MESALAMINE: 19,475 Adverse Event Reports & Safety Profile

Each mesalamine delayed-release tablet for oral administration contains 800 mg of mesalamine USP, an aminosalicylate. Mesalamine, USP is 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, 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 and soluble in dilute hydrochloric acid and in dilute alkali hydroxides. Mesalamine delayed-release tablets 800 mg have single layered coating consisting of an acrylic based resin Eudragit S (methacrylic acid copolymer B, NF), which dissolves at pH 7 or greater, releasing mesalamine for topical anti-inflammatory action in the colon. Mesalamine (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid and its structural formula is: Each mesalamine delayed-release tablet contains 800 mg of mesalamine. In addition, each tablet contains the following inactive ingredients: acetyltributyl citrate, colloidal silicone dioxide, ferric oxide red, magnesium stearate, methacrylic acid copolymer type B, microcrystalline cellulose, povidone, sodium starch glycolate, talc and titanium dioxide. The tablet is printed with opacode black S-1-17823 which contains following ingredients: ammonium hydroxide, butyl alcohol, ferrosoferric oxide, isopropyl alcohol, propylene glycol and shellac.

Mesalamine

Delayed-release Tablets, USP

AND USAGE Mesalamine delayed-release capsules are an aminosalicylate indicated for: Treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older. ( 1.1 ) Maintenance of remission of ulcerative colitis in adults. ( 1.2 )

1.1 Treatment of Mildly to Moderately Active Ulcerative Colitis Mesalamine delayed-release capsules are indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older.

1.2 Maintenance of Remission of Ulcerative Colitis Mesalamine delayed-release capsules are indicated for the maintenance of remission of ulcerative colitis in adults.

AND ADMINISTRATION Important Administration Instruction s : Do not substitute two MESALAMINE delayed-release 400 mg capsules with one mesalamine delayed-release 800 mg tablet. ( 2.1 ) Evaluate renal function prior to initiation of MESALAMINE delayed-release capsules. ( 2.1 , 5.1 ) Take with or without food. ( 2.1 ) Swallow the capsules whole; do not cut, break, crush or chew. ( 2.1 ) For patients who are unable to swallow the capsules, the capsules can be opened and the inner tablets swallowed. ( 2.1 ) Drink an adequate amount of fluids. ( 2.1 , 5.7 ) T reatment of Mildly to Moderately Active Ulcerative Colitis : Adults: 800 mg (two 400 mg capsules) three times daily for 6 weeks Pediatric Patients 5 years or older: See weight-based dosing table in the full prescribing information; twice daily dosing for 6 weeks. ( 2.2 ) Maintenance of Remission of Ulcerative Colitis Adults: 1.6 grams (four 400 mg capsules) daily, in two to four divided doses. ( 2.3 ) 2. 1 Important Administration Instructions Do not substitute two MESALAMINE delayed-release 400 mg capsules with one mesalamine delayed-release 800 mg tablet. Evaluate renal function prior to initiation of MESALAMINE delayed-release capsules. Take MESALAMINE delayed-release capsules with or without food. Swallow the capsules whole; do not cut, break, crush or chew the capsules. For patients who are unable to swallow the capsules whole, carefully open the capsule(s) and swallow the contents (four 100 mg tablets). ○ Open the number of capsules required to make up a complete dose [see Dosage and Administration ( 2.2 , 2.3 )] . ○ There are 4 tablets per capsule. Ensure all tablets per capsule are swallowed and no tablets are retained in the mouth. ○ Swallow the tablets whole; do not cut, break, crush or chew the tablets. Drink an adequate amount of fluids [see Warnings and Precautions ( 5.7 )]. Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly. Protect MESALAMINE delayed-release capsules from moisture. Close the container tightly and leave any desiccant pouches present in the bottle along with the tablets. 2. 2 Dosage for Treatment of Mildly to Moderately Active Ulcerative Colitis Adults For adults, the recommended dosage of MESALAMINE delayed-release capsules is 800 mg (two 400 mg capsules) three times daily (total daily dosage of 2.4 grams) for a duration of 6 weeks [see Clinical Studies ( 14.1 )] .

Pediatrics

For pediatric patients 5 years of age and older, the recommended total daily dosage of MESALAMINE delayed-release capsules is weight-based (up to maximum of 2.4 grams per day) divided into two daily doses for a duration of 6 weeks (see Table 1 ).

Table

1.

Pediatric

Dosage by Weight Weight Group (kg)

Daily

Dosage (mg/kg/day)

Maximum Daily

Dosage (grams per day)

Morning Dosage Afternoon Dosage

17 to 32 36 to 71 1.2 two 400 mg capsules one 400 mg capsule 33 to 53 37 to 61 2 three 400 mg capsules two 400 mg capsules 54 to 90 27 to 44 2.4 three 400 mg capsules three 400 mg capsules 2. 3 Dosage for Maintenance of Remission of Ulcerative Colitis The recommended dosage of MESALAMINE delayed-release capsules in adults is 1.6 grams (four 400 mg capsules) daily in two to four divided doses.

Mesalamine delayed-release tablets are contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release tablets [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.2 ), and Description ( 11 )] . Known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release tablets. ( 4 , 5.3 )

REACTIONS The most serious adverse reactions seen in MESALAMINE delayed-release capsules clinical trials or with other products that contain or are metabolized to mesalamine are: 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 (≥5%) are: A dults : eructation, abdominal pain, constipation, dizziness, rhinitis, back pain, and rash. ( 6.1 ) P ediatric s : nasopharyngitis, headache, abdominal pain, dizziness, sinusitis, rash, cough and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC at 1-877-446-3679 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 safety of MESALAMINE delayed-release capsules has been established based on adequate and well-controlled studies of mesalamine delayed-release tablets. In total, mesalamine delayed-release 400 mg tablets have been evaluated in 2690 patients with ulcerative colitis in controlled and open-label trials. Below is a description of the adverse reactions of mesalamine delayed-release tablets in these adequate and well-controlled studies. Clinical studies supporting mesalamine delayed-release tablets use for the treatment of mildly to moderately active ulcerative colitis included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study of 2 dosage levels in children with mildly to moderately active ulcerative colitis (Study 3). Clinical studies supporting the use of mesalamine delayed-release tablets in the maintenance of remission of ulcerative colitis included a 6-month, randomized, double-blind, placebo-controlled, multi-center study (Study 4) and four active-controlled maintenance trials comparing mesalamine delayed-release with sulfasalazine. Mesalamine delayed-release tablets have been evaluated in 427 adults and 107 children with ulcerative colitis in these controlled studies. Treatment of Mildly to Moderately Active Ulcerative Colitis Adults In a 6-week placebo-controlled clinical study (Study 1) involving 105 patients, 53 of whom were randomized to mesalamine delayed-release tablets 2.4 grams per day <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> , 4% of the mesalamine delayed release tablets -treated patients in 2.4 grams per day group discontinued therapy because of adverse reactions as compared to 0% of the placebo-treated patients. The average age of patients was 41 years and 49 % of patients were male. Adverse reactions leading to withdrawal from mesalamine delayed-release tablets included (each in one patient): diarrhea and colitis flare; dizziness, nausea, joint pain, and headache. The most common adverse reactions in patients treated with mesalamine delayed release tablets 2.4 grams per day in Study 1 are listed in Table 2 below.

Table

2.

Most Common Adverse Reactions

Reported in Study 1 for the Treatment of Mild to Moderate Ulcerative Colitis in Adults* Adverse Reaction % of Patients with Adverse Reactions Mesalamine Delayed release 2.4 grams per day Placebo (n = 53) (n = 52)

Eructation

26 19 Abdominal pain 21 12 Constipation 11 0 Dizziness 9 8 Rhinitis 8 6 Back pain 6 4 Rash 6 4 Dyspepsia 4 0 Flu syndrome 4 2 * At Least 2% of Patients in the Mesalamine Delayed Release Tablets Group and at a Rate Greater than Placebo Pediatric Patients 5 to 17 Years Old A randomized, double-blind, 6-week study of 2 dosage levels of mesalamine delayed-release 400 mg tablets (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dosage (1.2, 2, and 2.4 grams per day for the respective body weight category) or a high dosage (2.0, 3.6, and 4.8 grams per day). The high dosage regimen is not recommended because it was not found to be more effective than the recommended low dosage regimen [see Dosage and Administration ( 2.2 ) , Clinical Studies ( 14.1 )] . Duration of exposure to mesalamine among the 82 patients in the study ranged from 12 to 50 days (mean of 40 days in each dosage group). The majority (88%) of patients in each group were treated for more than 5 weeks.

Table

3 provides a summary of the specific reported adverse reactions.

Table

3 .

Adverse

Reactions ≥ 5% Reported in Study 3 for the Treatment of Mild to Moderate Ulcerative Colitis in Pediatric Patients* Adverse Reaction % of Patients with Adverse Reactions Low Dosage High Dosage (n=41) (n=41)

Nasopharyngitis

15 12 Headache 10 5 Abdominal pain 10 2 Dizziness 7 2 Sinusitis 7 0 Rash 5 5 Cough 5 0 Diarrhea 5 0 Fatigue 2 10 Pyrexia 0 7 Increased Lipase 0 5 Low Dosage = mesalamine 400 mg delayed-release tablet 1.2 to 2.4 grams/day; High Dosage = mesalamine 400 mg delayed-release tablet 2.0 to 4.8 grams/day. Dosage was dependent on body weight.

Adverse

Reactions reported at the 1-week telephone follow-up visit are included. * At Least 5% of Patients in the low dosage or high dosage group Twelve percent of the patients in the low dosage group (5 patients) and 2% of the patients in the high dosage group (1 patient) had serious adverse reactions. The serious adverse reactions consisted of sinusitis, adenovirus infection, and pancreatitis in one patient each in the low dosage group. Abdominal pain and decreased body mass index occurred in one patient and bloody diarrhea and sclerosing cholangitis also occurred in one patient in the low dosage group. Anemia and syncope occurred in one patient in the high dosage group. Five patients were withdrawn from the study due to adverse reactions: 3 (7%) in the low dosage group (1 patient each with adenovirus infection, sclerosing cholangitis, and pancreatitis) and 2 patients (5%) in the high dosage group (1 patient with increased amylase and increased lipase, and 1 patient with upper abdominal pain). In general, the nature and severity of reactions in the pediatric population was similar to those reported in adult populations of patients with ulcerative colitis. Maintenance of Remission of Ulcerative Colitis Clinical studies supporting the use of mesalamine delayed release tablets in the maintenance of remission of ulcerative colitis in adults included a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration in 264 patients (Study 4) [see Clinical Studies ( 14.2 )] .

In Study

4, a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration, 87 patients were randomized to receive mesalamine delayed release tablets 1.6 grams per/day compared to 87 patients randomized to placebo. The average age of patients in Study 4 was 42 years and 55% of patients were male. Adverse reactions leading to study withdrawal in patients using mesalamine delayed release tablets included (each in one patient): anxiety, stomatitis and asthenia. In addition to the adverse reactions listed in Table 2, the following occurred at a frequency of 2% or greater in patients who received mesalamine delayed-release tablets in Study 4: abdominal enlargement, gastroenteritis, gastrointestinal hemorrhage, infection, joint disorder, nervousness, paresthesia, hemorrhoids, tenesmus, urinary frequency and vision abnormalities.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MESALAMINE delayed-release capsules 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: Neck pain, facial edema, edema, lupus-like syndrome, drug fever. Cardiovascular: Pericarditis, myocarditis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> . Endocrine: Nephrogenic diabetes insipidus. Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral ulcers, perforated peptic ulcer, bloody diarrhea. Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia, lymphadenopathy. Musculoskeletal: Gout. Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor, peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome, intracranial hypertension. Renal: Renal failure, interstitial nephritis, minimal change disease, nephrolithiasis <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.7 )]</span> . Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation, pleurisy/pleuritis. Skin: Alopecia, psoriasis, pyoderma gangrenosum, dry skin, erythema nodosum, urticaria, SJS/TEN, DRESS, and AGEP <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

Special

Senses: Eye pain, taste perversion, blurred vision, tinnitus. Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia. Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite containing bleach.

Laboratory

Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.

AND PRECAUTIONS Renal Impairment: Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits of using MESALAMINE delayed-release capsules in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. Discontinue MESALAMINE delayed-release capsules if renal function deteriorates. ( 5.1 , 7.1 , 8.6 , 13.2 ) Mesalamine-induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an ulcerative colitis exacerbation; monitor for worsening symptoms while on treatment; discontinue treatment, if acute intolerance syndrome is suspected. ( 5.2 )

Hypersensitivity

Reactions , including myocarditis and pericarditis : Evaluate patients immediately and discontinue MESALAMINE delayed-release capsules, if a hypersensitivity reaction is suspected. ( 5.3 )

Hepatic

Failur e : Evaluate the risks and benefits of using MESALAMINE delayed-release capsules 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: Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. ( 5.6 ) Nephrolithiasis: Mesalamine-containing stones undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment. ( 5.7 )

Iron

Content of MESALAMINE d elayed- r elease c apsules : Consider the iron content of MESALAMINE delayed-release capsules in patients taking iron supplementation and those at risk of iron overload. ( 5.8 ) Interference with Laboratory Tests : Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. ( 5.9 )

5.1 Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients taking products such as MESALAMINE delayed-release capsules that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 ) , Nonclinical Toxicology ( 13.2 ) ]</span> . Evaluate renal function prior to initiation of MESALAMINE delayed-release capsules and periodically while on therapy. Discontinue MESALAMINE delayed-release capsules if renal function deteriorates while on therapy. Evaluate the risks and benefits of using MESALAMINE delayed-release capsules in patients with known renal impairment or history of renal disease or taking concomitant nephrotoxic drugs <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.6 ) ]</span> .

5.2 Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, abdominal pain, bloody diarrhea, and sometimes fever, headache, malaise, pruritus, conjunctivitis and rash. Monitor patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with MESALAMINE delayed-release capsules.

5.3 Hypersensitivity Reactions Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to MESALAMINE delayed-release capsules 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 delayed-release capsules if an alternative etiology for the signs or 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. Evaluate the risk and benefits of using MESALAMINE delayed-release capsules 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Discontinue MESALAMINE delayed-release capsules at the first appearance of signs or symptoms of severe cutaneous adverse reactions, or other signs of hypersensitivity and consider further evaluation. 5. 6 Photosensitivity Patients treated with mesalamine or sulfasalazine who have 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, including stones of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with MESALAMINE delayed-release capsules. 5. 8 Iron Content of Mesalamine Delayed-Release Capsules MESALAMINE delayed-release capsules contains iron oxide as a colorant in the coating of the delayed-release capsules.

Each

400 mg delayed-release capsule contains 2.7 mg of iron. The total content of iron is 16.4 mg at the maximum recommended daily dosage in adults [see Dosage and Administration ( 2.2 )]. Before prescribing MESALAMINE delayed-release capsules to patients receiving iron supplementation or those at risk of developing iron overload, consider the combined daily amount of iron from all sources, including MESALAMINE delayed-release capsules. 5. 9 Interference with Laboratory Tests Use of MESALAMINE delayed-release capsules 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.

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 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 (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. Information for Patients Urine Discoloration Advise patients that urine may become discolored reddish-brown while taking mesalamine rectal suspension enema when it comes in contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, advise patients to observe their urine flow. Report to the healthcare provider only if urine is discolored on leaving the body, before contact with any surface or water (e.g., in the toilet). 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. Information for Patients - See patient instructions enclosed. 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 while a patient is on a drug since many drugs are excreted in human milk.

Pediatric

Use - Safety and effectiveness in pediatric patients have not been established.

Geriatric

Use - Clinical trials of mesalamine rectal suspension enema 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 rectal suspension enema who were 65 years or older compared to younger patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function. Consider monitoring complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine rectal suspension enema, especially if used concomitantly with anticoagulants. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing mesalamine rectal suspension enema. To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

INTERACTIONS Nephrotoxic Agents including NSAIDs : Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine­ related adverse reactions. ( 7.2 ) Azathioprine or 6-Mercaptopurine : Increased risk of blood disorders; monitor complete blood cell counts and platelet counts. ( 7.3 )

7.1 Antacids Because the dissolution of the coating of the granules in mesalamine extended-release capsules depends on pH, avoid co-administration of mesalamine extended-release capsules with antacids <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 )]</span>.

7.2 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>.

7.3 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 extended-release capsules and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

7.4 Interference with Urinary Normetanephrine Measurements Use of mesalamine extended-release capsules may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.9 )]</span> . Consider an alternative, selective assay for normetanephrine.