MESALAMINE

The active ingredient in mesalamine suppositories 1000 mg 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 anti-inflammatory drug. Each mesalamine 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 suppositories are indicated in adults for the treatment of mildly to moderately active ulcerative proctitis. Mesalamine suppositories are an aminosalicylate indicated in adults for the treatment of mildly to moderately active ulcerative proctitis.

Dosage The recommended dosage of mesalamine 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 suppositories beyond 6 weeks have not been established. Administration Instructions : • Evaluate renal function prior to initiation of mesalamine suppositories therapy and periodically while on therapy. • Do not cut or break the suppository. • Retain the suppository for one to three hours or longer, if possible. • If a dose of mesalamine suppositories is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two mesalamine suppositories at the same time to make up for a missed dose. • Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine 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 suppositories and periodically while on therapy ( 2.1 , 5.1 ) • Do not cut or break the suppository. • Retain the suppository for one to three hours or longer, if possible. • Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep MESALAMINE SUPPOSITORIES away from these surfaces to prevent staining.

Mesalamine 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 or to any ingredients in the formulation. ( 4 , 5 .3 )

The most serious adverse reactions seen in mesalamine suppositories 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) ] The most common adverse reactions (≥ 1%) are: dizziness, rectal pain, fever, rash, acne and colitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharmaceuticals, Inc. at 1-866-562-4597 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 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 suppositories is 1000 mg administered rectally once daily at bedtime [ see Dosage and Administration (2) ] . 6.2 Postmarketing Experience In addition to the adverse reactions reported above in clinical trials involving mesalamine suppositories, the adverse reactions listed below have been identified during post-approval use of mesalamine suppositories and 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 nephropathy [ see Warnings and Precautions (5.1) ] • Respiratory, Thoracic and Mediastinal Disorders : hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis) • Skin and Subcutaneous Tissue Disorder : alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria • Urogenital: reversible oligospermia

• 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 may increase the risk for blood disorders. If concomitant use of mesalamine suppositories and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. 7.3 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 (5.5) ].