These highlights do not include all the information needed to use MESALAMINE DELAYED-RELEASE TABLETS safely and effectively. See full prescribing information for MESALAMINE DELAYED-RELEASE TABLETS. MESALAMINE delayed-release tablets, for oral useInitial U.S. Approval: 1987

These highlights do not include all the information needed to use MESALAMINE DELAYED-RELEASE TABLETS safely and effectively. See full prescribing information for MESALAMINE DELAYED-RELEASE TABLETS. MESALAMINE delayed-release tablets, for oral useInitial U.S. Approval: 1987

Drug Labeling and Warnings

Drug Details

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MESALAMINE- mesalamine film coated tablet, delayed release 
Mylan Pharmaceuticals Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use MESALAMINE DELAYED-RELEASE TABLETS safely and effectively. See full prescribing information for MESALAMINE DELAYED-RELEASE TABLETS.
 
MESALAMINE delayed-release tablets, for oral use
Initial U.S. Approval: 1987

RECENT MAJOR CHANGES

Warnings and Precautions (5.6)     05/2018

INDICATIONS AND USAGE

Mesalamine delayed-release tablets are a locally acting 5-aminosalicylic acid (5-ASA) indicated for the induction of remission in adults with active, mild to moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis. (1)

DOSAGE AND ADMINISTRATION

For induction of remission of active, mild to moderate ulcerative colitis, two to four 1.2 g tablets taken once daily with food. (1, 2) For maintenance of remission of ulcerative colitis, two 1.2 g tablets taken once daily with food. (1, 2)

DOSAGE FORMS AND STRENGTHS

Delayed-Release Tablets: 1.2 g (3)

CONTRAINDICATIONS

Patients with known hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of mesalamine delayed-release tablets. (4)

WARNINGS AND PRECAUTIONS

  • Renal impairment may occur. Assess renal function at the beginning of treatment and periodically during treatment. (5.1)
  • Mesalamine-induced acute intolerance syndrome has been reported. Observe patients closely for worsening of these symptoms while on treatment. (5.2)
  • Use caution when treating patients who are hypersensitive to sulfasalazine. (5.3)
  • Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported. (5.3)
  • Hepatic failure has been reported in patients with pre-existing liver disease. Use caution when treating patients with liver disease. (5.4)
  • Upper GI tract obstruction may delay onset of action. (5.5)
  • Patients with pre-existing skin conditions have reported more severe photosensitivity reactions (5.6)
  • Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection. (5.7)

ADVERSE REACTIONS

  • The most common adverse reactions (incidence ≥ 2%) are ulcerative colitis, headache, flatulence, liver function test abnormality, and abdominal pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • Nephrotoxic agents including NSAIDs: renal reactions have been reported. (7.1)
  • Azathioprine or 6-mercaptopurine: blood disorders have been reported. (7.2)

USE IN SPECIFIC POPULATIONS

  • Renal Impairment: Use mesalamine delayed-release tablets with caution in patients with a history of renal disease. (5.1, 7.1, 8.5, 13.2)
  • Nursing Women: Caution should be exercised when administered to a nursing woman. (8.3)
  • Geriatric Patients: Monitor blood cell counts in geriatric patients. (8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2018

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Mesalamine delayed-release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis.

2 DOSAGE AND ADMINISTRATION

The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is two to four 1.2 g tablets taken once daily with a meal for a total daily dose of 2.4 g or 4.8 g. The recommended dosage for the maintenance of remission is two 1.2 g tablets taken once daily with a meal for a total daily dose of 2.4 g.

3 DOSAGE FORMS AND STRENGTHS

Mesalamine Delayed-Release Tablets, USP are available containing 1.2 g of mesalamine, USP.

  • The 1.2 g tablets are tan, film-coated, ellipsoidal, unscored tablets imprinted with M1200 in black ink on one side of the tablet and plain on the other side.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Renal Impairment

Renal impairment, including minimal change nephropathy, 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.

It is recommended that patients have an evaluation of renal function prior to initiation of mesalamine delayed-release tablet therapy and periodically while on therapy. Exercise caution when using mesalamine delayed-release tablets in patients with known renal dysfunction or a history of renal disease.

In animal studies, the kidney was the principal organ for toxicity. [See Drug Interactions (7.1) and Nonclinical Toxicology (13.2).]

5.2 Mesalamine-Induced Acute Intolerance Syndrome

Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. 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. Observe 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

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

Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with mesalamine delayed-release tablets and other mesalamine medications. Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis.

5.4 Hepatic Impairment

There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering mesalamine delayed-release tablets to patients with liver disease.

5.5 Upper GI 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.

5.6 Photosensitivity

Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions.

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 because of the similarity in the chromatograms of normetanephrine and mesalamine’s main metabolite, N-acetylaminosalicylic acid (N-Ac-5-ASA). An alternative, selective assay for normetanephrine should be considered.

6 ADVERSE REACTIONS

The most serious adverse reactions seen in mesalamine delayed-release tablet clinical trials or with other products that contain or are metabolized to mesalamine 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 delayed-release tablets have been evaluated in 1368 ulcerative colitis patients in controlled and open-label trials.

Induction of Remission

In two 8-week placebo-controlled clinical trials involving 535 ulcerative colitis patients, 356 received 2.4 g/day or 4.8 g/day mesalamine delayed-release tablets and 179 received placebo. The most frequent adverse reaction leading to discontinuation from mesalamine delayed-release tablet therapy was exacerbation of ulcerative colitis (0.8%). Pancreatitis occurred in less than 1% of patients during clinical trials and resulted in discontinuation of therapy with mesalamine delayed-release tablets in patients experiencing this event.

Adverse reactions occurring in mesalamine delayed-release tablet or placebo groups at a frequency of at least 1% in two 8-week, double blind, placebo-controlled trials are listed in Table 1. The most common adverse reactions with mesalamine delayed-release tablets 2.4 g/day and 4.8 g/day were headache (5.6% and 3.4%, respectively) and flatulence (4% and 2.8%, respectively).

Table 1: Adverse Reactions in Two Eight-Week Placebo-Controlled Trials Experienced by at Least 1% of the Mesalamine Delayed-Release Tablet Group and at a Rate Greater than Placebo*
  • * Adverse reactions for which the placebo rate equaled or exceeded the rate for at least one of the mesalamine delayed-release tablet treatment groups were abdominal pain, dizziness, dyspepsia, and nausea.
  • Adverse Reaction

    Mesalamine Delayed-Release Tablets

    2.4 g/day

    (n = 177)

    Mesalamine Delayed-Release Tablets

    4.8 g/day

    (n = 179)

    Placebo

    (n = 179)

    Headache

    10 (5.6%)

    6 (3.4%)

    1 (0.6%)

    Flatulence

    7 (4%)

    5 (2.8%)

    5 (2.8%)

    Liver Function Test Abnormal

    1 (0.6%)

    4 (2.2%)

    2 (1.1%)

    Alopecia

    0

    2 (1.1%)

    0

    Pruritus

    1 (0.6%)

    2 (1.1%)

    2 (1.1%)

    The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by mesalamine delayed-release tablet-treated ulcerative colitis patients in the two controlled trials:

    Cardiac Disorder: tachycardia

    Vascular Disorders: hypertension, hypotension

    Skin and Subcutaneous Tissue Disorders: acne, prurigo, rash, urticaria

    Gastrointestinal Disorders: abdominal distention, colitis, diarrhea, pancreatitis, rectal polyp, vomiting

    Investigations: decreased platelet count

    Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain

    Nervous System Disorders: somnolence, tremor

    Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain

    General Disorders and Administrative Site Disorders: asthenia, face edema, fatigue, pyrexia

    Ear and Labyrinth Disorders: ear pain

    Maintenance of Remission of Ulcerative Colitis

    The dose evaluated in three studies of mesalamine delayed-release tablets given for the maintenance of remission in patients with ulcerative colitis was 1.2 g twice daily or 2.4 g/once daily. One of these studies was a 6-month double-blind comparator study while two were 12- to 14-month open-label studies.

    The most common adverse reactions with mesalamine delayed-release tablets in the maintenance arms of long-term trials were colitis ulcerative (5.8%), headache (2.9%), liver function test abnormal (2.3%), and abdominal pain (2.2%). Of the 1082 subjects in the all maintenance studies pooled, 1.9% had severe adverse reactions. The most common severe adverse reactions were gastrointestinal disorders; these were mainly symptoms associated with ulcerative colitis.

    Table 2: Adverse Reactions in Three Maintenance Trials Experienced by at Least 1% of the Mesalamine Delayed-Release Tablet Group (maintenance phases of trials)

    Adverse Reaction

    All Mesalamine Delayed-Release Tablets

    (n = 1082)

    n

    %

    Colitis Ulcerative

    63

    (5.8%)

    Headache

    31

    (2.9%)

    Liver Function Test Abnormal

    25

    (2.3%)

    Abdominal Pain

    24

    (2.2%)

    Diarrhea

    18

    (1.7%)

    Abdominal Distension

    14

    (1.3%)

    Abdominal Pain Upper

    13

    (1.2%)

    Dyspepsia

    13

    (1.2%)

    Back Pain

    13

    (1.2%)

    Rash

    13

    (1.2%)

    Arthralgia

    12

    (1.1%)

    Fatigue

    11

    (1.0%)

    Hypertension

    10

    (1.0%)

    The following adverse reactions, presented by body system, were reported infrequently (less than 1%) by mesalamine delayed-release tablet-treated ulcerative colitis patients in the three long-term maintenance trials (maintenance phases of these trials):

    Cardiac Disorder: tachycardia

    Skin and Subcutaneous Tissue Disorders: acne, alopecia, pruritis, urticaria

    Gastrointestinal Disorders: colitis, flatulence, nausea, pancreatitis, rectal polyp, vomiting

    Nervous System Disorders: dizziness

    Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain

    General Disorders and Administrative Site Disorders: asthenia, pyrexia

    Ear and Labyrinth Disorders: ear pain

    6.2 Postmarketing Experience

    In addition to the adverse reactions reported above in clinical trials involving mesalamine delayed-release tablets, the adverse reactions listed below have been identified during post-approval use of mesalamine delayed-release tablets and other mesalamine-containing products. 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: lupus-like syndrome, drug fever

    Cardiac Disorders: pericarditis, pericardial effusion, myocarditis

    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

    Immune System Disorders: anaphylactic reaction, angioedema,Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS)

    Musculoskeletal and Connective Tissue Disorders: myalgia, lupus-like syndrome

    Neurological/Psychiatric: peripheral neuropathy, Guillain-Barre syndrome, transverse myelitis, intracranial hypertension

    Renal Disorders: interstitial nephritis, nephrogenic diabetes insipidus

    Respiratory, Thoracic and Mediastinal Disorders: interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis)

    Skin: psoriasis, pyoderma gangrenosum, erythema nodosum, photosensitivity

    Urogenital: reversible oligospermia

    7 DRUG INTERACTIONS

    No investigations of interaction between mesalamine delayed-release tablets and other drugs except for certain antibiotics have been performed [see Clinical Pharmacology (12.3)]. However, the following drug-drug interactions have been reported for products containing mesalamine:

    7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs

    The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of renal reactions.

    7.2 Azathioprine or 6-mercaptopurine

    The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders.

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at doses up to 1000 mg/kg/day (1.8 times the maximum recommended human dose based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (2.9 times the maximum recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

    Mesalamine is known to cross the placental barrier.

    8.3 Nursing Mothers

    Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised if mesalamine delayed-release tablets are administered to a nursing woman.

    8.4 Pediatric Use

    Safety and effectiveness of mesalamine delayed-release tablets in pediatric patients have not been established.

    8.5 Geriatric Use

    Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products such as mesalamine delayed-release tablets. Caution should be taken to closely monitor blood cell counts during mesalamine therapy.

    Clinical trials of mesalamine delayed-release tablets did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic exposures are increased in elderly subjects [see Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients.

    10 OVERDOSAGE

    Mesalamine delayed-release tablets are an aminosalicylate, and symptoms of salicylate toxicity may include tinnitus, vertigo, headache, confusion, drowsiness, sweating, seizures, hyperventilation, dyspnea, vomiting, and diarrhea. Severe intoxication may lead to disruption of electrolyte balance and blood-pH, hyperthermia, dehydration, and end organ damage.

    There is no specific known antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Adequate renal function should be maintained.

    11 DESCRIPTION

    Each mesalamine delayed-release tablet, USP for oral administration contains 1.2 g of 5-amino-salicylic acid (5-ASA; mesalamine), an anti-inflammatory agent. Mesalamine also has the chemical name 5-amino-2-hydroxybenzoic acid and its structural formula is:

    Mesalamine Structural Formula

    Molecular formula: C7H7NO3          Molecular weight: 153.14

    The tablet is coated with a pH dependent polymer film, which breaks down at or above pH 6.8, normally in the terminal ileum where mesalamine then begins to be released from the tablet core. The tablet core contains mesalamine with hydrophilic excipients and provides for extended release of mesalamine.

    The inactive ingredients of mesalamine delayed-release tablets are carboxymethyl cellulose sodium, colloidal silicon dioxide, hypromellose, lactose monohydrate, methacrylic acid copolymer type A, methacrylic acid copolymer type B, methacrylic acid copolymer dispersion, polyethylene glycol, red iron oxide, sodium starch glycolate (potato), stearic acid, talc, titanium dioxide, triacetin, triethyl citrate and yellow iron oxide. The black imprinting ink contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.

    USP Dissolution Test Pending.

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    The mechanism of action of mesalamine is not fully understood, but appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

    Mesalamine has the potential to inhibit the activation of nuclear factor kappa B (NFкB) and consequently the production of key pro-inflammatory cytokines. It has been proposed that reduced expression of PPARγ nuclear receptors (γ-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. There is evidence that mesalamine produces pharmacodynamic effects through direct activation of PPARγ receptors in the colonic/rectal epithelium.

    12.2 Pharmacodynamics

    The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosae local to the delivery of drug from mesalamine delayed-release tablets into the lumen. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalamine is inversely correlated with mucosal concentrations of mesalamine. Plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy.

    12.3 Pharmacokinetics

    Absorption

    The total absorption of mesalamine from mesalamine delayed-release tablets 2.4 g or 4.8 g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.

    Gamma-scintigraphy studies have shown that a single dose of mesalamine delayed-release tablets 1.2 g (one tablet) passed intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labeled tracer in the colon, suggesting that mesalamine had distributed through this region of the gastrointestinal tract.

    In a single dose study, mesalamine delayed-release tablets 1.2 g, 2.4 g and 4.8 g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalamine were detectable after 2 hours and reached a maximum by 9-12 hours on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects (Table 3). Mesalamine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was slightly more than dose proportional between 1.2 g and 4.8 g mesalamine delayed-release tablets. Maximum plasma concentrations (Cmax) of mesalamine increased approximately dose proportionately between 1.2 g and 2.4 g and sub-proportionately between 2.4 g and 4.8 g mesalamine delayed-release tablets, with the dose normalized value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means.

    Table 3: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of Mesalamine Delayed-Release Tablets Under Fasting Conditions
  • * Arithmetic mean of parameter values are presented except for Tmax and Tlag.
  • N = 43
  • N = 27
  • § N = 36
  • Median (min, max)
  • # N = 46
  • Þ N = 33
  • Parameter* of

    Mesalamine

    Mesalamine Delayed-Release Tablets 1.2 g

    (N = 47)

    Mesalamine Delayed-Release Tablets 2.4 g

    (N = 48)

    Mesalamine Delayed-Release Tablets 4.8 g

    (N = 48)

    AUC0-t (ng.h/mL)

    9039 (5054)

    20538 (12980)

    41434 (26640)

    AUC0-∞ (ng.h/mL)

    9578 (5214)

    21084 (13185)

    44775§ (30302)

    Cmax (ng/mL)

    857 (638)

    1595 (1484)

    2154 (1140)

    Tmax (h)

    9.0# (4.0-32.1)

    12.0 (4.0-34.1)

    12.0 (4.0-34.0)

    Tlag (h)

    2.0# (0-8.0)

    2.0 (1.0-4.0)

    2.0 (1.0-4.0)

    T1/2 (h) (Terminal Phase)

    8.56 (6.38)

    7.05Þ (5.54)

    7.25§ (8.32)

    Administration of a single dose of mesalamine delayed-release tablets 4.8 g with a high fat meal resulted in further delay in absorption, and plasma concentrations of mesalamine were detectable 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalamine (mean Cmax: ↑ 91%; mean AUC: ↑ 16%) compared to results in the fasted state. Mesalamine delayed-release tablets were administered with food in the controlled clinical trials that supported its approval.

    In a single and multiple dose pharmacokinetic study of mesalamine delayed-release tablets, 2.4 g or 4.8 g was administered once daily with standard meals to 28 healthy volunteers per dose group. Plasma concentrations of mesalamine were detectable after 4 hours and were maximal by 8 hours after the single dose. Steady state was achieved generally by 2 days after dosing. Mean AUC at steady state was only modestly greater (1.1- to 1.4-fold) than predictable from single dose pharmacokinetics.

    In a single dose pharmacokinetic study of mesalamine delayed-release tablets, 4.8 g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35 yrs); 28 elderly (65-75 yrs); 15 elderly (> 75 yrs)). Increased age resulted in increased systemic exposure (approximately 2-fold in Cmax), to mesalamine and its metabolite N-acetyl-5-aminosalicylic acid. Increased age resulted in a slower apparent elimination of mesalamine, though there was high between-subject variability. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.

    Table 4: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of Mesalamine Delayed-Release Tablets 4.8 g under Fasting Conditions to Young and Elderly Subjects
    Arithmetic mean (SD) data are presented, N = Number of subjects
  • * N = 15
  • N = 16
  • N = 13
  • § Median (min - max)
  • Parameter of 5-ASA

    Young Subjects

    (18-35 yrs)

    (N = 28)

    Elderly Subjects

    (65-75 yrs)

    (N = 28)

    Elderly Subjects

    (> 75 yrs)

    (N = 15)

    AUC0-t (ng.h/mL)

    51570 (23870)

    73001 (42608)

    65820 (25283)

    AUC0-∞ (ng.h/mL)

    58057* (22429)

    89612 (40596)

    63067 (22531)

    Cmax (ng/mL)

    2243 (1410)

    4999 (4381)

    4832 (4383)

    tmax§ (h)

    22.0 (5.98-48.0)

    12.5 (4.00-36.0)

    16.0 (4.00-26.0)

    tlag§ (h)

    2.00 (1.00-6.00)

    2.00 (1.00-4.00)

    2.00 (2.00-4.00)

    t1/2 (h), terminal phase

    5.68* (2.83)

    9.68 (7.47)

    8.67 (5.84)

    Renal clearance (L/h)

    2.05 (1.33)

    2.04 (1.16)

    2.13 (1.20)

    Distribution

    Mesalamine is approximately 43% bound to plasma proteins at the concentration of 2.5 µg/mL.

    Metabolism

    The only major metabolite of mesalamine (5-aminosalicylic acid) is N-acetyl-5-aminosalicylic acid. Its formation is brought about by N-acetyltransferase (NAT) activity in the liver and intestinal mucosa cells, principally by NAT-1.

    Elimination

    Elimination of mesalamine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21-22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The apparent terminal half-lives for mesalamine and its major metabolite after administration of mesalamine delayed-release tablets 2.4 g and 4.8 g were, on average, 7-9 hours and 8-12 hours, respectively.

    Drug Interactions

    The potential effect of mesalamine delayed-release tablets (4.8 g given once daily) on the pharmacokinetics of four commonly used antibiotics were evaluated in healthy subjects. The four antibiotics studied and their dosing regimens were as follows: amoxicillin (single 500 mg dose), ciprofloxacin XR (single 500 mg dose), metronidazole (750 mg twice daily for 3.5 days), and sulfamethoxazole/trimethoprim (800 mg/160 mg twice daily for 3.5 days). Coadministration of mesalamine delayed-release tablets did not result in clinically significant changes in the pharmacokinetics of any of the four antibiotics. The change in Cmax and AUC of amoxicillin, ciprofloxacin and metronidazole when they were co-administered with mesalamine delayed-release tablets were all ≤ 3%. There was an increase of 12% in Cmax and an increase of 15% in AUC of sulfamethoxazole when sulfamethoxazole/trimethoprim was coadministered with mesalamine delayed-release tablets [see Drug Interactions (7)].

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    In a 104-week dietary carcinogenicity study in CD-1 mice, mesalamine at doses up to 2500 mg/kg/day was not tumorigenic. This dose is 2.2 times the maximum recommended human dose (based on a body surface area comparison) of mesalamine delayed-release tablets. Furthermore, in a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800 mg/kg/day was not tumorigenic. This dose is 1.4 times the recommended human dose (based on a body surface area comparison) of mesalamine delayed-release tablets.

    Mutagenesis

    No evidence of mutagenicity was observed in an in vitro Ames test or an in vivo mouse micronucleus test.

    Impairment of Fertility

    No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 400 mg/kg/day (0.7 times the maximum recommended human dose based on a body surface area comparison).

    13.2 Animal Toxicology and/or Pharmacology

    In animal studies with mesalamine, a 13-week oral toxicity study in mice and 13-week and 52-week oral toxicity studies in rats and cynomolgus monkeys have shown the kidney to be the major target organ of mesalamine toxicity. Oral daily doses of 2400 mg/kg in mice and 1150 mg/kg in rats produced renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, tubular necrosis, and interstitial nephritis. In cynomolgus monkeys, oral daily doses of 250 mg/kg or higher produced nephrosis, papillary edema, and interstitial fibrosis.

    14 CLINICAL STUDIES

    14.1 Active, Mild to Moderate Ulcerative Colitis

    Two similarly designed, randomized, double-blind, placebo-controlled trials were conducted in 517 adult patients with active, mild to moderate ulcerative colitis. The study population was primarily Caucasian (80%), had a mean age of 42 years (6% age 65 years or older), and was approximately 50% male. Both studies used mesalamine delayed-release tablet doses of 2.4 g/day and 4.8 g/day administered once daily for 8 weeks except for the 2.4 g/day group in Study 1, which was given in two divided doses (1.2 g twice daily). The primary efficacy endpoint in both trials was to compare the percentage of patients in remission after 8 weeks of treatment for the mesalamine delayed-release tablet treatment groups versus placebo. Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) of ≤ 1, with scores of zero for rectal bleeding and for stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline.

    In both studies, the mesalamine delayed-release tablet doses of 2.4 g/day and 4.8 g/day demonstrated superiority over placebo in the primary efficacy endpoint (Table 5). Both mesalamine delayed-release tablet doses also provided consistent benefit in secondary efficacy parameters, including clinical improvement, treatment failure, clinical remission, and sigmoidoscopic improvement. Mesalamine delayed-release tablets 2.4 g/day and 4.8 g/day had similar efficacy profiles.

    Table 5: Patients in Remission at Week 8

    Dose

    Study 1

    (n = 262)

    n/N (%)

    Study 2

    (n = 255)

    n/N (%)

    Mesalamine Delayed-Release Tablets 2.4 g/day

    30/88 (34.1)

    34/84 (40.5)

    Mesalamine Delayed-Release Tablets 4.8 g/day

    26/89 (29.2)

    35/85 (41.2)

    Placebo

    11/85 (12.9)

    19/86 (22.1)

    14.2 Maintenance of Remission in Patients with Ulcerative Colitis

    A multicenter, randomized, double-blind, active comparator study was conducted in a total of 826 adult patients in remission from ulcerative colitis. The study population had a mean age of 45 years (8% age 65 years or older), were 52% male, and were primarily Caucasian (64%).

    Maintenance of remission was assessed using a modified Ulcerative Colitis Disease Activity Index (UC-DAI). For this trial, maintenance of remission was based on maintaining endoscopic remission defined as a modified UC-DAI endoscopy subscore of ≤ 1. An endoscopy subscore of 0 represented normal mucosal appearance with intact vascular pattern and no friability or granulation. For this trial the endoscopy score definition of 1 (mild disease) was modified such that it could include erythema, decreased vascular pattern, and minimal granularity; however, it could not include friability.

    Subjects were randomized in a 1:1 ratio to receive either mesalamine delayed-release tablets 2.4 g/day administered once daily or mesalamine delayed release 1.6 g/day administered as 0.8 g twice daily. The proportion of patients who maintained remission at Month 6 in this study using mesalamine delayed-release tablets 2.4 g once daily (83.7%) was similar to that seen using the comparator (mesalamine delayed release) 1.6 g/day (81.5%).

    16 HOW SUPPLIED/STORAGE AND HANDLING

    Mesalamine Delayed-Release Tablets, USP are available containing 1.2 g of mesalamine, USP.

    The 1.2 g tablets are tan, film-coated, ellipsoidal, unscored tablets imprinted with M1200 in black ink on one side of the tablet and plain on the other side. They are available as follows:

    NDC: 0378-7401-78
    bottles of 120 tablets

    NDC: 0378-7401-37
    bottles of 360 tablets

    Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

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

    17 PATIENT COUNSELING INFORMATION

    • Instruct patients not to take mesalamine delayed-release tablets if they have hypersensitivity to salicylates (e.g., aspirin) or other mesalamines.
    • Inform patients to let their physicians know all medications they are taking and if they:
      • ▪ are allergic to sulfasalazine, salicylates or mesalamine;
      • ▪ are taking non-steroidal anti-inflammatory drugs (NSAIDs) or other nephrotoxic agents;
      • ▪ are taking azathioprine, or 6-mercaptopurine;
      • ▪ experience cramping, abdominal pain, bloody diarrhea, fever, headache or rash;
      • ▪ have a history of myocarditis or pericarditis;
      • ▪ have kidney or liver disease;
      • ▪ have a history of stomach blockage;
      • ▪ are pregnant, intend to become pregnant or are breast-feeding;
      • ▪ have increased sensitivity of the skin to sun and ultraviolet light
    • Patients should be instructed to swallow mesalamine delayed-release tablets whole, taking care not to break the outer coating.

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Manufactured by:
    Mylan Laboratories Limited
    Hyderabad — 500 096, India

    75063045

    Revised: 5/2018
    MX:MSLMDR:R3

    PRINCIPAL DISPLAY PANEL – 1.2 g

    NDC: 0378-7401-78

    (ONCE DAILY)

    Mesalamine
    Delayed-Release
    Tablets, USP
    1.2 g

    Rx only   120 Tablets

    Each film-coated tablet contains:
    Mesalamine, USP 1.2 g

    Usual Dosage: See accompanying
    prescribing information.

    Keep this and all medication out of the
    reach of children.

    Store at 20° to 25°C (68° to 77°F). [See
    USP Controlled Room Temperature.]

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Made in India

    Mylan.com

    RMX7401DA1

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

    Keep container tightly closed.

    Code No.: MH/DRUGS/25/NKD/89

    Mesalamine Delayed-Release Tablets, USP 1.2 g Bottle Label
    MESALAMINE 
    mesalamine film coated tablet, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0378-7401
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    MESALAMINE (UNII: 4Q81I59GXC) (MESALAMINE - UNII:4Q81I59GXC) MESALAMINE1.2 g
    Inactive Ingredients
    Ingredient NameStrength
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    CARBOXYMETHYLCELLULOSE (UNII: 05JZI7B19X)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) (UNII: 74G4R6TH13)  
    METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    SHELLAC (UNII: 46N107B71O)  
    SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    TRIACETIN (UNII: XHX3C3X673)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    AMMONIA (UNII: 5138Q19F1X)  
    Product Characteristics
    ColorBROWN (tan) Scoreno score
    ShapeOVAL (ellipsoidal) Size21mm
    FlavorImprint Code M1200
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0378-7401-78120 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product12/14/2018
    2NDC: 0378-7401-37360 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product12/14/2028
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20357412/14/2018
    Labeler - Mylan Pharmaceuticals Inc. (059295980)

    Revised: 5/2018
     
    Mylan Pharmaceuticals Inc.


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