Submission Control Number: 110717

(r)

Registered Trade-Mark of F. Hoffmann-La Roche AG, used under license

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Copyright 2002-2007 of Hoffmann-La Roche Limited

CDS Version 2.0

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 15 DOSAGE AND ADMINISTRATION 19 SPECIAL HANDLING INSTRUCTIONS 22 ACTION AND CLINICAL PHARMACOLOGY 23 STORAGE AND STABILITY 26 SPECIAL HANDLING INSTRUCTIONS 26 DOSAGE FORMS, COMPOSITION AND PACKAGING 27

PART II: SCIENTIFIC INFORMATION 28

PHARMACEUTICAL INFORMATION 28 CLINICAL TRIALS 29 DETAILED PHARMACOLOGY 32 MICROBIOLOGY 36 TOXICOLOGY 38 REFERENCES 47

PART III: CONSUMER INFORMATION. 49

PRVALCYTE(r) Valganciclovir hydrochloride

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

VALCYTE (valganciclovir hydrochloride) is contraindicated in patients with known hypersensitivity to valganciclovir, ganciclovir or to any component of the product (see DOSAGE FORMS, COMPOSITION AND PACKAGING). Due to the similarity of the chemical structure of valganciclovir and that of acyclovir and valacyclovir, a cross-hypersensitivity reaction between these drugs is possible.

WARNINGS AND PRECAUTIONS

General

The clinical toxicity of VALCYTE (valganciclovir hydrochloride) includes granulocytopenia, anemia and thrombocytopenia. In animal and in-vitro studies ganciclovir was mutagenic, carcinogenic, teratogenic and caused aspermatogenesis. Therefore it should be considered a potential teratogen and carcinogen in humans. VALCYTE is indicated for use only in immunocompromised patients, where the potential benefit outweighs the risks. Safety and efficacy of VALCYTE have not been established for congenital or neonatal CMV disease; nor for the treatment of established CMV disease other than retinitis; nor for use in non-immunocompromised individuals.

Strict adherence to dosage recommendations is essential to avoid overdose.

Specific Solid Organ Transplant (SOT) Subgroups

Liver:

In an unpowered subanalysis of the SOT study, PV16000, there was a higher incidence of tissue-invasive CMV disease in liver transplant patients treated with VALCYTE compared with the oral ganciclovir group (see CLINICAL STUDIES). The clinical significance of this is unknown.

Other:

The safety and efficacy of VALCYTE for the prevention of CMV disease in other SOT patients not mentioned in the INDICATIONS & CLINICAL USE section, such as lung transplant patients, have not been established.

Carcinogenesis and Mutagenesis

No long-term carcinogenicity studies have been conducted with valganciclovir. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a potential carcinogen (see TOXICOLOGY: Carcinogenesis, Mutagenesis for discussion on animal data).

Hematologic

VALCYTE should not be administered if the absolute neutrophil count is less than 500 cells/mL, the platelet count is less than 25,000/mL, or the hemoglobin is less than 80 g/L.

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with VALCYTE tablets (and ganciclovir) (see WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION: Dosing Considerations).

VALCYTE should, therefore, be used with caution in patients with pre-existing cytopenias, or who have received or are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may increase with continued dosing. Cell counts usually begin to recover within 3 to 7 days of discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil counts in patients receiving ganciclovir for treatment of CMV retinitis.

Renal

Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. If renal function is impaired, dosage adjustments are required for VALCYTE. Such adjustments should be based on measured or estimated creatinine clearance values (see DOSAGE AND ADMINISTRATION: Dosage Adjustment, Renal Impairment).

Patients undergoing hemodialysis:

Dosage adjustment is necessary for patients on hemodialysis (CrCl < 10mL/min) (see DOSAGE AND ADMINISTRATION: Dosing Considerations and Dosage Adjustment and ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Hemodialysis).

Sexual Function/Reproduction

Animal data indicate that administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses (see TOXICOLOGY: Carcinogenesis). It is considered probable that in humans, valganciclovir at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Animal data also indicate that suppression of fertility in females may occur. Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing potential should be advised to use effective contraception during treatment. Similarly, men should be advised to practice barrier contraception during, and for at least 90 days following, treatment with VALCYTE (see TOXICOLOGY: Carcinogenesis, Mutagenesis). In animal studies, ganciclovir was found to be mutagenic and carcinogenic. Valganciclovir should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see SPECIAL HANDLING INSTRUCTIONS). For further discussion on animal data see TOXICOLOGY: Reproduction.

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. VALCYTE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see TOXICOLOGY: Reproduction).

Nursing Women:

It is not known whether ganciclovir or valganciclovir is excreted in human milk. However, many drugs are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely. Mothers should be instructed to discontinue the drug or discontinue nursing if they are receiving VALCYTE.

Pediatrics: Safety and efficacy of VALCYTE in children have not been established. The use of VALCYTE in children warrants extreme caution due to the probability of long-term carcinogenicity and reproductive toxicity. Administration to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh these considerable risks.

VALCYTE has not been studied in pediatric patients, and the pharmacokinetic characteristics of VALCYTE in this population are not known.

Geriatrics (> 65 years of age)

: The pharmacokinetic profiles of VALCYTE in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of VALCYTE (see DOSAGE AND ADMINISTRATION).

Clinical studies of VALCYTE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. VALCYTE is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Renal Insufficiency and DOSAGE AND ADMINISTRATION: Dosage Adjustment, Renal Impairment).

Monitoring and Laboratory Tests

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving VALCYTE (see ADVERSE REACTIONS), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/mL at the beginning of treatment. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, it is recommended that treatment with hematopoietic growth factors and/or dose interruption be considered. Increased serum creatinine levels have been observed in trials evaluating VALCYTE tablets. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION: Dosage Adjustment, Renal Impairment).

DRUG INTERACTIONS

Overview

Drug Interaction Studies Conducted with Valganciclovir: Valganciclovir is rapidly and extensively converted to ganciclovir; therefore interactions associated with ganciclovir will be expected for VALCYTE (valganciclovir hydrochloride). In a rat in situ model of intestinal permeability, there was no interaction of valacyclovir, didanosine, nelfinavir, cyclosporine, omeprazole and mycophenolate mofetil with valganciclovir.

Drug Interaction Studies Conducted With Ganciclovir:

Binding of ganciclovir to plasma proteins is only about 1% to 2%, and drug interactions involving binding site displacement are not anticipated.

Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of VALCYTE and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.

Drug-Drug Interactions

Table 4: Results of Drug Interaction Studies With Ganciclovir: Effects of Coadministered Drug on Ganciclovir Plasma AUC and Cmax Values

Table 5: Results of Drug Interaction Studies With Ganciclovir: Effects of Ganciclovir on Plasma AUC and Cmax Values of Coadministered Drug

Cyclosporine:

There was no evidence that introduction of ganciclovir affects the pharmacokinetics of cyclosporine based on the comparison of cyclosporine trough concentrations. However, there was some evidence of increases in the maximum serum creatinine value observed following initiation of ganciclovir therapy.

Didanosine:

Didanosine has been associated with pancreatitis. In three controlled trials, pancreatitis was reported in 2% of patients taking didanosine and CYTOVENE (ganciclovir sodium for injection) or ganciclovir capsules. The rates of pancreatitis were similar in the intravenous solution and capsule groups.

Other than laboratory abnormalities, concomitant treatment with zidovudine, didanosine, or zalcitabine did not appear to affect the type or frequency of reported adverse events, with the exception of moderately increased rates of diarrhea. Among patients taking CYTOVENE as ganciclovir sodium for injection or ganciclovir capsules, the diarrhea rates were 51% and 49% respectively with didanosine versus 39% and 35% respectively, without didanosine.

Imipenem-cilastatin:

Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. VALCYTE should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks.

Stavudine:

No statistically significant pharmacokinetic interaction was observed when stavudine and oral ganciclovir were given in combination.

Other Medications:

It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. In addition, toxicity may be enhanced when ganciclovir is coadministered with other drugs known to be associated with renal impairment. Therefore, drugs known to be myelosuppressive or associated with renal impairment, such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, doxorubicin, amphotericin B, trimethoprim/sulfamethoxazole combinations, other nucleoside analogues, or hydroxyurea, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Caution - Strict adherence to dosage recommendations is essential to avoid overdose.

VALCYTE (valganciclovir hydrochloride) is administered orally, and should be taken with food (see ACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics, Absorption). After oral administration, valganciclovir is rapidly and extensively converted into the active ingredient ganciclovir. The bioavailability of ganciclovir from VALCYTE is significantly higher than from oral ganciclovir. The dosage and administration of VALCYTE tablets or oral solution as described below should be closely followed (see WARNINGS AND PRECAUTIONS: General and OVERDOSAGE). Dosage adjustment is necessary for patients on hemodialysis (CrCl < 10mL/min) (see WARNINGS AND PRECAUTIONS: General and Patients undergoing hemodialysis, DOSAGE AND ADMINISTRATION: Dosage Adjustment and ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Hemodialysis). The ganciclovir systemic exposure following administration of 900 mg valganciclovir oral solution is equivalent to a 900 mg valganciclovir dose comprised of tablets (see CLINICAL TRIALS: Comparative Bioavailability Studies). Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with VALCYTE tablets (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/mL, or the hemoglobin is less than 80 g/L, or the platelet count is less than 25,000/mL (see WARNINGS AND PRECAUTIONS: Hematologic, and Monitoring and Laboratory Tests, and ADVERSE REACTIONS). Due to the frequency of leukopenia, granulocytopenia (neutropenia), anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia in patients taking VALCYTE, it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1000 cells/mL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION: Renal Impairment).

Recommended Dose For the Treatment of CMV Retinitis in Patients with Normal Renal Function

Induction Treatment:

For patients with active CMV retinitis, the recommended dosage is 900 mg twice a day (with food) for 21 days. Prolonged induction treatment may increase the risk of bone marrow toxicity (see WARNINGS AND PRECAUTIONS: Hematologic).

Maintenance Treatment:

Following induction treatment, or in patients with inactive CMV retinitis, the recommended dosage is 900 mg once daily (with food). Patients whose retinitis worsens may repeat induction treatment (see Induction Treatment).

Recommended Dose For the Prevention of CMV Disease in Solid Organ Transplantation

For patients who have received a solid organ transplant, the recommended dose is 900 mg once daily (with food) starting within 10 days of transplantation and continuing until 100 days posttransplantation.

Evidence for safety and efficacy of VALCYTE for the prevention of CMV disease in solid organ transplant patients beyond 6 months post-transplant is not available.

Dosage Adjustment

Reduction of Dose:

Dosage reductions in renally impaired patients are required for VALCYTE (see Renal Impairment). Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see ADVERSE REACTIONS). VALCYTE should not be administered in patients with severe neutropenia (ANC less than 500/mL), severe thrombocytopenia (platelets less than 25,000/mL), or severe anemia (hemoglobin less than 80 g/L).

Renal Impairment:

Serum creatinine or creatinine clearance levels should be monitored carefully. Dosage adjustment is required according to creatinine clearance as shown in tables 6 and 7 below (see WARNINGS AND PRECAUTIONS: Renal and ACTION AND CLINICAL

PHARMACOLOGY: Special Populations and Conditions, Renal Insufficiency). The dose-reduction algorithm was based on predicted ganciclovir exposures. The range of exposures in renally impaired patients may be greater than in renally sufficient patients. Thus, increased monitoring for cytopenias may be warranted in patients with renal impairment (see WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests).

Patients undergoing hemodialysis:

Dosage adjustment is necessary for patients on hemodialysis (CrCl < 10 mL/min) and a dosing recommendation is given in table 7 below (see WARNINGS AND PRECAUTIONS: Patients undergoing hemodialysis, DOSAGE AND ADMINISTRATION: Dosing Considerations and ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Hemodialysis).

Table 6: Valcyte Tablet Dose for Patients with Impaired Renal Function

Table 7: Valcyte Oral Solution Dose for Patients with Impaired Renal Function

*An estimated creatinine clearance can be related to serum creatinine by the following formulas: For males = (140 - age [years]) x (body weight [kg]) (72) x (0.011 x serum creatinine [micromol/L]) For females = 0.85 x male value

Missed Dose

The missed dose should be taken as soon as remembered, then the regular dosing schedule should be continued. Two doses of VALCYTE should not be taken at the same time.

Administration

VALCYTE should be administered orally, and should be taken with food (see ACTION AND CLINICAL PHARMACOLOGY: Absorption).

Reconstitution of Oral Solution

VALCYTE powder for oral solution requires reconstitution prior to oral administration. An oral dosing dispenser with 25 mg graduations up to 500 mg is provided with the powder for oral solution. It is recommended that this dispenser is used to measure and administer the dose. Since VALCYTE is considered a potential teratogen and carcinogen in humans, caution should be observed in handling the powder and the reconstituted solution. Avoid direct contact of the powder and solution with skin and mucous membranes. If such contact occurs, wash thoroughly with soap and water. If the powder or solution gets into the eyes, rinse eyes thoroughly with sterile water or plain water if sterile water is not available (see SPECIAL HANDLING INSTRUCTIONS). It is recommended that VALCYTE powder for oral solution be reconstituted by the pharmacist prior to dispensing to the patient.

Preparation of solution

1. Measure 91 mL of purified water in a graduated cylinder.

2. Remove the child resistant cap and add the water to the bottle. Shake the closed bottle until the powder is dissolved.

3. Remove the child resistant cap and push the bottle adapter into the neck of the bottle.

4. Close bottle with child resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.

5. Write the date of expiration of the reconstituted solution on the bottle label. The shelf-life of the reconstituted solution is 49 days when stored at 2 to 8degC (see STORAGE AND STABILITY).

Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g. CSHP, 1997) (see SPECIAL HANDLING INSTRUCTIONS).

OVERDOSAGE

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

Overdose Experience With VALCYTE (valganciclovir hydrochloride) Tablets

One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient's estimated degree of renal impairment (decreased creatinine clearance). It is expected that an overdose of VALCYTE could result in increased renal toxicity (see WARNINGS AND PRECAUTIONS: General and DOSAGE AND ADMINISTRATION: Dosage Adjustment, Renal Impairment). Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of VALCYTE. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered (see ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Hemodialysis).

Overdose Experience With Intravenous Ganciclovir

Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. In some of these cases no adverse reactions were reported. The majority of patients experienced one or more of the following adverse reactions:

Gastrointestinal toxicity

: abdominal pain, diarrhea, vomiting

Hematological toxicity

: pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia

Hepatotoxicity: hepatitis, liver function disorder Neurotoxicity: generalized tremor, convulsion

Renal toxicity

: worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Valganciclovir is an L-valyl ester salt (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of herpes viruses in vitro and in vivo. In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, UL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly. This has been shown to occur in CMV-infected cells (half-life 18 hours) and HSV-infected cells (half-life between 6 and 24 hours) after removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus- infected cells. The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation. The median concentration of ganciclovir that inhibits CMV replication (IC50) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.58 mg/mL (0.08 to 14.32 mM). Ganciclovir inhibits mammalian cell proliferation (CIC50) in vitro at higher concentrations ranging from 10.21 to >250 mg/mL (40 to >1000 mM). Bone marrow-derived colony-forming cells are more sensitive (CIC50 0.69 to 3.06 mg/mL; 2.7 to 12 mM). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Pharmacokinetics

Absorption: Valganciclovir, a prodrug of ganciclovir, is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from VALCYTE tablets following food was approximately 60% (3 studies, n=18; n=16; n=28). Dose proportionality with respect to ganciclovir AUC following administration of VALCYTE tablets in the dose range 450 to 2625 mg was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, was transient and low, and the AUC24 and Cmax values were approximately 1% and 3% of those of ganciclovir, respectively. When VALCYTE tablets were administered with food at a dose of 900 mg, the area under the plasma concentration time curve (AUC) over 24 hours was 28.0 +- 8.9 mg *h/mL (n=75), and the maximum plasma concentration (Cmax) was 5.37 +- 1.53 mg/mL (n=76). Following the administration of valganciclovir as an oral solution, equivalent systemic ganciclovir exposures were obtained compared to the tablet formulation (see CLINICAL TRIALS: Comparative Bioavailability Studies).

Food Effects:

When VALCYTE tablets were administered with a meal containing 569 calories (31.1 g fat, 51.6 g carbohydrates, and 22.2 g protein) at a dosage of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% CI: 12 to 51%), and the Cmax increased by 14% (95% CI: -5 to 36%), without any prolongation in time to peak plasma concentrations (Tmax). Therefore it is recommended that VALCYTE be administered with food (see DOSAGE AND ADMINISTRATION).

Distribution:

Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir was 1% to 2% over concentrations of 0.5 and 51 mg/mL. When ganciclovir was administered intravenously, the steady state volume of distribution of ganciclovir was 0.680 +- 0.161 L/kg (n=114).

After administration of VALCYTE tablets, no correlation was observed between ganciclovir AUC and weight; oral dosing of VALCYTE according to weight is not required.

Metabolism:

Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. No metabolite of orally-administered radiolabeled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the feces or urine.

Excretion:

The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of intravenously administered ganciclovir was 3.05 +- 0.81 mL/min/kg (n=86) while renal clearance was 2.40 +-

0.93 mL/min/kg (n=46). The terminal half-life (t1/2) of ganciclovir following oral administration of VALCYTE tablets to either healthy or HIV-positive/CMV-positive subjects was 4.18 +- 0.80 hours (n=244), and that following administration of intravenous ganciclovir was 3.85 +- 0.74 hours (n=87). In liver transplant recipients, the t1/2 of ganciclovir after oral administration of VALCYTE tablets (900 mg dose) was 5.10 +- 1.10 hours (n=28), compared to 5.17 +- 1.39 hours (n=27) after intravenous administration of ganciclovir.

Special Populations and Conditions

Pediatrics:

The pharmacokinetic characteristics of VALCYTE in pediatric patients have not been established (see WARNINGS AND PRECAUTIONS: Special Populations, Pediatrics).

Geriatrics:

No studies of VALCYTE have been conducted in adults older than 65 years of age (see WARNINGS AND PRECAUTIONS: Special Populations, Geriatrics).

Gender:

Insufficient data are available to demonstrate any effect of gender on the pharmacokinetics of valganciclovir.

Race:

Insufficient data are available to demonstrate any effect of race on the pharmacokinetics of valganciclovir.

Renal Insufficiency:

The pharmacokinetics of ganciclovir from a single oral dose of 900 mg VALCYTE tablets were evaluated in 24 otherwise healthy individuals with renal impairment.

Table 8: Pharmacokinetics of Ganciclovir From a Single Oral Dose of 900 mg VALCYTE Tablets

Decreased renal function resulted in decreased clearance of ganciclovir from valganciclovir, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients (see WARNINGS AND PRECAUTIONS: Renal and DOSAGE AND ADMINISTRATION: Dosage Adjustment, Renal Impairment).

Hemodialysis:

For patients receiving hemodialysis (CrCl < 10 mL/min) VALCYTE powder for oral solution is recommended to provide an individualized dose (see WARNINGS AND PRECAUTIONS: Patients undergoing hemodialysis and DOSAGE AND ADMINISTRATION: Dosing Considerations and Dosage Adjustment).

STORAGE AND STABILITY

VALCYTE tablets:

Store in tightly closed container between temperatures of 15 oC and 30 oC.

VALCYTE powder for oral solution:

Do not store dry powder above 30 oC. Store reconstituted solution in a refrigerator at 2 to 8degC. After reconstitution with purified water the solution should not be used for longer than 49 days. For preparation of the reconstituted medicinal product see DOSAGE AND ADMINISTRATION: Reconstitution of Oral Solution.

SPECIAL HANDLING INSTRUCTIONS

Caution should be exercised in the handling of VALCYTE (valganciclovir hydrochloride) tablets or powder for oral solution. Tablets should not be broken or crushed. Since valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets (see WARNINGS AND PRECAUTIONS: Sexual Function/Reproduction). Avoid direct contact of broken or crushed tablets, powder or reconstituted solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with sterile water or plain water if sterile water is not available. Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g. CSHP, 1997). Disposal of VALCYTE should follow provincial, municipal, and local hospital guidelines or requirements.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Film-Coated Tablet

Composition: Each tablet contains 496.3 mg of valganciclovir hydrochloride (corresponding to 450 mg valganciclovir). The non-medicinal ingredients are: crospovidone, microcrystalline cellulose, povidone K-30, and stearic acid powder. The film-coat applied to the tablets is Opadry(r) Pink, which contains hydroxypropyl methylcellulose, polyethylene glycol 400/macrogol, polysorbate 80, synthetic red iron oxide, and titanium dioxide. Availability: VALCYTE (valganciclovir hydrochloride) 450 mg tablets are available in plastic bottles of 60, as pink, convex, oval, film-coated tablets with "VGC" on one side and "450" on the other side.

Powder for Oral Solution

Composition: Each bottle contains 5.5 g valganciclovir hydrochloride (corresponding to 5g valganciclovir), in 12 g powder for oral solution. Following reconstitution, 1 mL solution contains 55 mg valganciclovir hydrochloride corresponding to 50 mg valganciclovir (free base). The non-medicinal ingredients are: fumaric acid, mannitol, povidone K30, sodium benzoate, sodium saccharin, tutti-frutti flavour (maltodextrins (maize), propylene glycol, arabic gum and natural identical flavouring substances mainly consisting of banana, pineapple, and peach flavour). Availability: VALCYTE powder for oral solution is available as a white to slightly yellow powder (granulate). Available in a carton containing an amber glass bottle with child-resistant plastic screw cap, a bottle adapter and a sealed bag containing 2 oral dispensers. Each bottle contains 12 g of powder for oral solution. When reconstituted, the volume of the solution is 100 mL, providing a minimal usable volume of 88 mL.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance:

Valganciclovir

Trade Name

VALCYTE

Common name

Valganciclovir hydrochloride

Chemical Name

L-Valine, ester with 9-[[2-Hydroxy-1-

(hydroxymethyl)ethoxy]methyl] guanine, monohydrochloride Molecular Formula C14H22N6O5HCl

Molecular Mass

390.83

Structural Formula

Physical Form

Valganciclovir hydrochloride is a white to off-white crystalline powder.

Solubility

Valganciclovir hydrochloride is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25 oC at a pH of 7.0

pKa and pH values

pKa = 7.6

Partition Co-efficient:

Valganciclovir hydrochloride has an n-octanol/water partition coefficient of 0.0095 at pH 7.0

Melting Point:

Valganciclovir hydrochloride melts with decomposition above 180 oC

CLINICAL TRIALS

Induction Therapy of CMV Retinitis: Study WV15376

In a randomized, open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either VALCYTE (valganciclovir hydrochloride) tablets (900 mg twice daily for 21 days, then 900 mg once daily for 7 days) or with CYTOVENE-IV (ganciclovir sodium for injection) (5 mg/kg twice daily for 21 days, then 5 mg/kg once daily for 7 days). Study participants were: male (91%), White (53%), Hispanic (31%), and Black (11%). The median age was 39 years, the median baseline HIV-1 RNA was 4.9 log10, and the median CD4 cell count was 23 cells/mm3. A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and week 4 was the primary outcome measurement of the three week induction therapy. Table 9 provides the outcomes at four weeks.

Table 9: Week 4 Masked Review of Retinal Photographs in Study WV15376

In evaluable patients, photographic evidence of progression was observed in 7 of 70 patients (10%) in the intravenous ganciclovir treatment group and in 7 of 71 patients (9.7%) treated with VALCYTE. The difference in the proportion progressing was 0.1% (95% CI = -9.7 to 10.0%). Based on the a priori definition of comparable efficacy, VALCYTE tablets 900 mg twice daily demonstrated similar efficacy to that of intravenous ganciclovir 5 mg/kg twice daily.

Maintenance Therapy of CMV Retinitis

No comparative clinical data are available on the efficacy of VALCYTE for the maintenance therapy of CMV retinitis because all patients in study WV15376 received open-label VALCYTE after week 4. However, the AUC for ganciclovir is similar following administration of 900 mg valganciclovir once daily and 5 mg/kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following valganciclovir administration compared to intravenous ganciclovir, it is higher than the Cmax obtained following oral ganciclovir administration (see Figure 1 in DETAILED PHARMACOLOGY). Therefore, use of valganciclovir as maintenance therapy is supported by a plasma concentration-time profile similar to that of two approved products for maintenance therapy of CMV retinitis.

Prevention of CMV Disease in Solid Organ Transplantation: Study PV16000

A double-blind, double-dummy clinical active comparator study has been conducted in 372 heart, liver and kidney transplant patients at high-risk for CMV disease (Donor seropositive/Recipient seronegative [(D+/R-)]). Patients were randomized (2 VALCYTE: 1 oral ganciclovir) to receive either VALCYTE tablets (900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 posttransplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue invasive disease during the first 6 months posttransplant was 12.1% in the patients treated with VALCYTE (N=239) compared with 15.2% in the oral ganciclovir arm (N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the group treated with VALCYTE compared with the ganciclovir group. These results are summarized in Table 10.

Table 10: Percentage of Patients with CMV Disease and Tissue-Invasive CMV Disease by Organ Type: Endpoint Committee, 6 Months ITT Population

GCV = oral ganciclovir; VGCV= VALCYTE

Number of Patients with CMV Disease = Number of Patients with Tissue-Invasive CMV Disease + Number of Patients with CMV Syndrome.

The majority of CMV disease events occurred after the end of the treatment phase, when patients were no longer receiving anti-CMV prophylaxis with either oral ganciclovir or valganciclovir. During this post-treatment period, time to CMV disease was generally shorter on the ganciclovir arm. The incidence of acute graft rejection up to 6 months post-transplant was slightly higher on the ganciclovir arm of the study (36.0%, versus 29.7% on the valganciclovir arm).

Comparative Bioavailability Studies

A multi-centre, randomized, cross-over, open-label study was conducted to compare the bioavailability of ganciclovir from the valganciclovir tutti-frutti oral solution and the 450mg tablet formulation at a dose of 900mg administered in the fed state to male and female kidney transplant recipients (n=21). The statistical results below indicate that the bioavailability of ganciclovir from the tutti-frutti oral solution and the marketed tablet are comparable. SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

*

Tutti-Frutti oral solution

+

Film-coated tablet (identical to the Canadian commercial product)

SS

Expressed only as arithmetic mean (CV%)

#

Calculated based on least-square mean estimates

DETAILED PHARMACOLOGY

Animal Pharmacology

A range of routine safety pharmacology studies was undertaken to assess the effect of valganciclovir on the major bodily systems. There were no clinically relevant effects detected with valganciclovir in safety pharmacology tests on renal, intestinal, autonomic nervous or cardio-respiratory systems and on gross behaviour.

Human Pharmacology

Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for VALCYTE (valganciclovir hydrochloride). For dosing instructions in patients with renal impairment, refer to DOSAGE AND ADMINISTRATION. The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV- seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients. The parameters which control the exposure of ganciclovir from valganciclovir are the oral absorption of valganciclovir and the renal excretion of ganciclovir. The ganciclovir pharmacokinetic measures following administration of 900 mg valganciclovir and 5 mg/kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir are summarized in Table 11.

Table 11: Mean Ganciclovir Pharmacokinetic * Measures in Healthy Volunteers and HIV-positive/CMV-positive Adults at Maintenance Dosage

*Data were obtained from single and multiple dose studies in healthy volunteers, HIV-positive patients, and HIV-positive/CMV-positive patients with and without retinitis. Patients with CMV retinitis tended to have higher ganciclovir plasma concentrations than patients without CMV retinitis.

The area under the plasma concentration-time curve (AUC) for ganciclovir administered as VALCYTE tablets is comparable to the ganciclovir AUC for intravenous ganciclovir. Ganciclovir AUC0-24, achieved by a single dose of 900 mg VALCYTE tablets under fed conditions was comparable to the AUC0-24 achieved following administration of 5 mg/kg intravenous ganciclovir (42.69 mg *h/mL vs 47.61 mg *h/mL, respectively). Ganciclovir Cmax following valganciclovir administration is 40% lower than following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC0-24hr and Cmax following oral ganciclovir administration (1000 mg three times daily) are lower relative to valganciclovir and intravenous ganciclovir. The ganciclovir Cmin following intravenous ganciclovir and valganciclovir administration are less than the ganciclovir Cmin following oral ganciclovir administration.

Figure 1: Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV- positive Patients *

12.00

10.00

Ganciclovir Concentration (ug/mL)

8.00

6.00

4.00

2.00

0 5 10 15 20 25 30

Time (h)

IV GCV (5 mg/kg once daily) GCV from VGCV (900 mg once daily) Oral GCV (1 g three times daily)

*Plasma concentration-time profiles for ganciclovir (GCV) from valganciclovir (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (WV15376 n=21 and n=18, respectively) in

HIV-positive/CMV-positive patients with CMV retinitis. The plasma concentration-time profile for oral ganciclovir was obtained from a multiple dose study (GAN2230 n=24) in HIV-positive/CMV-positive patients without CMV retinitis.

A study conducted with ganciclovir, GANS 2226, has demonstrated that ganciclovir AUC is the key pharmacokinetic parameter most predictive of clinical response. Increases in ganciclovir average AUC0-24 were associated with statistically significant increases in time to progression of CMV retinitis when fitted by the Cox regression model (P=.0002). Multivariate regression analysis showed the association between AUC0-24 and time to progression of CMV retinitis was highly statistically significant (P=.0019), while the association of Cmax and time to progression of CMV retinitis was not (P=.6022). These findings indicate that average AUC0-24 is a better predictor of time to progression, and that average Cmax does not add predictive value over average AUC0-24. In heart, kidney, kidney-pancreas, and liver transplant recipients, the mean systemic exposure to ganciclovir was 1.7 x higher following administration of 900 mg VALCYTE tablets once daily versus 1000 mg ganciclovir capsules three times daily, when both drugs were administered according to their renal function dosing algorithms. The steady state systemic exposure (AUC0-24) of solid organ transplant patients to ganciclovir after daily oral administration of valganciclovir and ganciclovir was 46.3 +- 15.2 ug *h/mL and 28.0 +- 10.9 ug *h/mL, respectively. The systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetics evaluation.

Table 12: Mean Ganciclovir Pharmacokinetic Measures by Organ Type (Study PV16000)

* Includes kidney-pancreas

The pharmacokinetics of VALCYTE tablets in stable liver transplant recipients were investigated in one open label 4-part crossover study (n=28). The absolute bioavailability of ganciclovir from valganciclovir following a single dose of 900 mg VALCYTE tablets under fed conditions was approximately 60%, in agreement with the estimates obtained in other patient populations. Ganciclovir AUC0-24, achieved following a single dose of 900 mg VALCYTE tablets under fed conditions, was 41.7 +- 9.9 mg *h/mL (n=28), compared to 48.2 +- 17.3 mg *h/mL (n=27) after 5 mg/kg of intravenous ganciclovir was administered.

MICROBIOLOGY

Antiviral Effect: Treatment of CMV Retinitis in AIDS Patients

In a study of VALCYTE (valganciclovir hydrochloride) tablets for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS), the antiviral effect of VALCYTE tablets was demonstrated by a decrease in CMV shedding (see Table 13).

Table 13: Antiviral Effect of VALCYTE Tablets

* 900 mg bid for 21 days followed by 900 mg daily for 7 days

+ 5 mg/kg bid for 21 days followed by 5 mg/kg daily for 7 days

Viral Suppression: Prevention of CMV Disease in Solid Organ Transplantation

In a study of VALCYTE tablets in the prevention of CMV disease in heart, kidney, kidney- pancreas, and liver transplant recipients, the incidence of viremia (CMV viral load above a detection limit of 400 copies/mL) was lower on the valganciclovir arm while patients were receiving prophylaxis with study drug (2.9%, versus 10.4% on the ganciclovir arm). By the 6 month post transplant time point, a comparable proportion of patients had experienced viremia on the two treatment arms (39.7% valganciclovir, 43.2% ganciclovir).

Antiviral Activity against Human Herpes Viruses

Sensitive human viruses include human cytomegalovirus (HCMV), herpes-simplex virus-1 and - 2 (HSV-1 and HSV-2), human herpes virus type 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein- Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus. The demonstration of antiviral activity against these viruses does not necessarily correlate to clinical response.

Viral Resistance

Viruses resistant to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in either the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or in the viral polymerase gene (UL54). Virus with mutations in the UL97 gene is resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene may show cross-resistance to other antivirals that target the viral polymerase. The current working definition of CMV resistance to ganciclovir in in vitro assays is IC50 >1.5 mg/mL (6.0 mM). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with ganciclovir. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Treatment of CMV Retinitis in AIDS Patients

Genotypic analysis of CMV in polymorphonuclear leukocyte (PMNL) samples from 148 AIDS patients with CMV retinitis enrolled in one clinical study has shown that 2.2%, 6.5%, 12.8% and 15.3% contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment.

Prevention of CMV Disease in Solid Organ Transplant Recipients

During a clinical study of valganciclovir (and ganciclovir) for the prevention of CMV disease in heart, kidney, kidney-pancreas and liver transplant recipients, resistance to ganciclovir was studied by genotypic analysis of CMV in white blood cell samples collected: 1) on Day 100 (end of study drug prophylaxis); and 2) in cases of suspected CMV disease with viremia up to 6 months post-transplant. At the end of study drug prophylaxis (Day 100), the incidence of resistance was 0/198 samples (0%) for patients receiving valganciclovir and 2/103 samples (1.9%) for patients receiving ganciclovir. For cases of CMV disease with viremia, the incidence of resistance was 0/50 samples (0%) for patients receiving valganciclovir and 2/29 samples (6.9%) for patients receiving ganciclovir.

TOXICOLOGY

Studies have shown that valganciclovir shares the same toxicity profile as ganciclovir.

Carcinogenesis:

In a study conducted over 18 months, ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day (approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration-time curve [AUC] comparisons). At the dose of 1000 mg/kg/day there was a significant increase in the incidence of tumours of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues and liver in females. At the dose of 20 mg/kg/day, a slightly increased incidence of tumours was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day (estimated as 0.01x the human dose based on AUC comparison). Except for histiocytic sarcoma of the liver, ganciclovir-induced tumours were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered a potential carcinogen in humans.

Reproduction:

Reprotoxicity studies have not been repeated with valganciclovir because of the rapid and extensive conversion to ganciclovir. Valganciclovir is expected to have similar reprotoxicity effects as ganciclovir. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 1.7x the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons). Ganciclovir caused decreased fertility in male mice after daily intravenous doses of >= 2 mg/kg and daily oral doses of >= 10 mg/kg. These effects were reversible after daily intravenous doses of 2 mg/kg and daily oral doses of 10 mg/kg, but were irreversible or incompletely reversible after daily intravenous doses of 10 mg/kg and daily oral doses of 100 or 1000 mg/kg. Ganciclovir has also caused hypospermatogenesis in rats after daily oral doses of >= 100 mg/kg and in dogs after daily intravenous and oral doses of

>= 0.4 mg/kg and 0.2 mg/kg, respectively. Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2x the human exposure based on AUC comparisons), respectively. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality. Daily intravenous doses of 90 mg/kg administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month- old male offspring, as well as pathologic changes in the nonglandular region of the stomach. The drug exposure in mice as estimated by the AUC was approximately 1.7x the human AUC. Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/mL and occurred by passive diffusion. Valganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. There are no adequate and well-controlled studies in pregnant women. VALCYTE (valganciclovir hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Note:

All dose comparisons presented in this subsection are based on the human AUC following administration of a single 5 mg/kg infusion of intravenous ganciclovir as used during the maintenance phase of treatment. Compared with the single 5 mg/kg intravenous infusion, human exposure is doubled during the intravenous induction phase (5 mg/kg bid). The cross-species dose comparisons should be multiplied by 2 for intravenous induction treatment with intravenous ganciclovir.

Acute Toxicity:

The acute toxicity of valganciclovir was assessed in single-dose oral studies in mice and dogs. The studies performed, and their results, are presented in the following table.

Table 14: Acute (oral gavage) Toxicity Studies Conducted with Valganciclovir

Multi-dose Toxicity:

Studies in the mouse, rat and dog with valganciclovir demonstrated that the reproductive, hematopoietic, renal and gastrointestinal systems were the main organs for induced toxicity.

An i.v. study in mice, where the systemic exposure of valganciclovir was 10 times that expected in man demonstrated that valganciclovir induced the same range of findings as ganciclovir with no additional findings. The male reproductive system was the most frequently affected target organ. Lesions seen were testicular epithelial cell atrophy, oligospermia, and changes in accessory sex organs at sub- therapeutic exposure levels. Female reproductive changes were confined to uterine, ovarian and clitoral atrophy. Valganciclovir induced intestinal mucosal and/or crypt degeneration in mice and dogs. A range of hematopoietic changes were induced which included lymphoreticular gland atrophy, leukopenia - particularly neutropenia, anemia, thrombocytopenia and bone marrow hypocellularity. Renal toxicity was recorded in mice as tubular basophilia, pelvic dilatation and necrosis with associated changes in clinical pathology. No studies were undertaken on the reproductive toxicology or on carcinogenicity. Since valganciclovir behaves as ganciclovir in all studies, it is assumed that the ter a togenicity, mutagenicity and carcinogenicity seen with ganciclovir will apply equally to valganciclovir. The multi-dose toxicity studies performed with valganciclovir are summarized in the following table.

Table 15: Multi-dose Studies Conducted with Valganciclovir

Mutagenesis: Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo, but did not cause point mutations in bacterial or yeast cells, dominant lethality in mice, or morphologically transformed cells in vitro. Bacterial mutation, mammalian cell mutation, and in vivo chr o mosome analysis studies were undertaken to assess the mutagenic and clastogenic potential of valganciclovir. Valganciclovir was mutagenic in the Mouse Lymphoma Assay with and without metabolic activation and clastogenic in the Micronucleus Assay at a cytotoxic dose. The mutagencity studies performed are summarized in the table below.

Table 16: Mutagenicity Studies

Page 46 of 55

REFERENCES

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2. Guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs). In: Canadian Society of Hospital Pharmacists. CSHP Official

Publications. Ottawa ON: Canadian Society of Hospital Pharmacists. 2001:93-104

Chou S, Marousek G, Guentzel S, Follansbee SE, Poscher ME, Lalezari JP, et al.

Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease. J Infect Dis 1997; 176 (3):786-789.

CYTOVENE (ganciclovir capsules and ganciclovir sodium for injection) Product Monograph. Mississauga, ON: Hoffmann-La Roche Limited; July 18, 2003.

Czock D et al. Pharmacokinetics of valganciclovir and ganciclovir in renal impairment.

Clin Pharmacol. Ther. 2000: 72 (2): 142-150

Faulds D, Heel RC. Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 1990; 39(4):597- 638.

Gilstrap LC, Bawdon RE, Roberts SW, Sobhi S. The transfer of nucleoside analog ganciclovir across the perfused human placenta. Am J Obstet Gynecol 1994; 170(4):967- 973.

Henderson GI, Hu ZQ, Yang Y, Perez TB, Devi BG, Frosto TA, et al. Ganciclovir transfer by human placenta and its effects on rat fetal cells. Am J Med Sci 1993; 306 (3):151-156.

Jung D, Griffy K, Wong R, Colburn W, Hulse J. Absolute bioavailability and dose proportionality of oral ganciclovir after ascending multiple doses in human immunodeficiency virus (HIV)-positive patients. J Clin Pharmacol 1998; 38 (12):1122- 1128.

Jung D, Griffy K, Dorr A. Effect of food on high-dose oral ganciclovir disposition in HIV-positive subjects. J Clin Pharmacol 1999; 39(2):161-165.

Jung D, Dorr A. Single dose pharmacokinetics of valganciclovir in HIV- and CMV- seropositive subjects. J Clin Pharmacol 1999; 39(8):800-804.

Lalezari JP, Friedberg DN, Bissett J, Giordano MF, Hardy WD, Drew WL, et al. High dose oral ganciclovir treatment for cytomegalovirus retinitis. J Clin Virol 2002; 24(1- 2):67-77.

Lalezari J, Lindley J, Walmsley S, Kuppermann B, Fisher M, Friedberg D, et al. A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis. J Acquir

Immune Defic Syndr 2002; 30(4):392-400.

Martin DF, Sierra Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, et al, for the Valganciclovir Study Group. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002; 346:1119-1126.

Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Tran 2004; 4: 611-620.

Pescovitz MD, Rabkin J, Merion RM, Paya CV, Pirsch J, Freeman RB, et al.

Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents & Chemother 2000; 44(10):2811-2815.

16.Sorbera LA, Castaner R, Castaner J. Valganciclovir hydrochloride. Anti- cytomegalovirus drug. Drugs Fut 2000; 25(5):474-480.

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IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrVALCYTE(r) Tablets Valganciclovir hydrochloride

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

ABOUT THIS MEDICATION

What the medication is used for:

• VALCYTE is a prescription medication that belongs to the family of drugs known as "antivirals"

• VALCYTE is used to treat cytomegalovirus (CMV) retinitis in people who have acquired immunodeficiency syndrome (AIDS).

• VALCYTE is also used to prevent cytomegalovirus (CMV) disease in people who have received a solid organ transplant and are at risk of developing CMV disease.

What it does:

VALCYTE works by slowing the growth of CMV virus, the virus that causes CMV retinitis as well as infection at other sites in the body. For most people with CMV retinitis, VALCYTE prevents CMV from progressing (spreading) into healthy cells as quickly as it would without treatment, thereby protecting eyesight from damage due to CMV disease.

VALCYTE does not cure CMV retinitis, and some people may experience progression of retinitis during or following treatment with VALCYTE. Therefore, you must follow your doctor's advice and have your eyes checked regularly.

For most patients who have received a solid organ transplant, VALCYTE prevents the occurrence of CMV disease up to 6 months after the transplant.

VALCYTE is a prodrug of ganciclovir. This means it is changed to ganciclovir once it is absorbed into the body. Ganciclovir is the active part of the drug that actually slows the growth of CMV virus.

When it should not be used:

Do not take VALCYTE if you have ever had a serious reaction to valganciclovir, ganciclovir (as VALCYTE or ganciclovir capsules or CYTOVENE(r)-IV). Do not take if you have had sensitivity reactions with acyclovir, ganciclovir and valacyclovir as a similar reaction can occur with VALCYTE. Do not take VALCYTE if you have any

reaction to any of the nonmedicinal ingredients (see "What the nonmedicial ingredients are").

What the medicinal ingredient is:

The medicinal ingredient found in VALCYTE is

valganciclovir hydrochloride.

What the nonmedicinal ingredients are:

VALCYTE tablets contain the following nonmedicinal ingredients: crospovidone, microcrystalline cellulose,

povidone K-30, and stearic acid powder. The film-coat

applied to the tablets is Opadry(r) Pink, which contains hydroxypropyl methylcellulose, polyethylene glycol 400/macrogol, polysorbate 80, synthetic red iron oxide, and titanium dioxide.

What dosage forms it comes in:

VALCYTE is available as a pink 450 mg valganciclovir film-coated tablet (as valganciclovir hydrochloride). .

VALCYTE is also available as a powder for oral solution. The solution will be prepared by your pharmacist and will be a fruit-flavoured liquid containing 50mg/ml valganciclovir (as valganciclovir hydrochloride).

WARNINGS AND PRECAUTIONS

BEFORE you use VALCYTE talk to your doctor or pharmacist if:

you have ever had a bad reaction to VALCYTE (valganciclovir) or any of the inactive ingredients shown above.

you have ever had a bad reaction to ganciclovir, acyclovir or valacyclovir.

you are allergic to other medicines, food and dyes.

you are taking ANY other medicines (prescription or nonprescription) including herbal or natural products.

you have any other illnesses/diseases, including a history of liver or kidney disease.

you are receiving hemodialysis as dosage adjustment is required.

you have blood problems

you or your partner are pregnant, plan on becoming pregnant, or are breast-feeding a child, as VALCYTE may cause birth defects in humans and should not be used during pregnancy. If there is any chance that you or your partner could become pregnant, it is very important for you to use effective contraception during and for at least 90 days following treatment with VALCYTE. For women this means using barrier protection (condoms) and one additional form of contraception (birth control pills, intrauterine device). For men this means using barrier protection (condoms).

Women who are HIV positive should not breast feed because HIV infection can be passed to the baby via the breast milk.

This information will help your doctor and you decide whether you should use VALCYTE and what extra care may need to be taken while you are on the medication. You should always consult your doctor or pharmacist before using other medications while on VALCYTE.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor or pharmacist about all medications that you are taking, including those you buy over the counter and herbal or natural products. VALCYTE may change the effect of other medications.

The following drugs may need to have their dose changed when taken with VALCYTE:

• Videx(r) (didanosine, ddI)

• Retrovir(r) (zidovudine, ZDV, AZT)

• BenurylTM (probenecid)

Talk to your doctor if you are taking imipenem-cilastin. Convulsions have occurred in patients taking imipenem- cilastin and ganciclovir. You may discuss different options with your doctor.

PROPER USE OF THIS MEDICATION

Dosing Considerations:

Your doctor has prescribed VALCYTE after carefully studying your case. Other people may not benefit from taking this medicine, even though their problems may seem similar to yours. Do not give your VALCYTE to anyone else.

To make sure that your therapy is as effective as possible, take your VALCYTE exactly as your doctor prescribes it. Do not skip any doses, or take more than the recommended dose.

Take VALCYTE with food.

Do not break or crush VALCYTE tablets. Avoid contact with broken VALCYTE tablets on your skin, mucous membranes or eyes. If contact occurs, wash your skin well with soap and water or rinse your eyes well with sterile or plain water if sterile water is not available.

Usual dose:

Treatment of CMV Retinitis in Patients with AIDS

The usual dosage for adults to get active CMV retinitis under control (induction therapy) is two 450 mg tablets twice a day for 21 days.

The usual dosage for adults to help keep CMV retinitis under control (maintenance therapy) is two 450 mg

tablets once a day.

Prevention of CMV Disease Solid Organ Transplantation

The usual dosage to prevent CMV in adults who received a solid organ transplant is two 450 mg tablets once a day starting within 10 days of transplant and continuing until 100 days after the transplant.

Overdose:

In cases of overdose or suspected overdose, contact the poison control centre or your physician immediately.

Missed Dose:

If you forget to take a dose of VALCYTE take it as soon as possible, then just carry on with the regular times you take your medication. If you remember your missed dose close to the time for your next dose, do not take the missed dose. Two doses of VALCYTE should not be taken at the same time.

Do not let your VALCYTE run out. The amount of virus in your blood may increase if your medicine is stopped, even for a short time.

It may be a good idea to ask your doctor or pharmacist ahead of time what to do about missed doses.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Unwanted effects are possible with all medicines. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking VALCYTE.

Blood problems.

VALCYTE can cause serious blood cell problems. These include reduced numbers of certain white blood cells (granulocytopenia, neutropenia, or leukopenia), reduced numbers of red blood cells (anemia), and reduced numbers of platelets (thrombocytopenia). VALCYTE may also cause blood creatinine elevation, increased potassium in the blood, and abnormal liver function. Your doctor should recommend that you have blood tests done on a regular basis.

Kidney problems.

VALCYTE can cause an increase in serum creatinine (an indicator of kidney function). An increase in serum creatinine may indicate abnormal kidney function. Your doctor may have blood tests done on a regular basis to monitor your serum creatinine.

Common side effects.

VALCYTE can cause other side effects. In studies, the most common side effects with the use of VALCYTE (although not necessarily related to VALCYTE) were diarrhea, nausea, vomiting, fever, headache, trembling, graft rejection, swelling of the legs, constipation, back pain, insomnia (sleeplessness), high blood pressure.

Other side effects.

Convulsions, sedation, dizziness, ataxia (unsteadiness) and/or confusion have also been reported with the use of VALCYTE. If they occur, these side effects may affect a person's ability to drive a car or operate machinery.

Although there is no supporting information from clinical trials in humans, animal studies indicate that VALCYTE may cause cancer in humans.

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:

By toll-free telephone; 866-234-2345 By 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 Health Products and Food Branch Health Canada

Tunney's Pasture, AL 070lC Ottawa ON KIA OK9

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.

MORE INFORMATION

REMINDER: This medicine has been prescribed only for you. Do not give it to anybody else. If you have any further questions, please ask your doctor or pharmacist.

This document plus the full product monograph, prepared for health professionals can be found at: www.rochecanada.com or by contacting the sponsor, Hoffmann-La Roche Limited, at: 1-888-762-4388.

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

HOW TO STORE IT

Keep out of the reach of children.

Store VALCYTE tablets in a clean dry area at room temperature (15-30degC).

Keep container tightly closed.

Do not use medication after the expiry date on the package.

This leaflet was prepared by Hoffmann-La Roche Limited.

VALCYTE and CYTOVENE are registered Trade-Marks of

F. Hoffmann-La Roche AG, used under license. Videx is a registered Trade-Mark of Bristol-Myers Squibb Company. Retrovir is a registered Trade-Mark of Glaxo Wellcome Inc.

Benuryl is a Trade-Mark of ICN Canada Ltd. Primaxin is a

registered Trade-Mark of Merck & Co., Inc. Opadry is a registered Trade-Mark of Colorcon Inc.

Last revised: March 2008

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrVALCYTE(r) Oral Solution Valganciclovir hydrochloride

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

ABOUT THIS MEDICATION

What the medication is used for:

VALCYTE is a prescription medication that belongs to the family of drugs known as "antivirals"

VALCYTE is used to treat cytomegalovirus (CMV) retinitis in people who have acquired immunodeficiency syndrome (AIDS).

VALCYTE is also used to prevent cytomegalovirus (CMV) disease in people who have received a solid organ transplant and are at risk of developing CMV disease.

What it does:

VALCYTE works by slowing the growth of CMV virus, the virus that causes CMV retinitis as well as infection at other sites in the body. For most people with CMV retinitis, VALCYTE prevents CMV from progressing (spreading) into healthy cells as quickly as it would without treatment, thereby protecting eyesight from damage due to CMV disease.

VALCYTE does not cure CMV retinitis, and some people may experience progression of retinitis during or following treatment with VALCYTE. Therefore, you must follow your doctor's advice and have your eyes checked regularly.

For most patients who have received a solid organ transplant, VALCYTE prevents the occurrence of CMV disease up to 6 months after the transplant.

VALCYTE is a prodrug of ganciclovir. This means it is changed to ganciclovir once it is absorbed into the body. Ganciclovir is the active part of the drug that actually slows the growth of CMV virus.

When it should not be used:

Do not take VALCYTE if you have ever had a serious reaction to valganciclovir, ganciclovir (as VALCYTE or ganciclovir capsules or CYTOVENE(r)-IV). Do not take if you have had sensitivity reactions with acyclovir, ganciclovir and valacyclovir as a similar reaction can occur with VALCYTE. Do not take VALCYTE if you have any

reaction to any of the nonmedicinal ingredients (see "What the nonmedicial ingredients are").

What the medicinal ingredient is:

The medicinal ingredient found in VALCYTE is

valganciclovir hydrochloride.

What the nonmedicinal ingredients are:

VALCYTE powder for oral solution contains the following nonmedicinal ingredients: povidone K30, fumaric acid,

sodium benzoate, sodium saccharin, mannitol, tutti-frutti

flavour (maltodextrins (maize), propylene glycol, arabic gum and natural identical flavouring substances mainly consisting of banana, pineapple, and peach flavour).

What dosage forms it comes in:

VALCYTE is available as a powder for oral solution. The

solution will be prepared by your pharmacist and will be a fruit-flavoured liquid containing 50mg/ml valganciclovir (as valganciclovir hydrochloride).

VALCYTE is also available as a pink 450 mg valganciclovir film-coated tablet (as valganciclovir hydrochloride). .

WARNINGS AND PRECAUTIONS

BEFORE you use VALCYTE talk to your doctor or pharmacist if:

*

you have ever had a bad reaction to VALCYTE (valganciclovir) or any of the inactive ingredients shown above.

*

you have ever had a bad reaction to ganciclovir, acyclovir or valacyclovir.

*

you are allergic to other medicines, food and dyes.

*

you are taking ANY other medicines (prescription or nonprescription) including herbal or natural products.

*

you have any other illnesses/diseases, including a history of liver or kidney disease.

*

you are receiving hemodialysis as dosage adjustment is required.

*

you have blood problems

*

you or your partner are pregnant, plan on becoming pregnant, or are breast-feeding a child, as VALCYTE may cause birth defects in humans and should not be used during pregnancy. If there is any chance that you or your partner could become pregnant, it is very important for you to use effective contraception during and for at least 90 days following treatment with VALCYTE. For women this means using barrier protection (condoms) and one additional form of contraception (birth control pills, intrauterine device). For men this means using barrier protection (condoms). Women who are HIV positive should not breast feed

because HIV infection can be passed to the baby via the breast milk.

This information will help your doctor and you decide whether you should use VALCYTE and what extra care may need to be taken while you are on the medication. You should always consult your doctor or pharmacist before using other medications while on VALCYTE.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor or pharmacist about all medications that you are taking, including those you buy over the counter and herbal or natural products. VALCYTE may change the effect of other medications.

The following drugs may need to have their dose changed when taken with VALCYTE:

- Videx(r) (didanosine, ddI)

- Retrovir(r) (zidovudine, ZDV, AZT)

- BenurylTM (probenecid)

Talk to your doctor if you are taking imipenem-cilastin. Convulsions have occurred in patients taking imipenem- cilastin and ganciclovir. You may discuss different options with your doctor.

1. Shake closed bottle well for about 5 seconds before each use.

2. Remove child-resistant cap.

3. Before inserting the tip of the dispenser into bottle adapter, push the plunger completely down toward the tip of the dispenser. Insert tip firmly into opening of the bottle adapter.

4. Turn the entire unit (bottle and dispenser) upside down.

5. Pull the plunger out slowly until the desired amount of medication is

withdrawn into the dispenser (see figure).

PROPER USE OF THIS MEDICATION

Dosing Considerations:

Your doctor has prescribed VALCYTE after carefully studying your case. Other people may not benefit from taking this medicine, even though their problems may seem similar to yours. Do not give your VALCYTE to anyone else.

To make sure that your therapy is as effective as possible, take your VALCYTE exactly as your doctor prescribes it. Do not skip any doses, or take more than the recommended dose.

Take VALCYTE with food.

You have to be careful when handling the VALCYTE solution. You should avoid getting the solution on your skin or in your eyes. If you accidentally get the solution on your skin, wash the area thoroughly with soap and water. If you accidentally get any solution in your eyes, rinse your eyes thoroughly with sterile water or plain water if sterile water is not available.

If your doctor has prescribed VALCYTE oral solution, follow the directions below to ensure proper dosing:

1. Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

2. Dispense directly into mouth.

3. Close bottle with child-resistant cap after each use. Return to a refrigerator (see section "How to store it").

4. Disassemble oral dispenser, rinse under

running tap water and air dry prior to next use.

It is important that you use the syringe provided in the pack to measure your dose of VALCYTE solution. Two syringes are provided in case one of them gets lost or damaged. Each syringe is designed to measure up to a 450 mg amount of VALCYTE. Remember to take the dose exactly as prescribed by your doctor.

• Always wash the syringe thoroughly and allow it to dry after you have taken your dose.

• Contact your doctor or pharmacist if both syringes become lost or damaged, and they will advise you about how to continue to take your medication.

Usual dose:

Treatment of CMV Retinitis in Patients with AIDS

The usual dosage for adults to get active CMV retinitis under control (induction therapy) is 900 mg of VALCYTE solution taken twice a day for 21 days. Use the syringe provided and take two 450 mg amounts of the solution in the morning and two 450 mg amounts in the evening.

The usual dosage for adults to help keep CMV retinitis under control (maintenance therapy) is 900 mg VALCYTE solution taken once a day. Use the syringe provided and take two 450 mg amounts of solution.You should try to take the solution at the same time each day.

Prevention of CMV Disease Solid Organ Transplantation

The usual dosage to prevent CMV in adults who received a solid organ transplant is 900 mg VALCYTE solution taken once a day starting within 10 days of transplant and continuing until 100 days after the transplant. Use the syringe provided and take two 450 mg amounts of solution once a day.

Patients with kidney problems: If your kidneys are not working properly, your doctor may instruct you to take a lower dose of VALCYTE solution each day. It is very important that you follow the dose prescribed by your doctor.

Overdose:

In cases of overdose or suspected overdose, contact the poison control centre or your physician immediately.

Missed Dose:

If you forget to take a dose of VALCYTE take it as soon as possible, then just carry on with the regular times you take your medication. If you remember your missed dose close to the time for your next dose, do not take the missed dose. Two doses of VALCYTE should not be taken at the same time.

Do not let your VALCYTE run out. The amount of virus in your blood may increase if your medicine is stopped, even for a short time.

It may be a good idea to ask your doctor or pharmacist ahead of time what to do about missed doses.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Unwanted effects are possible with all medicines. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking VALCYTE.

Blood problems.

VALCYTE can cause serious blood cell problems. These include reduced numbers of certain white blood cells (granulocytopenia, neutropenia, or leukopenia), reduced numbers of red blood cells (anemia), and reduced numbers of platelets (thrombocytopenia). VALCYTE may also cause blood creatinine elevation, increased potassium in the blood, and abnormal liver function. Your doctor should recommend that you have blood tests done on a regular basis.

Kidney problems.

VALCYTE can cause an increase in serum creatinine (an indicator of kidney function). An increase in serum creatinine may indicate abnormal kidney function. Your doctor may have blood tests done on a regular basis to monitor your serum creatinine.

Common side effects.

VALCYTE can cause other side effects. In studies, the most common side effects with the use of VALCYTE (although not necessarily related to VALCYTE) were diarrhea, nausea, vomiting, fever, headache, trembling, graft rejection, swelling of the legs, constipation, back pain, insomnia (sleeplessness), high blood pressure.

Other side effects.

Convulsions, sedation, dizziness, ataxia (unsteadiness) and/or confusion have also been reported with the use of VALCYTE. If they occur, these side effects may affect a person's ability to drive a car or operate machinery.

Although there is no supporting information from clinical trials in humans, animal studies indicate that VALCYTE may cause cancer in humans.

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:

By toll-free telephone; 866-234-2345 By 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 Health Products and Food Branch Health Canada

Tunney's Pasture, AL 070lC Ottawa ON KIA OK9

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.

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

HOW TO STORE IT

Keep out of the reach of children.

Store VALCYTE oral solution in its original labelled container in a refrigerator at 2 to 8degC. The pharmacist will write the date of expiration on the bottle label.

Keep the bottle tightly closed.

Do not use medication after the expiry date on the package.

MORE INFORMATION

REMINDER: This medicine has been prescribed only for you. Do not give it to anybody else. If you have any further questions, please ask your doctor or pharmacist.

This document plus the full product monograph, prepared for health professionals can be found at: www.rochecanada.com or by contacting the sponsor, Hoffmann-La Roche Limited, at: 1-888-762-4388.

This leaflet was prepared by Hoffmann-La Roche Limited VALCYTE and CYTOVENE are registered Trade-Marks of

F. Hoffmann-La Roche AG, used under license. Videx is a registered Trade-Mark of Bristol-Myers Squibb Company. Retrovir is a registered Trade-Mark of Glaxo Wellcome Inc. Benuryl is a Trade-Mark of ICN Canada Ltd. Primaxin is a registered Trade-Mark of Merck & Co., Inc.

Last revised: March 5, 2008