Prescription Drugs

CLINICAL PHARMACOLOGY Sulfasalazine is split by bacterial action in the colon into sulfapyridine (SP) and mesalamine (5-ASA). It is thought that the mesalamine component is therapeutically active in ulcerative colitis. The usual oral dose of sulfasalazine for active ulcerative colitis in adults is 2 to 4 g per day in divided doses. Four grams of sulfasalazine provide 1.6 g of free mesalamine to the colon. The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, ie, prostanoids, and through the lipoxygenase pathways, ie, leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon. Human Pharmacokinetics And Metabolism Absorption PENTASA is an ethylcellulose-coated, controlled-release formulation of mesalamine designed to release therapeutic quantities of mesalamine throughout the gastrointestinal tract. Based on urinary excretion data, 20% to 30% of the mesalamine in PENTASA is absorbed. In contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, mesalamine is approximately 80% absorbed. Plasma mesalamine concentration peaked at approximately 1 μg/mL 3 hours following a 1-g PENTASA dose and declined in a biphasic manner. The literature describes a mean terminal half-life of 42 minutes for mesalamine following intravenous administration. Because of the continuous release and absorption of mesalamine from PENTASA throughout the gastrointestinal tract, the true elimination half-life cannot be determined after oral administration. N-acetylmesalamine, the major metabolite of mesalamine, peaked at approximately 3 hours at 1.8 μg/mL, and its concentration followed a biphasic decline. Pharmacological activities of N-acetylmesalamine are unknown, and other metabolites have not been identified. Oral mesalamine pharmacokinetics were nonlinear when PENTASA capsules were dosed from 250 mg to 1 g four times daily, with steady-state mesalamine plasma concentrations increasing about nine times, from 0.14 μg/mL to 1.21 μg/mL, suggesting saturable first-pass metabolism. N-acetylmesalamine pharmacokinetics were linear. Elimination About 130 mg free mesalamine was recovered in the feces following a single 1-g PENTASA dose, which was comparable to the 140 mg of mesalamine recovered from the molar equivalent sulfasalazine tablet dose of 2.5 g. Elimination of free mesalamine and salicylates in feces increased proportionately with PENTASA dose. N-acetylmesalamine was the primary compound excreted in the urine (19% to 30%) following PENTASA dosing. Clinical Trials In two randomized, double-blind, placebo-controlled, dose-response trials (UC-1 and UC-2) of 625 patients with active mild to moderate ulcerative colitis, PENTASA, at an oral dose of 4 g/day given 1 g four times daily, produced consistent improvement in prospectively identified primary efficacy parameters, PGA, Tx F, and SI as shown in the table below. The 4-g dose of PENTASA also gave consistent improvement in secondary efficacy parameters, namely the frequency of trips to the toilet, stool consistency, rectal bleeding, abdominal/rectal pain, and urgency. The 4-g dose of PENTASA induced remission as assessed by endoscopic and symptomatic endpoints. In some patients, the 2-g dose of PENTASA was observed to improve efficacy parameters measured. However, the 2-g dose gave inconsistent results in primary efficacy parameters across the two adequate and well-controlled trials. Parameter Evaluated Clinical Trial UC-1 Clinical Trial UC-2 PL (n=90) PENTASA PL (n=83) PENTASA 4 g/day (n=95) 2 g/day (n=97) 4 g/day (n=85) 2 g/day (n=83) PGA 36% 59%* 57%* 31% 55%* 41% Tx F 22% 9%* 18% 31% 9%* 17%* SI -2.5 -5.0* -4.3* -1.6 -3.8* -2.6 Remission† 12% 26%* 24%* 12% 27%* 12% * p<0.05 vs placebo. PGA: Physician Global Assessment: proportion of patients with complete or marked improvement. Tx F: Treatment Failure: proportion of patients developing severe or fulminant UC requiring steroid therapy or hospitalization or worsening of the disease at 7 days of therapy, or lack of significant improvement by 14 days of therapy. SI: Sigmoidoscopic Index: an objective measure of disease activity rated by a standard (15-point) scale that includes mucosal vascular pattern, erythema, friability, granularity/ulcerations, and mucopus: improvement over baseline. † Defined as complete resolution of symptoms plus improvement of endoscopic endpoints. To be considered in remission, patients had a “1” score for one of the endoscopic components (mucosal vascular pattern, erythema, granularity, or friability) and “0” for the others.

CLINICAL PHARMACOLOGY Mechanism Of Action The mechanism of action of mesalamine is not fully understood, but appears to have a topical antiinflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. Mesalamine has the potential to inhibit the activation of nuclear factor kappa B (NF?B) and consequently the production of key pro-inflammatory cytokines. It has been proposed that reduced expression of PPAR? nuclear receptors (?-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. There is evidence that mesalamine produces pharmacodynamic effects through direct activation of PPAR? receptors in the colonic/rectal epithelium. Pharmacodynamics The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosae local to the delivery of drug from LIALDA into the lumen. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalamine is inversely correlated with mucosal concentrations of mesalamine. Plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy. Pharmacokinetics Absorption The total absorption of mesalamine from LIALDA 2.4 g or 4.8 g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose. Gamma-scintigraphy studies have shown that a single dose of LIALDA 1.2 g (one tablet) passed intact through the upper gastrointestinal tract of fasted healthy volunteers. 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, LIALDA 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 3). 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 LIALDA. Maximum plasma concentrations (C ) 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 LIALDA, with the dose normalized value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means. Table 3: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of LIALDA Under Fasting Conditions Parameter1 of Mesalamine LIALDA 1.2 g (N=47) LIALDA 2.4 g (N=48) LIALDA 4.8 g (N=48) AUC0-t (ng.h/mL) 9039† (5054) 20538 (12980) 41434 (26640) AUC0-∞ (ng.h/mL) 9578• (5214) 21084 (13185) 44775# (30302) Cmax (ng/mL) 857 (638) 1595 (1484) 2154 (1140) Tmax * (h) 9.0** (4.0-32.1) 12.0 (4.0-34.1) 12.0 (4.0-34.0) Tlag * (h) 2.0** (0-8.0) 2.0 (1.0-4.0) 2.0 (1.0-4.0) T1/2 (h) (Terminal Phase) 8.56• (6.38) 7.05§ (5.54) 7.25# (8.32) 1Arithmetic mean of parameter values are presented except for Tmax and Tlag. *Median (min, max); †N=43, •N=27, §N=33, #N=36, **N=46 Administration of a single dose of LIALDA 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 : ↑ 91%; mean AUC: ↑ 16%) compared to results in the fasted state. LIALDA was administered with food in the controlled clinical trials that supported its approval. In a single and multiple dose pharmacokinetic study of LIALDA, 2.4 g or 4.8 g was administered once daily with standard meals to 28 healthy volunteers 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. In a single dose pharmacokinetic study of LIALDA, 4.8 g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35yrs); 28 elderly (65-75yrs); 15 elderly (>75yrs)). Increased age resulted in increased systemic exposure (approximately 2-fold in C ), 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. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance. Table 4: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of LIALDA 4.8 g under Fasting Conditions to Young and Elderly Subjects Parameter of 5-ASA Young Subjects (18-35 yrs ) (N=28) Elderly Subjects (65-75 yrs ) (N=28) Elderly Subjects (>75 yrs ) (N=15) AUC0-t (ng.h/mL) 51570 (23870) 73001 (42608) 65820 (25283) AUC0-∞ (ng.h/mL) 58057b (22429) 89612c (40596) 63067d (22531) Cmax (ng/mL) 2243 (1410) 4999 (4381) 4832 (4383) t maxa (h) 22.0 (5.98 - 48.0) 12.5 (4.00 - 36.0) 16.0 (4.00 - 26.0) t laga (h) 2.00 (1.00 - 6.00) 2.00 (1.00 - 4.00) 2.00 (2.00 - 4.00) t 1/2 (h), terminal phase 5.68b (2.83) 9.68c (7.47) 8.67d (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 aMedian (min-max), bN=15, cN=16, dN=13 Distribution Mesalamine is approximately 43% bound to plasma proteins at the concentration of 2.5 µg/mL. 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. Elimination Elimination 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 21-22% 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 apparent terminal half-lives for mesalamine and its major metabolite after administration of LIALDA 2.4 g and 4.8 g were, on average, 7-9 hours and 8-12 hours, respectively. Drug Interactions: The potential effect of Lialda (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). Coadministration of Lialda did not result in clinically significant changes in the pharmacokinetics of any of the four antibiotics. The change in Cmax and AUC of amoxicillin, ciprofloxacin and metronidazole when they were co-administered with Lialda were all ≤ 3%. There was an increase of 12% in Cmax and an increase of 15% in AUC of sulfamethoxazole when sulfamethoxazole/trimethoprim was coadministered with Lialda [see DRUG INTERACTIONS]. Animal Toxicology And/Or Pharmacology In animal studies with mesalamine, a 13-week oral toxicity study in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys have shown the kidney to be the major target organ of mesalamine toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or higher produced nephrosis, papillary edema, and interstitial fibrosis. Clinical Studies Active, Mild To Moderate Ulcerative Colitis Two similarly designed, randomized, double blind, placebo-controlled trials were conducted in 517 adult patients with active, mild to moderate ulcerative colitis. The study population was primarily Caucasian (80%), had a mean age of 42 years (6% age 65 years or older), and was approximately 50% male. Both studies used LIALDA doses of 2.4 g/day and 4.8 g/day administered once daily for 8 weeks except for the 2.4 g/day group in Study 1, which was given in two divided doses (1.2 g twice daily). The primary efficacy end-point in both trials was to compare the percentage of patients in remission after 8 weeks of treatment for the LIALDA treatment groups versus placebo. Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) of ≤ 1, with scores of zero for rectal bleeding and for stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline. In both studies, the LIALDA doses of 2.4 g/day and 4.8 g/day demonstrated superiority over placebo in the primary efficacy endpoint (Table 5). Both LIALDA doses also provided consistent benefit in secondary efficacy parameters, including clinical improvement, treatment failure, clinical remission, and sigmoidoscopic improvement. LIALDA 2.4 g/day and 4.8 g/day had similar efficacy profiles. Table 5: Patients in Remission at Week 8 Dose Study 1 (n=262) n/N (%) Study 2 (n=255) n/N (%) LIALDA 2.4 g/day 30/88 (34.1) 34/84 (40.5) LIALDA 4.8 g/day 26/89 (29.2) 35/85 (41.2) Placebo 11/85 (12.9) 19/86 (22.1) Maintenance Of Remission In Patients With Ulcerative Colitis A multicenter, randomized, double-blind, active comparator study was conducted in a total of 826 adult patients in remission from ulcerative colitis. The study population had a mean age of 45 years (8% age 65 years or older), were 52% male, and were primarily Caucasian (64%). Maintenance of remission was assessed using a modified Ulcerative Colitis Disease Activity Index (UC-DAI). For this trial, maintenance of remission was based on maintaining endoscopic remission defined as a modified UC-DAI endoscopy subscore of ≤1. An endoscopy subscore of 0 represented normal mucosal appearance with intact vascular pattern and no friability or granulation. For this trial the endoscopy score definition of 1 (mild disease) was modified such that it could include erythema, decreased vascular pattern, and minimal granularity; however, it could not include friability. Subjects were randomized in a 1:1 ratio to receive either LIALDA 2.4 g/day administered once daily or mesalamine delayed release 1.6 g/day administered as 0.8 g twice daily. The proportion of patients who maintained remission at Month 6 in this study using LIALDA 2.4 g once daily (83.7%) was similar to that seen using the comparator (mesalamine delayed release) 1.6 g/day (81.5%).

CLINICAL PHARMACOLOGY Mechanism Of Action The mechanism of action of mesalamine is not fully understood, but appears to be topical rather than systemic. Although the pathology of inflammatory bowel disease is uncertain, both prostaglandins and leukotrienes have been implicated as mediators of mucosal injury and inflammation. Pharmacokinetics Absorption Mesalamine (5-ASA) administered as a rectal suppository is variably absorbed. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories, administered once every eight hours for six days, the mean mesalamine peak plasma concentration (Cmax) was 353 ng/mL (CV=55%) following the initial dose and 361 ng/mL (CV=67%) at steady state. The mean minimum steady state plasma concentration (Cmin) was 89 ng/mL (CV=89%). Absorbed mesalamine does not accumulate in the plasma. Distribution Mesalamine administered as a rectal suppository distributes in rectal tissue to some extent. Elimination In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, the mean elimination half-life was 5 hours (CV=73%) for 5-ASA and 5 hours (CV=63%) for N-acetyl-5-ASA, the active metabolite, following the initial dose. At steady state, the mean elimination half-life was 7 hours for both 5-ASA and N-acetyl-5-ASA (CV=102% for 5ASA and 82% for N-acetyl-5-ASA). Metabolism The absorbed mesalamine is extensively metabolized, mainly to N-acetyl-5-ASA in the liver and in the gut mucosal wall. In patients with ulcerative colitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days, the peak concentration (Cmax) of N-acetyl-5-ASA ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from 193 ng/mL to 1304 ng/mL at steady state. Excretion Mesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with mesalamine 500 mg as a rectal suppository every 8 hours for 6 days, 12% or less of the dose was eliminated in urine as unchanged 5-ASA and 8% to 77% was eliminated as N-acetyl-5-ASA following the initial dose. At steady state, 11% or less of the dose was eliminated in the urine as unchanged 5-ASA and 3% to 35% was eliminated as N-acetyl-5-ASA. Animal Toxicology And/Or Pharmacology Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at a single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose of CANASA, based on body surface area) and at intravenous doses of >214 mg/kg (about 1.2 times the recommended human intra-rectal dose of CANASA, based on body surface area). In a 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose of CANASA, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose of CANASA, based on body surface area). In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose of CANASA, based on body surface area) and above. In a 14day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose of CANASA, based on body surface area) was not associated with any adverse effects. In a six-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose of CANASA, based on body surface area) and higher caused renal pathology similar to that described for the rat. In a rectal toxicity study of mesalamine suppositories in dogs, a dose of 166.6 mg/kg (about 3 times the recommended human intra-rectal dose of CANASA, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose of CANASA, based on body surface area) and above. Clinical Studies Two double-blind, placebo-controlled, multicenter trials of mesalamine suppositories were conducted in North America in adult patients with mildly to moderately active ulcerative proctitis. The regimen in Study 1 was a 500 mg mesalamine suppository administered rectally three times daily and in Study 2 was a 500 mg mesalamine suppository administered rectally twice daily. In both trials, patients had an average extent of proctitis (upper disease boundary) of approximately 10 cm and approximately 80% of patients had multiple prior episodes of proctitis. A total of 173 patients were evaluated (Study 1, N=79; Study 2, N=94), of which 89 patients received mesalamine, and 84 patients received placebo. The mean age of patients was 39 years (range 17 to 73 years), 60% were female, and 97% were white. The primary measures of efficacy were clinical disease activity index (DAI) and histologic evaluations in both trials. The DAI is a composite index reflecting rectal bleeding, stool frequency, mucosal appearance at endoscopy, and a physician’s global assessment of disease. Patients were evaluated clinically and sigmoidoscopically after 3 and 6 weeks of treatment. Compared to placebo, mesalamine suppositories were statistically (p<0.01) superior to placebo in both trials with respect to improvement in stool frequency, rectal bleeding, mucosal appearance, disease severity, and overall disease activity after 3 and 6 weeks of treatment. The effectiveness of mesalamine suppositories was statistically significant irrespective of sex, extent of proctitis, duration of current episode, or duration of disease. An additional multicenter, open-label, randomized, parallel group study in 99 patients diagnosed with mildly to moderately ulcerative proctitis compared 1000 mg CANASA administered rectally once daily at bedtime (N=35) to 500 mg mesalamine suppository administered rectally twice daily, in the morning and at bedtime (N=46), for 6 weeks. The primary measures of efficacy included the clinical disease activity index (DAI) and histologic evaluations. Patients were evaluated clinically and sigmoidoscopically at 3 and 6 weeks of treatment. The efficacy at 6 weeks was not different between the treatment groups. Both were effective in the treatment of ulcerative proctitis and resulted in a significant decrease at 6 weeks in DAI: in the mesalamine 500 mg twice daily group, the mean DAI value decreased from 6.6 to 1.6, and in the 1000 mg at bedtime group, the mean DAI value decreased from 6.2 to 1.3, which represents a decrease of greater than 75% in both groups. After 6 weeks of treatment, a DAI score of less than 3 was achieved in 78% of patients in the mesalamine 500 mg twice daily group and 86% of patients in the CANASA 1000 mg once daily group. The recommended dosage of CANASA is 1000 mg administered rectally once daily at bedtime [see DOSAGE AND ADMINISTRATION].

Find Lowest Prices on PENTASA® (mesalamine) Controlled-Release Capsules 250 mg and 500 mg DESCRIPTION PENTASA (mesalamine) for oral administration is a controlled-release formulation of mesalamine, an aminosalicylate anti-inflammatory agent for gastrointestinal use. Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid. It has a molecular weight of 153.14. The structural formula is: Each 250 mg capsule contains 250 mg of mesalamine. It also contains the following inactive ingredients: acetylated monoglyceride, castor oil, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic acid, sugar, talc, and white wax. The capsule shell contains D&C Yellow #10, FD&C Blue #1, FD&C Green #3, gelatin, titanium dioxide, and other ingredients. Each 500 mg capsule contains 500 mg of mesalamine. It also contains the following inactive ingredients: acetylated monoglyceride, castor oil, colloidal silicon dioxide, ethylcellulose, hydroxypropyl methylcellulose, starch, stearic acid, sugar, talc, and white wax. The capsule shell contains FD&C Blue #1, gelatin, titanium dioxide, and other ingredients.

Find Lowest Prices on LIALDA® (mesalamine) Tablets DESCRIPTION Each LIALDA delayed-release tablet for oral administration contains 1.2 g 5-aminosalicylic acid (5- ASA; mesalamine), an anti-inflammatory agent. Mesalamine also has the chemical name 5-amino-2- hydroxybenzoic acid and its structural formula is: Molecular formula: C7H7NO3 Molecular weight: 153.14 The tablet is coated with a pH dependent polymer film, which breaks down at or above pH 6.8, normally in the terminal ileum where mesalamine then begins to be released from the tablet core. The tablet core contains mesalamine with hydrophilic and lipophilic excipients and provides for extended release of mesalamine. The inactive ingredients of LIALDA are sodium carboxymethylcellulose, carnauba wax, stearic acid, silica (colloidal hydrated), sodium starch glycolate (type A), talc, magnesium stearate, methacrylic acid copolymer types A and B, triethylcitrate, titanium dioxide, red ferric oxide and polyethylene glycol 6000.

Find Lowest Prices on CANASA® (mesalamine) Suppositories, for Rectal Use DESCRIPTION The active ingredient in CANASA 1000 mg suppositories for rectal use is mesalamine, also known as mesalazine or 5aminosalicylic acid (5-ASA). Chemically, mesalamine is 5-amino-2-hydroxybenzoic acid, and is classified as an anti-inflammatory drug. Each CANASA rectal suppository contains 1000 mg of mesalamine (USP) in a base of Hard Fat, NF. The empirical formula is C7H7NO3, representing a molecular weight of 153.14. The structural formula is:

INDICATIONS PENTASA is indicated for the induction of remission and for the treatment of patients with mildly to moderately active ulcerative colitis. DOSAGE AND ADMINISTRATION The recommended dosage for the induction of remission and the symptomatic treatment of mildly to moderately active ulcerative colitis is 1g (4 PENTASA 250 mg capsules or 2 PENTASA 500 mg capsules) 4 times a day for a total daily dosage of 4g. Treatment duration in controlled trials was up to 8 weeks. PENTASA capsules may be swallowed whole, or alternatively, the capsule may be opened and the entire contents sprinkled onto applesauce or yogurt. The entire contents should be consumed immediately. The capsules and capsule contents must not be crushed or chewed. Safety and efficacy of PENTASA in pediatric patients have not been established. HOW SUPPLIED PENTASA controlled-release 250 mg capsules are supplied in bottles of 240 capsules (NDC 54092-189-81). Each green and blue capsule contains 250 mg of mesalamine in controlled-release beads. PENTASA controlled-release capsules are identified with a pentagonal starburst logo and the number 2010 on the green portion and S429 250 mg on the blue portion of the capsules. PENTASA controlled-release 500 mg capsules are supplied in bottles of 120 capsules (NDC 54092-191-12). Each blue capsule contains 500 mg of mesalamine in controlled-release beads. PENTASA controlled-release capsules are identified with a pentagonal starburst logo and S429 500 mg on the capsules. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Manufactured for Shire US Inc. 300 Shire Way, Lexington, MA 02421, USA. Revised: Aug 2017

INDICATIONS LIALDA is indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis. DOSAGE AND ADMINISTRATION The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is two to four 1.2 g tablets taken once daily with a meal for a total daily dose of 2.4 g or 4.8 g. The recommended dosage for the maintenance of remission is two 1.2 g tablets taken once daily with a meal for a total daily dose of 2.4 g. HOW SUPPLIED Dosage Forms And Strengths The red-brown ellipsoidal delayed-release tablet containing 1.2 g mesalamine is debossed on one side and imprinted with S476. Storage And Handling LIALDA is available as red-brown ellipsoidal film coated delayed-release tablets containing 1.2 g mesalamine, and debossed on one side imprinted with S476. NDC 54092-476-12 HDPE Bottle with a child-resistant closure of 120 delayed-release tablets. Store at room temperature 15°C to 25°C (59°F to 77°F); excursions permitted to 30°C (86°F). See USP Controlled Room Temperature. Manufactured by: Cosmo S.p.A., Milan, Italy. Revised: July 2017

INDICATIONS CANASA is indicated in adults for the treatment of mildly to moderately active ulcerative proctitis. DOSAGE AND ADMINISTRATION Dosage The recommended dosage of CANASA in adults is 1000 mg administered rectally once daily at bedtime for 3 to 6 weeks depending on symptoms and sigmoidoscopic findings. Safety and effectiveness of CANASA beyond 6 weeks have not been established. Administration Instructions Evaluate renal function prior to initiation of CANASA therapy and periodically while on therapy. Do not cut or break the suppository. Retain the suppository for one to three hours or longer, if possible. If a dose of CANASA is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two CANASA suppositories at the same time to make up for a missed dose. CANASA suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep CANASA away from these surfaces to prevent staining. HOW SUPPLIED Dosage Forms And Strengths CANASA Suppository: 1000 mg mesalamine in a bullet shaped, light tan to grey suppository. Storage And Handling CANASA 1000 mg suppositories for rectal administration are available as bullet shaped, light tan to grey suppositories containing 1000 mg mesalamine supplied in boxes of 30 and 42 individually plastic wrapped suppositories (NDC 58914-501-56 and 58914-50142). Store below 25°C (77°F), may be refrigerated. Keep away from direct heat, light or humidity. Distributed by: Allergan USA, Inc. Irvine, CA 92612. Revised: Sep 2016

PATIENT INFORMATION No information provided. Please refer to the PRECAUTIONS section.

PATIENT INFORMATION CANASA (Kay-nay-suh) (mesalamine) Suppositories, for Rectal Use What is CANASA? CANASA is a prescription medicine used to treat adults with active ulcerative proctitis (ulcerative rectal colitis). It is not known if CANASA is safe and effective in children. Do not use CANASA if you are: allergic to medicines that contain salicylates, including aspirin. allergic to mesalamine or any of the ingredients in CANASA. See the end of this Patient Information leaflet for a complete list of ingredients in CANASA. Ask your doctor if you are not sure if your medicine is listed above. Before using CANASA, tell your doctor if you: have a history of allergic reaction to the medicine sulfasalazine (Azulfidine). have kidney problems. have ever had inflammation of the sac around your heart (pericarditis). have liver problems. have any other medical conditions. are pregnant or plan to become pregnant. It is not known if CANASA can harm your unborn baby. are breastfeeding or plan to breastfeed. CANASA can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you use CANASA. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Using CANASA with certain other medicines may affect each other. Using CANASA with other medicines can cause serious side effects. Especially tell your doctor if you take nonsteroidal anti-inflammatory drugs (NSAIDS), or medicines that contain azathioprine or 6-mercaptopurine. Taking CANASA with NSAIDS may cause kidney problems. Taking CANASA with azathioprine or 6-mercaptopurine may cause blood problems. You doctor may do certain tests during treatment with CANASA. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I use CANASA? Use CANASA exactly as prescribed by your doctor. Your doctor will tell you how long to continue using CANASA. CANASA comes as a suppository that you insert into your rectum. Do not cut or break the suppository. Use CANASA 1 time each day at bedtime, for 3 to 6 weeks. It is not known if CANASA is safe and effective for use for longer than 6 weeks. After you insert CANASA in your rectum, try to keep (retain) the suppository in your rectum for 1 to 3 hours or longer if possible. If you miss a dose of CANASA, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time. CANASA can stain surfaces including clothing and other fabrics, flooring, painted surfaces, marble, granite, vinyl and enamel. Keep CANASA away from these surfaces to prevent staining. What are the possible side effects of CANASA? CANASA may cause serious side effects, including: Kidney problems. Your doctor will do certain tests before you start using CANASA and during your treatment with CANASA. Acute Intolerance Syndrome or Other Allergic Reactions. Some people who use CANASA can have allergic type reactions, including “Acute Intolerance Syndrome.” Other allergic reactions can cause heart problems including an inflammation of the sac around the heart (pericarditis), blood problems, and problems with other organs in the body including the kidneys, liver and lungs. These problems usually happen in people who have had an allergic reaction to medicines containing sulfasalazine. Stop using CANASA and tell your doctor right away if you get any of these symptoms: cramps stomach (abdominal) pain bloody diarrhea fever headache rash chest pain decrease in the amount of urine shortness of breath fatigue Liver problems. This can happen in people who have a history of liver problems and have taken other medicines that contain mesalamine. Tell your doctor right away if you get any of these symptoms while using CANASA: yellowing of your eyes itchy skin flu-like symptoms nausea or vomiting feeling very tired The most common side effects of CANASA include: dizziness acne inflammation of the large intestine (colitis) rectal pain fever rash These are not all of the possible side effects of CANASA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store CANASA? Store CANASA at room temperature below 77°F (25°C). CANASA may be refrigerated. Keep CANASA away from direct heat, light, or humidity. Keep CANASA and all medicines out of the reach of children. General information about the safe and effective use of CANASA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CANASA for a condition for which it was not prescribed. Do not give CANASA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about CANASA that is written for health professionals. What are the ingredients in CANASA? Active ingredients: mesalamine Inactive ingredients: Hard Fat base

OVERDOSE Single oral doses of mesalamine up to 5 g/kg in pigs or a single intravenous dose of mesalamine at 920 mg/kg in rats were not lethal. There is no clinical experience with PENTASA overdosage. PENTASA is an aminosalicylate, and symptoms of salicylate toxicity may be possible, such as: tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting, and diarrhea. Severe intoxication with salicylates can lead to disruption of electrolyte balance and blood-pH, hyperthermia, and dehydration. Treatment Of Overdosage ince PENTASA is an aminosalicylate, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. This includes prevention of further gastrointestinal tract absorption by emesis and, if necessary, by gastric lavage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained. CONTRAINDICATIONS PENTASA is contraindicated in patients who have demonstrated hypersensitivity to mesalamine, any other components of this medication, or salicylates.

OVERDOSE LIALDA is an aminosalicylate, and symptoms of salicylate toxicity may include tinnitus, vertigo, headache, confusion, drowsiness, sweating, seizures, hyperventilation, dyspnea, vomiting, and diarrhea. Severe intoxication may lead to disruption of electrolyte balance and blood-pH, hyperthermia, dehydration, and end organ damage. There is no specific known antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained. CONTRAINDICATIONS LIALDA is contraindicated in patients with known hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of LIALDA [see WARNINGS AND PRECAUTIONS, DESCRIPTION, ADVERSE REACTIONS].

OVERDOSE There have been no documented reports of serious toxicity in man resulting from massive overdosing with mesalamine suppository. Under ordinary circumstances, mesalamine absorption from the colon is limited. CONTRAINDICATIONS CANASA is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any ingredients in the suppository vehicle [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and DESCRIPTION].

SIDE EFFECTS In combined domestic and foreign clinical trials, more than 2100 patients with ulcerative colitis or Crohn’s disease received PENTASA therapy. Generally, PENTASA therapy was well tolerated. The most common events (ie, greater than or equal to 1%) were diarrhea (3.4%), headache (2.0%), nausea (1.8%), abdominal pain (1.7%), dyspepsia (1.6%), vomiting (1.5%), and rash (1.0%). In two domestic placebo-controlled trials involving over 600 ulcerative colitis patients, adverse events were fewer in PENTASA® (mesalamine)-treated patients than in the placebo group (PENTASA 14% vs placebo 18%) and were not dose-related. Events occurring in more than 1% are shown in the table below. Of these, only nausea and vomiting were more frequent in the PENTASA group. Withdrawal from therapy due to adverse events was more common on placebo than PENTASA (7% vs 4%). Table 1. Adverse Events Occurring in More than 1% of Either Placebo or PENTASA Patients in Domestic Placebo-controlled Ulcerative Colitis Trials. (PENTASA Comparison to Placebo) Event PENTASA n=451 Placebo n=173 Diarrhea 16 (3.5%) 13 (7.5%) Headache 10 (2.2%) 6 (3.5%) Nausea 14 (3.1%) - Abdominal Pain 5 (1.1%) 7 (4.0%) Melena (Bloody Diarrhea) 4 (0.9%) 6 (3.5%) Rash 6 (1.3%) 2 (1.2%) Anorexia 5 (1.1%) 2 (1.2%) Fever 4 (0.9%) 2 (1.2%) Rectal Urgency 1 (0.2%) 4 (2.3%) Nausea and Vomiting 5 (1.1%) - Worsening of Ulcerative Colitis 2 (0.4%) 2 (1.2%) Acne 1 (0.2%) 2 (1.2%) Clinical laboratory measurements showed no significant abnormal trends for any test, including measurement of hematological, liver, and kidney function. The following adverse events, presented by body system, were reported infrequently (ie, less than 1%) during domestic ulcerative colitis and Crohn’s disease trials. In many cases, the relationship to PENTASA has not been established. Gastrointestinal: abdominal distention, anorexia, constipation, duodenal ulcer, dysphagia, eructation, esophageal ulcer, fecal incontinence, GGTP increase, GI bleeding, increased alkaline phosphatase, LDH increase, mouth ulcer, oral moniliasis, pancreatitis, rectal bleeding, SGOT increase, SGPT increase, stool abnormalities (color or texture change), thirst Dermatological: acne, alopecia, dry skin, eczema, erythema nodosum, nail disorder, photosensitivity, pruritus, sweating, urticaria Nervous System: depression, dizziness, insomnia, somnolence, paresthesia Cardiovascular: palpitations, pericarditis, vasodilation Other: albuminuria, amenorrhea, amylase increase, arthralgia, asthenia, breast pain, conjunctivitis, ecchymosis, edema, fever, hematuria, hypomenorrhea, Kawasaki-like syndrome, leg cramps, lichen planus, lipase increase, malaise, menorrhagia, metrorrhagia, myalgia, pulmonary infiltrates, thrombocythemia, thrombocytopenia, urinary frequency One week after completion of an 8-week ulcerative colitis study, a 72-year-old male, with no previous history of pulmonary problems, developed dyspnea. The patient was subsequently diagnosed with interstitial pulmonary fibrosis without eosinophilia by one physician and bronchiolitis obliterans with organizing pneumonitis by a second physician. A causal relationship between this event and mesalamine therapy has not been established. Published case reports and/or spontaneous postmarketing surveillance have described infrequent instances of pericarditis, fatal myocarditis, chest pain and T-wave abnormalities, hypersensitivity pneumonitis, pancreatitis, nephrotic syndrome, interstitial nephritis, hepatitis, aplastic anemia, pancytopenia, leukopenia, agranulocytosis, or anemia while receiving mesalamine therapy. Anemia can be a part of the clinical presentation of inflammatory bowel disease. Allergic reactions, which could involve eosinophilia, can be seen in connection with PENTASA therapy. Postmarketing Reports The following events have been identified during post-approval use of the PENTASA brand of mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine: Gastrointestinal Reports of hepatotoxicity, including elevated liver enzymes (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), hepatitis, 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. Other Postmarketing reports of anaphylactic reaction, Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), pneumonitis, granulocytopenia, systemic lupus erythematosus, lupus-like syndrome, acute renal failure, interstitial lung disease, Hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), chronic renal failure, nephrogenic diabetes insipidus, intracranial hypertension and angioedema have been received in patients taking PENTASA. DRUG INTERACTIONS There are no data on interactions between PENTASA and other drugs.

SIDE EFFECTS The most serious adverse reactions seen in Lialda clinical trials or with other products that contain or are metabolized to mesalamine are: Renal impairment, including renal failure [See WARNINGS AND PRECAUTIONS] Mesalamine-induced acute intolerance syndrome [See WARNINGS AND PRECAUTIONS] Hypersensitivity reactions [See WARNINGS AND PRECAUTIONS] Hepatic impairment, including hepatic failure [See WARNINGS AND PRECAUTIONS] 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. LIALDA has been evaluated in 1368 ulcerative colitis patients in controlled and open-label trials. Induction Of Remission In two 8-week placebo-controlled clinical trials involving 535 ulcerative colitis patients, 356 received 2.4 g/day or 4.8 g/day LIALDA tablets and 179 received placebo. The most frequent adverse reaction leading to discontinuation from LIALDA therapy was exacerbation of ulcerative colitis (0.8%). Pancreatitis occurred in less than 1% of patients during clinical trials and resulted in discontinuation of therapy with LIALDA in patients experiencing this event. Adverse reactions occurring in LIALDA or placebo groups at a frequency of at least 1% in two 8- week, double blind, placebo-controlled trials are listed in Table 1. The most common adverse reactions with LIALDA 2.4 g/day and 4.8 g/day were headache (5.6% and 3.4%, respectively) and flatulence (4% and 2.8%, respectively). Table 1: Adverse Reactions in Two Eight-Week Placebo-Controlled Trials Experienced by at Least 1% of the LIALDA Group and at a Rate Greater than Placeboa Adverse Reaction LIALDA 2.4 g/day (n = 177) LIALDA 4.8 g/day (n = 179) Placebo (n = 179) Headache 10 (5.6%) 6 (3.4%) 1 (0.6%) Flatulence 7 (4%) 5 (2.8%) 5 (2.8%) Liver Function Test Abnormal 1 (0.6%) 4 (2.2%) 2 (1.1%) Alopecia 0 2 (1.1%) 0 Pruritus 1 (0.6%) 2 (1.1%) 2 (1.1%) a: Adverse reactions for which the placebo rate equalled or exceeded the rate for at least one of the LIALDA treatment groups were abdominal pain, dizziness, dyspepsia, and nausea. The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by LIALDA-treated ulcerative colitis patients in the two controlled trials. Cardiac Disorder: tachycardia Vascular Disorders: hypertension, hypotension Skin and Subcutaneous Tissue Disorders: acne, prurigo, rash, urticaria Gastrointestinal Disorders: abdominal distention, colitis, diarrhea, pancreatitis, rectal polyp, vomiting Investigations: decreased platelet count Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain Nervous System Disorders: somnolence, tremor Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain General Disorders and Administrative Site Disorders: asthenia, face edema, fatigue, pyrexia Ear and Labyrinth Disorders: ear pain Maintenance Of Remission Of Ulcerative Colitis The dose evaluated in three studies of LIALDA given for the maintenance of remission in patients with ulcerative colitis was 1.2 g twice daily or 2.4 g/once daily. One of these studies was a 6-month doubleblind comparator study while two were 12- to 14-month open-label studies. The most common adverse reactions with LIALDA in the maintenance arms of long-term trials were colitis ulcerative (5.8%), headache (2.9%), liver function test abnormal (2.3%), and abdominal pain (2.2%). Of the 1082 subjects in the all maintenance studies pooled, 1.9% had severe adverse reactions. The most common severe adverse reactions were gastrointestinal disorders; these were mainly symptoms associated with ulcerative colitis. Table 2: Adverse Reactions in Three Maintenance Trials Experienced by at Least 1% of the LIALDA Group (maintenance phases of trials ) All LIALDA (n=1082) Adverse Reaction n % Colitis ulcerative 63 (5.8%) Headache 31 (2.9%) Liver function test abnormal 25 (2.3%) Abdominal pain 24 (2.2%) Diarrhea 18 (1.7%) Abdominal distension 14 (1.3%) Abdominal pain upper 13 (1.2%) Dyspepsia 13 (1.2%) Back pain 13 (1.2%) Rash 13 (1.2%) Arthralgia 12 (1.1%) Fatigue 11 (1.0%) Hypertension 10 (1.0%) The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by LIALDA-treated ulcerative colitis patients in the three long-term maintenance trials (maintenance phases of these trials): Cardiac Disorder: tachycardia Skin and Subcutaneous Tissue Disorders: acne, alopecia, pruritis, urticaria Gastrointestinal Disorders: colitis, flatulence, nausea, pancreatitis, rectal polyp, vomiting Nervous System Disorders: dizziness Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain General Disorders and Administrative Site Disorders: asthenia, pyrexia Ear and Labyrinth Disorders: ear pain Postmarketing Experience In addition to the adverse reactions reported above in clinical trials involving LIALDA, the adverse reactions listed below have been identified during post-approval use of LIALDA and other mesalaminecontaining 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: lupus-like syndrome, drug fever Cardiac Disorders: pericarditis, pericardial effusion, myocarditis Gastrointestinal: pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer Hepatic: jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, Kawasaki-like syndrome including changes in liver enzymes Hematologic: agranulocytosis, aplastic anemia Immune System Disorders: anaphylactic reaction, angioedema, Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS) Musculoskeletal and Connective Tissue Disorders: myalgia Neurological/Psychiatric: peripheral neuropathy, Guillain-Barre syndrome, transverse myelitis, intracranial hypertension Renal Disorders: interstitial nephritis, nephrogenic diabetes insipidus Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis) Skin: psoriasis, pyoderma gangrenosum, erythema nodosum Urogenital: reversible oligospermia Descriptions Of Selected Adverse Reactions: Intracranial hypertension: Cases of intracranial hypertension (increased intracranial pressure) with papilledema (pseudotumor cerebri or benign intracranial hypertension) have been reported with mesalamine use. If undetected, this condition may result in constriction of the visual field and permanent vision loss. Mesalamine should be discontinued, if clinically possible, if this syndrome occurs. Nephrogenic diabetes insipidus: Cases of nephrogenic diabetes insipidus have been reported with mesalamine use. DRUG INTERACTIONS No investigations of interaction between LIALDA and other drugs except for certain antibiotics have been performed [see CLINICAL PHARMACOLOGY]. However, the following drug-drug interactions have been reported for products containing mesalamine: Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal antiinflammatory drugs (NSAIDs) may increase the risk of renal reactions. Azathioprine Or 6-Mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders.

SIDE EFFECTS The most serious adverse reactions seen in CANASA clinical trials or with other products that contain or are metabolized to mesalamine are: Renal Impairment [see WARNINGS AND PRECAUTIONS] Mesalamine-Induced Acute Intolerance Syndrome [see WARNINGS AND PRECAUTIONS] Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS] Hepatic Failure [see WARNINGS AND PRECAUTIONS] 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 most common adverse reactions in adult patients with mildly to moderately active ulcerative proctitis in double-blind, placebo-controlled trials are summarized in the Table 1 below. Table 1: Adverse Reactions Occurring In More Than 1% of Mesalamine Suppository Treated Patients (Comparison to Placebo) Symptom Mesalamine (n = 177) Placebo (n = 84) N % N % Dizziness 5 3 2 2.4 Rectal Pain 3 1.8 0 0 Fever 2 1.2 0 0 Rash 2 1.2 0 0 Acne 2 1.2 0 0 Colitis 2 1.2 0 0 In a multicenter, open-label, randomized, parallel group study in 99 patients comparing the CANASA 1000 mg suppository administered nightly to that of the mesalamine 500 mg suppository twice daily. The most common adverse reactions in both groups were headache (14%), flatulence (5%), abdominal pain (5%), diarrhea (3%), and nausea (3%). Three (3) patients discontinued medication because of an adverse reaction; one of these adverse reactions (headache) was deemed possibly related to study medication. The recommended dosage of CANASA is 1000 mg administered rectally once daily at bedtime [see DOSAGE AND ADMINISTRATION]. Postmarketing Experience In addition to the adverse reactions reported above in clinical trials involving CANASA, the adverse reactions listed below have been identified during post-approval use of CANASA and 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: drug fever, fatigue, lupus-like syndrome, medication residue Cardiac Disorders: myocarditis, pericarditis, pericardial effusion [see WARNINGS AND PRECAUTIONS] Eye disorders: eye swelling Gastrointestinal Disorders: abdominal cramps, abdominal distension, anal pruritus, anorectal discomfort, constipation, feces discolored, flatulence, frequent bowel movements, gastrointestinal bleeding, mucus stools, nausea, painful defecation, pancreatitis, proctalgia, rectal discharge, rectal tenesmus, stomach discomfort, vomiting Hepatic Disorders: cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver necrosis, liver failure Hematologic Disorders: agranulocytosis, aplastic anemia, thrombocytopenia Neurological/Psychiatric Disorders: Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis Renal Disorders: interstitial nephritis, renal failure, minimal change nephropathy [see WARNINGS AND PRECAUTIONS] Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis) Skin and Subcutaneous Tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria Urogenital: reversible oligospermia DRUG INTERACTIONS Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalaminerelated adverse reactions [see WARNINGS AND PRECAUTIONS]. Azathioprine Or 6-Mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders. If concomitant use of CANASA and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts. Urinary Normetanephrine Measurements 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-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine [see WARNINGS AND PRECAUTIONS].

WARNINGS No Information Provided PRECAUTIONS General Caution should be exercised if PENTASA is administered to patients with impaired hepatic function. 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. If acute intolerance syndrome is suspected, prompt withdrawal is required. If a rechallenge is performed later in order to validate the hypersensitivity, it should be carried out under close medical supervision at reduced dose and only if clearly needed. Renal Caution should be exercised if PENTASA is administered to patients with impaired renal function. Single reports of nephrotic syndrome and interstitial nephritis associated with mesalamine therapy have been described in the foreign literature. There have been rare reports of interstitial nephritis in patients receiving PENTASA. In animal studies, a 13-week oral toxicity study in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys have shown the kidney to be the major target organ of mesalamine toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or higher produced nephrosis, papillary edema, and interstitial fibrosis. Patients with preexisting renal disease, increased BUN or serum creatinine, or proteinuria should be carefully monitored, especially during the initial phase of treatment. Mesalamine-induced nephrotoxicity should be suspected in patients developing renal dysfunction 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, Nacetylaminosalicylic acid (N-Ac-5-ASA). An alternative, selective assay for normetanephrine should be considered. Carcinogenesis, Mutagenesis, Impairment Of Fertility In a 104-week dietary carcinogenicity study of mesalamine, CD-1 mice were treated with doses up to 2500 mg/kg/day and it was not tumorigenic. For a 50 kg person of average height (1.46 m2 body surface area), this represents 2.5 times the recommended human dose on a body surface area basis (2960 mg/m2/day). In a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800 mg/kg/day was not tumorigenic. This dose represents 1.5 times the recommended human dose on a body surface area basis. No evidence of mutagenicity was observed in an in vitro Ames test and in an in vivo mouse micronucleus test. No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 400 mg/kg/day (0.8 times the recommended human dose based on body surface area). Semen abnormalities and infertility in men, which have been reported in association with sulfasalazine, have not been seen with PENTASA capsules during controlled clinical trials. Pregnancy Category B Reproduction studies have been performed in rats at doses up to 1000 mg/kg/day (5900 mg/M²) and rabbits at doses of 800 mg/kg/day (6856 mg/M²) and have revealed no evidence of teratogenic effects or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PENTASA should be used during pregnancy only if clearly needed. Mesalamine is known to cross the placental barrier. Nursing Mothers Minute quantities of mesalamine were distributed to breast milk and amniotic fluid of pregnant women following sulfasalazine therapy. When treated with sulfasalazine at a dose equivalent to 1.25 g/day of mesalamine, 0.02 μg/mL to 0.08 μg/mL and trace amounts of mesalamine were measured in amniotic fluid and breast milk, respectively. Nacetylmesalamine, in quantities of 0.07 μg/mL to 0.77 μg/mL and 1.13 μg/mL to 3.44 μg/mL, was identified in the same fluids, respectively. Caution should be exercised when PENTASA is administered to a nursing woman. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhea in the infant cannot be excluded. Pediatric Use Safety and efficacy of PENTASA in pediatric patients have not been established.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as LIALDA that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of LIALDA therapy and periodically while on therapy. Exercise caution when using LIALDA in patients with known renal dysfunction or a history of renal disease. In animal studies, the kidney was the principal organ for toxicity. [See DRUG INTERACTIONS and Nonclinical Toxicology] 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 patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimes fever, headache, and rash. Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with LIALDA. Hypersensitivity Reactions Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to LIALDA tablets or to other compounds that contain or are converted to mesalamine. Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with LIALDA and other mesalamine medications. Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering LIALDA to patients with liver disease. Upper GI Tract Obstruction Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of LIALDA which would delay mesalamine release in the colon. 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-acetylaminosalicylic acid (NAc- 5-ASA). An alternative, selective assay for normetanephrine should be considered. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis In a 104-week dietary carcinogenicity study in CD-1 mice, mesalamine at doses up to 2500 mg/kg/day was not tumorigenic. This dose is 2.2 times the maximum recommended human dose (based on a body surface area comparison) of LIALDA. Furthermore, in a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800 mg/kg/day was not tumorigenic. This dose is 1.4 times the recommended human dose (based on a body surface area comparison) of LIALDA. Mutagenesis No evidence of mutagenicity was observed in an in vitro Ames test or an in vivo mouse micronucleus test. Impairment Of Fertility No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 400 mg/kg/day (0.7 times the maximum recommended human dose based on a body surface area comparison). Use In Specific Populations Pregnancy Pregnancy Category B Reproduction studies with mesalamine have been performed in rats at doses up to 1000 mg/kg/day (1.8 times the maximum recommended human dose based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (2.9 times the maximum recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Mesalamine is known to cross the placental barrier. Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised if LIALDA is administered to a nursing woman. Pediatric Use Safety and effectiveness of LIALDA in pediatric patients have not been established. Geriatric Use Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products such as LIALDA. Caution should be taken to closely monitor blood cell counts during mesalamine therapy. Clinical trials of LIALDA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic exposures are increased in elderly subjects. [see CLINICAL PHARMACOLOGY]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as CANASA that contain mesalamine or are converted to mesalamine [see ADVERSE REACTIONS]. Evaluate renal function prior to initiation of CANASA therapy and periodically while on therapy. Evaluate the risks and benefits of using CANASA in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. In animal studies, the kidney was the principal organ for toxicity [see DRUG INTERACTIONS, Use In Specific Populations and Nonclinical Toxicology]. 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 patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, and 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 CANASA. Hypersensitivity Reactions Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to CANASA 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 CANASA if an alternative etiology for the signs and symptoms cannot be established. 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 CANASA in patients with known liver impairment. Interaction With Laboratory Test For Urinary Normetanephrine 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-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine. Patient Counseling Information Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION) Administration Advise patients: Do not cut or break the suppository. Retain the suppository for one to three hours or longer, if possible. If a dose of CANASA is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two CANASA suppositories at the same time to make up for a missed dose. CANASA suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep CANASA away from these surfaces to prevent staining. Renal Impairment Inform patients that CANASA may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, including NSAIDs, and periodic monitoring of renal function will be performed while they are on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]. Mesalamine-Induced Acute Intolerance Syndrome And Other Hypersensitivity Reactions Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking CANASA and report to their healthcare provider if they experience new or worsening symptoms Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see WARNINGS AND PRECAUTIONS]. Hepatic Failure Inform patients with known liver disease of the signs and symptoms of worsening liver function and advise them to report to their healthcare provider if they experience such signs or symptoms [see WARNINGS AND PRECAUTIONS]. Blood Disorders Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood disorders and the need for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see DRUG INTERACTIONS, Use In Specific Populations]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a two-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet (about 1.7 times the recommended human intra-rectal dose of CANASA, based on body surface area). Mesalamine was not mutagenic in the Ames test, the mouse lymphoma cell (TK+/-) forward mutation test, or the mouse micronucleus test. No effects on fertility or reproductive performance of the male and female rats were observed at oral mesalamine doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of CANASA, based on body surface area). Use In Specific Populations Pregnancy Risk Summary Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No evidence of teratogenicity was observed in rats or rabbits when treated during gestation with orally administered mesalamine at doses greater than the recommended human intra-rectal dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. 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. Data Animal Data Reproduction studies have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of CANASA, based on body surface area) and in rabbits at oral doses up to 495 mg/kg/day (about 5.4 times the recommended human intra-rectal dose of CANASA, based on body surface area) following administration during the period of organogenesis, and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. Lactation Risk Summary Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts [see Data]. There are limited reports of diarrhea in breastfed infants. There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of CANASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CANASA and any potential adverse effects on the breastfed child from CANASA or from the underlying maternal conditions. Clinical Considerations Monitor breastfed infants for diarrhea. Data In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid. Pediatric Use The safety and effectiveness of CANASA in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. CANASA was evaluated for the treatment of ulcerative proctitis in a 6-week, open-label, single-arm study in 49 patients 5 to 17 years of age, which only included 14 patients with histologically-confirmed cases of ulcerative proctitis. However, efficacy was not demonstrated. Adverse reactions seen in pediatric patients in this trial (abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea and vomiting) were similar to those seen in adult patients. Geriatric Use Clinical trials of CANASA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Systemic exposures are increased in elderly subjects [See CLINICAL PHARMACOLOGY]. 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 CANASA who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with CANASA. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients should be considered when prescribing CANASA [see Renal Impairment]. Renal Impairment 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 CANASA therapy. Monitor patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and ADVERSE REACTIONS].