Mesalamine

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

DOSAGE AND ADMINISTRATION The recommended adult dosage of Mesalamine Rectal Suspension Enema in 60 mL units is one rectal instillation (4 grams) once a day, preferably at bedtime, and retained for approximately eight hours. While the effect of Mesalamine Rectal Suspension Enema may be seen within 3 to 21 days, the usual course of therapy would be from 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. Studies available to date have not assessed if Mesalamine Rectal Suspension Enema will modify relapse rates after the 6-week short-term treatment. Mesalamine Rectal Suspension Enema is for rectal use only. Drink an adequate amount of fluids during treatment. Patients should be instructed to shake the bottle well to make sure the suspension is homogeneous. The patient should remove the protective sheath from the applicator tip. Holding the bottle at the neck will not cause any of the medication to be discharged. The position most often used is obtained by lying on the left side (to facilitate migration into the sigmoid colon); with the lower leg extended and the upper right leg flexed forward for balance. An alternative is the knee-chest position. The applicator tip should be gently inserted in the rectum pointing toward the umbilicus. A steady squeezing of the bottle will discharge most of the preparation. The preparation should be taken at bedtime with the objective of retaining it all night. Patient instructions are included with every seven units.

3 DOSAGE FORMS AND STRENGTHS Rectal Suspension: 4 g/60 mL enema bottle; off-white to tan colored suspension Rectal Suspension: 4 g/60 mL enema bottle ( 3 )

4 CONTRAINDICATIONS Mesalamine rectal suspension enema 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 enema. ( 4 , 5.1 )

ADVERSE REACTIONS Clinical Adverse Experience Mesalamine Rectal Suspension Enema is usually well tolerated. Most adverse effects have been mild and transient. ADVERSE REACTIONS OCCURRING IN MORE THAN 0.1%OF MESALAMINE RECTAL SUSPENSION TREATED PATIENTS (COMPARISON TO PLACEBO) SYMPTOM Mesalamine Rectal Suspension Enema N = 815 Placebo N=128 N % N % Abdominal Pain/Cramps/Discomfort 66 8.10 10 7.81 Headache 53 6.50 16 12.50 Gas/Flatulence 50 6.13 5 3.91 Nausea 47 5.77 12 9.38 Flu 43 5.28 1 0.78 Tired/Weak/Malaise/Fatigue 28 3.44 8 6.25 Fever 26 3.19 0 0.00 Rash/Spots 23 2.82 4 3.12 Cold/Sore Throat 19 2.33 9 7.03 Diarrhea 17 2.09 5 3.91 Leg/Joint Pain 17 2.09 1 0.78 Dizziness 15 1.84 3 2.34 Bloating 12 1.47 2 1.56 Back Pain 11 1.35 1 0.78 Pain on Insertion of Enema Tip 11 1.35 1 0.78 Hemorrhoids 11 1.35 0 0.00 Itching 10 1.23 1 0.78 Rectal Pain 10 1.23 0 0.00 Constipation 8 0.98 4 3.12 Hair Loss 7 0.86 0 0.00 Peripheral Edema 5 0.61 11 8.59 UTI/Urinary Burning 5 0.61 4 3.12 Rectal Pain/Soreness/Burning 5 0.61 3 2.34 Asthenia 1 0.12 4 3.12 Insomnia 1 0.12 3 2.34 In addition, the following adverse events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice: nephrotoxicity, pancreatitis, fibrosing alveolitis, elevated liver enzymes, nephrogenic diabetes insipidus, intracranial hypertension and nephrolithiasis. Cases of pancreatitis and fibrosing alveolitis have been reported as manifestations of inflammatory bowel disease as well. Published case reports and/or spontaneous post marketing surveillance have described rare instances of aplastic anemia, agranulocytosis, thrombocytopenia, eosinophilia, pancytopenia, neutropenia, oligospermia, and infertility in men. Anemia, leukocytosis, and thrombocytosis can be part of the clinical presentation of inflammatory bowel disease. Postmarketing cases of severe cutaneous adverse reactions (SJS/TEN, DRESS, and AGEP) and pleurisy/pleuritis have been reported. Hair Loss Mild hair loss characterized by “more hair in the comb” but no withdrawal from clinical trials has been observed in 7 of 815 mesalamine patients but none of the placebo-treated patients. In the literature there are at least six additional patients with mild hair loss who received either mesalamine or sulfasalazine. Retreatment is not always associated with repeated hair loss. 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. Renal Disorders • Urine discoloration occurring ex-vivo caused by contact of mesalamine including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach (see PRECAUTIONS: Information for Patients ).

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 enema 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 enema 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 Human Data Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of mesalamine rectal suspension enema, 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. The lack of clinical data during lactation precludes a clear determination of the risk of mesalamine rectal suspension enema 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 enema and any potential adverse effects on the breastfed child from mesalamine rectal suspension enema 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-aminosa …

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.

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 enema is supplied as a suspension for rectal administration. Each rectal suspension enema unit contains 4 grams of mesalamine. The inactive ingredients are carbomer 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. Structural Formula

10 OVERDOSAGE Mesalamine rectal suspension enema 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.

HOW SUPPLIED Mesalamine Rectal Suspension Enema for rectal administration 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: Carton of 7 Bottles: NDC 62559-420-07 Mesalamine Rectal Suspension Enemas are for rectal use only. KEEP OUT OF REACH OF CHILDREN Patient instructions are included. Storage Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted, please refer to current USP. 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. NOTE: Mesalamine Rectal Suspension Enema will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing a suitable location for administration of this product. Rx only Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 9819 Rev 10/23 For Medical Inquiries, Call Toll Free: 1-800-308-6755 ani