ascertained, 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 Mesalamine Rectal Suspension. 5.4 Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. Evaluate the risks and benefits of using Mesalamine Rectal Suspension 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) ] . Discontinue Mesalamine Rectal Suspension 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. 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 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 the labeling: Hypersensitivity reactions [see Warnings and Precautions (5.1) ] Renal impairment [see Warnings and Precautions (5.2) ] Mesalamine-induced acute intolerance syndrome [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) ] Most common adverse reactions (≥1%) are: gas/flatulence, flu, fever, leg/joint pain, hemorrhoids, rectal pain and hair loss. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact KLM Laboratories Private Limited at 1-866-547-5097 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials 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. Table 1: Adverse Reactions reported in 1% or more of Mesalamine Rectal Suspension-treated patients and greater than placebo in Clinical Trials of Mesalamine Rectal Suspension in Adult Patients with Ulcerative Colitis, Proctosigmoiditis or Proctitis Adverse Reaction Mesalamine Rectal Suspension (N=815) % Placebo (N=128) % Gas/Flatulence 6 4 Flu 5 1 Fever 3 0 Leg/Joint pain 2 1 Hemorrhoids 1 1 Rectal pain 1 0 Hair loss 1 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of mesalamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: myocarditis, pericarditis [see Warnings and Precautions (5.1) ] Gastrointestinal Disorders: pancreatitis Hematologic Disorders: agranulocytosis, aplastic anemia, eosinophilia, leukopenia, neutropenia, pancytopenia, thrombocytopenia Hepatic Disorders: elevated liver enzymes, hepatic failure [see Warnings and Precautions (5.4) ] Nervous System: intracranial hypertension Renal and Urinary Disorders: acute renal failure, chronic renal failure, interstitial nephritis, nephrogenic diabetes insipidus, nephrolithiasis, nephrotoxicity [see Warnings and Precautions (5.2) , ( 5.7 )] • Urine discoloration occurring ex-vivo caused by contact of mesalamine including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach Reproductive System and Breast Disorders: reversible oligospermia Respiratory, Thoracic, and Mediastinal Disorders: fibrosing alveolitis, pleurisy/pleuritis Skin and Subcutaneous Tissue Disorders: AGEP, DRESS, SJS/TEN [see Warnings and Precautions (5.5) ]

<table cellspacing="0" cellpadding="0" border="0"><caption>Table 1: Adverse Reactions<footnote ID="fn67">reported in 1% or more of Mesalamine Rectal Suspension-treated patients and greater than placebo</footnote> in Clinical Trials of Mesalamine Rectal Suspension in Adult Patients with Ulcerative Colitis, Proctosigmoiditis or Proctitis </caption><colgroup><col width="33.3333333333333%"/><col width="33.3333333333333%"/><col width="33.3333333333333%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"><content styleCode="bold">Adverse Reaction</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Mesalamine Rectal Suspension</content> <content styleCode="bold">(N=815)</content> <content styleCode="bold">%</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=128)</content> <content styleCode="bold">%</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">Gas/Flatulence </td><td styleCode="Rrule" align="center" valign="middle">6 </td><td styleCode="Rrule" align="center" valign="middle">4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">Flu </td><td styleCode="Rrule" align="center" valign="middle">5 </td><td styleCode="Rrule" align="center" valign="middle">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">Fever </td><td styleCode="Rrule" align="center" valign="middle">3 </td><td styleCode="Rrule" align="center" valign="middle">0 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">Leg/Joint pain </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">Hemorrhoids </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle">Rectal pain </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">0 </td></tr><tr><td styleCode="Lrule Rrule" align="center" valign="middle">Hair loss </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">0 </td></tr></tbody></table>

7 DRUG INTERACTIONS Nephrotoxic Agents including Non-Steroidal Anti-inflammatory Drugs (NSAIDs) : Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. ( 7.1 ) Azathioprine or 6-Mercaptopurine : Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. ( 7.2 ) 7.1 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 (5.2) ]. 7.2 Azathioprine or 6-Mercaptopurine The concurrent use of mesalamine with azathioprine or 6‑mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of Mesalamine Rectal Suspension and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. 7.3 Interference with Urinary Normetanephrine Measurements Use of Mesalamine Rectal Suspension may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions (5.8) ] . Consider an alternative, selective assay for normetanephrine.

8 USE IN SPECIFIC POPULATIONS Geriatric Patients : Increased risk of blood dyscrasias; monitor complete 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 ) . There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations ) . In animal reproduction studies, rats and rabbits administered mesalamine during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, did not reveal any evidence of harm to the embryo or the fetus (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 H uman Data Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of Mesalamine Rectal Suspension, 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 increase 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 have been performed with mesalamine in rats and rabbits during organogenesis at oral doses up to 5 and 8 times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus. 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 0.1% or less for mesalamine (see Data ) . There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations ) . There is no information on the effects of mesalamine on milk production.

minosalicylic acid in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine (see Data ) . There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations ) . There is no information on the effects of mesalamine on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of Mesalamine Rectal Suspension to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mesalamine Rectal Suspension and any potential adverse effects on the breastfed child from Mesalamine Rectal Suspension 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 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 of mesalamine (RID 0% to 0.1%) and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical trials of Mesalamine Rectal Suspension did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as Mesalamine Rectal Suspension who were 65 years or older compared to younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function. Consider monitoring complete blood cell counts and platelet counts in patients 65 years and over during treatment with Mesalamine Rectal Suspension. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in patients 65 years and over when prescribing Mesalamine Rectal Suspension. 8.6 Renal Impairment Mesalamine is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on Mesalamine Rectal Suspension 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 Mesalamine Rectal Suspension if renal function deteriorates while on therapy [see Warnings and Precautions (5.2) ].

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 ) . There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in pregnancy (see Clinical Considerations ) . In animal reproduction studies, rats and rabbits administered mesalamine during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, did not reveal any evidence of harm to the embryo or the fetus (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 H uman Data Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of Mesalamine Rectal Suspension, 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 increase 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 have been performed with mesalamine in rats and rabbits during organogenesis at oral doses up to 5 and 8 times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus.

8.5 Geriatric Use Clinical trials of Mesalamine Rectal Suspension did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as Mesalamine Rectal Suspension who were 65 years or older compared to younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function. Consider monitoring complete blood cell counts and platelet counts in patients 65 years and over during treatment with Mesalamine Rectal Suspension. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in patients 65 years and over when prescribing Mesalamine Rectal Suspension.

10 OVERDOSAGE Mesalamine Rectal Suspension 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) involvement. 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.

11 DESCRIPTION The active ingredient in Mesalamine Rectal Suspension, USP Enema, a disposable (60 mL) unit, is mesalamine, also known as 5-aminosalicylic acid (5-ASA). Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid. The empirical formula is C 7 H 7 NO 3 , representing a molecular weight of 153.14. The structural formula is: Mesalamine Rectal Suspension, USP Enema is supplied as a suspension for rectal administration. Each rectal suspension enema unit contains 4 grams of mesalamine. The inactive ingredients are carbomer homopolymer type B (carbopol 974P), edetate disodium, potassium acetate, potassium metabisulfite, purified water and xanthan gum. Sodium benzoate is added as a preservative. The disposable unit consists of an applicator tip protected by a polyethylene cover and lubricated with USP white petrolatum. The unit has a one-way valve to prevent back flow of the dispensed product. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of 5-ASA (mesalamine) is not fully understood, but appears to be a topical 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 mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of mesalamine have not been fully characterized. 12.3 Pharmacokinetics Absorption Mesalamine administered rectally as Mesalamine Rectal Suspension is poorly absorbed from the colon and is excreted principally in the feces during subsequent bowel movements. The extent of absorption is dependent upon the retention time of the drug product, and there is considerable individual variation. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of 2 mcg/mL, about two-thirds of which was the N-acetyl metabolite. In addition, steady state plasma levels demonstrated a lack of accumulation of either parent drug or N-acetyl metabolite during repeated daily rectal administrations. Distribution Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. The poor colonic absorption of rectally administered mesalamine is substantiated by the low serum concentration of 5-ASA and N-acetyl-5-ASA seen in ulcerative colitis patients after dosage with mesalamine. Elimination Metabolism It is known that the compound undergoes acetylation but whether this process takes place at colonic or systemic sites has not been elucidated. Excretion Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N- acetyl-5-ASA metabolite. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. While the elimination half-life of mesalamine is short (0.5 to 1.5 hours), the acetylated metabolite exhibits a half-life of 5 to 10 hours.

12.3 Pharmacokinetics Absorption Mesalamine administered rectally as Mesalamine Rectal Suspension is poorly absorbed from the colon and is excreted principally in the feces during subsequent bowel movements. The extent of absorption is dependent upon the retention time of the drug product, and there is considerable individual variation. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of 2 mcg/mL, about two-thirds of which was the N-acetyl metabolite. In addition, steady state plasma levels demonstrated a lack of accumulation of either parent drug or N-acetyl metabolite during repeated daily rectal administrations. Distribution Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. The poor colonic absorption of rectally administered mesalamine is substantiated by the low serum concentration of 5-ASA and N-acetyl-5-ASA seen in ulcerative colitis patients after dosage with mesalamine. Elimination Metabolism It is known that the compound undergoes acetylation but whether this process takes place at colonic or systemic sites has not been elucidated. Excretion Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N- acetyl-5-ASA metabolite. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. While the elimination half-life of mesalamine is short (0.5 to 1.5 hours), the acetylated metabolite exhibits a half-life of 5 to 10 hours.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study in Wistar rats fed up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison). of mesalamine admixed with diet, mesalamine did not cause an increase in the incidence of neoplastic lesions over controls. Mutagenesis Mesalamine is not mutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, TA1538. There were no reverse mutations in an assay using E. coli strain WP2UVRA. There were no evidence of genotoxicity in an in vivo mouse micronucleus assay at 600 mg/kg and in an in vivo sister chromatid exchange assay at doses up to 610 mg/kg. Impairment of Fertility Mesalamine had no effects on fertility in rats at doses up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison). 13.2 Animal Pharmacology and/or Toxicology Preclinical studies have shown the kidney to be the major target organ for mesalamine toxicity. Adverse renal function changes were observed in rats after a single 600 mg/kg oral dose, but not after a 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after a single oral >900 mg/kg dose, and after I.V. doses of >214 mg/kg. Mice responded similarly. In a 13-week oral (gavage) dose study in rats, the high dose of 640 mg/kg/day mesalamine caused deaths, probably due to renal failure, and dose-related renal lesions (papillary necrosis and/or multifocal tubular injury) were seen in most rats given the high dose (males and females) as well as in males receiving lower doses 160 mg/kg/day. Renal lesions were not observed in the 160 mg/kg/day female rats. Minimal tubular epithelial damage was seen in the 40 mg/kg/day males and was reversible. In a six-month oral study in dogs, the no-observable dose level of mesalamine was 40 mg/kg/day and doses of 80 mg/kg/day and higher caused renal pathology similar to that described for the rat. In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration in kidneys was observed at doses of 100 mg/kg/day and above admixed with diet for 52 weeks, and at 127 weeks increased incidence of kidney degeneration and hyalinization of basement membranes and Bowman's capsule were seen at 100 mg/kg/day and above. In the 12-month eye toxicity study in dogs, Keratoconjunctivitis Sicca (KCS) occurred at oral doses of 40 mg/kg/day and above. The oral preclinical studies were done with a highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred.

13.2 Animal Pharmacology and/or Toxicology Preclinical studies have shown the kidney to be the major target organ for mesalamine toxicity. Adverse renal function changes were observed in rats after a single 600 mg/kg oral dose, but not after a 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after a single oral >900 mg/kg dose, and after I.V. doses of >214 mg/kg. Mice responded similarly. In a 13-week oral (gavage) dose study in rats, the high dose of 640 mg/kg/day mesalamine caused deaths, probably due to renal failure, and dose-related renal lesions (papillary necrosis and/or multifocal tubular injury) were seen in most rats given the high dose (males and females) as well as in males receiving lower doses 160 mg/kg/day. Renal lesions were not observed in the 160 mg/kg/day female rats. Minimal tubular epithelial damage was seen in the 40 mg/kg/day males and was reversible. In a six-month oral study in dogs, the no-observable dose level of mesalamine was 40 mg/kg/day and doses of 80 mg/kg/day and higher caused renal pathology similar to that described for the rat. In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration in kidneys was observed at doses of 100 mg/kg/day and above admixed with diet for 52 weeks, and at 127 weeks increased incidence of kidney degeneration and hyalinization of basement membranes and Bowman's capsule were seen at 100 mg/kg/day and above. In the 12-month eye toxicity study in dogs, Keratoconjunctivitis Sicca (KCS) occurred at oral doses of 40 mg/kg/day and above. The oral preclinical studies were done with a highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred.

14 CLINICAL STUDIES In a 6-week placebo-controlled trial, international, multicenter trial of 153 patients with active distal ulcerative colitis, proctosigmoiditis or proctitis, Mesalamine Rectal Suspension Enema reduced the overall disease activity index (DAI) and individual components as follows: EFFECT OF TREATMENT ON SEVERITY OF DISEASE DATA FROM U.S.-CANADA TRIAL COMBINED RESULTS OF EIGHT CENTERS Each parameter has a 4-point scale with a numerical rating: 0 = normal, 1 = mild, 2 = moderate, 3 = severe. The four parameters are added together to produce a maximum overall DAI of 12. Activity Indices, mean N Baseline Day 22 End Point Change Baseline to End Point Percent change for overall DAI only (calculated by taking the average of the change for each individual patient). Overall DAI Mesalamine Rectal Suspension Enema Placebo 76 77 7.42 7.40 4.05 Significant Mesalamine Rectal Suspension Enema/placebo difference. p < 0.01 6.03 3.37 Significant Mesalamine Rectal Suspension Enema/placebo difference. p < 0.001 5.83 -55.07% -21.58% Stool Frequency Mesalamine Rectal Suspension Enema Placebo 1.58 1.92 1.11 Significant Mesalamine Rectal Suspension Enema/placebo difference. p < 0.05 1.47 1.01 1.50 -0.57 -0.41 Rectal Bleeding Mesalamine Rectal Suspension Enema Placebo 1.82 1.73 0.59 1.21 0.51 1.11 -1.30 -0.61 Mucosal Inflammation Mesalamine Rectal Suspension Enema Placebo 2.17 2.18 1.22 1.74 0.96 1.61 -1.21 -0.56 Physician’s Assessment of Disease Severity Mesalamine Rectal Suspension Enema Placebo 1.86 1.87 1.13 1.62 0.88 1.55 -0.97 -0.30 Differences between Mesalamine Rectal Suspension Enema and placebo were also statistically different in subgroups of patients on concurrent sulfasalazine and in those having an upper disease boundary between 5 and 20 or 20 and 40 cm. Significant differences between Mesalamine Rectal Suspension Enema and placebo were not achieved in those subgroups of patients on concurrent prednisone or with an upper disease boundary between 40 and 50 cm.

<table cellspacing="0" cellpadding="0" border="0" width="1278.13"><caption>EFFECT OF TREATMENT ON SEVERITY OF DISEASE DATA FROM U.S.-CANADA TRIAL COMBINED RESULTS OF EIGHT CENTERS</caption><colgroup><col width="23.6212278876171%"/><col width="26.2226847034339%"/><col width="5.20291363163371%"/><col width="7.59625390218522%"/><col width="7.90842872008325%"/><col width="8.84495317377731%"/><col width="20.6035379812695%"/></colgroup><tfoot><tr><td colspan="56">Each parameter has a 4-point scale with a numerical rating: 0 = normal, 1 = mild, 2 = moderate, 3 = severe. The four parameters are added together to produce a maximum overall DAI of 12. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7" valign="top"><content styleCode="bold">Activity Indices, mean</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">N</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Baseline</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Day 22</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">End Point</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Change Baseline to End Point<footnote ID="fn60">Percent change for overall DAI only (calculated by taking the average of the change for each individual patient).</footnote></content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Overall DAI</content> </td><td styleCode="Rrule" valign="top">Mesalamine Rectal Suspension Enema Placebo </td><td styleCode="Rrule" align="center" valign="middle">76 77 </td><td styleCode="Rrule" align="center" valign="middle">7.42 7.40 </td><td styleCode="Rrule" align="center" valign="middle">4.05<footnote ID="fn61">Significant Mesalamine Rectal Suspension Enema/placebo difference. p &lt; 0.01</footnote> 6.03 </td><td styleCode="Rrule" align="center" valign="middle">3.37<footnote ID="fn62">Significant Mesalamine Rectal Suspension Enema/placebo difference. p &lt; 0.001</footnote> 5.83 </td><td styleCode="Rrule" align="center" valign="middle">-55.07%<footnoteRef IDREF="fn62"/> -21.58% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Stool Frequency</content> </td><td styleCode="Rrule" valign="top">Mesalamine Rectal Suspension Enema Placebo </td><td styleCode="Rrule" align="center" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle">1.58 1.92 </td><td styleCode="Rrule" align="center" valign="middle">1.11<footnote ID="fn63">Significant Mesalamine Rectal Suspension Enema/placebo difference.

">Mesalamine Rectal Suspension Enema Placebo </td><td styleCode="Rrule" align="center" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle">1.58 1.92 </td><td styleCode="Rrule" align="center" valign="middle">1.11<footnote ID="fn63">Significant Mesalamine Rectal Suspension Enema/placebo difference. p &lt; 0.05</footnote> 1.47 </td><td styleCode="Rrule" align="center" valign="middle">1.01<footnoteRef IDREF="fn61"/> 1.50 </td><td styleCode="Rrule" align="center" valign="middle">-0.57<footnoteRef IDREF="fn63"/> -0.41 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Rectal Bleeding</content> </td><td styleCode="Rrule" valign="top">Mesalamine Rectal Suspension Enema Placebo </td><td styleCode="Rrule" align="center" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle">1.82 1.73 </td><td styleCode="Rrule" align="center" valign="middle">0.59<footnoteRef IDREF="fn62"/> 1.21 </td><td styleCode="Rrule" align="center" valign="middle">0.51<footnoteRef IDREF="fn62"/> 1.11 </td><td styleCode="Rrule" align="center" valign="middle">-1.30<footnoteRef IDREF="fn62"/> -0.61 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Mucosal Inflammation</content> </td><td styleCode="Rrule" valign="top">Mesalamine Rectal Suspension Enema Placebo </td><td styleCode="Rrule" align="center" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle">2.17 2.18 </td><td styleCode="Rrule" align="center" valign="middle">1.22<footnoteRef IDREF="fn61"/> 1.74 </td><td styleCode="Rrule" align="center" valign="middle">0.96<footnoteRef IDREF="fn62"/> 1.61 </td><td styleCode="Rrule" align="center" valign="middle">-1.21<footnoteRef IDREF="fn61"/> -0.56 </td></tr><tr><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Physician&#x2019;s Assessment of Disease Severity</content> </td><td styleCode="Rrule" valign="top">Mesalamine Rectal Suspension Enema Placebo </td><td styleCode="Rrule" align="center" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle">1.86 1.87 </td><td styleCode="Rrule" align="center" valign="middle">1.13<footnoteRef IDREF="fn62"/> 1.62 </td><td styleCode="Rrule" align="center" valign="middle">0.88<footnoteRef IDREF="fn62"/> 1.55 </td><td styleCode="Rrule" align="center" valign="middle">-0.97<footnoteRef IDREF="fn62"/> -0.30 </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Mesalamine Rectal suspension is an off-white to tan colored suspension. Each disposable enema bottle contains 4 grams of mesalamine in 60 mL aqueous suspension. Enema bottles are supplied in boxed, foil-wrapped trays as follows: NDC 84725-002-04................... Carton of 7 Bottles Mesalamine Rectal Suspension is for rectal use only. Storage Store at controlled room temperature 20°C to 25°C (68°F to 77°F); Excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Once the foil wrapped unit of seven bottles is opened, all enemas should be used promptly as directed by your physician. Contents of enemas removed from the foil pouch may darken with time. Slight darkening will not affect potency, however, enemas with dark brown contents should be discarded.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Instructions for Use ). Renal Impairment Inform patients that Mesalamine Rectal Suspension may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, 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) ]. Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions Instruct patients to stop taking Mesalamine Rectal Suspension 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 Advise patients with known liver disease to contact their healthcare provider if they experience signs or symptoms of worsening liver function [ 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 Mesalamine Rectal Suspension 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 (5.7) ]. 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 (5.8) ]. 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 (7.2) , Use in Specific Populations (8.5) ]. Administration Advise patients that Mesalamine Rectal Suspension will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Administer the product in a suitable location. Instruct patients: Shake the bottle to ensure the suspension is homogeneous Remove the protective sheath from the applicator tip. Lie on the left side with the lower leg extended and the upper right leg flexed forward for balance. Alternatively, alternative is the knee-chest position. Gently insert the applicator tip in the rectum pointing toward the umbilicus. Steadily squeeze the bottle to discharge the medication. Administer at bedtime with the objective of retaining it all night. Drink an adequate amount of fluids during treatment [ see Warnings and Precautions (5.7) ]. Advise patients that urine may become discolored reddish-brown while taking Mesalamine Rectal Suspension when it comes in contact with surfaces or water treated with hypochlorite-containing bleach.

ive of retaining it all night. Drink an adequate amount of fluids during treatment [ see Warnings and Precautions (5.7) ]. Advise patients that urine may become discolored reddish-brown while taking Mesalamine Rectal Suspension 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). Distributed by: One2Zee LLC 61 Bay Hill Blvd, Monroe Township, NJ 08831 For Medical Inquiries, Call Toll Free: 1-866-547-5097

INSTRUCTION FOR USE MESALAMINE rectal suspension This Instructions for Use contains information on how to use MESALAMINE rectal suspension. Read these Instructions for Use that come with your MESALAMINE rectal suspension before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. How should I Store MESALAMINE rectal suspension? Store MESALAMINE rectal suspension at room temperature between 68°F to 77°F (20°C to 25°C) MESALAMINE rectal suspension is an off-white to tan colored suspension. The medicine removed from the foil pouch may darken with time. Slight darkening will not affect how well MESALAMINE rectal suspension works. Throw away MESALAMINE rectal suspension with dark brown medicine. K eep MESALAMINE rectal suspension and all medicines out of the reach of children. Important Information You Need to Know Before Using MESALAMINE rectal suspension MESALAMINE rectal suspension is for rectal use only. Do not share MESALAMINE rectal suspension with other people, it may harm them. If a caregiver is giving MESALAMINE rectal suspension make sure they read and understand these Instructions for Use. Use MESALAMINE rectal suspension exactly as your healthcare provider tells you to use it. It is recommended to use 1 MESALAMINE rectal suspension bottle each day. After the foil wrapped unit of 7 bottles is opened, use each bottle of MESALAMINE rectal suspension right away. Empty bowels right before the medicine is given. Give at bedtime. MESALAMINE rectal suspension will stain some surfaces including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing the right place for giving the MESALAMINE rectal suspension. Preparing to use MESALAMINE rectal suspension S tep 1. Remove the bottles. Remove all the bottles from the protective foil pouch by using scissors at the top of the foil pouch (See Figure A). Be careful not to squeeze or puncture bottles. Step 2. Prepare to give the medicine. Shake the first bottle well to make sure that the medicine is mixed well. Remove the protective sheath from the applicator tip. Hold the bottle at the neck so as not to cause any of the medicine to be released (See Figure B) . Step 3. Get in position. Lay on your left side with your left leg extended and your right leg flexed forward for balance (See Figure C). or Get in the knee-chest position as shown here (See Figure D) . Step 4. Giving the medicine. Lubricate the applicator tip. Gently insert the lubricated applicator tip into the rectum pointing slightly toward the belly button (navel) to prevent damage to the rectal wall. Grasp the bottle firmly, then tilt slightly so that the nozzle is aimed toward the back. Squeeze the bottle slowly to release the medicine into the rectum (See Figure E) . Steady hand pressure will release most of the medicine. After giving the medicine, withdraw the applicator tip. Remain in position for at least 30 minutes to allow the medicine to spread inside the body. Throw away (discard) the bottle. Try to keep the medicine inside your body all night, if possible. Distributed by: One2Zee LLC 61 Bay Hill Blvd, Monroe Township, NJ 08831 For Medical Inquiries, Call Toll Free: 1-866-547-5097 fig-a fig-b fig-c fig-d fig-e