Submission Control Number: 122319

*MYFORTIC is a registered trademark

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY 15 STORAGE AND STABILITY 17 SPECIAL HANDLING INSTRUCTIONS 17 DOSAGE FORMS, COMPOSITION AND PACKAGING 17

PART II: SCIENTIFIC INFORMATION 19

PHARMACEUTICAL INFORMATION 19 CLINICAL TRIALS 19 TOXICOLOGY 21 REFERENCES 23

PART III: CONSUMER INFORMATION. 24

PrMYFORTIC * (mycophenolate sodium)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

MYFORTIC (mycophenolate sodium) Enteric-Coated Tablets, deliver the active moiety mycophenolic acid (MPA), an immunosuppressive agent.

CONTRAINDICATIONS

MYFORTIC ( mycophenolate sodium) Enteric-Coated Tablets are contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil, or to any of its excipients (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

WARNINGS AND PRECAUTIONS

Warning

Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of solid organ transplant patients should prescribe MYFORTIC (mycophenolate sodium) Enteric-Coated Tablets. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow up of the patient.

General

Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections, and sepsis. Patients receiving MYFORTIC should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding, or any other manifestation of bone marrow suppression. During treatment with MYFORTIC, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil (MMF). Hemiparesis, apathy, confusion, cognitive deficiencies and ataxia were the most frequent clinical features observed. Mycophenolate mofetil (MMF) is metabolized to mycophenolic acid (MPA), the active ingredient in Myfortic and the active form of the drug. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune functions. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.

Carcinogenesis

Patients receiving immunosuppressive regimens involving combinations of drugs, including MYFORTIC, as part of an immunosuppressive regimen are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimize the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Gastrointestinal

Because mycophenolic acid derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, MYFORTIC should be administered with caution in patients with active serious digestive system disease. Gastrointestinal adverse events are common in patients receiving MPA treatment. Gastrointestinal bleeding (requiring hospitalization), gastrointestinal tract ulceration, and perforation have rarely been reported in de novo renal transplant patients or maintenance patients treated with MYFORTIC Enteric Coated Tablets during clinical trials. Most patients receiving MYFORTIC were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with MYFORTIC.

Drug Interactions

In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of Myfortic with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of Myfortic.

Hematologic

Patients receiving MYFORTIC should be monitored for neutropenia (see WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Tests). The development of neutropenia may be related to MYFORTIC itself, concomitant medications, viral infections, or some combination of these events. If neutropenia develops (ANC < 1.3x103 /uL), dosing with MYFORTIC should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION).

Inborn Disorders of Metabolism

On theoretical grounds, because MYFORTIC is an IMPDH Inhibitor, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Renal

Subjects with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) may present higher plasma MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG. In the de novo study, 18.3% of MYFORTIC patients versus 16.7% in the MMF group experienced delayed graft function (DGF). Patients with DGF experienced a higher incidence of certain adverse events such as anemia, leukopenia, and hyperkalemia than patients without DGF, but these events in DGF patients were not more frequent in patients receiving MYFORTIC than MMF. No dose adjustment is recommended for these patients; however, such patients should be carefully observed (see DOSAGE AND ADMINISTRATION).

Sexual Function/Reproduction

Mycophenolate sodium had no effect on fertility of male rats at oral doses up to 40 mg/kg/day. The systemic exposure at this dose represents approximately 9 times the clinical exposure at the tested clinical dose of 1.44 g/day MYFORTIC. No effects on female fertility were seen up to a dose of 20 mg/kg, a dose at which maternal toxicity and embryotoxicity were already observed and yielding an exposure similar to that observed at the maximum recommended clinical dose.

Special Populations

Pregnant Women:

In a teratology study performed with mycophenolate sodium in rats, at a dose as low as 1 mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day MYFORTIC. In teratology studies in rabbits fetal resorptions and malformations occurred from 80 mg/kg/day, in the absence of maternal toxicity (dose levels are equivalent to about 0.8 times the recommended clinical dose, corrected for BSA). There are no relevant qualitative or quantitative differences in the teratogenic potential of mycophenolate sodium and mycophenolate mofetil.

There are no adequate and well-controlled studies in pregnant women conducted with either MYFORTIC or mycophenolate mofetil. Based on data from the National Transplant Pregnancy Registry (NTPR), congenital disorders (congenital malformations of heart, ear, face, hand, eye, vertebrae, oesophagus, and multiple congenital abnormalities) have been reported in infants of patients exposed to mycophenolate mofetil in combination with other immunosupressants during pregnancy. The postmarketing data of pregnant women exposed to mycophenolate mofetil suggest that use of MPA during pregnancy may be associated with an increased risk of first trimester pregnancy loss. Mycophenolate mofetil is converted to mycophenolic acid following oral or IV administration. Since MPA may cause fetal harm when administered to a pregnant woman, MYFORTIC should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 1 week prior to beginning therapy. It is recommended that MYFORTIC therapy should not be initiated by the physician until a report of a negative pregnancy test has been obtained. Effective contraception must be used before beginning MYFORTIC therapy, during therapy, and for 6 weeks following discontinuation of therapy, even where there has been a history of infertility, unless due to hysterectomy. Two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method. If pregnancy does occur during treatment, the patient should inform the physician immediately, and should discuss the potential risk to the fetus with him/her (see CONSUMER INFORMATION).

Nursing Women:

It is not known whether MPA is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from mycophenolate sodium, a decision should be made whether to discontinue the drug or to discontinue nursing while on treatment or

within 6 weeks after stopping therapy, taking into account the importance of the drug to the mother.

Pediatrics

: Safety and efficacy in pediatric patients have not been established. Limited pharmacokinetic data are available for pediatric renal transplant patients (see ACTION AND CLINICAL PHARMACOLOGY).

Geriatrics: Patients > 65 years may generally be at increased risk of adverse drug reactions due to an immunosuppression. Based on the controlled MYFORTIC clinical trials, patients > 65 receiving MYFORTIC as part of a combination immunosuppressive regimen, did not show an increased risk of adverse reactions, compared to younger patients. No dose adjustment is required in this patient population.

Monitoring and Laboratory Tests

Complete blood count should be performed weekly during the first month, twice monthly for the second and the third month of treatment, then monthly through the first year. If neutropenia develops (ANC < 1.3x103 /uL) dosing with MYFORTIC should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly (see WARNINGS AND PRECAUTIONS).

DRUG INTERACTIONS

Overview

MYFORTIC has been administered in combination with the following agents in clinical trials: antilymphocyte/thymocyte immunoglobulin, Simulect * (basiliximab), daclizumab, muromonab, cyclosporine, Prograf(r) (tacrolimus) and corticosteroids. The efficacy and safety of the use of MYFORTIC with other immunosuppressive agents have not been studied.

Drug-Drug Interactions

Table 4: Established or Predicted Drug-Drug Interactions

Table 4: Established or Predicted Drug-Drug Interactions

Drug-Food Interactions

Compared to the fasting state, administration of MYFORTIC 720mg with a high fat meal (55g fat, 1000 calories) had no effect on the systemic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentration (Cmax) of MPA, significant delays in absorption of MPA (Tmax delayed up to 20 hours) were observed. To avoid variations in MPA absorption between doses, MYFORTIC should be taken on an empty stomach (see DOSAGE AND ADMINISTRATION).

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

The recommended dose in adults is 720 mg (four 180 mg or two 360 mg tablets) administered twice daily (1.440 g total daily dose). MYFORTIC (mycophenolic acid as mycophenolate sodium) Enteric-Coated Tablets should be used in combination with cyclosporine and corticosteroid therapy. MYFORTIC should be taken on an empty stomach, one hour before or two hours after food intake (see Food Drug Interactions). Patients are to be instructed that MYFORTIC tablets should not be crushed, chewed, or cut prior to ingesting but to be swallowed whole in order to maintain the integrity of the enteric coating.

Dose Adjustments

Geriatric Use

: No dose adjustments are required. The recommended dose is 720 mg administered twice daily.

Pediatric Use

: Safety and efficacy in pediatric patients have not been established. Limited pharmacokinetic data are available for pediatric renal transplant patients. (see ACTION AND CLINICAL PHARMACOLOGY).

Treatment during Rejection Episodes

: Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of MYFORTIC is not required.

Patients with Renal Impairment: No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively. Patients with severe chronic renal impairment (GFR < 25 mL/min1/1.73 m2) should be carefully followed.

Patients with Hepatic Impairment

: No dose adjustments are needed for renal transplant patients with hepatic parenchymal disease.

Patients Developing Neutropenia: If neutropenia develops (ANC < 1.3x103 /uL), dosing with MYFORTIC should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS AND PRECAUTIONS).

OVERDOSAGE

There has been no reported experience of acute overdose of MYFORTIC (mycophenolate sodium) Enteric-Coated Tablets in humans. Possible signs and symptoms of acute overdose could include the following: hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea and vomiting, and dyspepsia. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA due to the 98% plasma protein binding of MPA. By interfering with enterohepatic circulation of MPA, activated charcoal or bile acid sequestrants, such as cholestyramine, may reduce the systemic MPA exposure.

ACTION AND CLINICAL PHARMACOLOGY

MYFORTIC (mycophenolate sodium) Enteric-Coated Tablets, deliver the active moiety, mycophenolic acid (MPA). MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has a potent cytostatic effect on lymphocytes. Thus the mode of action is complementary to calcineurin inhibitors which interfere with cytokine transcription and resting T-lymphocytes. Mycophenolate sodium has been shown to prevent the occurrence of acute rejection in models of kidney allotransplantation, of heart allotransplantation and of heart xenotransplantation associated or not with other immunosuppressive treatment. Mycophenolate sodium also inhibited proliferative arteriopathy in experimental models of aortic allografts in rats as well as antibody production in mice.

Pharmacokinetics

Table 5: Mean (+-SD) Pharmacokinetic Parameters for MPA following Oral Administration of MYFORTIC to Renal Transplant Patients on cyclosporine Based Immunosuppression

* median (range), * * AUC0-8, * * * age range of 5 - 16 years

The mean pharmacokinetic parameters for MPA following the administration of MYFORTIC in renal transplant patients on cyclosporine based immunosuppression are shown in Table 5. Single dose MYFORTIC pharmacokinetics predict multiple dose pharmacokinetics. However, in the early post transplant period, mean MPA AUC and Cmax were approximately one-half of those measured six months post transplant. After near equimolar dosing of MYFORTIC (720 mg BID) and MMF (1000 mg BID) in both the single and multiple dose cross-over trials, mean systemic MPA exposure was similar. Absorption: In vitro studies demonstrated that the MYFORTIC Enteric Coated Tablet does not release MPA under acidic conditions (pH < 5) as in the stomach but is highly soluble in neutral pH conditions as in the intestine. Following MYFORTIC oral administration without food, consistent with its enteric-coated formulation, the median time to maximum concentration (Tmax) of MPA was 1.5 - 2.5 hours (range: 1.5 to 8 hours) compared to 1 hour (range: 0.5 to 3 hours) for mycophenolate mofetil (MMF). In stable renal transplant patients on cyclosporine based immunosuppression, gastrointestinal absorption of MPA was 93% and absolute bioavailability 71%. MYFORTIC pharmacokinetics is dose proportional over the dose range of 180 to 2160 mg.

Food effect:

Compared to the fasting state, administration of MYFORTIC 720mg with a high fat meal (55g fat, 1000 calories) had no effect on the systemic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentration (Cmax) of MPA, significant delays in absorption of MPA (Tmax delayed up to 20 hours) were observed. To avoid variations in MPA absorption between doses, MYFORTIC should be taken on an empty stomach (see DOSAGE AND ADMINISTRATION).

Distribution:

The volume of distribution at steady-state for MPA is 54.3 (+- 25.2) L . MPA is highly protein bound to albumin, >98%. The protein binding of mycophenolic acid glucuronide (MPAG) is 82%. The free MPA concentration may increase under conditions of decreased protein binding (uremia, hepatic failure, and hypoalbuminemia). This may put patients at an increased risk of MPA-related adverse events.

Metabolism:

The half-life of MPA is 11.7 (+- 3.2) hours and the clearance is 8.4 (+- 1.8) L/hr. MPA is metabolized principally by glucuronyl transferase to the phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG). MPAG is the predominant metabolite of MPA and does not manifest pharmacological activity. In stable renal transplant patients on cyclosporine based immunosuppression, approximately 28% of the oral MYFORTIC dose is converted to MPAG by pre-systemic metabolism. The half-life of MPAG is longer than MPA, approximately

15.7 (+- 3.9) hours and its clearance is 0.45 (+- 0.15) L/hr.

Elimination:

The majority of MPA (>60% of the dose) is eliminated in the urine primarily as MPAG and <3% as MPA. MPAG secreted in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed. Approximately 6-8 hours after MYFORTIC dosing, a second peak of MPA concentration can be measured which is consistent with reabsorption of the deconjugated MPA.

Special Populations and Conditions

Pediatrics: Limited data are available on the use of Myfortic at a dose of 450 mg/m2 body surface area in children. The mean MPA pharmacokinetic parameters for stable pediatric renal transplant patients, 5-16 years, on cyclosporine are shown in Table 5. At the same dose administered based on body surface area, the respective mean Cmax and AUC of MPA determined in children were higher by 33% and 18% than those determined for adults. The clinical impact of the increase in MPA exposure is not known.

Geriatric:

Pharmacokinetics in the elderly have not been formally studied.

Gender:

There are no significant gender differences in MYFORTIC pharmacokinetics.

Hepatic Insufficiency:

In a single dose (1g MMF) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when the pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC compared to healthy volunteers in other studies, thus making comparison between volunteers with alcoholic cirrhosis and health volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies may show a different effect.

Renal Insufficiency:

No specific pharmacokinetic studies in individuals with renal impairment were conducted with Myfortic. MPA pharmacokinetic was unchanged over the range of normal to severely impaired renal function based on studies with mycophenolate mofetil. In contrast, MPAG exposure increased with decreased renal function; MPAG exposure being approximately 8 fold higher in the setting of anuria. Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the high plasma protein binding of MPA.

STORAGE AND STABILITY

Store at 15degC - 30degC. Protect from moisture. Dispense in a tight container.

SPECIAL HANDLING INSTRUCTIONS

Tablets should not be crushed or cut.

DOSAGE FORMS, COMPOSITION AND PACKAGING

MYFORTIC (mycophenolate sodium) Enteric-Coated Tablets are available in the following strengths which are equivalent to mycophenolic acid 180 mg and 360 mg: 180 mg Enteric-Coated tablet: Lime green film-coated round tablet with bevelled edges and the imprint (debossing) 'C' on one side, containing 180 mg mycophenolic acid as mycophenolate sodium. Provided in unit dose of 10 tablets/blister pack; 12 packs/carton. 360 mg Enteric-Coated tablet: Pale orange red film-coated ovaloid tablet with imprint (debossing) 'CT' on one side, containing 360 mg mycophenolic acid as mycophenolate sodium. Provided in unit dose of 10 tablets/blister pack; 12 packs/carton. Each enteric-coated tablet also contains: colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, povidone (K-30), and starch. The enteric coating of the tablet consists of hypromellose phthalate, titanium dioxide, iron oxide yellow, and indigotine (180 mg enteric-coated tablet) or iron oxide red (360 mg enteric-coated tablet).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: mycophenolate sodium Chemical name: (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid sodium salt Molecular formula: C17H19O6 Na Molecular Weight: 342.32 Structural formula:

O O

OH

O

+

O Na

Physicochemical properties: Physical Form: White to off-white, crystalline powder

Solubility

: Slightly soluble in aqueous media at physiological pH and practically insoluble in hydrochloric acid 0.1N

CLINICAL TRIALS

The safety and efficacy of MYFORTIC (mycophenolate sodium) Enteric-Coated Tablets in combination with cyclosporine and corticosteroids for the prevention of organ rejection was assessed in two multicenter, randomized, double-blind trials in de novo and maintenance renal transplant patients compared to MMF .

Study Results

The de novo study was conducted in 423 renal transplant patients (ages 18-75 years) with the objective to confirm that MYFORTIC and MMF were therapeutically equivalent. Patients were administered either MYFORTIC 1.44 g/day or MMF 2 g/day within 48 hours post- transplant for 12 months in combination with cyclosporine and corticosteroids. In the MYFORTIC and MMF groups, 39.4% and 42.9% respectively, received antibody therapy as an induction treatment. The primary efficacy endpoint was the incidence of biopsy-proven acute rejection, graft loss, death or loss to follow-up at 6 months. The incidence of biopsy-proven acute rejection, graft loss, death or loss to follow-up was similar in MYFORTIC- and MMF-treated patients at 6 months, and met criteria confirming therapeutic equivalence, with similar results seen at 12 months (Table 6).

Table 6: Efficacy in de novo Renal Transplant Patients (Percent of Patients) at 6 and 12 Months of Treatment When Administered in Combination with cyclosporine and Corticosteroids

Endpoints

Myfortic (N=213) n (%)

MMF (N=210) n (%)

Difference in event rate (Myfortic- MMF)

95% CI

(Myfortic- MMF)

'Lost to follow-up' endpoint calculated for the primary composite endpoint (biopsy-proven acute rejection, graft loss, death, or loss to follow-up).

The maintenance study was conducted in 322 renal transplant patients (ages 18-75 years), who were at least 6 months post-transplant receiving 2 g/day MMF in combination with cyclosporine, with or without corticosteroids for at least four weeks prior to entry in the study. Patients were randomized to MYFORTIC 1.44 g/day or MMF 2 g/day for 12 months. The efficacy endpoint was the incidence of biopsy-proven acute rejection, graft loss, death, or loss to follow-up at 6 and 12 months. The rates of biopsy-proven acute rejection, graft loss, death or loss to follow-up at 12 months were similar between MYFORTIC- and MMF-treated patients (Table 8).

Table 7: Efficacy in Maintenance Transplant Patients Parameters (Percent of Patients) at 6 and 12 Months of Treatment when Administered in Combination with cyclosporine and with or without Corticosteroids

Months 0 to 6 Months 0 to 12

1. In addition, one patient (MMF group) withdrew consent on Day 273, and was

discontinued from the study. Patient died post-study on Day 290. Patient was included in the composite variable as a 'lost to follow-up').

'Lost to follow-up' endpoint calculated for the primary composite endpoint (biopsy-proven acute rejection, graft loss, death, or lost to follow-up.

TOXICOLOGY

The hematopoetic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate sodium in rats and mice. These effects occurred at systemic exposure levels which are equivalent to or less than the clinical exposure at the recommended dose of 1.44 g/day of MYFORTIC in renal transplant patients. The nonclinical toxicity profile of mycophenolate sodium appears to be consistent with adverse events observed in humans exposed to MPA, which now provide safety data of more relevance to the patient population (see ADVERSE REACTIONS). Mycophenolate sodium had no effect on fertility of male rats at oral doses up to 40 mg/kg/day. The systemic exposure at this dose represents approximately 9 times the clinical exposure at the tested clinical dose of 1.44 g of MYFORTIC per day. No effects on female fertility were seen up to a dose of 20 mg/kg, a dose at which maternal toxicity and embryotoxicity were already observed. In a teratology study performed with mycophenolate sodium in rats, at a dose as low as 1mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day of MYFORTIC. Single oral doses of MPA are moderately well tolerated in rats (LD50 of 350-700 mg/kg), well tolerated in mice or monkeys (LD50 of more than 1000 mg/kg), and extremely well tolerated in rabbits (LD50 of more than 6000 mg/kg). The genotoxic potential of mycophenolate sodium was determined in five assays. MPA was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay or the chromosomal aberration assay in human lymphocytes. The lowest dose showing genotoxic effects in a mouse bone marrow micronucleus resulted in approximately 3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the tested clinical dose of 1.44 g of MYFORTIC per day. It is probable that the mutagenic activity observed was due to a shift in the relative abundance of the nucleotides in the cellular pool used for DNA synthesis. There are no relevant qualitative or quantitative differences in the genotoxic potential of mycophenolate sodium and mycophenolate mofetil. It is probable that the mutagenic activity observed was due to a shift in the relative abundance of the nucleotides in the cellular pool used for DNA synthesis. These effects can be related to the pharmacodynamic mode of action of MPA through its inhibition of nucleotide synthesis in sensitive cells. In a 104-week oral carcinogenicity study in rats, mycophenolate sodium at daily doses up to 9mg/kg was not tumorigenic. The highest dose tested resulted in approximately 0.6-1.2 times the systemic exposure observed in renal transplant patients at the recommended dose of 1.44g/day. Similar results were observed in a parallel study in rats performed with mycophenolate mofetil. In a 26-week oral carcinogenicity assay in a P53+- (heterozygous) transgenic mouse model, mycophenolate sodium at daily doses up to 200 mg/kg was not tumorigenic. The highest dose tested was 200 mg/kg, resulting in approximately 5 times the systemic exposure observed in renal transplant patients (1.44 g/day).

REFERENCES

1. Manuscript (Study ERLB 301): Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients.

2. Manuscript (Study ERLB 302): Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study.

3. Heinschink A, Raab M, Daxecker H, et al. In vitro effects of mycophenolic acid on cell cycle and activation of human lymphocytes. Clin Chim Acta 2000; 300:23-8.

4. Johnson HJ et al. The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function. Clin. Pharmacol Ther 1998; 63:512- 518.

5. Parker G, et al. Pharmacokinetics of oral mycophenolate mofetil in volunteer subjects with varying degrees of hepatic oxidative impairment. J Clin Pharmacol 1996; 36:332-44.

6. Lee HJ, Pawlak K, Nguyen BT, Bobins K and Sadee W. Biochemical differences among four inosinate dehydrogenase inhibitors, mycophenolic acid, ribavirin, tiazofurin, and selenazofurin, studied in mouse lymphoma cell culture. Cancer Research , 1985; 45:5512-5520.

7. Schmouder R, Arns W, Merkel F, et al. Pharmacokinetics of ERL080: A new enteric coated formulation of mycophenolic acid sodium. Transplantation 1999; 67(suppl):S203.

8. Weber LT, Shipkova M, Lamersdorf T, et al. Pharmacokinetics of mycophenolic acid (MPA) and determinants of MPA free fraction in pediatric and adult renal transplant recipients. J Am Soc Nephrol; 9:1511-1520.

9. B302 Budde K, Curtis G, Knoll G,Chan L, Seifu Y, et al Enteric coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1 year study. Am J Transplant 2004; 4: 237 43.

10. B301 Salvadori M., Holzer H, de Mattos A, Sollinger H, Arns W, Oppenheimer F, et al.

Enteric coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004; 4: 231 236 Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ and Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82 (12): 1698-1702.

PART III: CONSUMER INFORMATION

Pr

MYFORTIC *

(mycophenolate sodium)

This leaflet is part III of a three-part "Product Monograph" published when MYFORTIC was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about MYFORTIC. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

MYFORTIC is the brand name for a drug called mycophenolate sodium . MYFORTIC belongs to the class of drugs known as immunosuppressants. Immunosuppressants reduce your body's response to anything that it sees as "foreign" - which includes transplant organs.

What it does:

MYFORTIC is used to prevent your body from rejecting a transplanted kidney.

Your body's immune system works to protect you from infections and other foreign material. When you receive a transplant, your immune system recognizes the new organ as "foreign", and will try to reject it. MYFORTIC works to reduce this reaction, so that your body is more likely to accept the transplanted kidney.

MYFORTIC is used together with other medicines containing cyclosporine and corticosteroids (e.g. prednisone, prednisolone, methyl prednisolone, prednisolone acetate, methyl prednisolone acetate) which also suppress your immune system. Together these drugs help prevent the rejection of your transplanted kidney.

When it should not be used:

Do not take MYFORTIC if you are allergic (hypersensitive) to mycophenolic acid, mycophenolate sodium or mycophenolate mofetil or to any of the other ingredients of MYFORTIC (see below).

If you think you may be allergic, ask your doctor for advice.

What the medicinal ingredient is:

MYFORTIC contains mycophenolate sodium, equivalent to 180 mg or 360 mg mycophenolic acid.

What the non-medicinal ingredients are:

Colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, povidone (K-30), and starch. The enteric coating of the tablet consists of hypromellose phthalate, titanium dioxide, iron oxide yellow, and indigotine (180 mg tablets) or iron oxide red (360 mg tablets).

What dosage forms it comes in:

MYFORTIC comes in the form of enteric-coated tablets (coated to dissolve only in the intestine).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Myfortic may increase your risk of infection and development of cancer of the lymphoid tissues (called

lymphoma) and other cancers.

Myfortic will only be prescribed for you by a doctor with experience in transplantation medicine.

Follow your doctor's instructions carefully.

For Female Patients:

• MYFORTIC causes fetal malformations. Therefore, MYFORTIC should not be used in pregnant women unless clearly necessary. Should you become pregnant while on therapy with MYFORTIC, inform your doctor at once. You will want to discuss the possible benefits and risks of continuing with this drug.

• Women of childbearing potential should have a negative serum (blood) or urine pregnancy test within 1 week prior to beginning therapy. Effective contraception must be used before beginning MYFORTIC therapy, during therapy, and for 6 weeks following discontinuation of therapy.

• Breast-feeding is not recommended while on therapy with MYFORTIC, or up to 6 weeks after you have stopped taking MYFORTIC. MYFORTIC may pass into breast milk and may harm your baby.

• It is not known what effect MYFORTIC has on the effectiveness of vaccinations and on the risk of getting an illness from vaccination with a live vaccine. Discuss this with your doctor before you get any vaccinations or immunizations.

Special precautions to be taken:

Make sure you know if you are to stop, or to continue, the other immunosuppressant drugs you had been taking. Be sure to discuss this with your doctor.

Exposure to sunlight should be limited. MYFORTIC reduces your body's defence mechanism, causing an increased risk of skin cancer. You should therefore limit your exposure to sunlight and ultraviolet (or UV) light by wearing appropriate protective clothing and frequently applying a sunscreen with a high protection factor.

Be sure to keep all appointments at your transplant clinic.

During these visits blood tests to determine the number of blood cells you have will need to be conducted weekly during the first month, twice monthly for the second and third month of treatment, then monthly through the first year. In addition, your doctor may order additional blood tests.

BEFORE you use MYFORTIC talk to your doctor or pharmacist:

if you are pregnant or are planning to become pregnant;

to ensure that you are using an appropriate method of contraception;

if you are breast-feeding or plan to breast-feed;

about all other medical conditions you have now or have had, including problems with your kidneys, stomach (e.g. ulcers caused by the action of stomach acid) or gastrointestinal tract

(e.g. ulcers, bleeding, and perforation);

if you need to receive vaccines (live attenuated vaccines);

if you have a family history of a genetic disease known as Lesch-Nyhan or Kelley-Seegmiller syndrome;

if you are allergic (hypersensitive) to mycophenolic acid, mycophenolate sodium or mycophenolate mofetil or to any of the other ingredients of MYFORTIC;

if you have any diseases of the blood.

INTERACTIONS WITH THIS MEDICATION

Tell all health professionals you see (doctors, dentists, nurses, pharmacists) that you are taking MYFORTIC.

Do not take any other drugs without asking your doctor or pharmacist first. This includes anything you can buy off the shelf such as over-the-counter medicines (e.g. antacids) and natural health product.

Drugs that may interact with MYFORTIC include:

Immunosuppressive agents other than cyclosporine or corticosteroids (e.g. azathioprine, mycophenolate mofetil, tacrolimus).

Cholestyramine, (a medicine used to treat high blood

cholesterol levels).

Acyclovir (a medicine used to treat herpes infection).

Gancyclovir (a medicine used to treat cytomegalovirus (CMV) infection).

Non-prescription medications, including antacids or any natural health product.

PROPER USE OF THIS MEDICATION

Usual dose:

The recommended dose in adult is 720 mg administered twice daily. This means:

-Taking 4 x 180 mg tablets in the morning and 4 x 180 mg tablets in the evening.

OR

-Taking 2 x 360 mg tablets in the morning and 2 x 360 mg tablets in the evening.

How it is taken:

Never

crush, chew or cut MYFORTIC tablets. The tablets should be swallowed whole

Space your two doses of MYFORTIC as evenly as you can throughout the day leaving about 12 hours between each dose.

Try to take your doses at the same times each day. This will help keep a constant amount of drug in your body so it can continue to protect your transplanted organ. Taking your medicine at the same time each day will also help you remember each dose.

MYFORTIC should be taken on an empty stomach, one hour before or two hours after food intake.

Vomiting or diarrhea may prevent MYFORTIC from being taken up into your body. Always call your doctor if you have either of these episodes.

Your doctor has decided the dose of MYFORTIC you should take based on your medical condition and response to the drug. Follow your doctor's instruction carefully. Do not take any more or any less of the drug than your doctor has told you. Do not change the dose on your own, no matter how you are feeling.

How long is treatment continued:

Treatment will continue for as long as you need immunosuppression to prevent you from rejecting your transplanted kidney.

Overdose:

If you have accidentally taken too many tablets, talk to your doctor or poison control center straight away. You may require medical attention, contact the Emergency Room of the nearest hospital.

Missed Dose:

Missing even a few doses of MYFORTIC may lead to rejection of your transplanted kidney. That is why it is so important to take each dose of MYFORTIC as prescribed.

If you have trouble remembering doses, or if you are uncertain about how to take them talk to your doctor, nurse or pharmacist and be sure to discuss any concerns you have about taking the drug as prescribed.

If you ever do miss a dose of MYFORTIC, do not double dose or catch up on your own; instead call your doctor or pharmacist right away for advice. It is also a good idea to ask your doctor ahead of time what to do about missed doses.

Never allow your medication to run out between refills. Plan to order your refills about one week ahead of time. That way you will always have a supply in case the pharmacy is closed

or out of the drug. Also be sure to take enough medication with you when you go on a holiday.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines, MYFORTIC can have side effects in some people, even when used as directed.

Some effects could be serious:

If you have symptoms of infection including fever, chills, sweating, fatigue, drowsiness, or lack of energy. If you are taking MYFORTIC you may be more susceptible to infections than usual. These may affect various body systems, the most common being the urinary tract, the respiratory tract and the skin.

If you experience vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and muscle weakness, these can be the signs and symptoms of an infection of the brain called progressive multifocal leukoencephalopathy.

If you have enlarged glands, new or enlarging skin growths, or a change in an existing mole. As can happen in patients taking immunosuppressive medication a very small number of MYFORTIC patients have developed cancer of the skin or lymph nodes.

If you experience unusual tiredness, headache, shortness of breath with exercise or at rest, dizziness, chest pain, looking pale. These are all symptoms of anaemia (decrease in red blood cells).

If you experience any of these, tell your doctor straight away.

Other side effects may include:

Very common side effects (> 1 in 10 patients).

diarrhea;

reduction in the number of white blood cells.

Common side effects (<= 10 in every 100 patients).

bleeding or bruising more easily than normal (signs of decreased number of platelets);

headache;

cough;

pain (e.g. in the abdomen, stomach, or joints);

constipation;

indigestion;

flatulence;

loose stools;

nausea;

vomiting;

tiredness;

fever;

abnormal tests of liver or kidney function.

Uncommon side effects (<1 in 100 patients).

cyst containing lymph fluid;

difficulty in sleeping;

shakiness;

lung congestion;

shortness of breath;

belching;

bad breath;

bowel obstruction;

inflammation of the oesophagus;

bloody or black stools;

tongue discoloration;

dry mouth;

heartburn;

inflammation of the gums;

inflammation of the lining of the abdominal cavity;

flu-like symptoms;

swelling of ankles and feet;

loss of appetite;

hair loss;

bruise of the skin;

palpitation or irregular heart beat;

discharge of the eye with itching, redness and swelling;

vision blurred;

kidney disorders;

abnormal narrowing of the tube through which urine passes to the outside of the body;

inability to get or maintain an erection.

Additional side effects have been reported with the class of drugs which Myfortic belongs.

Inflammation of the colon or of the oesophagus;

abdominal pain;

vomiting;

loss of appetite;

nausea;

inflammation of the pancreas;

intestinal perforation;

stomach or intestine bleeding;

stomach pain with or without bloody or black stools;

bowel obstruction;

serious infections;

reduction in the number of specific white blood cells or of all blood cells.

If any of these affects you, tell your doctor. However, do not stop your medicines unless you have discussed this with your doctor first.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

toll-free telephone: 866-234-2345

toll-free fax: 866-678-6789

Online: www. healthcanada.gc.ca/medeffect

By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

+ Do not stop your medicines unless you have discussed this with your doctor first.

This is not a complete list of side effects. For any unexpected effects while taking MYFORTIC, contact your doctor or pharmacist.

HOW TO STORE IT

• Store MYFORTIC between 15degC to 30degC.

• Protect from moisture.

• Store MYFORTIC in the original package.

• Do not use MYFORTIC after the expiry date printed on the container.

• Keep MYFORTIC out of the reach and sight of children.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.novartis.ca

or by contacting Novartis at: 1-800-363-8883

Please consult your doctor or pharmacist with any questions or concerns you may have regarding your individual condition.

This leaflet was prepared by

Novartis Pharmaceuticals Canada Inc. 385 Bouchard Blvd.

Dorval, QC H9S 1A9

Last revised: August 6th , 2008