mesalamine 250 MG Extended Release Oral Capsule [Pentasa]

INDICATIONS 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.

DOSAGE AND ADMINISTRATION Important Administration Instructions : 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 ) Treatment 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 capsules. 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 capsules 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.

WARNINGS 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 Failure: 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 Delayed-Release Capsules: 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 [see Adverse Reactions ( 6.2 ), Nonclinical Toxicology ( 13.2 )]. 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 [see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.6 )] . 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 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 [see Adverse Reactions ( 6.2 )] . 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 0.589 mg of iron. The total content of iron is 3.54 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.

CONTRAINDICATIONS 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 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of mesalamine is not fully understood, but it appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, 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. 12.3 Pharmacokinetics Absorption The total absorption of mesalamine from mesalamine delayed-release tablets 2.4 g or 4.8 g given once daily for 14 days to healthy subjects was found to be approximately 21% to 22% of the administered dose. Gamma-scintigraphy studies have shown that a single dose of mesalamine delayed-release tablets 1.2 g (one tablet) passed intact through the upper gastrointestinal tract of fasted healthy subjects. Scintigraphic images showed a trail of radio-labeled tracer in the colon, suggesting that mesalamine had distributed through this region of the gastrointestinal tract. In a single-dose study, mesalamine delayed-release tablets 1.2 g, 2.4 g, and 4.8 g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalamine were detectable after 2 hours and reached a maximum by 9-12 hours on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects (Table 4). Mesalamine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was slightly more than dose proportional between 1.2 g and 4.8 g mesalamine delayed-release tablets. Maximum plasma concentrations (C max ) of mesalamine increased approximately dose proportionately between 1.2 g and 2.4 g and sub-proportionately between 2.4 g and 4.8 g of mesalamine delayed-release tablets, with the dose normalized value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means. Table 4: Mean (SD) Pharmacokinetic Parameters for Mesalamine Following Single-Dose Administration of Mesalamine Delayed-Release Tablets Under Fasting Conditions Parameter * of Mesalamine Mesalamine Delayed-Release Tablets 1.2 g (N=47) Mesalamine Delayed-Release Tablets 2.4 g (N=48) Mesalamine Delayed-Release Tablets 4.8 g (N=48) AUC 0-t (ng∙h/mL) 9,039 † (5,054) 20,538 (12,980) 41,434 (26,640) AUC 0- ∞ (ng∙h/mL) 9,578 ‡ (5,214) 21,084 (13,185) 44,775 § (30,302) C max (ng/mL) 857 (638) 1,595 (1,484) 2,154 (1,140) T max ¶ (h) 9.0 # (4.0-32.1) 12.0 (4.0-34.1) 12.0 (4.0-34.0) T lag ¶ (h) 2.0 # (0-8.0) 2.0 (1.0-4.0) 2.0 (1.0-4.0) T 1/2 (h) (Terminal Phase) 8.56 ‡ (6.38) 7.05 Þ (5.54) 7.25 § (8.32) * Arithmetic mean of parameter values are presented except for T max and T lag . † N=43 ‡ N=27 § N=36 ¶ Median (min, max) # N=46 Þ N=33 Food Effects Administration of a single dose of mesalamine delayed-release tablets 4.8 g with a high-fat meal resulted in further delay in absorption, and plasma concentrations of mesalamine were detectable 4 hours following dosing. However, a high-fat meal increased systemic exposure of mesalamine (mean C max : increased 91%; mean AUC: increased 16%) compared to results in the fasted state. Mesalamine delayed-release tablets were administered with food in the controlled clinical trials [see Dosage and Administration (2) ] . In a single- and multiple-dose pharmacokinetic study of mesalamine delayed-release tablets, 2.4 g or 4.8 g was administered once daily with standard meals to 28 healthy subjects per dose group. Plasma concentrations of mesalamine were detectable after 4 hours and were maximal by 8 hours after the single dose. Steady state was achieved generally by 2 days after dosing. Mean AUC at steady state was only modestly greater (1.1- to 1.4-fold) than predictable from single dose pharmacokinetics. Distribution Mesalamine is approximately 43% bound to plasma proteins at the concentration of 2.5 mcg/mL. Elimination Metabolism The only major metabolite of mesalamine (5-aminosalicylic acid) is N-acetyl-5-aminosalicylic acid. Its formation is brought about by N-acetyltransferase (NAT) activity in the liver and intestinal mucosa cells, principally by NAT-1. Excretion Excretion of mesalamine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation); however, there is also limited excretion of the parent drug in urine. Of the approximately 21% to 22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The mean renal clearance (CL R ) in adults ranged from 1.8 L/h to 2.9 L/h following single dose administration and ranged from 5.5 L/h to 6.4 L/h after a multiple dosing for 14 days. The apparent terminal half-lives for mesalamine and its major metabolite after administration of mesalamine delayed-release tablets 2.4 g and 4.8 g were, on average, 7 to 9 hours and 8 to 12 hours, respectively. Systemic exposures in adult subjects were inversely correlated with renal function as assessed by estimated creatinine clearance [see Use in Specific Populations (8.6) ]. Specific Populations Geriatric Patients In a single-dose pharmacokinetic study of mesalamine delayed-release tablets, 4.8 g was administered in the fasted state to 71 healthy male and female subjects (28 young (18-35 years); 28 elderly (65-75 years); 15 elderly (>75 years)). Increased age resulted in increased systemic exposure (approximately 2-fold in C max ) to mesalamine and its metabolite N-acetyl-5-aminosalicylic acid. Increased age resulted in a slower apparent elimination of mesalamine, though there was high between-subject variability. Table 5: Mean (SD) Pharmacokinetic Parameters for Mesalamine Following Single-Dose Administration of Mesalamine Delayed-Release Tablets 4.8 g under Fasting Conditions to Young and Elderly Subjects Parameter of 5-ASA Young Subjects (18 to 35 years) (N=28) Elderly Subjects (65 to 75 years) (N=28) Elderly Subjects (75 years and older) (N=15) AUC 0-t (ng∙h/mL) 51,570 (23,870) 73,001 (42,608) 65,820 (25,283) AUC 0-∞ (ng∙h/mL) 58,057 * , (22,429) 89,612 † , (40,596) 63,067 ‡ , (22,531) C max (ng/mL) 2,243 (1,410) 4,999 (4,381) 4,832 (4,383) t max § (h) 22.0 (5.98–48.0) 12.5 (4.00–36.0) 16.0 (4.00–26.0) t lag § (h) 2 (1–6) 2 (1–4) 2 (2–4) t ½ (h), terminal phase 5.68 * (2.83) 9.68 † (7.47) 8.67 ‡ (5.84) Renal clearance (L/h) 2.05 (1.33) 2.04 (1.16) 2.13 (1.20) Arithmetic mean (SD) data are presented, N = Number of subjects; 5-ASA = 5-aminosalicylic acid * N=15, † N=16, ‡ N=13, § Median (min-max) Pediatric use information is approved for Takeda Pharmaceuticals U.S.A., Inc.’s LIALDA (mesalamine) delayed-release tablets. However, due to Takeda Pharmaceuticals U.S.A., Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. Drug Interaction Studies The potential effect of mesalamine delayed-release tablets (4.8 g given once daily) on the pharmacokinetics of four commonly used antibiotics were evaluated in healthy subjects. The four antibiotics studied and their dosing regimens were as follows: amoxicillin (single 500-mg dose), ciprofloxacin XR (single 500-mg dose), metronidazole (750 mg twice daily for 3.5 days), and sulfamethoxazole/trimethoprim (800 mg/160 mg twice daily for 3.5 days). The change in C max and AUC of amoxicillin, ciprofloxacin, and metronidazole when they were co-administered with mesalamine delayed-release tablets were all 3% or less. There was an increase of 12% in C max and an increase of 15% in AUC of sulfamethoxazole when sulfamethoxazole/trimethoprim was coadministered with mesalamine delayed-release tablets. Coadministration of mesalamine delayed-release tablets did not result in clinically significant changes in the pharmacokinetics of any of the four antibiotics.