Mesalamine

MESALAMINE- mesalamine tablet, delayed release
Sun Pharmaceutical Industries, Inc.

1 INDICATIONS AND USAGE

Mesalamine delayed-release tablets are indicated for the:

induction and maintenance of remission in adult patients with mildly to moderately active ulcerative colitis.

Pediatric use information is approved for Takeda Pharmaceuticals U.S.A., Inc.’s LIALDA (mesalamine) delayed-release tablets. However, due to Takeda Pharmaceuticals U.S.A., Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2 DOSAGE AND ADMINISTRATION

Administration Instructions

Evaluate renal function prior to initiation of mesalamine delayed-release tablets and periodically while on therapy.
Swallow mesalamine delayed-release tablets whole; do not split or crush.
Administer mesalamine delayed-release tablets with food [see Clinical Pharmacology (12.3)].
Drink an adequate amount of fluids [see Warnings and Precautions (5.8)].

Adults

The recommended dosage for the induction of remission in adult patients with mildly to moderately active ulcerative colitis is 2.4 g to 4.8 g (two to four 1.2-g tablets) taken once daily.
The recommended dosage for the maintenance of remission is 2.4 g (two 1.2-g tablets) taken once daily.

Pediatric use information is approved for Takeda Pharmaceuticals U.S.A., Inc.’s LIALDA (mesalamine) delayed-release tablets. However, due to Takeda Pharmaceuticals U.S.A., Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

3 DOSAGE FORMS AND STRENGTHS

Mesalamine delayed-release tablets, USP containing 1.2 g mesalamine are reddish brown, oval-shaped, film-coated tablets printed with “RG70 ” in black color on one side and plain on other side.

4 CONTRAINDICATIONS

Mesalamine delayed-release tablets are contraindicated in patients with known or suspected hypersensitivity to salicylates, aminosalicylates, or to any of the ingredients of mesalamine delayed-release tablets [ see Warnings and Precautions (5.3), Adverse Reactions (6.2), Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Renal Impairment

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as mesalamine delayed-release tablets 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 therapy and periodically while on therapy. Evaluate the risks and benefits of using mesalamine in patients with known renal impairment, history of renal disease, or taking concomitant nephrotoxic drugs [see Drug Interactions (7.1), Use in Specific Populations (8.6)].

5.2 Mesalamine-Induced Acute Intolerance Syndrome

Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain, and bloody diarrhea, and sometimes fever, headache, and rash. Monitor patients closely for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine delayed-release tablets.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some of these patients may have a similar reaction to mesalamine delayed-release 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 a hypersensitivity reaction are present. Discontinue mesalamine 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 mesalamine in patients with known liver impairment.

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, such as 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 at the first appearance of signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Upper Gastrointestinal Tract Obstruction

Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of mesalamine delayed-release tablets, which would delay mesalamine release in the colon. Avoid mesalamine in patients at risk of upper gastrointestinal tract obstruction.

5.7 Photosensitivity

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.

5.8 Nephrolithiasis

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

5.9 Interference With Laboratory Tests

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

6 ADVERSE REACTIONS

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

Renal impairment, including renal failure [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)]
Upper gastrointestinal tract obstruction [see Warnings and Precautions (5.6)]
Photosensitivity [see Warnings and Precautions (5.7)]
Nephrolithiasis [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

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

Adults

Induction

The most common adverse reactions occurring in at least 1% of mesalamine-or placebo-treated adult patients with mildly to moderately active ulcerative colitis in two eight-week, randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) [see Clinical Studies (14.1)] are listed in Table 2.

Table 2: Adverse Reactions* in Two Eight-Week, Placebo-Controlled Trials of Induction Therapy (Study 1 and Study 2) in Adults with Mildly to Moderately Active Ulcerative Colitis

Adverse Reaction

Mesalamine delayed-release tablets

2.4 g once daily

(n = 177)

Mesalamine delayed-release tablets

4.8 g once daily

(n = 179)

Placebo

(n = 179)

Headache

6%

3%

< 1%

Flatulence

4%

3%

3%

Liver Function Test Abnormal

< 1%

2%

1%

Alopecia

0

1%

0

Pruritus

< 1%

1%

1%

*Reported in at least 1% of patients in at least one mesalamine delayed-release tablets group and greater than placebo

Pancreatitis occurred in less than 1% of patients during induction in clinical trials and resulted in discontinuation of therapy with mesalamine in patients experiencing this event.

Maintenance of Remission

A mesalamine dosage of 2.4 g/day, administered as either 1.2 g twice daily or 2.4 g once daily, was evaluated for safety in three maintenance trials in patients with mildly to moderately active ulcerative colitis: a 6-month double-blind, active-controlled study (Study 3) [see Clinical Studies (14.1)] and two 12-to 14-month open-label studies. The most common adverse reactions with mesalamine in these maintenance trials are listed in Table 3.

Table 3: Adverse Reactions* in Three Trials of Maintenance of Remission in Adults with Ulcerative Colitis

Mesalamine delayed-release tablets
2.4 g/day

(n = 1082)

Adverse Reaction
%
Headache
3%
Liver function test abnormal
2%
Abdominal pain
2%
Diarrhea
2%
Abdominal distension
1%
Abdominal pain upper
1%
Dyspepsia
1%
Back pain
1%
Rash
1%
Arthralgia
1%
Fatigue
1%
Hypertension
1%

* Reported in at least 1% of patients

Administered either as 1.2 g twice daily or 2.4 g once daily

The following adverse reactions, presented by body system, were reported in less than 1% of mesalamine delayed-release tablets-treated patients with ulcerative colitis in either induction or maintenance trials:

Cardiac Disorder:

tachycardia

Ear and Labyrinth Disorders:

ear pain

Gastrointestinal Disorders:

abdominal distention, colitis, diarrhea, flatulence, nausea, pancreatitis, rectal polyp, vomiting

General Disorders and Administrative Site Disorders:

asthenia, face edema, fatigue, pyrexia

Investigations:

decreased platelet count

Musculoskeletal and Connective Tissue Disorders:

arthralgia, back pain

Nervous System Disorders:

dizziness, somnolence, tremor

Respiratory, Thoracic and Mediastinal Disorders:

pharyngolaryngeal pain

Skin and Subcutaneous Tissue Disorders:

acne, prurigo, rash, alopecia, pruritus, urticaria

Vascular Disorders:

hypertension, hypotension

Pediatric use information is approved for Takeda Pharmaceuticals U.S.A., Inc.’s LIALDA (mesalamine) delayed-release tablets. However, due to Takeda Pharmaceuticals U.S.A., Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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