Mesalamine

Warnings and Precautions Renal Impairment ( 5.1 ) 11/2022

1 INDICATIONS AND USAGE 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Dosage The recommended dosage of mesalamine suppositories in adults is 1,000 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 [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 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 1,000 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 , 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 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. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Mesalamine Suppository, USP: 1,000 mg mesalamine in an off white to light brown opaque bullet shaped suppository. Suppository: 1,000 mg ( 3 )

4 CONTRAINDICATIONS 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 )

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 Annora Pharma Private Limited at 1-866-495-1995 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 1,000 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 1,000 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 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 )] o Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite containing bleach • Respiratory, Thoracic and Mediastinal Disorders : hypersensitivity pneumonitis (incl …

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 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 )].

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 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 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 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 suppositories and any potential adverse effects on the breastfed child from mesalamine 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-5aminosalicylic 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 suppositories in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. Mesalamine 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 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 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 supp …

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.

11 DESCRIPTION The active ingredient in Mesalamine suppositories, USP 1000 mg 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 suppository, USP contains 1000 mg of mesalamine, USP (micronized) in a base of hard fat. Mesalamine, USP (micronized) are light tan to pink colored, needle-shaped crystals. Color may darken on exposure to air. It is odorless or may have a slight characteristic odor. It is slightly soluble in water; very slightly soluble in methanol, in dehydrated alcohol, and in acetone; practically insoluble in n-butyl alcohol, in chloroform, in ether, in ethyl acetate, in n-hexane, in methylene chloride, and in n-propyl alcohol; soluble in dilute hydrochloric acid and in dilute alkali hydroxides. The molecular formula is C 7 H 7 NO 3 , representing a molecular weight of 153.14. The structural formula is: Mesalamine rectal suppository

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

16 HOW SUPPLIED/STORAGE AND HANDLING Mesalamine suppositories, USP 1,000 mg for rectal administration are available as off white to light brown opaque bullet shaped suppositories containing 1,000 mg mesalamine, USP. They are supplied as: Carton NDC Unit Dose NDC (Each Suppository) 72 rectal suppositories (12 strips of 6 suppositories) NDC 16571-246-72 NDC 16571-246-16 30 rectal suppositories (5 strips of 6 suppositories) NDC 16571-246-03 NDC 16571-246-16 Store below 25oC (77oF), may be refrigerated. Keep away from direct heat, light or humidity.