Mesalamine

1 INDICATIONS & 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)

2 DOSAGE & ADMINISTRATION Evaluate renal function before initiating therapy with mesalamine rectal suspension enema [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: Lie on the left side with the lower leg extended and the upper right leg flexed forward for balance. 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 mesalamine rectal suspension enema 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)

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Sulfite-related reactions (mesalamine rectal suspension enema contains potassium metabisulfite) and sulfasalazine-associated reactions (myocarditis and pericarditis) can occur; evaluate patients immediately and discontinue mesalamine rectal suspension enema 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 enema in patients with known renal impairment or taking nephrotoxic drug. Discontinue mesalamine rectal suspension enema 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 enema 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 : 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 enema 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. Sulfasalazine-Associated Reactions Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine rectal suspension enema 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 enema 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 enema 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 enema 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 …

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)

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.

8.1 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.

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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 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 * in Clinical Trials of Mesalamine Rectal Suspension Enema in Adult Patients with Ulcerative Colitis, Proctosigmoiditis or Proctitis Adverse Reaction Mesalamine Rectal Suspension Enema (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 * reported in 1% or more of mesalamine rectal suspension enema-treated patients and greater than placebo 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)]