Mesalamine Rectal

6. ADVERSE REACTIONS The following serious or clinically significant adverse reactions are described elsewhere in labeling: Renal Impairment [see Warnings and Precautions (5.1) ] Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Hepatic Failure [see Warnings and Precautions (5.4) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Photosensitivity [see Warnings and Precautions (5.6) ] Nephrolithiasis [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥ 1%) are: dizziness, rectal pain, fever, rash, acne and colitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amring Pharmaceuticals Inc. at 1-844-Amring1 (1-844-267-4641) 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 most common adverse reactions in adult patients with mildly to moderately active ulcerative proctitis in double-blind, placebo-controlled trials are summarized in the Table 1 below. Table 1: Adverse Reactions Occurring in More Than 1% of Mesalamine Suppository Treated Patients (Comparison to Placebo) Symptom Mesalamine (n = 177) Placebo (n = 84) N % N % Dizziness 5 3 2 2.4 Rectal Pain 3 1.8 0 0 Fever 2 1.2 0 0 Rash 2 1.2 0 0 Acne 2 1.2 0 0 Colitis 2 1.2 0 0 In a multicenter, open-label, randomized, parallel group study in 99 patients comparing the Mesalamine Rectal Suppository 1000 mg suppository administered nightly to that of the mesalamine 500 mg suppository twice daily. The most common adverse reactions in both groups were headache (14%), flatulence (5%), abdominal pain (5%), diarrhea (3%), and nausea (3%). Three (3) patients discontinued medication because of an adverse reaction; one of these adverse reactions (headache) was deemed possibly related to study medication. The recommended dosage of Mesalamine Rectal Suppositories is 1000 mg administered rectally once daily at bedtime [see Dosage and Administration (2) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Mesalamine Rectal Suppositories 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: drug fever, fatigue, lupus-like syndrome, medication residue Cardiac Disorders: myocarditis, pericarditis, pericardial effusion [see Warnings and Precautions (5.3) ] Endocrine: Nephrogenic diabetes insipidus Eye disorders: eye swelling Gastrointestinal Disorders: abdominal cramps, abdominal distension, anal pruritus, anorectal discomfort, constipation, feces discolored, flatulence, frequent bowel movements, gastrointestinal bleeding, mucus stools, nausea, painful defecation, pancreatitis, proctalgia, rectal discharge, rectal tenesmus, stomach discomfort, vomiting Hepatic Disorders: cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver necrosis, liver failure Hematologic Disorders: agranulocytosis, aplastic anemia, thrombocytopenia Neurological/Psychiatric Disorders: Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis, intracranial hypertension Renal Disorders: interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1 , 5.7) ] Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis), pleuritis/pleurisy Skin and Subcutaneous Tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria, SJS/TEN, DRESS and AGEP [see Warnings and Precautions (5.5) ] Urogenital: reversible oligospermia

4. CONTRAINDICATIONS Mesalamine Rectal Suppositories are contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any ingredients in the suppository vehicle [see Warnings and Precautions (5.3) , Adverse Reactions (6.2) , and Description (11) ] . Known or suspected hypersensitivity to salicylates or aminosalicylates or to any ingredients in the formulation. ( 4 , 5.3 )

11. DESCRIPTION The active ingredient in Mesalamine Rectal Suppository 1000 mg suppositories for rectal use is mesalamine, also known as mesalazine or 5- aminosalicylic acid (5-ASA). Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid, and is classified as an aminosalicylate. Each Mesalamine Rectal Suppository contains 1000 mg of mesalamine (USP) in a base of Hard Fat, NF. The empirical formula is C 7 H 7 NO 3 , representing a molecular weight of 153.14. The structural formula is: Mesalamine Structural Formula

2. DOSAGE AND ADMINISTRATION Dosage The recommended dosage of Mesalamine Rectal Suppositories in adults is 1000 mg administered rectally once daily at bedtime for 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. Safety and effectiveness of Mesalamine Rectal Suppositories beyond 6 weeks have not been established. Administration Instructions: Evaluate renal function prior to initiation of Mesalamine Rectal Suppository therapy [see Warnings and Precautions (5.1) ] . Do not cut or break the suppository. Retain the suppository for one to three hours or longer, if possible. Drink an adequate amount of fluids [see Warnings and Precautions (5.7) ] If a dose of Mesalamine Rectal Suppositories is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two Mesalamine Rectal Suppositories at the same time to make up for a missed dose. Mesalamine Rectal Suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep Mesalamine Rectal Suppositories away from these surfaces to prevent staining. Dosage The recommended adult dosage is 1000 mg administered rectally once daily at bedtime for 3 to 6 weeks. Safety and effectiveness beyond 6 weeks have not been established. ( 2 ) Administration Instructions: Evaluate renal function prior to initiation of Mesalamine Rectal Suppositories and periodically while on therapy. ( 2 , 5.1 ) Do not cut or break the suppository. ( 2 ) Drink an adequate amount of fluids. ( 2 , 5.7 ) Retain the suppository for one to three hours or longer, if possible. ( 2 ) Mesalamine Rectal Suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep Mesalamine Rectal Suppositories away from these surfaces to prevent staining. ( 2 )

1. INDICATIONS AND USAGE Mesalamine Rectal Suppositories are indicated in adults for the treatment of mildly to moderately active ulcerative proctitis. Mesalamine Rectal Suppositories are an aminosalicylate indicated in adults for the treatment of mildly to moderately active ulcerative proctitis. ( 1 )

10. OVERDOSAGE Mesalamine absorption from the colon is limited; however, Mesalamine Rectal Suppositories are 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. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function.

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 nonsteroidal 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 Rectal Suppositories 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 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 mesalamine's main metabolite, N-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine [see Warnings and Precautions (5.8) ] .

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, 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 (5-ASA) administered as a rectal suppository is variably absorbed. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories, administered once every eight hours for six days, the mean mesalamine peak plasma concentration (C max ) was 353 ng/mL (CV=55%) following the initial dose and 361 ng/mL (CV=67%) at steady state. The mean minimum steady state plasma concentration (C min ) was 89 ng/mL (CV=89%). Absorbed mesalamine does not accumulate in the plasma. Distribution Mesalamine administered as a rectal suppository distributes in rectal tissue to some extent. Elimination In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, the mean elimination half-life was 5 hours (CV=73%) for 5-ASA and 5 hours (CV=63%) for N-acetyl-5-ASA, the active metabolite, following the initial dose. At steady state, the mean elimination half-life was 7 hours for both 5-ASA and N-acetyl-5-ASA (CV=102% for 5-ASA and 82% for N-acetyl-5-ASA). Metabolism The absorbed mesalamine is extensively metabolized, mainly to N-acetyl-5-ASA in the liver and in the gut mucosal wall. In patients with ulcerative colitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days, the peak concentration (C max ) of N-acetyl-5-ASA ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from 193 ng/mL to 1304 ng/mL at steady state. Excretion Mesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, 12% or less of the dose was eliminated in urine as unchanged 5-ASA and 8% to 77% was eliminated as N-acetyl-5-ASA following the initial dose. At steady state, 11% or less of the dose was eliminated in the urine as unchanged 5-ASA and 3% to 35% was eliminated as N-acetyl-5-ASA.

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, 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 (5-ASA) administered as a rectal suppository is variably absorbed. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories, administered once every eight hours for six days, the mean mesalamine peak plasma concentration (C max ) was 353 ng/mL (CV=55%) following the initial dose and 361 ng/mL (CV=67%) at steady state. The mean minimum steady state plasma concentration (C min ) was 89 ng/mL (CV=89%). Absorbed mesalamine does not accumulate in the plasma. Distribution Mesalamine administered as a rectal suppository distributes in rectal tissue to some extent. Elimination In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, the mean elimination half-life was 5 hours (CV=73%) for 5-ASA and 5 hours (CV=63%) for N-acetyl-5-ASA, the active metabolite, following the initial dose. At steady state, the mean elimination half-life was 7 hours for both 5-ASA and N-acetyl-5-ASA (CV=102% for 5-ASA and 82% for N-acetyl-5-ASA). Metabolism The absorbed mesalamine is extensively metabolized, mainly to N-acetyl-5-ASA in the liver and in the gut mucosal wall. In patients with ulcerative colitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days, the peak concentration (C max ) of N-acetyl-5-ASA ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from 193 ng/mL to 1304 ng/mL at steady state. Excretion Mesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, 12% or less of the dose was eliminated in urine as unchanged 5-ASA and 8% to 77% was eliminated as N-acetyl-5-ASA following the initial dose. At steady state, 11% or less of the dose was eliminated in the urine as unchanged 5-ASA and 3% to 35% was eliminated as N-acetyl-5-ASA.

20230109

6

3. DOSAGE FORMS AND STRENGTHS Mesalamine Rectal Suppository: 1000 mg mesalamine in a torpedo shaped, white to beige suppository. Suppository: 1000 mg ( 3 )

Mesalamine Rectal Mesalamine MESALAMINE MESALAMINE FAT, HARD white to beige torpedo shaped suppository

13.2 Animal Toxicology and/or Pharmacology Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at a single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and at intravenous doses of >214 mg/kg (about 1.2 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area). In a 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area). In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and above. In a 14-day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) was not associated with any adverse effects. In a six-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and higher caused renal pathology similar to that described for the rat. In a rectal toxicity study of mesalamine suppositories in dogs, a dose of 166.6 mg/kg (about 3 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and above.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a two-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet (about 1.7 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area). Mesalamine was not mutagenic in the Ames test, the mouse lymphoma cell (TK +/- ) forward mutation test, or the mouse micronucleus test. No effects on fertility or reproductive performance of the male and female rats were observed at oral mesalamine doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area).

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a two-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet (about 1.7 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area). Mesalamine was not mutagenic in the Ames test, the mouse lymphoma cell (TK +/- ) forward mutation test, or the mouse micronucleus test. No effects on fertility or reproductive performance of the male and female rats were observed at oral mesalamine doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area). 13.2 Animal Toxicology and/or Pharmacology Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at a single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and at intravenous doses of >214 mg/kg (about 1.2 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area). In a 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area). In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and above. In a 14-day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) was not associated with any adverse effects. In a six-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and higher caused renal pathology similar to that described for the rat. In a rectal toxicity study of mesalamine suppositories in dogs, a dose of 166.6 mg/kg (about 3 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose of Mesalamine Rectal Suppository, based on body surface area) and above.

ANDA208362

Mesalamine Rectal

Mesalamine

69918-560

HUMAN PRESCRIPTION DRUG

RECTAL

PRINCIPAL DISPLAY PANEL – 1000 mg NDC 69918- 560 -30 Rx Only Mesalamine Rectal Suppositories 1000 mg For Rectal Use Only 30 Suppositories Mesalamine Rectal Suppository, 1000 mg Store below 25°C (77°F), may be refrigerated. Rev. 07/2019 I6104-02 Mesalamine Rectal Suppositories 1000 mg Carton Label Mesalamine Rectal Suppositories 1000 mg Carton Label

• Warnings and Precautions Renal Impairment ( 5.1 ) 11/2022

17. PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information) Administration [see Dosage and Administration (2) ] Advise patients: Do not cut or break the suppository. Retain the suppository for one to three hours or longer, if possible. Drink an adequate amount of fluids. If a dose of Mesalamine Rectal Suppositories is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two Mesalamine Rectal Suppositories at the same time to make up for a missed dose. Mesalamine Rectal Suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep Mesalamine Rectal Suppositories away from these surfaces to prevent staining. Renal Impairment Inform patients that Mesalamine Rectal Suppositories 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 Rectal Suppositories and report to their healthcare provider if they experience new or worsening symptoms 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. Instruct patients to stop taking Mesalamine Rectal Suppositories and report to their healthcare provider at first appearance of a severe cutaneous adverse reaction or any other sign of hypersensitivity [see Warnings and Precautions (5.5) ]. Photosensitivity Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.6) ] . Nephrolithiasis Instruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of a kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.7) ] . 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 for: Amring Pharmaceuticals Inc. Berwyn, PA 19312 www.amringusa.com The Amring Logo and the “A” Logo are trademarks of Amring Pharmaceuticals Inc. Manufactured by: Confab Laboratories Inc. St-Hubert, Canada J3Y 3X3 Origin Canada For more information, call 1-844-Amring1 (1-844-267-4641) Revised: 12/2022 301944-06 company

14. CLINICAL STUDIES Two double-blind, placebo-controlled, multicenter trials of mesalamine suppositories were conducted in North America in adult patients with mildly to moderately active ulcerative proctitis. The regimen in Study 1 was a 500 mg mesalamine suppository administered rectally three times daily and in Study 2 was a 500 mg mesalamine suppository administered rectally twice daily. In both trials, patients had an average extent of proctitis (upper disease boundary) of approximately 10 cm and approximately 80% of patients had multiple prior episodes of proctitis. A total of 173 patients were evaluated (Study 1, N=79; Study 2, N=94), of which 89 patients received mesalamine, and 84 patients received placebo. The mean age of patients was 39 years (range 17 to 73 years), 60% were female, and 97% were white. The primary measures of efficacy were clinical disease activity index (DAI) and histologic evaluations in both trials. The DAI is a composite index reflecting rectal bleeding, stool frequency, mucosal appearance at endoscopy, and a physician’s global assessment of disease. Patients were evaluated clinically and sigmoidoscopically after 3 and 6 weeks of treatment. Compared to placebo, mesalamine suppositories were statistically (p<0.01) superior to placebo in both trials with respect to improvement in stool frequency, rectal bleeding, mucosal appearance, disease severity, and overall disease activity after 3 and 6 weeks of treatment. The effectiveness of mesalamine suppositories was statistically significant irrespective of sex, extent of proctitis, duration of current episode, or duration of disease. An additional multicenter, open-label, randomized, parallel group study in 99 patients diagnosed with mildly to moderately ulcerative proctitis compared 1000 mg Mesalamine Rectal Suppositories administered rectally once daily at bedtime (N=35) to 500 mg mesalamine suppository administered rectally twice daily, in the morning and at bedtime (N=46), for 6 weeks. The primary measures of efficacy included the clinical disease activity index (DAI) and histologic evaluations. Patients were evaluated clinically and sigmoidoscopically at 3 and 6 weeks of treatment. The efficacy at 6 weeks was not different between the treatment groups. Both were effective in the treatment of ulcerative proctitis and resulted in a significant decrease at 6 weeks in DAI: in the mesalamine 500 mg twice daily group, the mean DAI value decreased from 6.6 to 1.6, and in the 1000 mg at bedtime group, the mean DAI value decreased from 6.2 to 1.3, which represents a decrease of greater than 75% in both groups. After 6 weeks of treatment, a DAI score of less than 3 was achieved in 78% of patients in the mesalamine 500 mg twice daily group and 86% of patients in the Mesalamine Rectal Suppositories 1000 mg once daily group. The recommended dosage of Mesalamine Rectal Suppository is 1000 mg administered rectally once daily at bedtime [see Dosage and Administration (2) ] .

8.5 Geriatric Use Clinical trials of Mesalamine Rectal Suppositories 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 Suppositories who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with Mesalamine Rectal Suppositories. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing Mesalamine Rectal Suppositories [see Use in Specific Populations (8.6) ] .

8.4 Pediatric Use The safety and effectiveness of Mesalamine Rectal Suppositories in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. Mesalamine Rectal Suppositories were evaluated for the treatment of ulcerative proctitis in a 6-week, open-label, single-arm study in 49 patients 5 to 17 years of age, which only included 14 patients with histologically-confirmed cases of ulcerative proctitis. However, efficacy was not demonstrated. Adverse reactions seen in pediatric patients in this trial (abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea and vomiting) were similar to those seen in adult patients.

8.1 Pregnancy Risk Summary Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No evidence of teratogenicity was observed in rats or rabbits when treated during gestation with orally administered mesalamine at doses greater than the recommended human intra-rectal dose (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area) and in rabbits at oral doses up to 495 mg/kg/day (about 5.4 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area) following administration during the period of organogenesis, and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine.

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 Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No evidence of teratogenicity was observed in rats or rabbits when treated during gestation with orally administered mesalamine at doses greater than the recommended human intra-rectal dose (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area) and in rabbits at oral doses up to 495 mg/kg/day (about 5.4 times the recommended human intra-rectal dose of Mesalamine Rectal Suppositories, based on body surface area) following administration during the period of organogenesis, and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. 8.2 Lactation Risk Summary Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts (see Data ). There are limited reports of diarrhea in breastfed infants. There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of Mesalamine Rectal Suppositories 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 Suppositories and any potential adverse effects on the breastfed child from Mesalamine Rectal Suppositories or from the underlying maternal conditions. Clinical Considerations Monitor breastfed infants for diarrhea. Data 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 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid. 8.4 Pediatric Use The safety and effectiveness of Mesalamine Rectal Suppositories in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. Mesalamine Rectal Suppositories were evaluated for the treatment of ulcerative proctitis in a 6-week, open-label, single-arm study in 49 patients 5 to 17 years of age, which only included 14 patients with histologically-confirmed cases of ulcerative proctitis. However, efficacy was not demonstrated. Adverse reactions seen in pediatric patients in this trial (abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea and vomiting) were similar to those seen in adult patients. 8.5 Geriatric Use Clinical trials of Mesalamine Rectal Suppositories 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 Suppositories who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with Mesalamine Rectal Suppositories. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing Mesalamine Rectal Suppositories [see Use in Specific Populations (8.6) ] . 8.6 Renal Impairment Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on Mesalamine Rectal Suppository 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 if renal function deteriorates while on therapy [see Warnings and Precautions (5.1) , Adverse Reactions (6.2) , Drug Interactions (7.1) ] .

16. HOW SUPPLIED/STORAGE AND HANDLING Mesalamine Rectal Suppositories 1000 mg for rectal administration are available as torpedo shaped, white to beige suppositories containing 1000 mg mesalamine supplied in boxes of 30 (NDC 69918-560-30). Store below 25ºC (77ºF), may be refrigerated. Keep away from direct heat, light or humidity.