Mezavant Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ............................................................................................................... 2

Table of Contents ................................................................................................................................ 2

Part 1: Healthcare Professional Information ........................................................................................ 4

1 Indications .............................................................................................................................. 4

1.1 Pediatrics ...........................................................................................................................4

1.2 Geriatrics ............................................................................................................................4

2 Contraindications ................................................................................................................... 4

4 Dosage and Administration .................................................................................................... 4

4.1 Dosing Considerations .......................................................................................................4

4.2 Recommended Dose and Dosage Adjustment ..................................................................5

4.4 Administration ...................................................................................................................5

4.5 Missed Dose .......................................................................................................................5

5 Overdose ................................................................................................................................ 5

6 Dosage Forms, Strengths, Composition and Packaging ............................................................ 6

7 Warnings and Precautions ...................................................................................................... 6

General .......................................................................................................................................6

Carcinogenesis and Genotoxicity ...............................................................................................7

Cardiovascular ............................................................................................................................7

Gastrointestinal ..........................................................................................................................7

Hematologic ...............................................................................................................................7

Hepatic/Biliary/Pancreatic .........................................................................................................7

Neurologic .................................................................................................................................8

Renal .........................................................................................................................................8

Respiratory .................................................................................................................................8

Skin .........................................................................................................................................8

7.1 Special Populations ............................................................................................................9

7.1.1 Pregnancy .......................................................................................................................9

7.1.2 Breastfeeding ...................................................................................................................9

7.1.3 Pediatrics .........................................................................................................................9

7.1.4 Geriatrics ..........................................................................................................................9

8 Adverse Reactions .................................................................................................................. 9

8.1 Adverse Reaction Overview ...............................................................................................9

8.2 Clinical Trial Adverse Reactions ...................................................................................... 10

8.3 Less Common Clinical Trial Adverse Reactions ............................................................... 12

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ......................................................................................................................... 12

8.5 Post-Market Adverse Reactions ...................................................................................... 12

9 Drug Interactions .................................................................................................................. 13

9.2 Drug Interactions Overview ............................................................................................ 13

9.3 Drug-Behaviour Interactions ........................................................................................... 14

9.4 Drug-Drug Interactions ................................................................................................... 14

9.5 Drug-Food Interactions ................................................................................................... 14

9.6 Drug-Herb Interactions ................................................................................................... 15

9.7 Drug-Laboratory Test Interactions .................................................................................. 15

10 Clinical Pharmacology ........................................................................................................... 15

10.1 Mechanism of Action ...................................................................................................... 15

10.2 Pharmacodynamics ......................................................................................................... 15

10.3 Pharmacokinetics ............................................................................................................ 16

11 Storage, Stability and Disposal .............................................................................................. 19

Part 2: Scientific Information ............................................................................................................ 20

13 Pharmaceutical Information ................................................................................................. 20

14 Clinical Trials ........................................................................................................................ 20

14.1 Clinical Trials by Indication.............................................................................................. 20

15 Microbiology ........................................................................................................................ 27

16 Non-Clinical Toxicology ......................................................................................................... 27

Patient Medication Information ........................................................................................................ 28

Part 1: Healthcare Professional Information

1 Indications

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.

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥65 years of age): Clinical trials of MEZAVANT did not include sufficient numbers of patients aged 65 years and over to determine whether elderly patients respond differently from younger patients. Evidence from the pharmacokinetic study indicates that systemic exposure to mesalazine and its metabolite N-acetyl-5-aminosalicylic acid in geriatrics subjects is up to 2-fold higher than in adult subjects (18-35 years). The potential impact on the safe use of MEZAVANT in the elderly population in clinical practice should be considered (7.1.4 WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics; 10.3 Pharmacokinetics, Absorption).

2 Contraindications

MEZAVANT is contraindicated in:

• Patients who are hypersensitive to any salicylates (including mesalamine) or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing (see 6 Dosage Forms, Strengths, Composition and Packaging).
• Patients with severe renal impairment (GFR <30 mL/min/1.73 m2) and/or severe hepatic impairment (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic).

4 Dosage and Administration

4.1 Dosing Considerations

• Administration of a single dose of MEZAVANT 4.8 g 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 9.5 Drug Interactions, Drug-Food Interactions and 10.3 Clinical Pharmacology, Pharmacokinetics, Absorption).

• 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 7 Warnings and Precautions, Renal).

4.2 Recommended Dose and Dosage Adjustment

MEZAVANT is intended for once daily, oral administration with food.

The recommended dose for the induction of remission in patients with mild to moderate ulcerative colitis is two to four 1.2 g tablets to be taken once daily for a total daily dose of 2.4 to 4.8 g.

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

As for tablets needing to be swallowed whole, consideration should be given to the ability to swallow the intact tablet.

Pediatrics:

Health Canada has not authorized an indication for pediatric use.

Geriatrics:

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. 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 7 Warnings and Precautions, Renal; 7.1.4 Special Populations, Geriatrics; and 10.3 Pharmacokinetics Special Populations and Conditions).

4.4 Administration

The tablets should be swallowed whole with liquid and should not be crushed or chewed 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.

4.5 Missed Dose

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

5 Overdose

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. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy. Maintain adequate renal function.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844-POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition and Packaging

Table 1: Dosage Forms, Strengths, Composition and Packaging.

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

The MEZAVANT delayed- and extended-release tablet contains a core of 1200 mg mesalamine (5-aminosalicylic acid; 5-ASA), formulated with a matrix of lipophilic and hydrophilic excipients. 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) (MMX Multi Matrix System®), 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 combination of the matrix of lipophilic and hydrophilic excipients (MMX Multi Matrix System®) and gastro-resistant coating facilitate the delayed and extended delivery of effective concentrations of mesalamine through the entire colon with limited systemic absorption.

MEZAVANT tablets do not contain gluten, lactose or phthalates.

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

7 Warnings and Precautions

General

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.

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 impaired liver function, mesalamine products should be used only if the expected benefits outweigh the risks to the patient. Caution should be exercised (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic).

Carcinogenesis and Genotoxicity

Preclinical carcinogenicity and mutagenicity studies demonstrated mesalamine was not tumorigenic and there was no evidence of mutagenicity (see 16 Non-Clinical Toxicology).

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 7.Warnings and Precautions/General.

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 9 Drug Interactions, Drug-Drug Interactions). 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 2 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.

Neurologic

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving mesalazine. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances or tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of mesalazine should be considered.

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.

Cases of nephrolithiasis have been reported with the use of mesalazine, including stones with a 100% mesalazine content. Ensure adequate fluid intake during treatment.

Mesalamine is contraindicated in patients with severe renal impairment (see 2 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 based on clinical judgment taking baseline renal function into account (see 10.3 Pharmacokinetics). Treatment should be discontinued if renal function deteriorates.

Respiratory

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

Skin

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

Hypersensitivity:

Use of mesalazine has been associated with the following serious and life-threatening skin reactions:

• Drug reaction with eosinophilia and systemic symptoms (DRESS),
• Severe cutaneous adverse reactions (SCARs),
• Stevens-Johnson syndrome (SJS),
• Toxic epidermal necrolysis (TEN).

At the time of prescription, patients should be informed of the signs and symptoms of SJS, TEN and DRESS, and be advised to monitor closely for skin reactions. Discontinue mesalazine at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

7.1 Special Populations

7.1.1 Pregnancy

There are no adequate and well-controlled studies of mesalamine in pregnant women. Mesalamine is known to cross the placental barrier. Premature labor, congenital malformations, and other adverse pregnancy outcomes (including serious events such as ectrodactyly, oligohydramnios, congenital nephrotic syndrome, and fetal tachycardia) were reported in infants born to mothers who were exposed to mesalamine during pregnancy. One case each of fetal anemia and hydrops fetalis were also reported in one infant. MEZAVANT should therefore only be used during pregnancy if the benefits outweigh the risks.

7.1.2 Breastfeeding

Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. There is limited experience in breastfeeding women using mesalamine. Serious cases of diarrhea has been reported in breastfed infants of mothers exposed to mesalamine.

When MEZAVANT is used in nursing women, infants should be monitored for changes in stool consistency as hypersensitivity reactions manifested as diarrhea in the infants have been reported. If the infant develops diarrhea, breastfeeding should be discontinued. Caution should be exercised if MEZAVANT is administered to a nursing mother and used only if the benefits outweigh the risks.

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

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(see 7 Warnings and Precautions, Renal and 10.3 Pharmacokinetics)

8 Adverse Reactions

8.1 Adverse 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 ulcerative colitis, headache, abdominal pain, liver function test abnormal, diarrhea and nausea.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect the frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Induction of Remission, Including Clinical Remission and Mucosal Healing

In two 8-week double blind placebo-controlled clinical studies involving 621 (ITT Population) (Study SPD476-301 and SPD476-302) mild to moderate ulcerative colitis patients, 356 received 2.4 g/day or 4.8 g/day MEZAVANT tablets. More adverse events occurred in the placebo group (119) than in each of the MEZAVANT treatment groups (109 in 2.4 g/day, 92 in 4.8 g/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 these 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 2.4 g/day, 2.2% in MEZAVANT 4.8 g/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 these two trials are listed in Table 2.

^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.

Pooled Safety Analysis

The pooled safety analysis of patients with ulcerative colitis who received at least one dose of study medication and participated in clinical studies (short- and long-term, n=1368). Subjects from studies SPD476-301 and SPD476-302 were eligible for enrolment into the longterm extension (ie 12-14 months) safety and tolerability study SPD476-303, which consists of an 8-week acute phase using SPD476 4.8g/day BID and a randomised maintenance phase, to provide long-term safety data on SPD476 2.4g/day QD vs 2.4g/day BID. 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 3.

Table 3: Adverse Drug Reactions Associated with MEZAVANT from Pooled Safety Analysis

8.3 Less Common Clinical Trial Adverse Reactions

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 (Study SPD476-301 and SPD476-302).

Blood and lymphatic system disorders: thrombocytopenia

Cardiac Disorders: Tachycardia

Ear and Labyrinth Disorders: Ear pain

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

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

Investigations: Elevated total bilirubin

Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain

Nervous System Disorders: Somnolence, tremor

Respiratory, Thoracic and Mediastinal Disorders: Laryngeal pain

Skin and Subcutaneous Tissue Disorders: Acne, rash, urticaria

Vascular Disorders: Hypertension, hypotension.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

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

8.5 Post-Market Adverse Reactions

The following Post-Market Adverse Reactions have been seen with MEZAVANT and other mesalamine products.

Blood and Lymphatic System Disorders: Agranulocytosis, aplastic anemia, leucopenia, neutropenia, pancytopenia.

Cardiac Disorders: Myocarditis, pericarditis.

Congenital, Familial and Genetic disorders:, congenital nephrotic syndrome, ectrodactyly

General Disorders and Administration Site Conditions: Chest pain and discomfort.

Hepatobiliary Disorders: Cholelithiasis, hepatitis, hepatotoxicity.

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

Musculoskeletal and Connective Tissue Disorders: Lupus-like syndrome, myalgia.

Nervous System Disorders: Idiopathic intracranial hypertension (see 7 Warnings and Precautions, Idiopathic Intracranial hypertension, neuropathy peripheral.

Pregnancy and Puerperium and Perinatal Conditions: premature labor, foetal anemia, hydrops foetalis, oligohydramnios, fetal tachycardia.

Renal and Urinary Disorders: Chromaturia (see below), nephrogenic diabetes insipidus (see below), nephrotic syndrome, nephrolithiasis, renal failure, tubulointerstitial nephritis.

Reproductive System and Breast Disorders: Oligospermia (reversible).

Respiratory, Thoracic and Mediastinal Disorders: Acute interstitial pneumonitis, allergic asthma hypersensitivity pneumonitis, bronchospasm, eosinophilic pneumonia, interstitial lung disease, pleurisy.

Skin and Subcutaneous Tissue Disorders: Photosensitivity

Descriptions of Selected Adverse Reactions

Chromaturia: Mesalazine may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches).

Nephrogenic diabetes insipidus: Cases of nephrogenic diabetes insipidus have been reported with mesalamine use. The main symptoms of nephrogenic diabetes insipidus are polyuria (excessive urine production/excretion), nocturia (nocturnal polyuria), and polydipsia (excessive thirst). Other symptoms can include tiredness, loss of appetite and weight loss.

9 Drug Interactions

9.2 Drug Interactions Overview

No investigations of interaction between MEZAVANT and other drugs except for four commonly used antibiotics have been performed. The studies demonstrated there were no clinically significant interactions of MEZAVANT with these antibiotics (see 9.4 Drug-Drug Interactions).

Drug interactions with nephrotoxic agents, including non-steroidal anti-inflammatory drugs and azathioprine or 6-mercaptopurine have been reported for products containing mesalamine. The reported interactions indicated the concurrent use of mesalamine can increase the potential for blood disorders (especially leucopenia), bone marrow failure, associated complications, and may increase the risk of renal reactions with the respective concurrent drugs (see 9.4 Drug-Drug Interactions).

9.3 Drug-Behaviour Interactions

The interaction of MEZAVANT with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4 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.

The drugs listed in Table 4 have been reported for products containing mesalamine.

Table 4 – Established or Potential Drug – Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Administration of a single dose of MEZAVANT 4.8 g with a high fat meal¹ 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 C_max: ↑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.

¹ The high-fat meal, or equivalent, was two eggs fried in butter, two strips of bacon, two slices of toast with butter, 113 g (4 ounces) of hash brown potatoes and 237 mL (8 ounces) of whole milk.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test 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.

10 Clinical Pharmacology

10.1 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.

In non-clinical studies, mesalamine has been shown to possess anti-oxidant properties in a range of systems in vitro. It also stimulates phospholipase D activity which may inhibit pro-inflammatory events. Mesalamine has also been shown to inhibit the production of the metabolites of arachidonic acid, particularly leukotriene B4 (LTB4), an important mediator in chronic inflammatory diseases.

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.

10.2 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.

10.3 Pharmacokinetics

Table 5: Mean (SD) Pharmacokinetic Parameters for Mesalamine Following Single-Dose Administration of MEZAVANT under Fasting Conditions

¹ Arithmetic mean of parameter values are presented except for T_max and T_lag

* Median (min, max); ⁺n=43, ^•n=27, ^§n=33, ^#n=36, **n=46

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 1.2 g 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 2.4 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. Steady-state was achieved generally by 2 days after dosing.

Gamma-scintigraphy studies have shown that a single dose of MEZAVANT 1.2 g (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 4.8 g, 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 4.8 g 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 2.4 g to 4.8 g. However there was no evidence of steady-state systemic exposure increasing more than proportionately with dose.

In a single dose study, MEZAVANT 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 (see Table 5). 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 MEZAVANT. Maximum plasma concentrations (C_max) 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 MEZAVANT, with the dose-normalized value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means.

Administration of a single dose of MEZAVANT 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 C_max: ↑91%; mean AUC: ↑16%) compared to results in the fasted state.

In a single-dose pharmacokinetic study of MEZAVANT, 4.8 g 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 AUC_0-t, AUC_0-∞ and C_max) to mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, but did not affect the percentage of mesalamine absorbed (see Table 6). 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 6: Mean (SD) Pharmacokinetic Parameters for Mesalamine Following Single-Dose Administration of MEZAVANT 4.8 g Fasting Conditions to Young and Elderly Subjects

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 18 L, 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 mcg/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.

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 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 2.4 g and 4.8 g 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 7 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 4.8 g single dose of MEZAVANT (see 10 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 7 Warnings and Precautions, Special Populations, Geriatrics).
• Sex: No consistent trend effect was observed in the clinical trials based on sex.
• 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.
• Ethnic Origin: No pharmacokinetic information is available that examines MEZAVANT in different ethnic origins.
• Hepatic Insufficiency: No pharmacokinetic information is available for patients with hepatic impairment (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic; 8 Adverse Reactions).
• Renal Insufficiency: No pharmacokinetic information is available for patients with mild, moderate and severe renal impairment (see 7 Warnings and Precautions, Renal; 8 Adverse Reactions).

11 Storage, Stability and Disposal

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

Keep out of reach and sight of children

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Proper name: mesalamine

Chemical name: 5-amino-2-hydroxybenzoic acid

Molecular formula and molecular mass: C₇H₇NO₃ 153.14

Structural formula:

Physicochemical properties:

Mesalamine is an almost white to light pink/gray/brown powder or crystals that decomposes at 280°C and is very slightly soluble in water.

The pH of 2.5% aqueous suspension is 3.5 - 4.5.

pKa value: 5.8

14 Clinical Trials

14.1 Clinical Trials by Indication

Active, Mild to Moderate Ulcerative Colitis:

Two similarly designed, randomized, double-blind, placebo-controlled trials were conducted in adult patients with active, mild to moderate ulcerative colitis. Study SPD476-301 assessed the efficacy and safety of MEZAVANT 2.4 g/day (1.2 g given twice daily) and 4.8 g/day (given once daily) against placebo in 280 patients. Study SPD476-302 assessed the safety and efficacy of MEZAVANT 2.4 g/day and 4.8 g/day (both given once daily) against placebo in 341 patients. A pH dependent delayed-release mesalamine 2.4 g/day (administered as two 400 mg tablets given three times daily) was included in this study as a reference arm; the study was not designed to demonstrate non-inferiority of MEZAVANT against pH dependent delayed release mesalamine.

Maintenance of remission:

A multicenter, randomized, double-blind, double-dummy, parallel-group, non-inferiority, active comparator study (SPD476-304) was designed to assess the number of subjects who remained in endoscopic remission (maintenance of mucosal healing) following 6 months of study treatment. Subjects were randomized in a 1:1 ratio to receive either MEZAVANT 2.4 g/day administered once daily (QD) or pH-dependent delayed-release mesalamine 1.6 g/day administered as two 400 mg tablets given twice daily (BID).

HO

COOH

NH₂

Table 7: Summary of Baseline Demographic Characteristics for Patients with Ulcerative Colitis

^a Based on ITT population

^b Based on Per Protocol population

Induction of Remission, Including Clinical Remission and Mucosal Healing

The primary efficacy endpoint in studies SPD476-301 and SPD476-302 was to compare the percentage of patients in remission, a composite endpoint indicative of clinical remission and mucosal healing, after 8 weeks of treatment for the MEZAVANT treatment groups vs. placebo. Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) score of ≤1. To be considered in remission, a subject was required to have no blood in stools and normal stool frequency. Also, they could have either a Physician Global Assessment of 1 (mild disease) or improvement of the mucosal appearance that lead to a maximum sigmoidoscopy score of 1 (mild erythema, decreased vascularity, minimal granularity) as long as there had been at least a 1-point drop from baseline in the sigmoidoscopy score.

The scoring system used for sigmoidoscopy was modified to be more stringent than the standard UC-DAI system, which allows patients with mild friability to be given a sigmoidoscopy score of 1. Results for the primary variable of remission in study SPD476-301 are shown in Table 8. Both MEZAVANT 2.4 g/day (1.2 g given twice daily) and 4.8 g/day (given once daily) demonstrated superiority over placebo. Results for study SPD476-302 are also shown in Table 8. Both MEZAVANT 2.4 g/day and 4.8 g/day (both given once daily) demonstrated superiority over placebo.

Table 8: Summary of Primary Efficacy Results for Studies SPD476-301 and SPD476-302 in Mild to Moderate, Active Ulcerative Colitis – ITT Population

^a pH-dependent delayed-release mesalamine was included in this study as a reference arm; the study was not designed to demonstrate non-inferiority of MEZAVANT against pH-dependent delayed-release mesalamine.

* Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) score of ≤1. To be considered in remission, a subject was required to have no blood in stools and normal stool frequency. Also, they could have either a Physician Global Assessment of 1 (mild disease) or improvement of the mucosal appearance that lead to a maximum sigmoidoscopy score of 1 (mild erythema, decreased vascularity, minimal granularity) as long as there had been at least a 1-point drop from baseline in the sigmoidoscopy score. The scoring system used for sigmoidoscopy was modified to be more stringent than the standard UC-DAI system, which allows patients with mild friability to be given a sigmoidoscopy score of 1.

^‡ Values from the chi-squared test.

^† Study-wise false-positive error rate was controlled using the Bonferroni-Holm method. The treatment comparison with the smaller p-value was evaluated at the 0.025 significance level. If this was significant, the treatment comparison with the larger p-value was evaluated at the 0.05 significance level. Confidence Intervals (CI) presented are analogous to the significance level, i.e., 97.5% and 95%.

The studies were not powered to look at differences between MEZAVANT doses. There was no statistically significant difference in remission rates between MEZAVANT 2.4 g/day twice daily and MEZAVANT 4.8 g/day once daily or between MEZAVANT 2.4 g/day once daily and MEZAVANT 4.8 g/day once daily. The secondary efficacy parameters, including clinical improvement and change in UC-DAI score and its components (including assessment of treatment failure, clinical remission and sigmoidoscopy) supported the primary findings by demonstrating statistical significance over placebo (results are shown in Table 9 and Table 10). There was no statistically significant difference between MEZAVANT 2.4 g/day and 4.8 g/day dose groups in clinical improvement, clinical remission and sigmoidoscopic improvement; however, MEZAVANT 4.8 g/day showed trends for improved efficacy over MEZAVANT 2.4 g/day after 8 weeks of treatment in terms of sigmoidoscopic outcome (one of four components of the UC DAI) and clinical improvement (defined as a drop in the UC-DAI score of at least 3 points).

Table 9: Study SPD476-301: Secondary Efficacy Results (% Patients)

Table 10: Study SPD476-302: Secondary Efficacy Results (% Patients)

Maintenance of remission, including clinical remission and mucosal healing

The primary efficacy endpoint in study SPD476-304 was the proportion of subjects in endoscopic remission at Month 6 using the Per Protocol population. Endoscopic remission (mucosal healing) was defined by a modified UC-DAI endoscopy component score of ≤1. MEZAVANT met the primary endpoint of non-inferiority of -10% versus pH-dependent delayed release mesalamine in the proportion of subjects in endoscopic remission (maintenance of mucosal healing) at 6 months.

Table 11: Summary of Primary Efficacy Results for Study SPD476-304 in Mild to Moderate Ulcerative Colitis

Analysis of the Proportion of Subjects in Endoscopic Remission at Month 6

(Mucosal Healing) (Per Protocol Population)

MEZAVANT 2.4 g/day (given QD)

n=343

Month 6

Subjects in endoscopic remission* (n, %)

287 (83.7)

* Endoscopic remission (mucosal healing) was defined by a modified UC-DAI endoscopy component score of ≤1. The scoring system used for sigmoidoscopy was modified to be more stringent than the standard UC-DAI system, which allows patients with mild friability to be given a sigmoidoscopy score of 1.

The proportion of subjects who reached remission in this study using MEZAVANT 2.4 g/day QD (83.7%) was similar to that seen using the comparator (pH-dependent delayed-release mesalamine 1.6 g/day [0.8 g BID]; 81.5%).

Secondary endpoint analyses demonstrated that MEZAVANT achieved a similarly high proportion of subjects in endoscopic remission (mucosal healing) with no or mild symptoms, clinical remission, improved or same endoscopy scores, and improved or same Physician Global Assessment scores, as compared to pH-dependent delayed-release mesalamine as well as similar changes in modified UC-DAI scores.

A randomized, open-label extension study to studies SPD476-301 and SPD476-302 was designed to assess the long-term safety and tolerability of MEZAVANT 2.4 g/day administered once daily and in 2 divided doses (1.2 g BID) in the maintenance of ulcerative colitis in remission over 12 months. This study, study SPD476-303, included an 8-week Acute Extension Phase during which MEZAVANT 4.8 g/day dose was administered BID, and a 12-month Maintenance Phase during which MEZAVANT 2.4 g/day dose was administered either (1.2 g) BID or QD. Efficacy was a secondary objective of this extension study.

The 12-month safety results from the SPD476-303 study are consistent with previously reported safety data. The efficacy endpoints were time to relapse for the Maintenance Phase; and the percentage of subjects in remission at the end of the study for the Acute and Maintenance phases.

Time to relapse was defined as the time at which a subject withdrew from the Maintenance Phase due to a requirement for alternative ulcerative colitis medication denoted by “Lack of Efficacy/Relapse.” The proportion of subjects withdrawing due to a need for alternative ulcerative colitis medication in the Maintenance Phase Efficacy population was low. Both treatment groups had similar times to relapse for the duration of the Maintenance Phase. At 12 months (360 days), the proportion of subjects who had not relapsed (i.e., relapse free) was approximately 88% in the MEZAVANT 2.4 g/day QD group and 92% in the MEZAVANT 1.2 g BID (total 2.4 g/day) group.

Remission was defined as modified UC-DAI score ≤1 with a score of 0 for rectal bleeding and stool frequency, and at least a 1-point reduction from parent study baseline in the sigmoidoscopy score. Overall 59.5% of subjects achieved remission at the end of the Acute Extension Phase (Month 2). At Month 12 of the Maintenance Phase, 64.4% of subjects in the MEZAVANT 2.4 g/day QD group and 68.5% of subjects in the MEZAVANT 1.2 g BID (total 2.4 g/day) group met the strict remission criteria; no statistically significant differences were observed between treatment groups.

An open-label study (SPD476-404) was designed to assess clinical recurrence related to compliance with treatment with MEZAVANT 2.4 g/day given once daily for the maintenance of quiescent ulcerative colitis. Subjects entered the 12-month Maintenance Phase either directly or after completion of an 8-week acute phase. The primary analysis was the proportion of subjects with clinical recurrence at Month 6 of the Maintenance Phase. 76.5% of subjects who had sufficient data to calculate clinical recurrence at Month 6 did not have disease recurrence after 6 months of maintenance treatment with MEZAVANT.

The results of the secondary efficacy parameters (clinical recurrence at 12 months, proportion of subjects with quiescent ulcerative colitis, endoscopic remission, and time to clinical recurrence) supported the primary findings of consistently maintaining quiescence of ulcerative colitis through 12 months of maintenance treatment with MEZAVANT. Another study objective was also to assess health-related quality of life (QoL) at baseline of the Acute Phase, Week 8 Acute Phase/Baseline Maintenance Phase, 6 months, and 12 months. Non quiescent UC subjects who received MEZAVANT treatment during the Acute Phase showed statistically and clinically significant improvement on almost all measured aspects of health related QoL measures using the three questionnaires (Medical Outcomes Study 12 Item Short Form Health Survey, the Short Inflammatory Bowel Disease Questionnaire, and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem v2.0), particularly on physical role, disease-related QoL (such as pain, urgency, and anxiety), and work productivity loss and activity impairment.

Pharmacokinetics

In a parallel-group, two-period pharmacokinetic study of MEZAVANT 2.4 g/day or 4.8 g/day, where single and multiple doses were 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. Steady-state was achieved generally by 2 days after dosing. 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. There was no evidence of steady-state systemic exposure increasing more than proportionately with dose. The principal pharmacokinetic parameters are presented in Table 12.

Table 12: Principal Pharmacokinetic Parameters of 5-ASA following Administration of MEZAVANT in a 2.4 g/day and 4.8 g/day Single and Multiple Dose Study

N/A: Not Applicable

15 Microbiology

No microbiological information is required for this drug product.

16 Non-Clinical Toxicology

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

Carcinogenicity: In a 104-week dietary carcinogenicity study of mesalamine, CD-1 mice were treated with doses up to 2500 mg/kg/day and it was not tumorigenic. This dose is 2.2 times the maximum recommended human dose (based on body surface area comparison) of MEZAVANT. 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 body surface area comparison) of MEZAVANT.

Reproductive and Developmental Toxicology: No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 296 mg/kg/day.

Reproduction studies have been performed in rats at doses up to 480 mg/kg/day and have revealed no evidence of teratogenic effects or harm to the fetus due to mesalamine. Animal reproduction studies are not always predictive of human response.