Mesalamine: Package Insert and Label Information

MESALAMINE- mesalamine tablet, delayed release
American Health Packaging

1 INDICATIONS AND USAGE

Mesalamine delayed-release tablets are indicated for the treatment of moderately active ulcerative colitis in adults.

Limitations of Use: Safety and effectiveness of mesalamine delayed-release tablets beyond 6 weeks have not been established.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

  • Do not substitute one mesalamine delayed-release tablet 800 mg for two mesalamine delayed-release 400 mg oral products [see Clinical Pharmacology (12.3)].
  • Evaluate renal function prior to initiation of mesalamine delayed-release tablets.
  • Take mesalamine delayed-release tablets on an empty stomach, at least 1 hour before and 2 hours after a meal [see Clinical Pharmacology (12.3)].
  • Swallow mesalamine delayed-release 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 mesalamine delayed-release tablets from moisture.

2.2 Dosage Information

For the treatment of moderately active ulcerative colitis, the recommended dosage of mesalamine delayed-release tablets in adults is 1600 mg (two 800 mg tablets) three times daily (total daily dosage of 4.8 grams) for a duration of 6 weeks.

3 DOSAGE FORMS AND STRENGTHS

Mesalamine delayed-release tablets are available as reddish-brown colored, capsule-shaped, biconvex, enteric coated tablets, imprinted with “435” on one side and plain on other side.

4 CONTRAINDICATIONS

Mesalamine delayed-release tablets are contraindicated in patients with known or suspected hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release tablets [see Warnings and Precautions (5.3), Adverse Reactions (6.2), and 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 taking products such as mesalamine delayed-release tablets 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 mesalamine delayed-release tablets and periodically while on therapy. Evaluate the risks and benefits of using mesalamine delayed-release tablets 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 mesalamine-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 mesalamine delayed-release tablets as well as other mesalamine products. Symptoms usually abate when mesalamine delayed-release tablets are discontinued. Monitor patients 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 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 delayed-release tablets 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 delayed-release tablets 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 mesalamine delayed-release tablets 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 a 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 mesalamine delayed-release tablets.

5.9 Interference with Laboratory Tests

Use of mesalamine delayed-release tablets 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 serious or clinically significant adverse reactions described elsewhere in labeling are:

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.

Mesalamine has been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six-week, active-controlled studies were conducted comparing mesalamine 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 the mesalamine delayed-release tablet, 800 mg and 732 patients were dosed with mesalamine delayed-release tablets, 400 mg.

The most common reactions reported in the mesalamine group were headache (4.7%), nausea (2.8%), nasopharyngitis (2.5%), abdominal pain (2.3%), diarrhea (1.7%), and dyspepsia (1.7%); Table 1 enumerates adverse reactions that occurred in the three studies. The most common reactions in patients with moderately active ulcerative colitis (602 patients dosed with mesalamine delayed-release tablet, 800 mg and 618 patients dosed with the mesalamine delayed-release tablet, 400 mg) were the same as all treated patients.

Discontinuations due to adverse reactions occurred in 3.9% of patients in the mesalamine delayed-release tablet, 800 mg group and in 4.2% of patients in the mesalamine delayed-release tablet, 400 mg comparator group. The most common cause for discontinuation was gastrointestinal symptoms associated with ulcerative colitis.

Serious adverse reactions occurred in 0.8% of patients in the mesalamine delayed-release tablet, 800 mg group and in 1.8% of patients in the mesalamine delayed-release tablet, 400 mg comparator group. The majority involved the gastrointestinal system.

Table 1 Adverse Reactions Occurring in ≥1% of All Treated Patients (Three studies combined)
N = number of patients within specified treatment group
Percent = percentage of patients in category and treatment group

Adverse Reaction

Mesalamine delayed-release 2.4 grams per day (400 mg Tablet) (N = 732)

Mesalamine delayed-release 4.8 grams per day (800 mg Tablet) (N = 727)

Headache

4.9 %

4.7 %

Nausea

2.9 %

2.8 %

Nasopharyngitis

1.4 %

2.5 %

Abdominal pain

2.3 %

2.3 %

Diarrhea

1.9 %

1.7 %

Dyspepsia

0.8 %

1.7 %

Vomiting

1.6 %

1.4 %

Flatulence

0.7 %

1.2 %

Influenza

1.2 %

1.0 %

Pyrexia

1.2 %

0.7 %

Cough

1.4 %

0.3 %

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mesalamine delayed-release tablet 800 mg or other mesalamine-containing products or products that are metabolized to mesalamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

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

Endocrine
Nephrogenic diabetes insipidus

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

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

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

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

Neurological/Psychiatric
Anxiety, depression, somnolence, insomnia, nervousness, confusion, emotional lability, dizziness, vertigo, tremor, paresthesia, hyperesthesia, peripheral neuropathy (rare), Guillain-Barré 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.

7 DRUG INTERACTIONS

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