These Highlights Do Not Include All The Information Needed To Use Mesalamine Extended-release Capsules Safely And Effectively. See Full Prescribing Information For Mesalamine Extended-release Capsules.

Dosage

The recommended dosage in adults is 1.5 g (four 0.375 g capsules) orally once daily in the morning.

Storage:

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure.

Keep out of reach of children.

Because the dissolution of the coating of the granules in mesalamine extended-release capsules depends on pH, avoid co-administration of mesalamine extended-release capsules with antacids [see Dosage and Administration (2)] .

Mesalamine extended-release capsules are 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) damage. 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 further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function. Mesalamine extended-release capsules are a pH-dependent delayed-release product and this factor should be considered when treating a suspected overdose.

Each Mesalamine Extended-Release Capsule, USP is a delayed- and extended-release dosage form for oral administration. Each capsule contains 0.375 g of mesalamine USP (5-aminosalicylic acid, 5-ASA), an aminosalicylate. The structural formula of mesalamine is:

Molecular Weight: 153.14

Molecular Formula: C ₇H ₇NO ₃

Each Mesalamine Extended-Release Capsule, USP contains granules composed of mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above.

The inactive ingredients of Mesalamine Extended-Release Capsules, USP are: ethylcellulose, FD&C Blue No. 1, gelatin, hypromellose, methacrylic acid and methyl methacrylate copolymer, silicon dioxide, sodium lauryl sulfate, sugar spheres (corn starch and sucrose), talc, titanium dioxide and triethyl citrate.

The imprinting ink has the following ingredients: ferrosoferric oxide, potassium hydroxide and shellac.

FDA approved dissolution test specifications differ from USP.

Safety and effectiveness of mesalamine extended-release capsules in pediatric patients have not been established.

Clinical studies of mesalamine extended-release capsules did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a 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 mesalamine extended-release capsules. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine extended-release capsules. 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 mesalamine extended-release capsules [see Use in Specific Populations (8.6)] .

Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. The study populations had a mean age of 46 years (11% age 65 years or older), were 53% female, and were primarily white (92%).

Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician's rating of disease activity. Each subscore can range from 0 to 3, for a total possible DAI score of 12.

At baseline, approximately 80% of patients had a total DAI score of 0 or 1.0. Patients were randomized 2:1 to receive either mesalamine extended-release capsules 1.5 g or placebo once daily in the morning for six months. Patients were assessed at baseline, 1 month, 3 months, and 6 months in the clinic, with endoscopy performed at baseline, at end of study, or if clinical symptoms developed. Relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal appearance subscale score of 2 or more using the DAI. The analysis of the intent-to-treat population was a comparison of the proportions of patients who remained relapse-free at the end of six months of treatment. For the table below (Table 3) all patients who prematurely withdrew from the study for any reason were counted as relapses.

In both studies, the proportion of patients who remained relapse-free at six months was greater for mesalamine extended-release capsules than for placebo.

Examination of gender subgroups did not identify difference in response to mesalamine extended-release capsules among these subgroups. There were too few elderly and too few African-American patients to adequately assess difference in effects in those populations.

The use of mesalamine extended-release capsules for treating ulcerative colitis beyond six months has not been evaluated in controlled clinical trials.

Mesalamine Extended-Release Capsules are contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of Mesalamine Extended-Release Capsules [see Warnings and Precautions (5.3), Adverse Reactions (6.2), Description (11)] .

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 mesalamine extended-release capsules in patients with known liver impairment.

Cases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with mesalamine extended-release capsules.

The following clinically significant adverse reactions are described elsewhere in labeling:

• 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)]

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

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as mesalamine extended-release capsules that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions (6.2), Nonclinical Toxicology (13.2)] .

Evaluate renal function prior to initiation of mesalamine extended-release capsules therapy and periodically while on therapy. Evaluate the risks and benefits of using mesalamine extended-release capsules in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Discontinue mesalamine extended-release capsules if renal function deteriorates while on therapy [see Drug Interactions (7.2), Use in Specific Populations (8.6)] .

Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine extended-release capsules 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. Discontinue mesalamine extended-release capsules if renal function deteriorates while on therapy [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.2)] .

Mesalamine Extended-Release Capsules are indicated for the maintenance of remission of ulcerative colitis in adults.

The mechanism of action of mesalamine (5-ASA) is not fully understood, but appears to be a local anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites.

• Renal Impairment: Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. Discontinue if renal function deteriorates. ( 5.1, 7.2, 8.6)
• Mesalamine-Induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis; monitor for worsening symptoms; discontinue treatment if acute intolerance syndrome is suspected. ( 5.2)
• Hypersensitivity Reactions, including Myocarditis and Pericarditis: Evaluate patients immediately and discontinue if a 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 a broad-spectrum sunscreen when outdoors. ( 5.6)
• Nephrolithiasis: Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment. ( 5.7)
• 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)

Dosage

The recommended dosage is 1.5 g (four 0.375 g capsules) once daily in the morning. ( 2)

Administration Instructions

• Evaluate renal function before initiating therapy with mesalamine extended-release capsules. ( 2)
• Swallow the capsules whole. Do not cut, break, crush or chew the capsules. ( 2)
• Avoid co-administration with antacids. ( 2, 7.1)
• Drink an adequate amount of fluids. ( 2, 5.7)
• Take mesalamine extended-release capsules without regard to meals. ( 2)

Mesalamine Extended-Release Capsules, USP are supplied as:

0.375 g mesalamine in a capsule with opaque powder blue cap and body, imprinted with '

The following adverse reactions have been identified during post approval use of mesalamine extended-release capsules or other mesalamine-containing products. Because many of these reactions are reported voluntarily from a population of unknown 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

Cardiovascular: pericarditis, pericardial effusion, myocarditis [see Warnings and Precautions (5.3)]

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

Nervous System: intracranial hypertension

Neurological/Psychiatric: peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis

Renal and Urinary: nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.7)]

• Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.

Respiratory/Pulmonary: eosinophilic pneumonia, interstitial pneumonitis, pleurisy/pleuritis

Skin: psoriasis, pyoderma gangrenosum, erythema nodosum, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5)]

Renal/Urogenital: reversible oligospermia

Geriatric Patients: Increased risk of blood dyscrasias; monitor blood cell counts and platelet counts. ( 8.5)

Some patients have experienced a hypersensitivity reaction to sulfasalazine. Some patients may have a similar reaction to mesalamine extended-release capsules or to other compounds that contain or are converted to mesalamine.

As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue mesalamine extended-release capsules if an alternative etiology for the signs and symptoms cannot be established.

Because clinical studies 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 data described below reflect exposure to mesalamine extended-release capsules in 557 patients, including 354 exposed for at least 6 months and 250 exposed for greater than one year. Mesalamine extended-release capsules were studied in two placebo-controlled trials (n=367 treated with mesalamine extended-release capsules) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of mesalamine extended-release capsules 1.5 g administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study.

In the two placebo-controlled trials, the most common reactions reported in at least 3% of mesalamine extended-release capsules-treated patients and at a greater rate than placebo are shown in Table 1 below.

The following adverse reactions, presented by body system, were reported at a frequency less than 3% in patients treated with mesalamine extended-release capsules for up to 24 months in controlled and open-label trials.

Ear and Labyrinth Disorders: tinnitus, vertigo

Dermatological Disorder: alopecia

Gastrointestinal: lower abdominal pain, rectal hemorrhage

Laboratory Abnormalities: increased triglycerides, decreased hematocrit and hemoglobin

General Disorders and Administration Site Disorders: fatigue

Hepatic: hepatitis cholestatic, transaminases increased

Renal Disorders: creatinine clearance decreased, hematuria

Musculoskeletal: pain, arthralgia

Respiratory: dyspnea

Mesalamine Extended-Release Capsules, USP, 0.375 g are available as follows:

Capsule with opaque powder blue cap and body, imprinted with '

Bottles of 120 capsules with a child-resistant closure, NDC 0832-6056-12

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of mesalamine extended-release capsules and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine [see Adverse Reactions (6.2)] . Discontinue mesalamine extended-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

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

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, 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 mesalamine extended-release capsules.

NDC 0832-6056-12

Mesalamine

Extended-Release

Capsules, USP

0.375 g

120 Capsules

Rx only

UPSHER-SMITH

Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2,000 mg/kg/day. These doses are about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight assumed or 1,110 mg/m ²), respectively, based on body surface area.

Mesalamine was negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.

No effects on fertility or reproductive performance in male and female rats were observed with oral mesalamine doses up to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area).

Use of mesalamine extended-release capsules 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.

The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1)] .

Dosage

The recommended dosage in adults is 1.5 g (four 0.375 g capsules) orally once daily in the morning.

Storage:

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure.

Keep out of reach of children.

Because the dissolution of the coating of the granules in mesalamine extended-release capsules depends on pH, avoid co-administration of mesalamine extended-release capsules with antacids [see Dosage and Administration (2)] .

Mesalamine extended-release capsules are 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) damage. 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 further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function. Mesalamine extended-release capsules are a pH-dependent delayed-release product and this factor should be considered when treating a suspected overdose.

Each Mesalamine Extended-Release Capsule, USP is a delayed- and extended-release dosage form for oral administration. Each capsule contains 0.375 g of mesalamine USP (5-aminosalicylic acid, 5-ASA), an aminosalicylate. The structural formula of mesalamine is:

Molecular Weight: 153.14

Molecular Formula: C ₇H ₇NO ₃

Each Mesalamine Extended-Release Capsule, USP contains granules composed of mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above.

The inactive ingredients of Mesalamine Extended-Release Capsules, USP are: ethylcellulose, FD&C Blue No. 1, gelatin, hypromellose, methacrylic acid and methyl methacrylate copolymer, silicon dioxide, sodium lauryl sulfate, sugar spheres (corn starch and sucrose), talc, titanium dioxide and triethyl citrate.

The imprinting ink has the following ingredients: ferrosoferric oxide, potassium hydroxide and shellac.

FDA approved dissolution test specifications differ from USP.

Safety and effectiveness of mesalamine extended-release capsules in pediatric patients have not been established.

Clinical studies of mesalamine extended-release capsules did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than younger subjects. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a 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 mesalamine extended-release capsules. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine extended-release capsules. 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 mesalamine extended-release capsules [see Use in Specific Populations (8.6)] .

Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. The study populations had a mean age of 46 years (11% age 65 years or older), were 53% female, and were primarily white (92%).

Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician's rating of disease activity. Each subscore can range from 0 to 3, for a total possible DAI score of 12.

At baseline, approximately 80% of patients had a total DAI score of 0 or 1.0. Patients were randomized 2:1 to receive either mesalamine extended-release capsules 1.5 g or placebo once daily in the morning for six months. Patients were assessed at baseline, 1 month, 3 months, and 6 months in the clinic, with endoscopy performed at baseline, at end of study, or if clinical symptoms developed. Relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal appearance subscale score of 2 or more using the DAI. The analysis of the intent-to-treat population was a comparison of the proportions of patients who remained relapse-free at the end of six months of treatment. For the table below (Table 3) all patients who prematurely withdrew from the study for any reason were counted as relapses.

In both studies, the proportion of patients who remained relapse-free at six months was greater for mesalamine extended-release capsules than for placebo.

Examination of gender subgroups did not identify difference in response to mesalamine extended-release capsules among these subgroups. There were too few elderly and too few African-American patients to adequately assess difference in effects in those populations.

The use of mesalamine extended-release capsules for treating ulcerative colitis beyond six months has not been evaluated in controlled clinical trials.

Mesalamine Extended-Release Capsules are contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of Mesalamine Extended-Release Capsules [see Warnings and Precautions (5.3), Adverse Reactions (6.2), Description (11)] .

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 mesalamine extended-release capsules in patients with known liver impairment.

Cases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with mesalamine extended-release capsules.

The following clinically significant adverse reactions are described elsewhere in labeling:

• 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)]

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

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as mesalamine extended-release capsules that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions (6.2), Nonclinical Toxicology (13.2)] .

Evaluate renal function prior to initiation of mesalamine extended-release capsules therapy and periodically while on therapy. Evaluate the risks and benefits of using mesalamine extended-release capsules in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Discontinue mesalamine extended-release capsules if renal function deteriorates while on therapy [see Drug Interactions (7.2), Use in Specific Populations (8.6)] .

Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.

Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine extended-release capsules 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. Discontinue mesalamine extended-release capsules if renal function deteriorates while on therapy [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.2)] .

Mesalamine Extended-Release Capsules are indicated for the maintenance of remission of ulcerative colitis in adults.

The mechanism of action of mesalamine (5-ASA) is not fully understood, but appears to be a local anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites.

• Renal Impairment: Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. Discontinue if renal function deteriorates. ( 5.1, 7.2, 8.6)
• Mesalamine-Induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis; monitor for worsening symptoms; discontinue treatment if acute intolerance syndrome is suspected. ( 5.2)
• Hypersensitivity Reactions, including Myocarditis and Pericarditis: Evaluate patients immediately and discontinue if a 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 a broad-spectrum sunscreen when outdoors. ( 5.6)
• Nephrolithiasis: Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment. ( 5.7)
• 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)

Dosage

The recommended dosage is 1.5 g (four 0.375 g capsules) once daily in the morning. ( 2)

Administration Instructions

• Evaluate renal function before initiating therapy with mesalamine extended-release capsules. ( 2)
• Swallow the capsules whole. Do not cut, break, crush or chew the capsules. ( 2)
• Avoid co-administration with antacids. ( 2, 7.1)
• Drink an adequate amount of fluids. ( 2, 5.7)
• Take mesalamine extended-release capsules without regard to meals. ( 2)

Mesalamine Extended-Release Capsules, USP are supplied as:

0.375 g mesalamine in a capsule with opaque powder blue cap and body, imprinted with '

The following adverse reactions have been identified during post approval use of mesalamine extended-release capsules or other mesalamine-containing products. Because many of these reactions are reported voluntarily from a population of unknown 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

Cardiovascular: pericarditis, pericardial effusion, myocarditis [see Warnings and Precautions (5.3)]

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

Nervous System: intracranial hypertension

Neurological/Psychiatric: peripheral neuropathy, Guillain-Barré syndrome, transverse myelitis

Renal and Urinary: nephrogenic diabetes insipidus, interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.7)]

• Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach.

Respiratory/Pulmonary: eosinophilic pneumonia, interstitial pneumonitis, pleurisy/pleuritis

Skin: psoriasis, pyoderma gangrenosum, erythema nodosum, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5)]

Renal/Urogenital: reversible oligospermia

Geriatric Patients: Increased risk of blood dyscrasias; monitor blood cell counts and platelet counts. ( 8.5)

Some patients have experienced a hypersensitivity reaction to sulfasalazine. Some patients may have a similar reaction to mesalamine extended-release capsules or to other compounds that contain or are converted to mesalamine.

As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue mesalamine extended-release capsules if an alternative etiology for the signs and symptoms cannot be established.

Because clinical studies 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 data described below reflect exposure to mesalamine extended-release capsules in 557 patients, including 354 exposed for at least 6 months and 250 exposed for greater than one year. Mesalamine extended-release capsules were studied in two placebo-controlled trials (n=367 treated with mesalamine extended-release capsules) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of mesalamine extended-release capsules 1.5 g administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study.

In the two placebo-controlled trials, the most common reactions reported in at least 3% of mesalamine extended-release capsules-treated patients and at a greater rate than placebo are shown in Table 1 below.

The following adverse reactions, presented by body system, were reported at a frequency less than 3% in patients treated with mesalamine extended-release capsules for up to 24 months in controlled and open-label trials.

Ear and Labyrinth Disorders: tinnitus, vertigo

Dermatological Disorder: alopecia

Gastrointestinal: lower abdominal pain, rectal hemorrhage

Laboratory Abnormalities: increased triglycerides, decreased hematocrit and hemoglobin

General Disorders and Administration Site Disorders: fatigue

Hepatic: hepatitis cholestatic, transaminases increased

Renal Disorders: creatinine clearance decreased, hematuria

Musculoskeletal: pain, arthralgia

Respiratory: dyspnea

Mesalamine Extended-Release Capsules, USP, 0.375 g are available as follows:

Capsule with opaque powder blue cap and body, imprinted with '

Bottles of 120 capsules with a child-resistant closure, NDC 0832-6056-12

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of mesalamine extended-release capsules and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of mesalamine [see Adverse Reactions (6.2)] . Discontinue mesalamine extended-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

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

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, 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 mesalamine extended-release capsules.

NDC 0832-6056-12

Mesalamine

Extended-Release

Capsules, USP

0.375 g

120 Capsules

Rx only

UPSHER-SMITH

Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2,000 mg/kg/day. These doses are about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight assumed or 1,110 mg/m ²), respectively, based on body surface area.

Mesalamine was negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.

No effects on fertility or reproductive performance in male and female rats were observed with oral mesalamine doses up to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area).

Use of mesalamine extended-release capsules 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.

The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.1)] .