ZALDYON is indicated for the treatment of moderately active ulcerative colitis in adults.

Limitations of Use:

Safety and effectiveness of ZALDYON beyond 6 weeks have not been established.

2.1 Important Administration Instructions

• Do not substitute one ZALDYON 800 mg  tablet for two mesalamine delayed-release 400 mg oral products [see Clinical Pharmacology (12.3)].
• Evaluate renal function prior to initiation of ZALDYON.
• Take ZALDYON tablets on an empty stomach, at least 1 hour before and 2 hours after a meal [see Clinical Pharmacology (12.3)] .
• Swallow ZALDYON tablets whole. Do not cut, break or chew the tablets.
• Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their physician if this occurs repeatedly.
• Protect ZALDYON tablets from moisture.

2.2 Dosage Information

For the treatment of moderately active ulcerative colitis, the recommended dosage of

ZALDYON in adults is 1600 mg (two 800 mg tablets) three times daily (total daily dosage of 4.8 grams) for a duration of 6 weeks.

ZALDYON (mesalamine) delayed-release tablets are available as reddish-brown colored, capsule-shaped, biconvex, enteric coated tablets, imprinted with "435" on one side and plain on other side.

ZALDYON is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of ZALDYON [see Warnings and Precautions (5.3), Adverse Reactions (6.2), and Description (11)].

5.1 Renal Impairment

Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients taking products such as ZALDYON that contain or are converted to mesalamine [see Adverse Reactions (6.2)].

Evaluate renal function prior to initiation of ZALDYON and periodically while on therapy. Evaluate the risks and benefits of using ZALDYON 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) and Nonclinical Toxicology (13.2)].

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. Exacerbation of the symptoms of colitis has been reported in 2.3% of ZALDYON-treated patients in controlled clinical trials. This acute reaction, characterized by cramping, abdominal pain, bloody diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has been reported after the initiation of ZALDYON as well as other mesalamine products. Symptoms usually abate when ZALDYON are discontinued.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to ZALDYON 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 ZALDYON 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. Caution should be exercised when administering ZALDYON tablets to patients with liver impairment.

The most serious adverse reactions seen in ZALDYON clinical trials or with other products that contain mesalamine or are metabolized to mesalamine were:

• Renal Impairment [see Warnings and Precautions (5.1)]
• Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Hepatic Failure [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ZALDYON has been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six-week, active-controlled studies were conducted comparing ZALDYON 4.8 grams per day with mesalamine-delayed release tablets 2.4 grams per day in patients with mildly to moderately active ulcerative colitis. In these studies, 727 patients were dosed with ZALDYON tablets and 732 patients were dosed with mesalamine delayed-release tablets, 400 mg.

The most common reactions reported in the ZALDYON group were headache (4.7%), nausea (2.8%), nasopharyngitis (2.5%), abdominal pain (2.3%), diarrhea (1.7%), and dyspepsia (1.7%); Table 1 enumerates adverse reactions that occurred in the three studies. The most common reactions in patients with moderately active ulcerative colitis (602 patients dosed with ZALDYON and 618 patients dosed with the mesalamine delayed-release tablet, 400 mg) were the same as all treated patients.

Discontinuations due to adverse reactions occurred in 3.9% of patients in the ZALDYON group and in 4.2% of patients in the mesalamine delayed-release tablet, 400 mg comparator group. The most common cause for discontinuation was gastrointestinal symptoms associated with ulcerative colitis.

Serious adverse reactions occurred in 0.8% of patients in the ZALDYON group and in 1.8% of patients in the mesalamine delayed-release tablet, 400 mg comparator group. The majority involved the gastrointestinal system.

6.2 Postmarketing Experience

In addition to the adverse reactions reported above in clinical trials involving the

ZALDYON tablet, the adverse events listed below have been reported in postmarketing experience with other mesalamine-containing products or products that are metabolized to mesalamine. 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

Facial edema, edema, peripheral edema, asthenia, chills, infection, malaise, pain, neck pain, chest pain, back pain, abdominal enlargement, lupus-like syndrome, drug fever (rare).

Cardiovascular

Pericarditis (rare) and myocarditis (rare) [see Warnings and Precautions (5.3)], pericardial effusion, vasodilation, migraine.

Endocrine: Nephrogenic diabetes insipidus.

Gastrointestinal

Dry mouth, stomatitis, oral ulcers, anorexia, increased appetite, eructation, pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer (rare), constipation, hemorrhoids, rectal hemorrhage, bloody diarrhea, tenesmus, stool abnormality.

Hepatic

There have been rare reports of hepatotoxicity, including jaundice, cholestatic jaundice, hepatitis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. Asymptomatic elevations of liver enzymes which usually resolve during continued use or with discontinuation of the drug have also been reported. One case of Kawasaki-like syndrome, that included changes in liver enzymes, was also reported [see Warnings and Precautions (5.4)].

Hematologic

Agranulocytosis (rare), aplastic anemia (rare), anemia, thrombocytopenia, leukopenia, eosinophilia, lymphadenopathy.

Musculoskeletal

Gout, rheumatoid arthritis, arthritis, arthralgia, joint disorder, myalgia, hypertonia.

Neurological/Psychiatric

Anxiety, depression, somnolence, insomnia, nervousness, confusion, emotional lability, dizziness, vertigo, tremor, paresthesia, hyperesthesia, peripheral neuropathy (rare), Guillain-Barre syndrome (rare), and transverse myelitis (rare), intracranial hypertension.

Respiratory/Pulmonary

Sinusitis, rhinitis, pharyngitis, asthma exacerbation, pleuritis, bronchitis, eosinophilic pneumonia, interstitial pneumonitis.

Skin

Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), erythema nodosum, acne, dry skin, sweating, pruritus, urticaria, rash.

Special Senses

Ear pain, tinnitus, ear congestion, ear disorder, conjunctivitis, eye pain, blurred vision, vision abnormality, taste perversion.

Renal/Urogenital

Renal failure (rare), interstitial nephritis, minimal change nephropathy [see Warnings and Precautions (5.1)], dysuria, urinary frequency and urgency, hematuria, epididymitis, decreased libido, dysmenorrhea, menorrhagia.

Laboratory Abnormalities

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

7.1 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 renal nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1)].

7.2 Azathioprine or 6-Mercaptopurine

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders. If concomitant use of ZALDYON and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

8.1 Pregnancy:

Risk Summary

Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 0.97 times (rat) and 1.95 times (rabbit) the recommended human dose [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. 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 with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day. There was no evidence of harm to the fetus. These mesalamine doses were about 0.97 times (rat) and 1.95 times (rabbit) the recommended human dose of 4.8 grams per day, based on body surface area.

8.2 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 developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZALDYON and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Clinical Considerations

Monitor breastfed infants for diarrhea.

Data

Human 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 Nacetyl-5-aminosalicylic 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.

8.4 Pediatric Use

Safety and effectiveness of ZALDYON in pediatric patients have not been established. See the prescribing information for other approved mesalamine products for the safety and effectiveness of these products in pediatric patients.

8.5 Geriatric Use

Clinical studies of ZALDYON did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and postmarketing experience for another oral formulation of mesalamine suggest a higher incidence of blood dyscrasias (agranulocytosis, neutropenia, pancytopenia) in patients who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during therapy with ZALDYON.

In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing ZALDYON [see Use in Specific Populations (8.6)].

8.6 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 ZALDYON 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 (5.1), Drug Interactions (7.1) and Adverse Reactions (6.2)].

12.1 Mechanism of Action

The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic acids, 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.

12.3 Pharmacokinetics

Absorption

Plasma concentrations of mesalamine (5-aminosalicylic acid; 5-ASA) and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) are highly variable following administration of ZALDYON tablets. Following single dose oral administration of ZALDYON 800 mg tablet in healthy subjects (N = 139) under fasted conditions, the mean Cmax, AUC8-48h and AUC0-tldc values were 208 ng/mL, 2296 ng.h/mL, and 2533 ng.h/mL, respectively. The median [range] Tmax for mesalamine following administration of ZALDYON 800 mg tablet was approximately 24 hours [4 to 72 hours], reflecting the delayed-release characteristics of the formulation.

Based on cumulative urinary recovery of mesalamine and N-Ac-5-ASA from single dose studies in healthy subjects, approximately 20% of the orally administered mesalamine in ZALDYON is systemically absorbed.

Food Effect: A high calorie (800 to 1000 calories), high fat (approximately 50 % of total caloric content) meal increased mesalamine Cmax by 2.4-fold and mesalamine systemic exposure (AUC8-48 and AUC0-tldc) by 2.8-fold; the median lag-time increased by 8 hours and median tmax by 6 hours (from 24 to 30 hours) [see Dosage and Administration (2.1)].

Comparative exposure between one ZALDYON 800 mg tablet and two mesalamine delayed-release 400 mg oral products is unknown [see Dosage and Administration (2.1)].

Elimination

Metabolism

The absorbed mesalamine is acetylated in the gut mucosal wall and by the liver to N-Ac- 5-ASA.

Excretion

Absorbed mesalamine is excreted mainly by the kidneys as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2000 mg/kg/day. These doses are approximately 0.97 and 2.0 times the 4.8 grams per day ZALDYON dose (based on body surface area). Mesalamine was not genotoxic in the Ames test, the Chinese hamster ovary cell chromosomal aberration assay, and the mouse micronucleus test. Mesalamine, at oral doses up to 480 mg/kg/day (about 0.97 times the recommended human treatment dose based on body surface area), was found to have no effect on fertility or reproductive performance of male and female rats.

13.2 ANIMAL PHARMACOLOGY AND OR TOXICOLOGY

In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 4.8 grams per day dose for a 60 kg person).

Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (1.5 to 2.0 times the recommended human dose). Doses of 170 and 360 mg/kg/day (about 0.3 and 0.73 times the recommended human dose) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia.

In mice, oral doses of 4000 mg/kg/day (approximately 4.1 times the recommended human dose) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.

In dogs, single doses of 6000 mg (approximately 6.25 times the recommended human dose) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (0.5 times the recommended human dose).

14.1 Moderately Active Ulcerative Colitis

The efficacy of ZALDYON at 4.8 grams per day was studied in a six-week, randomized, double-blind, active-controlled study in 772 patients with moderately active ulcerative colitis (UC). Moderately active UC was defined as a Physician's Global Assessment (PGA) score of 2; the PGA is a four-point scale (0 to 3) that encompasses the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy findings.

Patients were randomized 1:1 to the ZALDYON 4.8 grams per day group (two ZALDYON three times a day) or the mesalamine delayed-release 2.4 grams per day group (two mesalamine delayed-release 400 mg tablets three times a day).

Patients characteristically had a history of previous use of oral 5-ASAs (86%), steroids (41%), and rectal therapies (49%), and demonstrated clinical symptoms of three or more stools over normal per day (87%) and obvious blood in the stool most or all of the time (70%). The study population was primarily Caucasian (97%), had a mean age of 43 years (8% aged 65 years or older), and included slightly more males (56%) than females (44%).

The primary endpoint was treatment success defined as improvement from baseline to Week 6 based on the PGA. Treatment success rates were similar in the two groups: 70% in the ZALDYON group and 66% in the mesalamine delayed-release 400 mg group (difference: 5%; 95% CI: [-1.9%, 11.2%]).

A second controlled study supported the efficacy of ZALDYON at 4.8 grams per day. Treatment success was 72% in patients with moderately active UC treated with mesalamine.