ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious or clinically significant adverse described elsewhere in labeling are:Renal Impairment see Warnings and Precautions (5.1) Mesalamine-Induced Acute Intolerance Syndrome see Warnings and Precautions (5.2) Hypersensitivity Reactions see Warnings and Precautions (5.3) Hepatic Failure see Warnings and Precautions (5.4) Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) Photosensitivity [see Warnings and Precautions (5.6) Nephrolithiasis [see Warnings and Precautions (5.7) . Renal Impairment see Warnings and Precautions (5.1) . Mesalamine-Induced Acute Intolerance Syndrome see Warnings and Precautions (5.2) . Hypersensitivity Reactions see Warnings and Precautions (5.3) . Hepatic Failure see Warnings and Precautions (5.4) . Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) . Photosensitivity [see Warnings and Precautions (5.6) . Nephrolithiasis [see Warnings and Precautions (5.7) . The most common adverse reactions (>=2%) are headache, nausea, nasopharyngitis, abdominal pain, and worsening of ulcerative colitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Asacol HD has been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six- week, active-controlled studies were conducted comparing Asacol HD 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 Asacol HD tablets and 732 patients were dosed with mesalamine delayed-release tablets. The most common reactions reported in the Asacol HD group were headache (4.7%), nausea (2.8%), nasopharyngitis (2.5%), abdominal pain (2.3%), diarrhea (1.7%), and dyspepsia (1.7%); Table enumerates adverse reactions that occurred in the three studies. The most common reactions in patients with moderately active ulcerative colitis (602 patients dosed with Asacol HD and 618 patients dosed with mesalamine delayed-release 400 mg) were the same as all treated patients.Discontinuations due to adverse reactions occurred in 3.9% of patients in the Asacol HD group and in 4.2% of patients in the mesalamine delayed-release tablet 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 Asacol HD group and in 1.8% of patients in the mesalamine delayed-release tablet comparator group. The majority involved the gastrointestinal system.Table 1. Adverse Reactions Occurring in >=1% of All Treated Patients (Three studies combined)Mesalamine delayed-release 2.4 grams per dayAsacol HD4.8 grams per day(400 mg Tablet)(800 mg Tablet)Adverse Reaction(N 732)(N 727) Headache4.9 %4.7 Nausea2.9 %2.8 Nasopharyngitis1.4 %2.5 Abdominal pain2.3 %2.3 Diarrhea1.9 %1.7 Dyspepsia0.8 %1.7 Vomiting1.6 %1.4 Flatulence0.7 %1.2 Influenza1.2 %1.0 Pyrexia1.2 %0.7 Cough1.4 %0.3 %N number of patients within specified treatment groupPercent percentage of patients in category and treatment group. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Asacol HD or other mesalamine-containing products or products that are metabolized to mesalamine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as 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), transverse myelitis (rare), and intracranial hypertension.Respiratory/Pulmonary: Sinusitis, rhinitis, pharyngitis, asthma exacerbation, pleuritis/pleurisy, bronchitis, eosinophilic pneumonia, interstitial pneumonitis.Skin: Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), erythema nodosum, acne, dry skin, sweating, pruritus, urticaria, rash, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5) ].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 disease, nephrolithiasis see Warnings and Precautions (5.1 5.7 ], 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. 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 4.8 grams per day dose for 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 Asacol HD 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of mesalamine is not fully understood, but appears to be topical anti-inflammatory effect on colonic epithelial cells. 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 ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.. 12.3 Pharmacokinetics. AbsorptionPlasma 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 Asacol HD tablets. Following single dose oral administration of Asacol HD 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 Asacol HD 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 Asacol HD tablets is systemically absorbed. Food Effect: 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 hours and median tmax by hours (from 24 to 30 hours) s ee Dosage and Administration (2.1) ].Comparative exposure between one Asacol HD 800 mg tablet and two mesalamine delayed-release 400 mg oral products is unknown [see Dosage and Administration (2.1) ]. EliminationMetabolismThe absorbed mesalamine is acetylated in the gut mucosal wall and by the liver to N-Ac-5-ASA.ExcretionAbsorbed mesalamine is excreted mainly by the kidneys as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of Asacol HD at 4.8 grams per day was studied in six-week, randomized, double-blind, active-controlled study in 772 patients with moderately active ulcerative colitis (UC). Moderately active UC was defined as Physicians Global Assessment (PGA) score of 2; the PGA is 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 Asacol HD 4.8 grams per day group (two Asacol HD tablets three times day) or the mesalamine delayed-release 2.4 grams per day group (two mesalamine delayed-release 400 mg tablets three times day). Patients characteristically had 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 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 based on the PGA. Treatment success rates were similar in the two groups: 70% in the Asacol HD group and 66% in the Asacol group (difference: 5%; 95% CI: [-1.9%, 11.2%]).A second controlled study supported the efficacy of Asacol HD at 4.8 grams per day. Treatment success was 72% in patients with moderately active UC treated with Asacol HD.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Asacol HD has been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six- week, active-controlled studies were conducted comparing Asacol HD 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 Asacol HD tablets and 732 patients were dosed with mesalamine delayed-release tablets. The most common reactions reported in the Asacol HD group were headache (4.7%), nausea (2.8%), nasopharyngitis (2.5%), abdominal pain (2.3%), diarrhea (1.7%), and dyspepsia (1.7%); Table enumerates adverse reactions that occurred in the three studies. The most common reactions in patients with moderately active ulcerative colitis (602 patients dosed with Asacol HD and 618 patients dosed with mesalamine delayed-release 400 mg) were the same as all treated patients.Discontinuations due to adverse reactions occurred in 3.9% of patients in the Asacol HD group and in 4.2% of patients in the mesalamine delayed-release tablet 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 Asacol HD group and in 1.8% of patients in the mesalamine delayed-release tablet comparator group. The majority involved the gastrointestinal system.Table 1. Adverse Reactions Occurring in >=1% of All Treated Patients (Three studies combined)Mesalamine delayed-release 2.4 grams per dayAsacol HD4.8 grams per day(400 mg Tablet)(800 mg Tablet)Adverse Reaction(N 732)(N 727) Headache4.9 %4.7 Nausea2.9 %2.8 Nasopharyngitis1.4 %2.5 Abdominal pain2.3 %2.3 Diarrhea1.9 %1.7 Dyspepsia0.8 %1.7 Vomiting1.6 %1.4 Flatulence0.7 %1.2 Influenza1.2 %1.0 Pyrexia1.2 %0.7 Cough1.4 %0.3 %N number of patients within specified treatment groupPercent percentage of patients in category and treatment group.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Asacol HD is contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of Asacol HD see Warnings and Precautions (5.3) Adverse Reactions (6.2) and Description (11) ].. Known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of Asacol HD tablets (4, 5.3).

DESCRIPTION SECTION.

11 DESCRIPTION. Each Asacol HD delayed-release tablet for oral administration contains 800 mg of mesalamine, an aminosalicylate. Asacol HD delayed-release tablets have an outer protective coat consisting of combination of acrylic based resins, Eudragit (methacrylic acid and methyl methacrylate copolymer (1:2), NF) and Eudragit (methacrylic acid and methyl methacrylate copolymer (1:1), NF). The inner coat consists of an acrylic based resin, Eudragit S, which dissolves at pH or greater, releasing mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colon. Mesalamine (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid; its structural formula is:Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl sebacate, edible black ink, ferric oxide red (6.15 mg), ferric oxide yellow (1.10 mg), lactose monohydrate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer (1:2) (Eudragit S), methacrylic acid and methyl methacrylate copolymer (1:1) (Eudragit L), polyethylene glycol, povidone, sodium starch glycolate, and talc.. The structural formula of Mesalamine (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Important Administration Instructions:Do not substitute one Asacol HD 800 tablet for two mesalamine delayed-release 400 mg oral products. (2.1) Evaluate renal function prior to initiation of Asacol HD. (2.1, 5.1) Take on an empty stomach, at least hour before and hours after meal. (2.1) Swallow whole; do not cut, break or chew the tablets. (2.1) Drink an adequate amount of fluids. (2.1, 5.7)Treatment of Moderately Active Ulcerative Colitis:Recommended dosage is 1600 mg (two 800 mg tablets) three times daily for weeks. (2.2). Do not substitute one Asacol HD 800 tablet for two mesalamine delayed-release 400 mg oral products. (2.1) Evaluate renal function prior to initiation of Asacol HD. (2.1, 5.1) Take on an empty stomach, at least hour before and hours after meal. (2.1) Swallow whole; do not cut, break or chew the tablets. (2.1) Drink an adequate amount of fluids. (2.1, 5.7). Recommended dosage is 1600 mg (two 800 mg tablets) three times daily for weeks. (2.2). 2.1 Important Administration Instructions. Do not substitute one Asacol HD 800 tablet for two mesalamine delayed-release 400 mg oral products [see Clinical Pharmacology (12.3) ]. Evaluate renal function prior to initiation of Asacol HD. Take Asacol HD tablets on an empty stomach, at least hour before and hours after meal [see Clinical Pharmacology (12.3) ]. Swallow Asacol HD tablets whole. Do not cut, break or chew the tablets. Drink an adequate amount of fluids [see Warnings and Precautions (5.7) ]. Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly. Protect Asacol HD tablets from moisture. Do not substitute one Asacol HD 800 tablet for two mesalamine delayed-release 400 mg oral products [see Clinical Pharmacology (12.3) ]. Evaluate renal function prior to initiation of Asacol HD. Take Asacol HD tablets on an empty stomach, at least hour before and hours after meal [see Clinical Pharmacology (12.3) ]. Swallow Asacol HD tablets whole. Do not cut, break or chew the tablets. Drink an adequate amount of fluids [see Warnings and Precautions (5.7) ]. Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly. Protect Asacol HD tablets from moisture. 2.2 Dosage Information. For the treatment of moderately active ulcerative colitis, the recommended dosage of Asacol HD in adults is 1600 mg (two 800 mg tablets) three times daily (total daily dosage of 4.8 grams) for duration of weeks.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Asacol HD delayed-release tablets: 800 mg (red-brown, capsule-shaped and imprinted with WC 800 in black).. Delayed-release tablets: 800 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Nephrotoxic Agents including NSAIDs: Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. (7.1) Azathioprine or 6-Mercaptopurine: Increased risk of blood disorders; monitor complete blood cell counts and platelet counts. (7.2). Nephrotoxic Agents including NSAIDs: Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. (7.1) Azathioprine or 6-Mercaptopurine: Increased risk of blood disorders; monitor complete blood cell counts and platelet counts. (7.2). 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 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 and/or other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of Asacol HD and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.. 7.3 Interference With Urinary Normetanephrine Measurements Use of Asacol HD may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions (5.9) ]. Consider an alternative, selective assay for normetanephrine.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of Asacol HD did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, and pancytopenia) in patients who were 65 years or older compared to younger patients taking mesalamine-containing products such as Asacol HD. Monitor complete blood cell counts and platelet counts in elderly patients during therapy with Asacol HD.In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients when prescribing Asacol HD [see Use in Specific Populations (8.6) ].

HEPATIC IMPAIRMENT SUBSECTION.

5.4 Hepatic Failure. There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Evaluate the risks and benefits of using Asacol HD in patients with known liver impairment.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Asacol(R) HD (mesalamine) delayed-release tablets are available as red-brown, capsule-shaped tablets containing 800 mg mesalamine and imprinted with WC 800 in black.NDC 0023-5901-18 Bottle of 180 tabletsProtect from moisture. Tablets can be dispensed without desiccant for up to weeks.Store at controlled room temperature, 20 to 25 (68 to 77 F); excursions are permitted 15 to 30 (59 to 86 F). [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Asacol HD is indicated for the treatment of moderately active ulcerative colitis in adults. Limitations of Use:Safety and effectiveness of Asacol HD beyond weeks have not been established.. Asacol HD is an aminosalicylate indicated for the treatment of moderately active ulcerative colitis in adults. (1) Limitation of Use: Safety and effectiveness of Asacol HD beyond weeks have not been established (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Administration [see Dosage and Administration (2.1) Inform patients that if they are switching from previous oral mesalamine therapy to Asacol HD to discontinue their previous oral mesalamine therapy and follow the dosing instructions for Asacol HD. One Asacol HD 800 mg tablet is not substitutable for two mesalamine delayed-release 400 mg oral products. Inform patients to take Asacol HD tablets on an empty stomach, at least hour before and hours after meal. Instruct patients to swallow the Asacol HD tablets whole, taking care not to break, cut, or chew the tablets, because the coating is an important part of the delayed-release formulation. Drink an adequate amount of fluids. Inform patients that intact, partially intact, and/or tablet shells have been reported in the stool. Instruct patients to contact their healthcare provider if this occurs repeatedly. Instruct patients to protect Asacol HD tablets from moisture. Renal Impairment Inform patients that Asacol HD 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 (5.1) Drug Interactions (7.1) ]. Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity ReactionsInform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking Asacol HD and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2 5.3 ].Hepatic FailureInform 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 (5.4) ].Severe Cutaneous Adverse ReactionsInform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking Asacol HD and report to their healthcare provider at first appearance of severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.5) ].PhotosensitivityAdvise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.6) ].NephrolithiasisInstruct patients to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.7) ].Iron Content of Asacol HDAdvise patients to inform their healthcare provider if they take iron-containing supplements [see Warnings and Precautions (5.8) . Blood DisordersInform 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 (7.2) Use in Specific Populations (8.5) ]. Distributed by:Allergan USA, Inc.Madison, NJ 07940(C) 2021 Allergan. All rights reserved.Allergan(R) and its design are trademarks of Allergan, Inc.Patented. See www.allergan.com/patentsAsacol(R) is registered trademark of Medeva Pharma Suisse AG, licensed to Allergan Pharmaceuticals International Limited.v4.0USPI5901. Inform patients that if they are switching from previous oral mesalamine therapy to Asacol HD to discontinue their previous oral mesalamine therapy and follow the dosing instructions for Asacol HD. One Asacol HD 800 mg tablet is not substitutable for two mesalamine delayed-release 400 mg oral products. Inform patients to take Asacol HD tablets on an empty stomach, at least hour before and hours after meal. Instruct patients to swallow the Asacol HD tablets whole, taking care not to break, cut, or chew the tablets, because the coating is an important part of the delayed-release formulation. Drink an adequate amount of fluids. Inform patients that intact, partially intact, and/or tablet shells have been reported in the stool. Instruct patients to contact their healthcare provider if this occurs repeatedly. Instruct patients to protect Asacol HD tablets from moisture. Inform patients that Asacol HD 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 (5.1) Drug Interactions (7.1) ]. Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking Asacol HD and report to their healthcare provider if they experience new or worsening symptoms of Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2 5.3 ].. 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 (5.4) ].. Inform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking Asacol HD and report to their healthcare provider at first appearance of severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.5) ].. Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.6) ].. Instruct patients to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.7) ].. Advise patients to inform their healthcare provider if they take iron-containing supplements [see Warnings and Precautions (5.8) . 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 (7.2) Use in Specific Populations (8.5) ].

LACTATION SECTION.

8.2 Lactation Risk SummaryMesalamine 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 mothers clinical need for Asacol HD and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. Clinical ConsiderationsMonitor breastfed infants for diarrhea.DataHuman DataIn published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism of action of mesalamine is not fully understood, but appears to be topical anti-inflammatory effect on colonic epithelial cells. 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 ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Instructions. Do not substitute one Asacol HD 800 tablet for two mesalamine delayed-release 400 mg oral products [see Clinical Pharmacology (12.3) ]. Evaluate renal function prior to initiation of Asacol HD. Take Asacol HD tablets on an empty stomach, at least hour before and hours after meal [see Clinical Pharmacology (12.3) ]. Swallow Asacol HD tablets whole. Do not cut, break or chew the tablets. Drink an adequate amount of fluids [see Warnings and Precautions (5.7) ]. Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly. Protect Asacol HD tablets from moisture. Do not substitute one Asacol HD 800 tablet for two mesalamine delayed-release 400 mg oral products [see Clinical Pharmacology (12.3) ]. Evaluate renal function prior to initiation of Asacol HD. Take Asacol HD tablets on an empty stomach, at least hour before and hours after meal [see Clinical Pharmacology (12.3) ]. Swallow Asacol HD tablets whole. Do not cut, break or chew the tablets. Drink an adequate amount of fluids [see Warnings and Precautions (5.7) ]. Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to contact their healthcare provider if this occurs repeatedly. Protect Asacol HD tablets from moisture.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Geriatric Patients: Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. (8.5). 8.1 Pregnancy. Risk SummaryLimited published data on mesalamine use in pregnant women are insufficient to inform 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 to 4% and 15 to 20%, respectively.DataAnimal DataReproduction 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 SummaryMesalamine 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 mothers clinical need for Asacol HD and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. Clinical ConsiderationsMonitor breastfed infants for diarrhea.DataHuman DataIn published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 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 Asacol HD 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 Asacol HD did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, and pancytopenia) in patients who were 65 years or older compared to younger patients taking mesalamine-containing products such as Asacol HD. Monitor complete blood cell counts and platelet counts in elderly patients during therapy with Asacol HD.In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients when prescribing Asacol HD [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 Asacol HD 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) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Renal Impairment: Assess renal function at the beginning to treatment and periodically during treatment. Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. (5.1, 7.1, 8.6) Mesalamine-induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an ulcerative colitis exacerbation; monitor for worsening symptoms; discontinue if acute intolerance syndrome suspected. (5.2)Hypersensitivity Reactions, including Myocarditis and Pericarditis: Evaluate patients immediately and discontinue if hypersensitivity reaction is suspected. (5.3) Hepatic Failure: Evaluate the risks and benefits in patients with known liver impairment. (5.4) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. (5.5)Photosensitivity: Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors. (5.6)Nephrolithiasis: Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. (5.7) Iron Content of Asacol HD: Consider the iron content of Asacol HD in patients taking iron supplementation and those at risk of iron overload. (5.8)Interference with Laboratory Tests: Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. (5.9). Renal Impairment: Assess renal function at the beginning to treatment and periodically during treatment. Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. (5.1, 7.1, 8.6) Mesalamine-induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an ulcerative colitis exacerbation; monitor for worsening symptoms; discontinue if acute intolerance syndrome suspected. (5.2). Hypersensitivity Reactions, including Myocarditis and Pericarditis: Evaluate patients immediately and discontinue if hypersensitivity reaction is suspected. (5.3) Hepatic Failure: Evaluate the risks and benefits in patients with known liver impairment. (5.4) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. (5.5). Photosensitivity: Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors. (5.6). Nephrolithiasis: Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. (5.7) Iron Content of Asacol HD: Consider the iron content of Asacol HD in patients taking iron supplementation and those at risk of iron overload. (5.8). Interference with Laboratory Tests: Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. (5.9). 5.1 Renal Impairment. Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients taking products such as Asacol HD that contain or are converted to mesalamine [see Adverse Reactions (6.2) ]. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions (6.2) Nonclinical Toxicology (13.2) ]. Evaluate renal function prior to initiation of Asacol HD and periodically while on therapy. Evaluate the risks and benefits of using Asacol HD in patients with known renal impairment or history of renal disease or taking concomitant nephrotoxic drugs see Drug Interactions (7.1) Use in Specific Populations (8.6) ].. 5.2 Mesalamine-Induced Acute Intolerance Syndrome. Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Exacerbation of the symptoms of colitis has been reported in 2.3% of Asacol HD-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 Asacol HD tablets as well as other mesalamine products. Symptoms usually abate when Asacol HD tablets are discontinued. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with Asacol HD.. 5.3 Hypersensitivity Reactions. Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have similar reaction to Asacol HD tablets 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 hypersensitivity reaction are present. Discontinue Asacol HD if an alternative etiology for the signs or symptoms cannot be established. 5.4 Hepatic Failure. There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Evaluate the risks and benefits of using Asacol HD in patients with known liver impairment.. 5.5 Severe Cutaneous Adverse Reactions. Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with use of mesalamine [see Adverse Reactions (6.2) ]. Discontinue Asacol HD at the first appearance of signs or symptoms of severe cutaneous adverse reactions, or other signs of hypersensitivity and consider further evaluation.. 5.6 Photosensitivity. Patients treated with mesalamine or sulfasalazine who have pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors.. 5.7 Nephrolithiasis Cases of nephrolithiasis have been reported with the use of mesalamine, including stones of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with Asacol HD. 5.8 Iron Content of Asacol HD Asacol HD contains iron oxide as colorant in the coating of the delayed-release tablets. Each 800 mg delayed-release tablet contains 4.9 mg of iron. The total content of iron is 29.2 mg at the recommended daily dosage [see Dosage and Administration (2.2) ]. Before prescribing Asacol HD to patients receiving iron supplementation or those at risk for developing iron overload, consider the combined daily amount of iron from all sources, including Asacol HD.. 5.9 Interference with Laboratory Tests Use of Asacol HD may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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 Asacol HD 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 Toxicology and/or Pharmacology. 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 4.8 grams per day dose for 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).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Asacol HD is an aminosalicylate, and symptoms of salicylate toxicity include nausea, vomiting and abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) involvement. There is no specific antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent of further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function. Asacol HD is pH dependent delayed-release product and this factor should be considered when treating suspected overdose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display PanelNDC 0023-5901-18Asacol(R) HD(mesalamine)delayed-release tablets800 mg per tablet180 TabletsRx Only. NDC 0023-5901-18Asacol(R) HD(mesalamine)delayed-release tablets800 mg per tablet180 TabletsRx Only.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of Asacol HD 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionPlasma 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 Asacol HD tablets. Following single dose oral administration of Asacol HD 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 Asacol HD 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 Asacol HD tablets is systemically absorbed. Food Effect: 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 hours and median tmax by hours (from 24 to 30 hours) s ee Dosage and Administration (2.1) ].Comparative exposure between one Asacol HD 800 mg tablet and two mesalamine delayed-release 400 mg oral products is unknown [see Dosage and Administration (2.1) ]. EliminationMetabolismThe absorbed mesalamine is acetylated in the gut mucosal wall and by the liver to N-Ac-5-ASA.ExcretionAbsorbed mesalamine is excreted mainly by the kidneys as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Asacol HD or other mesalamine-containing products or products that are metabolized to mesalamine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as 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), transverse myelitis (rare), and intracranial hypertension.Respiratory/Pulmonary: Sinusitis, rhinitis, pharyngitis, asthma exacerbation, pleuritis/pleurisy, bronchitis, eosinophilic pneumonia, interstitial pneumonitis.Skin: Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), erythema nodosum, acne, dry skin, sweating, pruritus, urticaria, rash, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5) ].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 disease, nephrolithiasis see Warnings and Precautions (5.1 5.7 ], 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited published data on mesalamine use in pregnant women are insufficient to inform 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 to 4% and 15 to 20%, respectively.DataAnimal DataReproduction 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.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions Severe Cutaneous Adverse Reactions (5.5) 11/2021. Warnings and Precautions.

RENAL IMPAIRMENT SUBSECTION.

5.1 Renal Impairment. Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients taking products such as Asacol HD that contain or are converted to mesalamine [see Adverse Reactions (6.2) ]. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions (6.2) Nonclinical Toxicology (13.2) ]. Evaluate renal function prior to initiation of Asacol HD and periodically while on therapy. Evaluate the risks and benefits of using Asacol HD 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) ].

LABORATORY TESTS SECTION.

5.9 Interference with Laboratory Tests Use of Asacol HD may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.