Dipentum

1 INDICATIONS AND USAGE DIPENTUM is indicated for the maintenance of remission of ulcerative colitis in adult patients who are intolerant of sulfasalazine. DIPENTUM is an aminosalicylate indicated for the maintenance of remission of ulcerative colitis in adult patients who are intolerant of sulfasalazine. ( 1 )

2 DOSAGE AND ADMINISTRATION Evaluate renal function before initiating therapy with DIPENTUM [see Warnings and Precautions (5.1) ]. The recommended dosage is 500 mg orally twice daily. Drink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7) ] . • Evaluate renal function prior to initiation of DIPENTUM and periodically while on therapy. ( 2 , 5.1 ) • The recommended dosage is 500 mg orally twice daily. ( 2 ) • Drink an adequate amount of fluids. ( 2 , 5.7 )

4 CONTRAINDICATIONS DIPENTUM is contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or to any of the excipients in DIPENTUM [see Warnings and Precautions (5.3) , Description (11) ] . Known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of DIPENTUM. ( 4 , 5.3 )

5 WARNINGS AND PRECAUTIONS • Renal Impairment : Assess renal function at the beginning of treatment and periodically during treatment. Discontinue DIPENTUM 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 ) • Hypersensitivity Reactions, including myocarditis and pericarditis : Discontinue DIPENTUM if a hypersensitivity reaction is suspected. ( 5.3 ) • Hepatic Failure : Evaluate the risks and benefits of using DIPENTUM 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 Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given DIPENTUM 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 DIPENTUM 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 on DIPENTUM therapy. Discontinue DIPENTUM if renal function deteriorates while on therapy [see Drug Interactions (7.1) , Use in Specific Populations (8.6) ] . 5.2 Mesalamine-Induced Acute Intolerance Syndrome Olsalazine is converted to mesalamine, which has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with DIPENTUM. 5.3 Hypersensitivity Reactions Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to DIPENTUM or to other compounds that contain or are converted to mesalamine. 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 DIPENTUM if an alternative etiology for the signs and symptoms cannot be established. 5.4 Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Because olsalazine is converted to mesalamine, evaluate the risks and benefits of using DIPENTUM in patients with known liver impairment. 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine, the active moiety in DIPENTUM [see Adverse Reactions (6.2) ] . Discontinue DIPENTUM at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.6 Photosensitivity Patients with pre‑existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. 5.7 Nephrolithiasis Cases of nephrolithiasis have been reported with the use of mesalamine, the active moiety in DIPENTUM, including stones with 100% mesalamine content. Mesalamine‑containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment. 5.8 Interference with Laboratory Tests Use of DIPENTUM, which is converted to 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 the main metabolite of mesalamine, N‑acetyl‑5‑aminosalicylic acid (N‑Ac‑5‑ASA). Consider an alternative, selective assay for normetanephrine.

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 ) • Low Molecular Weight Heparins or Heparinoids : Increased risk of bleeding following neuraxial anesthesia; if possible, discontinue DIPENTUM or closely monitor for bleeding. ( 7.1 ) • Varicella Vaccine : Avoid use for 6 weeks after vaccination. ( 7.4 ) 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 (5.1) ] . 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 (e.g., thioguanine) may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of DIPENTUM and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. 7.3 Low Molecular Weight Heparins or Heparinoids The co-administration of salicylates and low molecular weight heparins or heparinoids may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue DIPENTUM prior to the initiation of a low molecular weight heparin or heparinoid. If this is not possible, it is recommended to monitor patients closely for bleeding. 7.4 Varicella Vaccine Avoid DIPENTUM, and other salicylates, for six weeks after the varicella vaccine to avoid a possible increased risk of developing Reye’s syndrome. 7.5 Interference With Urinary Normetanephrine Measurements Use of DIPENTUM, which is converted to mesalamine, 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the 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 following adverse reactions have been identified from clinical studies or postmarketing reports of olsalazine. 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. In double-blind, placebo- and active-controlled clinical trials of ulcerative colitis, discontinuations due to adverse reactions were reported in 10% of DIPENTUM-treated patients (N=441) and 7% of placebo-treated patients (N=208). Both sulfasalazine-tolerant and intolerant patients were included. The most common adverse reactions leading to discontinuation in DIPENTUM-treated patients were diarrhea/loose stools (6%), abdominal pain (1%), and rash/itching (1%). In these controlled trials, adverse reactions reported in 1% or more of patients treated with DIPENTUM and greater than placebo are provided in Table 1. Table 1 Adverse Reactions reported in at least 1% of patients in the DIPENTUM group and greater than placebo in Patients with Ulcerative Colitis in Double-Blind, Controlled Clinical Trials Adverse Reaction DIPENTUM (N=441) % Placebo (N=208) % Diarrhea 11 7 Abdominal pain/cramps 10 7 Nausea 5 4 Arthralgia/Joint Pain 4 3 Rash 2 1 Upper Respiratory Infection 2 0 Depression 2 0 Vomiting 1 0 Stomatitis 1 0 Vertigo/Dizziness 1 0 Itching 1 0 Other adverse reactions reported in clinical trials or post-marketing experience: Blood and Lymphatic System Disorders aplastic anemia, anemia, eosinophilia, hemolytic anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, reticulocytosis, thrombocytopenia Cardiac Disorders chest pains, heart block second degree, myocarditis, palpitations, pericarditis, peripheral edema, shortness of breath, tachycardia A patient who developed thyroid disease 9 days after starting DIPENTUM was given propranolol and radioactive iodine and subsequently developed shortness of breath and nausea. The patient died 5 days later with signs and symptoms of acute diffuse myocarditis. Ear and Labyrinth Disorders tinnitus Eye Disorders dry eyes, vision blurred, watery eyes Gastrointestinal Disorders abdominal pain (upper), diarrhea with dehydration, dry mouth, epigastric discomfort, flare in symptoms, flatulence, increased blood in stool, pancreatitis, rectal bleeding, rectal discomfort General Disorders and Administration Site Conditions fever chills, hot flashes, irritability, pyrexia, rigors Hepatobiliary Disorders hepatic enzyme increased, hepatitis (including cholestasis, granulomatous, and non-specific, reactive), increased bilirubin Reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported. Immune System Disorders bronchospasm, erythema nodosum Musculoskeletal and Connective Tissue Disorders myalgia, muscle cramps Nervous System Disorders insomnia, paraesthesia, peripheral neuropathy, tremors Psychiatric Disorders mood swings Renal and Urinary Disorders dysuria, hematuria, interstitial nephritis, nephrolithiasis, nephrotic syndrome, proteinuria, urinary frequency • Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach [see Warnings and Precautions (5.7) ] . Reproductive System and Breast Disorders impotence, menorrhagia, reversible oligospermia Respiratory, Thoracic and Mediastinal Disorders dyspnea, interstitial lung disease, pleurisy/pleuritis Skin and Subcutaneous Tissue Disorders AGEP, alopecia, angioneurotic edema, DRESS, erythema, photosensitivity reaction, SJS/TEN Vascular Disorders hypertension, orthostatic hypotension Most common adverse reactions (≥2%) are: diarrhea, abdominal pain/cramps, nausea, arthralgia/joint pain, rash, upper respiratory infection and depression. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-888-380-3276 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety in DIPENTUM, 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, there were adverse developmental effects observed after oral administration of olsalazine sodium in pregnant rats during organogenesis at doses of 5 to 20 times the maximum recommended human dose (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 in DIPENTUM, 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 increased 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 Olsalazine has been shown to produce adverse fetal developmental effects including reduced fetal weights, retarded ossifications, and immaturity of the fetal visceral organs when given during organogenesis to pregnant rats at doses of 100 to 400 mg/kg (5 to 20 times the maximum recommended human dose.