Mesalamine 4 g/60mL Suspension — NDC 72162-2302-4 (Billing 72162-2302-04)

WARNINGS 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. Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given products that contain mesalamine or are converted to mesalamine.

In animal studies, the kidney was the principal organ of mesalamine toxicity. 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. Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.

Evaluate renal function in all patients prior to initiation and periodically while on Mesalamine Rectal Suspension Enema therapy. Discontinue Mesalamine Rectal Suspension Enema if renal function deteriorates while on therapy. Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease.

Although the exact frequency of occurrence cannot be ascertained, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. 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 Mesalamine Rectal Suspension Enema.

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 ENEMA 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

7.81Headache 53 6.50 16

12.50Gas/Flatulence 50 6.13 5

3.91Nausea 47 5.77 12

9.38Flu 43 5.28 1

0.78Tired/Weak/Malaise/Fatigue 28 3.44 8

6.25Fever 26 3.19 0

0.00Rash/Spots 23 2.82 4

3.12Cold/Sore Throat 19 2.33 9

7.03Diarrhea 17 2.09 5

3.91Leg/Joint Pain 17 2.09 1

0.78Dizziness 15 1.84 3

2.34Bloating 12 1.47 2

1.56Back Pain 11 1.35 1

0.78Pain on Insertion of Enema Tip 11 1.35 1

0.78Hemorrhoids 11 1.35 0

0.00Itching 10 1.23 1

0.78Rectal Pain 10 1.23 0

0.00Constipation 8 0.98 4

3.12Hair Loss 7 0.86 0

0.00Peripheral Edema 5 0.61 11

8.59UTI/Urinary Burning 5 0.61 4

3.12Rectal Pain/Soreness/Burning 5 0.61 3

2.34Asthenia 1 0.12 4

3.12Insomnia 1 0.12 3

2.34In 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.

Drug Interactions 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. 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.

PRECAUTIONS Hepatic Failure There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. Evaluate the risks and benefits of using Mesalamine Rectal Suspension Enema in patients with known liver impairment. Severe Cutaneous Adverse Reaction 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 (see ADVERSE REACTIONS ).

Discontinue Mesalamine Rectal Suspension Enema at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 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.

Nephrolithiasis Cases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment.

Interference with Laboratory Tests 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-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine. Drug Interactions 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. 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a 2-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet. Mesalamine is not mutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, TA1538. There were no reverse mutations in an assay using E. coli strain WP2UVRA.

There were no effects in an in vivo mouse micronucleus assay at 600 mg/kg and in an in vivo sister chromatid exchange at doses up to 610 mg/kg. No effects on fertility were observed in rats receiving up to 320 mg/kg/day. The oligospermia and infertility in men associated with sulfasalazine has very rarely been reported among patients treated with mesalamine.

Pregnancy Teratologic studies have been performed in rats and rabbits at oral doses up to five and eight times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus. There are, however, no adequate and well-controlled studies in pregnant women for either sulfasalazine or 5-ASA. Because animal reproduction studies are not always predictive of human response, 5-ASA should be used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether mesalamine or its metabolite(s) are excreted in human milk. As a general rule, nursing should not be undertaken w… [Excerpted — this section continues on DailyMed.]