Mezavant: Indications, Dosage, Precautions, Adverse Effects
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Mezavant - Product Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Crohn's Disease, Maintenance, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Ulcerative Colitis, Active, Ulcerative Colitis, Maintenance, Ulcerative Proctitis
Class: 5-aminosalicylates
Form: Tablets
Ingredients: mesalamine, carnauba wax, magnesium stearate, methacrylic acid – methyl methacrylate copolymer (1:1), methacrylic acid – methyl methacrylate copolymer (1:2), red ferric oxide (E172), polyethylene glycol (macrogol) 6000, silica (colloidal hydrated), sodium carboxymethylcellulose, sodium starch glycolate (type A), stearic acid, talc, titanium dioxide (E171) and triethylcitrate

mesalamine Delayed- and Extended-Release Tablets

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
OralDelayed- and extended-release tablet 1.2gNone.
For a complete listing see Dosage Forms, Composition and Packaging Section.

Indications and Clinical Use

MEZAVANT (mesalamine delayed- and extended-release tablets) is indicated for:

  • Induction of remission (clinical and endoscopic) in patients with active, mild to moderate ulcerative colitis.
  • Maintenance of clinical and endoscopic remission (mucosal healing) in patients with ulcerative colitis.

Geriatrics (≥65 years of age):

Clinical trials of MEZAVANT did not include sufficient numbers of patients aged 65 years 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. Results of a single-dose study on the comparative pharmacokinetic profiles in elderly healthy subjects versus young healthy subjects indicate that systemic exposure to mesalamine increased by up to approximately 2- fold in elderly subjects (>65 years) compared with younger adult subjects (18-35 years) after a 4.8g single dose of MEZAVANT. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance. The potential impact on the safe use of MEZAVANT in the elderly population in clinical practice should be considered (see Warnings and PrecautionsSpecial Populations, Geriatrics, and Action and Clinical Pharmacology Pharmacokinetics, Absorption).

Pediatrics (<18 years of age):

The safety and effectiveness of mesalamine has not been established in children.

Contraindications

  • Patients who are hypersensitive to any salicylates (including mesalamine) or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.
  • Patients with severe renal impairment (GFR <30mL/min/1.73m2) and/or severe hepatic impairment (see Warnings & Precautions, Renal and Hepatic/Biliary/Pancreatic).

Warnings and Precautions

General

Mesalamine products should not be used in patients with existing gastric or duodenal ulcer, unless the expected benefit outweighs the risks. Extreme caution should be exercised and adequate care given to those patients.

Mesalamine products should not be used in patients with urinary tract obstruction, unless the expected benefit outweighs the risks. Extreme caution should be exercised and renal/urinary function should be closely monitored.

Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to MEZAVANT tablets or other compounds that contain or are converted to mesalamine. Therefore, caution should be exercised when treating patients allergic to sulfasalazine due to the potential risk of cross sensitivity reactions between sulfasalazine and mesalamine.

Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. 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. If acute intolerance syndrome is suspected, prompt withdrawal is required.

In patients with mild to moderate renal impairment, mesalamine products should be used only if the benefits outweigh the risks. Therefore, caution should be exercised, and it is recommended that all patients have an evaluation of renal function prior to initiation of therapy, and periodically while on treatment (see Renal).

In patients with mild to moderate impaired liver function, mesalamine products should be used only if the expected benefits outweigh the risks to the patient. Caution should be exercised (see Hepatic/Biliary/Pancreatic).

Patients should be instructed to swallow MEZAVANT tablets whole, taking care not to break the outer coating. The outer coating is designed to remain intact until at least pH 7, normally in the terminal ileum, to protect the active ingredient, mesalamine, and ensure its availability throughout the colon.

Administration of a single dose of MEZAVANT 4.8g with a high-fat meal in healthy volunteers increased systemic exposure of mesalamine compared to results in the fasted state (see Dosage and Administration, Drug Interactions – Drug-Food Interactions).

Cardiovascular

Mesalamine induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely with MEZAVANT and other mesalamine-containing preparations. Caution should be taken in prescribing this medication to patients with conditions predisposing to the development of myocarditis or pericarditis.

Gastrointestinal

Organic or functional obstruction in the upper gastrointestinal tract may delay onset of action of the product.

Mesalamine products should not be used in patients with existing gastric or duodenal ulcer, unless the expected benefit outweighs the risks. Extreme caution should be exercised and adequate care given to those patients.

Acute intolerance syndrome: See General sub-section above.

Hematologic

Following mesalamine treatment, serious blood dyscrasias (including myelosuppression) have been reported rarely. The risk is further increased when mesalamine products are used concomitantly with 6-mercaptopurine or azathioprine (see Drug Interactions – Drug-DrugInteractions). If the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat, haematological investigations should be performed. If there is suspicion of blood dyscrasia, mesalamine treatment should be discontinued.

Hepatic/Biliary/Pancreatic

There have been reports of hepatic failure and increased liver enzymes in patients with pre-existing liver disease when treated with mesalamine products. Therefore, mesalamine is contraindicated in patients with severe hepatic impairment (see Contraindications). In patients with mild to moderate liver function impairment, caution should be exercised and mesalamine products should only be used if the expected benefit clearly outweighs the risks to the patients. Appropriate assessment and monitoring of liver function should be performed.

Renal

Reports of renal impairment, including minimal change nephropathy, acute or chronic interstitial nephritis and renal failure have been associated with mesalamine products and pro-drugs of mesalamine. Mesalamine is contraindicated in patients with severe renal impairment (see Contraindications). In patients with mild to moderate renal dysfunction, caution should be exercised and mesalamine products should be used only if the benefits outweigh the risks. It is recommended that all patients have an evaluation of renal function prior to initiation of therapy and periodically while on treatment.

Respiratory

Patients with chronic lung function impairment, especially asthma, are at risk of hypersensitivity reactions with mesalamine products and should be closely monitored.

Special Populations

Pregnant Women: There are no adequate and well-controlled studies of mesalamine in pregnant women. Mesalamine is known to cross the placental barrier. MEZAVANT should only be used during pregnancy if the benefits outweigh the risks.

Nursing Women: Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. While there is limited experience of lactating women using mesalamine, caution should be exercised if MEZAVANT is administered to a nursing mother and used only if the benefits outweigh the risks.

Pediatrics (<18 years of age): Safety and effectiveness of MEZAVANT in pediatric patients who are less than 18 years of age have not been established.

Geriatrics (≥65 years of age): Clinical trials of MEZAVANT did not include sufficient numbers of patients aged 65 years 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. Results of a single-dose study on the comparative pharmacokinetic profiles in elderly healthy subjects versus young healthy subjects indicate that systemic exposure to mesalamine increased by up to approximately 2-fold in elderly subjects (>65 years) compared with younger adult subjects (18-35 years) after a 4.8g single dose of MEZAVANT (see Action and Clinical Pharmacology – Pharmacokinetics, Absorption). Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance. The potential impact on the safe use of MEZAVANT in the elderly population in clinical practice should be considered. 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.

Adverse Reactions

Adverse Drug Reaction Overview

MEZAVANT tablets have been evaluated in 1368 ulcerative colitis patients in controlled and open-label studies.

In the pooled safety analysis of patients with ulcerative colitis who participated in the clinical studies, the majority of subjects did not experience adverse drug reactions associated with MEZAVANT. Of the events reported, the majority were mild or moderate in severity. The most frequently reported adverse drug reactions within the pooled safety analysis of the ulcerative colitis patient clinical studies were colitis, headache, abdominal pain, liver function test abnormal, diarrhea and nausea.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Induction of Remission, including clinical remission and mucosal healing

In two 8-week placebo-controlled clinical studies involving 621 (Safety Population) ulcerative colitis patients, 356 received 2.4g/day or 4.8g/day MEZAVANT tablets. More adverse events occurred in the placebo group (119) than in each of the MEZAVANT treatment groups (109 in 2.4g/day, 92 in 4.8g/day). The most common adverse events with MEZAVANT were headache (4.5%) and flatulence (3.4%). A lower percentage of the 356 MEZAVANT patients discontinued therapy due to adverse events compared to placebo (2.2% vs. 7.3%). The most frequent adverse event leading to discontinuation from MEZAVANT therapy was exacerbation of ulcerative colitis (0.8%).

The majority of adverse events in the double-blind, placebo-controlled trials were mild or moderate in severity. The percentage of patients with severe adverse events was higher in the placebo treatment group (6.1% in placebo, 1.1% in MEZAVANT 2.4g/day, 2.2% in MEZAVANT 4.8g/day). The most common severe adverse events were gastrointestinal disorders which were mainly symptoms associated with ulcerative colitis. Pancreatitis occurred in less than 1% of patients during clinical trials and resulted in discontinuation of therapy with MEZAVANT in patients experiencing this event.

Overall, the percentage of patients who experienced any adverse event was similar across treatment groups. Treatment- related adverse events occurring in MEZAVANT or placebo groups at a frequency of at least 1% in two Phase 3, 8-week, double-blind, placebo-controlled trials are listed in Table 1.

Table 1: Treatment-Related Adverse Events in two Phase 3 Trials Experienced by at least 1% of the MEZAVANT Group and at a Rate Greater than Placebo
EventbMEZAVANTa
2.4g/day
n=177
(%)
MEZAVANTa
4.8g/day
n=179
(%)
Placeboa

n=179
(%)
Gastrointestinal Disorders
Flatulence3%2%2%
Investigations
Increased alanine aminotransferase1%1%0%
Nervous System Disorders
Headache3%2%0%
Skin and Subcutaneous Tissue Disorders
Pruritus1%1%0%
Alopecia0%1%0%

a Percentages are based on the number of patients in the safety population for each treatment group.
b Treatment-related adverse events for which the placebo rate equals or exceeds the rate for MEZAVANT are abdominal pain, decreased weight (placebo only), dizziness, dyspepsia, nausea, and ulcerative colitis.

The following treatment-related adverse events, presented by body system, were reported infrequently (less than 1%) by MEZAVANT-treated ulcerative colitis patients in controlled trials.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Cardiac Disorders: Uncommon: Tachycardia

Ear and Labyrinth Disorders: Uncommon: Ear pain

Gastrointestinal Disorders: Uncommon: Abdominal distension, diarrhea, pancreatitis, rectal polyp, vomiting

General Disorders and Administration Site Conditions: Uncommon: Asthenia, face edema, fatigue, pyrexia

Investigations: Uncommon: Elevated total bilirubin, thrombocytopenia

Musculoskeletal and Connective Tissue Disorders: Uncommon: Arthralgia, back pain

Nervous System Disorders: Uncommon: Somnolence, tremor

Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Pharyngolaryngeal pain

Skin and Subcutaneous Tissue Disorders: Uncommon: Acne, rash, urticaria

Vascular Disorders: Uncommon: Hypertension, hypotension.

Pooled Safety Analysis

In the pooled safety analysis of patients with ulcerative colitis who participated in the clinical studies (short- and long-term, n=1368), the majority of subjects did not experience treatment-emergent adverse events associated with MEZAVANT. Of the events reported, the majority were mild or moderate in severity. The most frequently reported adverse drug reactions within the pooled safety analysis of the ulcerative colitis patient clinical studies were colitis, headache, abdominal pain, liver function test abnormal, diarrhea and nausea. Adverse drug reactions observed during clinical trials (pooled safety analysis) are listed in Table 2.

Table 2: Adverse Drug Reactions Associated with MEZAVANT from Pooled Safety Analysis
System/Organ ClassIncidence CategoryAdverse Drug Reaction
Blood and Lymphatic System DisordersUncommon (≥0.1% and <1%)Thrombocytopenia
Cardiac DisordersUncommon (≥0.1% and <1%)Tachycardia
Ear and Labyrinth DisordersUncommon (≥0.1% and <1%)Ear pain
Gastrointestinal DisordersCommon (≥1% and <10%)Abdominal distension, Abdominal pain, Colitis, Diarrhea, Dyspepsia, Flatulence, Nausea, Vomiting
Uncommon (≥0.1% and <1%)Pancreatitis, Rectal polyp
General Disorders and Administration Site ConditionsCommon (≥1% and <10%)Asthenia, Fatigue, Pyrexia
Hepatobiliary DisordersCommon (≥1% and <10%)Liver Function Test abnormal (e.g. ALT, AST, Bilirubin)
Immune System DisordersCommon (≥1% and <10%)Hypersensitivity (including rash, pruritis, urticaria and face edema)
Musculoskeletal and Connective Tissue DisordersCommon (≥1% and <10%)Arthralgia, Back pain
Nervous System DisordersCommon (≥1% and <10%)Headache
Uncommon (≥0.1% and <1%)Dizziness, Somnolence, Tremor
Respiratory, Thoracic and Mediastinal DisordersUncommon (≥0.1% and <1%)Pharyngolaryngeal pain
Skin and Subcutaneous TissueDisordersUncommon (≥0.1% and <1%)Acne, Alopecia
Vascular DisordersCommon (≥1% and <10%)Hypertension
Uncommon (≥0.1% and <1%)Hypotension

Adverse Events Seen With Mezavant During Post-Marketing Surveillance

Blood and Lymphatic System Disorders: Agranulocytosis, leucopenia, neutropenia.

Cardiac Disorders: Myocarditis, pericarditis

General Disorders and Administration Site Conditions: Chest pain and discomfort

Hepatobiliary Disorders: Hepatitis

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

Musculoskeletal and Connective Tissue Disorders: Myalgia

Renal and Urinary Disorders: Interstitial nephritis, renal failure

Respiratory, Thoracic and Mediastinal Disorders: Asthma exacerbation in allergic patients, hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis).

Additional Adverse Events Seen With Other Mesalamine Products

Blood and Lymphatic System Disorders: Aplastic anemia, pancytopenia

Hepatobiliary Disorders: Cholelithiasis

Musculoskeletal and Connective Tissue Disorders: Systemic lupus erythematosus-like syndrome

Nervous System Disorders: Neuropathy

Renal and Urinary Disorders: Nephrotic syndrome

Reproductive System and Breast Disorders: Oligospermia

Respiratory, Thoracic and Mediastinal disorders: Bronchospasm.

Abnormal Hematologic and Clinical Chemistry Findings

In the pivotal studies conducted, there has been no notable change from baseline in mean hematology and biochemistry parameters.

Drug Interactions

Drug-Drug Interactions

Drug-drug interaction studies in healthy adult subjects have been conducted to investigate any effect of MEZAVANT on the pharmacokinetics and safety of four commonly used antibiotics. There were no clinically significant interactions of MEZAVANT with amoxicillin, ciprofloxacin XR, metronidazole or sulfamethoxazole. However, the following drug-drug interactions have been reported for products containing mesalamine:

  • The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) and azathioprine may increase the risk of renal reactions.
  • In patients receiving azathioprine or 6-mercaptopurine, concurrent use of mesalamine can increase the potential for blood disorders, especially leucopenia.

Drug-Food Interactions

Administration of a single dose of MEZAVANT 4.8g with a high -fat meal* in healthy volunteers resulted in further delay in absorption and plasma concentrations of mesalamine were detectable 4 hours following dosing. However, high-fat meal increased systemic exposure of mesalamine (mean Cmax: ↑91%; mean AUC: ↑16%) compared to results in the fasted state; consideration should be given to this observation when prescribing to patients expected to consume high-fat meals. However, MEZAVANT was administered with food, part of an unrestricted diet, in the pivotal Phase 3 trials.

* The high-fat meal, or equivalent, was two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces (113g) of hash brown potatoes and eight ounces (237mL) of whole milk.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.

Dosage and Administration

Recommended Dose and Dosage Adjustment

MEZAVANT is intended for once-daily, oral administration with food. The tablets should be swallowed whole with liquid and should not be crushed or chewed.

The recommended dose for the induction of remission in patients with mild to moderate ulcerative colitis is two to four 1.2g tablets to be taken once daily for a total daily dose of 2.4 to 4.8g. No difference in remission rates was noted between doses of 2.4g/day and 4.8g/day, but trends in improvement in the sigmoidoscopy score and clinical improvement (reduction in UC-DAI from baseline of 3 points) was noted at 4.8g/day dose versus 2.4g/day (see Clinical Trials). The studies were not powered to look at differences between MEZAVANT dosing regimens of 2.4g/day and 4.8g/day. Similar efficacy was shown when a total daily dose of 2.4g of MEZAVANT was given as one dose (QD) or when given in two divided doses (BID).

The recommended dose for the maintenance of clinical and endoscopic remission (mucosal healing) is two 1.2g tablets to be taken once daily for a total daily dose of 2.4g.

Administration of a single dose of MEZAVANT 4.8g with a high-fat meal in healthy volunteers increased systemic exposure of mesalamine compared to results in the fasted state; consideration should be given to this observation when prescribing to patients expected to consume high-fat meals. However, MEZAVANT was administered with food, part of an unrestricted diet, in the pivotal Phase 3 trials (see Drug Interactions - Drug-Food Interactions, Action and ClinicalPharmacology – Pharmacokinetics, Absorption).

Children: The safety and effectiveness of mesalamine has not been established in children. As for tablets needing to be swallowed whole, consideration should be given to the ability to swallow the intact tablet.

Elderly: 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.

Missed Dose

If a dose of this medication has been missed, it should be skipped and taken as usual the next day.

Overdosage

MEZAVANT is an aminosalicylate, and symptoms of salicylate toxicity may include confusion, diarrhea, drowsiness, headache, hyperventilation, sweating, tinnitus, vertigo, and vomiting. Severe intoxication may lead to disruption of electrolyte balance and blood-pH, hyperthermia, and dehydration.

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.

For management of a suspected drug overdose, contact your regional Poison Control Center.

Action and Clinical Pharmacology

The MEZAVANT tablet contains a core of mesalamine (5-aminosalicylic acid), 1.2g, formulated with MMX Multi Matrix System* technology. The tablet is coated with a gastro-resistant film of methacrylic acid – methyl methacrylate copolymer (1:1) and methacrylic acid – methyl methacrylate copolymer (1:2), which are designed to delay the initial release of mesalamine until exposure to approximately pH 7 and above, normally in the terminal ileum. A consistent and sustained release was observed across the pH range 6.8 to 7.2. The MMX* technology uses a matrix of lipophilic and hydrophilic excipients which, along with the gastro-resistant coating, facilitate the delayed and extended delivery of effective concentrations of mesalamine through the entire colon, with limited systemic absorption.

* MMX Multi Matrix System and MMX are registered trade-marks used under licence from Cosmo Technologies, Ltd.

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 (NFκB) and consequently the production of key pro-inflammatory cytokines. More recently, it has been proposed that impairment of PPAR-γ nuclear receptors (γ-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. PPAR-γ receptor agonists have shown efficacy in ulcerative colitis and evidence has been accumulating that the mechanism of action of mesalamine may be mediated by PPAR-γ receptors.

Pharmacodynamics

The pharmacodynamic actions of mesalamine occur in the colonic/rectal mucosa local to the delivery of drug from MEZAVANT 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. However, plasma concentrations representing systemically absorbed mesalamine are not believed to contribute extensively to efficacy.

Pharmacokinetics

The pharmacokinetic information in this section is based on data from Phase 1 studies with MEZAVANT and from studies carried out with other formulations of mesalamine.

MEZAVANT contains a 1.2g core of mesalamine formulated in a multi-matrix system. This system is coated with methacrylic acid – methyl methacrylate copolymer (1:1) and methacrylic acid – methyl methacrylate copolymer (1:2), which are designed to dissolve at pH 7 and above, facilitating the extended delivery of effective concentrations of mesalamine through the entire colon with limited systemic absorption.

Absorption

The total absorption of mesalamine from MEZAVANT 2.4g or 4.8g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose. Steady-state was achieved generally by 2 days after dosing.

Gamma-scintigraphy studies have shown that a single dose of MEZAVANT 1.2g (one tablet) passed rapidly and intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radiolabelled tracer throughout the colon and rectum, indicating that mesalamine had distributed throughout the targeted site of action. Complete disintegration of MEZAVANT and complete release of mesalamine occurred after approximately 17.4 hours. Availability of mesalamine in the colon begins at 6 hours after dosing and continues beyond 24 hours post-dose. Following a single dose of MEZAVANT 4.8g, detectable levels of mesalamine remain in the plasma for up to 72 hours post-dose.

In a single- and multiple-dose pharmacokinetic study, MEZAVANT 2.4 or 4.8g was administered once daily with standard meals in 56 healthy volunteers (28 per dose group). Plasma concentrations of mesalamine were detectable after 4 hours and were maximal by 8 hours after the single dose. Accumulation was found to be between 1.7- and 2.4-fold and was independent of dose. This extent of accumulation was only modestly greater (1.1- to 1.4-fold) than predictable from single-dose pharmacokinetics.

After a single dose of MEZAVANT, total systemic exposure of 5-ASA appeared to increase slightly more than dose proportionately, with area under the plasma concentration-time curve (AUC) increasing approximately 2.5-fold for a 2-fold dose increase from 2.4g to 4.8g. However there was no evidence of steady-state systemic exposure increasing more than proportionately with dose.

In a single-dose study, MEZAVANT 1.2g, 2.4g and 4.8g 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 (see Table 3). Mesalamine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was slightly more than dose proportional between 1.2g and 4.8g MEZAVANT. Maximum plasma concentrations (Cmax) of mesalamine increased approximately dose proportionately between 1.2g and 2.4g and sub-proportionately between 2.4g and 4.8g MEZAVANT, with the dose-normalized value at 4.8g representing, on average, 74% of that at 2.4g based on geometric means.

Table 3: Mean (SD) Pharmacokinetic Parameters for Mesalamine Following Single-Dose Administration of MEZAVANT under Fasting Conditions
Parameter1 of MesalamineMEZAVANT 1.2g
n=47
MEZAVANT 2.4g
n=48
MEZAVANT 4.8g
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)7.05§ (5.54)7.25# (8.32)

1 Arithmetic mean of parameter values are presented except for Tmax and Tlag
* Median (min, max); +n=43, n=27, §n=33, #n=36, **n=46

Administration of a single dose of MEZAVANT 4.8g 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.

In a single-dose pharmacokinetic study of MEZAVANT, 4.8g was administered in the fasted state to 71 healthy male and female volunteers [28 young (18-35 years); 28 elderly (65-75 years); 15 elderly (>75 years)]. Increased age resulted in increased systemic exposure (up to approximately 2-fold, based on AUC0-t, AUC0-∞ and Cmax) to mesalamine and its metabolite, N-acetyl-5 -aminosalicylic acid, but did not affect the percentage of mesalamine absorbed (see Table 4). 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) Pharmacokinetic Parameters for Mesalamine Following Single-Dose Administration of MEZAVANT 4.8g Fasting Conditions to Young and Elderly Subjects
Parameter of 5-ASAYoung Subjects
(18-35yrs)
n=28
Elderly Subjects
(65-75yrs)
n=28
Elderly Subjects
(>75yrs)
n=15
AUC0-t (ng.h/mL)51570 (23870)73001 (4260865820 (25283)
AUC0-∞ (ng.h/mL)58057b (22429)89612c (40596)63067d (22531)
Cmax (ng/mL)2243 (1410)4999 (4381)4832 (4383)
tmax a (h)22.0 (5.98 - 48.0)12.5 (4.00 - 36.0)16.0 (4.00 - 26.0
tlag a (h)2.00 (1.00 - 6.00)2.00 (1.00 - 4.00)2.00 (2.00 - 4.00)
t1/2 (h), terminal phase5.68b (2.83)9.68c (7.47)8.67d (5.84)
Renal clearance (L/h)2.05 (1.33)2.04 (1.16)2.13 (1.20)

Arithmetic mean (SD) data are presented, n = number of subjects
a Median (min - max), bn=15, cn=16, dn=13

Distribution

Following dosing of MEZAVANT, the distribution profile of mesalamine is presumed to be the same as that for other mesalamine-containing products. Mesalamine has a relatively small volume of distribution of approximately 18L, confirming minimal extravascular penetration of systemically-available drug, which is consistent with the absence of any significant secondary pharmacology. Mesalamine is 43% bound to plasma proteins when in vitro plasma concentrations are 2.5 mg/mL.

Metabolism

The only major metabolite of mesalamine (5- aminosalicylic acid) is N-acetyl-5-aminosalicylic acid, which is pharmacologically inactive. Its formation is brought about by N-acetyltransferase (NAT) activity in the liver and in the cytosol of intestinal mucosal cells, principally by NAT-1. Although this enzyme is known to be subject to genetic polymorphism, NAT-1 genotypes have been shown not to be predictive of mesalamine efficacy or toxicity.

Excretion

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 at steady-state, 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 MEZAVANT 2.4g and 4.8g were, on average, 7-9 hours and 8-12 hours, respectively.

Special Populations and Conditions

Pediatrics

No information is available in patients who are less than 18 years of age (see Warnings and Precautions – Special Populations, Pediatrics).

Geriatrics

Systemic exposure to mesalamine increased by up to approximately 2-fold in elderly subjects (>65 years) compared with younger adult subjects (18-35 years) after a 4.8g single dose of MEZAVANT (see Action and Clinical Pharmacology - Pharmacokinetics, Absorption). Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance. The potential impact on the safe use of MEZAVANT in the elderly population in clinical practice should be considered (see Warnings andPrecautions – Special Populations, Geriatrics).

Gender

No consistent trend on gender effect was observed in the clinical trials.

Race

No pharmacokinetic information is available that examines MEZAVANT in different races.

Hepatic Insufficiency

No pharmacokinetic information is available for patients with hepatic impairment (see Warnings and Precautions – Hepatic/Biliary/Pancreatic, AdverseReactions).

Renal Insufficiency

No pharmacokinetic information is available for patients with mild, moderate and severe renal impairment (see Warnings and Precautions - Renal, AdverseReactions).

Genetic Polymorphism

Mesalamine is principally metabolised by NAT-1. Although this enzyme is known to be subject to genetic polymorphism, NAT-1 genotypes have been shown not to be predictive of mesalamine efficacy or toxicity.

Storage and Stability

Store at room temperature 15°C to 25°C; excursions permitted to 30°C.

Dosage Forms, Composition and Packaging

MEZAVANT tablets are available as red-brown ellipsoidal film-coated tablets containing 1.2g of mesalamine, and debossed on one side with S476.

The MEZAVANT delayed- and extended-release tablet contains a core of 5-aminosalicylic acid (5-ASA; mesalamine), 1200mg, formulated with MMX Multi Matrix System technology. The tablet is coated with a gastro-resistant film of methacrylic acid – methyl methacrylate copolymer (1:1) and methacrylic acid – methyl methacrylate copolymer (1:2), which are designed to delay the initial release of mesalamine until exposure to approximately pH 7 and above, normally in the terminal ileum. A consistent and sustained release was observed across the pH range 6.8 to 7.2. The MMX technology uses a matrix of lipophilic and hydrophilic excipients which, along with the gastro-resistant coating, facilitate the delayed and extended delivery of effective concentrations of mesalamine through the entire colon with limited systemic absorption.

The inactive ingredients of MEZAVANT tablets are carnauba wax, magnesium stearate, methacrylic acid – methyl methacrylate copolymer (1:1), methacrylic acid – methyl methacrylate copolymer (1:2), polyethylene glycol (macrogol) 6000, red ferric oxide (E172), silica (colloidal hydrated), sodium carboxymethylcellulose, sodium starch glycolate (type A), stearic acid, talc, titanium dioxide (E171), and triethylcitrate.

MEZAVANT tablets do not contain gluten, lactose or phthalates.

MEZAVANT tablets are supplied in opaque high density polyethylene (HDPE) bottles of 60 or 120 tablets with child-resistant closure.