Mylan-Valganciclovir Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

MYLAN-VALGANCICLOVIR (valganciclovir hydrochloride) is indicated for adult patients:

• For the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).
• For the prevention of cytomegalovirus (CMV) disease in solid organ transplant patients who are at risk. This indication is based on a double-blind, double-dummy, active comparator study in heart, liver, kidney and kidney-pancreas transplant patients at high risk for CMV disease (donor CMV seropositive/recipient seronegative [D+/R-] (see WARNINGS and PRECAUTIONS and CLINICAL TRIALS for information on specific solid organ transplant subgroups)).

CONTRAINDICATIONS

• MYLAN-VALGANCICLOVIR (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 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. MYLAN-VALGANCICLOVIR is indicated for use only in immunocompromised patients, where the potential benefit outweighs the risks. Safety and efficacy of valganciclovir hydrochloride 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 valganciclovir hydrochloride compared with the oral ganciclovir group (see CLINICAL TRIALS). The clinical significance of this is unknown.

Other: The safety and efficacy of valganciclovir hydrochloride 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

MYLAN-VALGANCICLOVIR should not be administered if the absolute neutrophil count is less than 500 cells/μL, the platelet count is less than 25,000/μL, 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 valganciclovir hydrochloride tablets (and ganciclovir) (see WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION: Dosing Considerations).

MYLAN-VALGANCICLOVIR 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 MYLAN-VALGANCICLOVIR. 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 MYLAN-VALGANCICLOVIR (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. MYLAN-VALGANCICLOVIR 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 MYLAN-VALGANCICLOVIR.

Pediatrics: Safety and efficacy of valganciclovir hydrochloride in pediatric patients have not been established. The use of MYLAN-VALGANCICLOVIR 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.

Geriatrics (> 65 years of age): The pharmacokinetic profiles of valganciclovir hydrochloride 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 MYLAN-VALGANCICLOVIR (see DOSAGE AND ADMINISTRATION).

Clinical studies of valganciclovir hydrochloride 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. Valganciclovir hydrochloride 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 MYLAN-VALGANCICLOVIR (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/μL 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 valganciclovir hydrochloride 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).

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

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

Adverse Drug Reaction Overview

Valganciclovir is a prodrug of ganciclovir, and is rapidly converted to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir usage can therefore be expected to occur with MYLAN-VALGANCICLOVIR (valganciclovir hydrochloride). All of the adverse events observed in clinical studies of valganciclovir hydrochloride have been previously observed with ganciclovir.

Treatment of CMV Retinitis in AIDS Patients

The safety profiles of valganciclovir and intravenous ganciclovir during 28 days of randomized study phase (21 days induction dose and 7 days maintenance) in 79 patients each were comparable. The most frequently reported events were diarrhea, neutropenia and pyrexia. More patients reported diarrhea, oral candidiasis, headache and fatigue in the oral valganciclovir arm, and nausea and injection site related events in the intravenous ganciclovir arm (see Table 1).

Table 1: Percentage of Patients with Selected Adverse Events Occurring During the

Randomized Study Phase

Table 2 shows the adverse events regardless of seriousness and drug relationship with an incidence of ≥ 5% obtained either from trials looking at the use of valganciclovir in patients with CMV retinitis or the use of valganciclovir in solid organ transplant patients.

The information in Table 2 pertaining to the patients with CMV retinitis is based on two clinical trials (n=370) where patients with CMV retinitis received valganciclovir hydrochloride at a dosage of 900 mg twice daily or once daily, corresponding to the induction or maintenance regimen, respectively.

A total of 370 patients received maintenance therapy with valganciclovir hydrochloride tablets 900 mg once daily, with approximately 252 (68%) of these patients receiving valganciclovir hydrochloride tablets for more than nine months (maximum duration was 36 months).

The most frequently reported adverse events (% of patients), regardless of seriousness and drug relationship in patients taking valganciclovir hydrochloride reported from these two clinical trials (n=370) were diarrhea (41%), pyrexia (31%), nausea (30%), neutropenia (27%) and anemia (26%). The majority of the adverse events were of mild or moderate intensity. The most frequently reported adverse reactions (% of patients), regardless of seriousness that were considered related (remotely, possibly or probably) to valganciclovir hydrochloride by the investigator were neutropenia (23%), anemia (17%), diarrhea (13%) and nausea (10%).

Prevention of CMV Disease in Solid Organ Transplantation

Table 2 shows the adverse events regardless of seriousness and drug relationship with an incidence of ≥ 5% from a clinical trial, PV16000 (up to 28 days after study treatment) where heart, kidney, kidney-pancreas, and liver transplant patients received valganciclovir (N=244) or oral ganciclovir (N=126) starting within 10 days of transplantation until Day 100 post-transplant. The most frequently reported adverse events (% of patients), regardless of seriousness and drug relationship in patients taking valganciclovir hydrochloride reported in this clinical trial (n=244) were diarrhea (30%), tremors (28%), graft rejection (24%), nausea (23%), headache (22%), edema lower limb (21%), constipation (20%), back pain (20%), insomnia (20%), hypertension (18%) and vomiting (16%). These events were also seen with oral ganciclovir at a comparable incidence. The majority of adverse events were of mild or moderate intensity.

The most frequently reported adverse reactions (% of patients), regardless of seriousness, that were considered related (remotely, possibly or probably) to valganciclovir hydrochloride by the investigator in solid organ transplant patients treated until Day 100 post-transplant were leukopenia (9%), diarrhea (7%), nausea (6%), neutropenia (5%). Leukopenia and neutropenia were more common in patients taking valganciclovir hydrochloride compared to the oral ganciclovir arm (4% and 1%, respectively).

Table 2: Percentage of Patients with Adverse Events Occurring in ≥ 5% of Patients in either CMV Retinitis or Solid Organ Transplantation Clinical Trials with Valganciclovir or Ganciclovir

Serious adverse events considered related by the company to the use of valganciclovir hydrochloride reported from these three clinical trials (n= 614) with a frequency of less than 5% and which are not mentioned in the two tables above, are listed below:

Bleeding complications: Potentially life-threatening bleeding associated with thrombocytopenia

Body as a whole: Valganciclovir hypersensitivity

Central and peripheral nervous system: Convulsion, psychotic disorder, hallucinations, confusion, agitation

Hemic and lymphatic system: Pancytopenia, bone marrow depression, aplastic anemia

Urogenital system: Decreased creatinine clearance

Experience with ganciclovir

Valganciclovir hydrochloride is rapidly converted to ganciclovir. Key adverse events reported with ganciclovir, and not mentioned above, are listed below. However, for a full listing of ganciclovir adverse reactions please refer to the current CYTOVENE product monograph.

Body as a whole - general disorders: asthenia, bacterial, fungal and viral infections, hemorrhage, malaise, mucous membrane disorder, photosensitivity reaction, rigors, sepsis.

Hepatic system disorders: hepatitis, jaundice.

Cardiovascular system disorders: arrhythmia (including ventricular arrhythmia), migraine, phlebitis, tachycardia, thrombophlebitis deep, vasodilatation.

Central and peripheral nervous system disorders: abnormal dreams, amnesia, ataxia, coma, dry mouth, emotional disturbance, hyperkinetic syndrome, hypertonia, libido decreased, myoclonic jerks, nervousness, somnolence, thinking abnormal.

Gastrointestinal system disorders: cholangitis, dysphagia, eructation, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal disorder, gastrointestinal hemorrhage, mouth ulceration, pancreatitis, tongue disorder.

Hemic and lymphatic: eosinophilia, leukocytosis, splenomegaly. Hepatic system disorders: hepatitis, jaundice.

Metabolic and nutritional disorders: blood alkaline phosphatase increased, blood creatine phosphokinase increased, blood glucose decreased, blood lactic dehydrogenase increased, diabetes mellitus, hypoproteinemia.

Musculoskeletal system disorders: musculoskeletal pain, myasthenic syndrome.

Respiratory system disorders: sinus congestion.

Skin and appendages disorders: alopecia, dry skin, sweating increased, urticaria.

Special senses: amblyopia, blindness, earache, eye hemorrhage, eye pain, deafness, glaucoma, taste disturbance, tinnitus, vision abnormal, vitreous disorder.

Urogenital system disorders: hematuria present, impotence, renal failure, urinary frequency.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory abnormalities reported with valganciclovir hydrochloride tablets in CMV retinitis studies and transplantation are listed below.

Table 3: Laboratory Abnormalities Reported in Two Clinical Studies in the Treatment of CMV Retinitis and One Clinical Study in Transplantation

Severe neutropenia (ANC <500/µL) is seen more frequently in CMV retinitis patients (19%) undergoing treatment with valganciclovir than in solid organ transplant patients receiving valganciclovir (5%) or oral ganciclovir (3%) until Day 100 post-transplant. There was a greater increase in serum creatinine seen in solid organ transplant patients treated until Day 100 post- transplant with both valganciclovir and oral ganciclovir when compared to CMV retinitis patients. Impaired renal function is a feature common to solid organ transplantation patients.

Post-Market Adverse Drug Reactions

As valganciclovir hydrochloride is rapidly and extensively converted to ganciclovir, any adverse events associated with ganciclovir might also occur with MYLAN-VALGANCICLOVIR. Adverse reactions from post-marketing spontaneous reports with intravenous and oral ganciclovir not mentioned in any section above, and for which a causal relationship cannot be excluded are listed below:

• Anaphylaxis
• Decreased fertility in males

Adverse events that have been reported during the post-marketing period are consistent with those seen in clinical trials with valganciclovir hydrochloride and ganciclovir. For a full listing of ganciclovir post-marketing adverse events please refer to the current CYTOVENE product monograph.

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 MYLAN-VALGANCICLOVIR (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 valganciclovir hydrochloride 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 C_max Values

Table 5: Results of Drug Interaction Studies With Ganciclovir: Effects of Ganciclovir on Plasma AUC and C_max 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. MYLAN-VALGANCICLOVIR 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, and pegylated interferons/ribavirin should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

Since ganciclovir is excreted through the kidney via glomerular filtration and active tubular secretion (seeACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics, Excretion), coadministration of valganciclovir with antiretroviral drugs that share the tubular secretion pathway, such as nucleos(t)ide reverse transcriptase inhibitors, may change the plasma concentrations of valganciclovir and/or the coadministered drug.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• Caution - Strict adherence to dosage recommendations is essential to avoid overdose.
• MYLAN-VALGANCICLOVIR (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 valganciclovir hydrochloride is significantly higher than from oral ganciclovir. The dosage and administration of MYLAN-VALGANCICLOVIR 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).
• Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with valganciclovir hydrochloride tablets (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/μL, or the hemoglobin is less than 80 g/L, or the platelet count is less than 25,000/μL (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 valganciclovir hydrochloride, 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/μL 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 Adult 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 Adult Patients with 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 post- transplantation.

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

Dosage Adjustment

Reduction of Dose: Dosage reductions in renally impaired patients are required for MYLAN-VALGANCICLOVIR (see Renal Impairment). Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see ADVERSE REACTIONS). MYLAN-VALGANCICLOVIR should not be administered in patients with severe neutropenia (ANC less than 500/μL), severe thrombocytopenia (platelets less than 25,000/μL), 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 for adult patients based on creatinine clearance as shown in Table 6 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: Valganciclovir hydrochloride Tablet Dose for Patients with Impaired Renal Function

*Creatinine clearance is calculated from 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 MYLAN-VALGANCICLOVIR should not be taken at the same time.

Administration

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

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

OVERDOSAGE

Overdose Experience with 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 valganciclovir hydrochloride 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 MYLAN-VALGANCICLOVIR. 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 post-marketing 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 μg/mL (0.08 to 14.32 μM). Ganciclovir inhibits mammalian cell proliferation (CIC₅₀) in vitro at higher concentrations ranging from

10.21 to >250 μg/mL (40 to >1000 μM). Bone marrow-derived colony-forming cells are more sensitive (CIC₅₀ 0.69 to 3.06 μg/mL; 2.7 to 12 μM). 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 valganciclovir hydrochloride tablets following food was approximately 60% (3 studies, n=18; n=16; n=28). Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir hydrochloride 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 C_max values were approximately 1% and 3% of those of ganciclovir, respectively.

When valganciclovir hydrochloride 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 μg•h/mL (n=75), and the maximum plasma concentration (C_max) was 5.37 ± 1.53 μg/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 valganciclovir hydrochloride 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 C_max increased by 14% (95% CI: -5 to 36%), without any prolongation in time to peak plasma concentrations (T_max). Therefore it is recommended that valganciclovir hydrochloride 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 μg/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 valganciclovir hydrochloride tablets, no correlation was observed between ganciclovir AUC and weight; oral dosing of valganciclovir hydrochloride 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 (t_½) of ganciclovir following oral administration of valganciclovir hydrochloride 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 t_½ of ganciclovir after oral administration of valganciclovir hydrochloride 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 valganciclovir hydrochloride in pediatric patients have not been well established (see WARNINGS AND PRECAUTIONS: Special Populations, Pediatrics and CLINICAL TRIALS).

Geriatrics: No studies of valganciclovir hydrochloride 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 valganciclovir hydrochloride tablets were evaluated in 24 otherwise healthy adult individuals with renal impairment.

Table 7: Pharmacokinetics of Ganciclovir From a Single Oral Dose of 900 mg valganciclovir hydrochloride 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).

STORAGE AND STABILITY

MYLAN-VALGANCICLOVIR tablets:

Preserve in tight container. Store at 25°C, excursion permitted between 15°C and 30°C.

SPECIAL HANDLING INSTRUCTIONS

Caution should be exercised in the handling of MYLAN-VALGANCICLOVIR (valganciclovir hydrochloride) tablets. 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.

Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Used established “collection systems” if available at your location. Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g. CSHP, 1997). Disposal of MYLAN-VALGANCICLOVIR 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 and stearic acid. The coating contains: hydroxypropyl methylcellulose, iron oxide red, polyethylene glycol 400/macrogol, polysorbate 80 and titanium dioxide.

Availability: MYLAN-VALGANCICLOVIR (valganciclovir hydrochloride) 450 mg tablets are available in HDPE bottles of 60, as pink film-coated, oval, biconvex, beveled edge tablets debossed with "M" on one side of the tablet and "V45" on the other side.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

CLINICAL TRIALS

Comparative Bioavailability Studies

A single oral dose, randomized, double-blind, two-period, two-treatment, two-sequence, cross-over bioequivalence study of Mylan-Valganciclovir (valganciclovir hydrochloride) 2 x 450 mg tablets (Mylan Pharmaceuticals ULC) and Valcyte® (valganciclovir hydrochloride) 2 x 450 mg tablets (Hoffmann-La Roche Limited, Canada) was performed in 21 healthy, adult male subjects under fed conditions.

A summary of the results is presented in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Mylan-Valganciclovir (valganciclovir hydrochloride) 450 mg tablets (Mylan Pharmaceuticals ULC).

^{† Pr}VALCYTE^® (valganciclovir hydrochloride) 450 mg tablets (Hoffmann-La Roche Limited, Canada) were purchased in Canada.

^§ Expressed as the median (range) only.

^€ Expressed as the arithmetic mean (CV %) only.

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 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 8: 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 valganciclovir hydrochloride. 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, valganciclovir hydrochloride 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 valganciclovir hydrochloride for the maintenance therapy of CMV retinitis because all patients in study WV15376 received open-label valganciclovir hydrochloride 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 C_max is lower following valganciclovir administration compared to intravenous ganciclovir, it is higher than the C_max 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 valganciclovir hydrochloride: 1 oral ganciclovir) to receive either valganciclovir hydrochloride tablets

(900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 post-transplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue invasive disease during the first 6 months post-transplant was 12.1% in the patients treated with valganciclovir hydrochloride (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 valganciclovir hydrochloride compared with the ganciclovir group. These results are summarized in Table 10.

Table 9: Percentage of Patients with CMV Disease and Tissue-Invasive CMV Disease by Organ Type: Endpoint Committee, 6 Months ITT Population

GCV = oral ganciclovir; VGCV= valganciclovir hydrochloride

¹ 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).

Extending prophylaxis with valganciclovir hydrochloride up to 200 days post-transplant may provide some benefit in high-risk D+/R-kidney transplant recipients. However, a higher frequency of treatment-related adverse events, including leukopenia and neutropenia, was observed when the prophylaxis was extended to 200 days post-transplant compared with 100 days post-transplant. The decision to extend the prophylaxis should be undertaken only where the potential benefits outweigh the risks (See WARNINGS and PRECAUTIONS).

Pediatric Use

The pharmacokinetics and safety of valganciclovir was studied in 109 pediatric SOT recipients. Common adverse events (reported in more than 10% of patients) observed in these patients included diarrhea (32%), pyrexia (24%), hypertension (22%), upper respiratory tract infection (22%), vomiting (21%), anemia (14%), neutropenia (13%), constipation (11%), nausea (11%), and transplant rejection (10%).

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 450 mg tablet formulation at a dose of 900 mg 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)

§ 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 MYLAN-VALGANCICLOVIR (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 10.

Table 10: 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 valganciclovir hydrochloride tablets is comparable to the ganciclovir AUC for intravenous ganciclovir. Ganciclovir AUC_0-24h, achieved by a single dose of 900 mg valganciclovir hydrochloride tablets under fed conditions was comparable to the AUC_0-24h achieved following administration of 5 mg/kg intravenous ganciclovir (42.69 mg•h/mL vs 47.61 mg•h/mL, respectively). Ganciclovir C_max following valganciclovir administration is 40% lower than following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC_0-24h and C_max following oral ganciclovir administration (1000 mg three times daily) are lower relative to valganciclovir and intravenous ganciclovir. The ganciclovir C_min following intravenous ganciclovir and valganciclovir administration are less than the ganciclovir C_min following oral ganciclovir administration.

G a n c i c l o v i r C o n c e n t r a t i o n (µ g / m L )

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

12.00

10.00

8.00

6.00

4.00

2.00

0.00

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 AUC_0-24h 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 AUC_0-24h and time to progression of CMV retinitis was highly statistically significant (P=.0019), while the association of C_max and time to progression of CMV retinitis was not (P=.6022). These findings indicate that average AUC_0-24h is a better predictor of time to progression, and that average C_max does not add predictive value over average AUC_0-24h.

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 valganciclovir hydrochloride 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(AUC_0-24h) of solid organ transplant patients to ganciclovir after daily oral administration of valganciclovir and ganciclovir was 46.3 ± 15.2 µg•h/mL and 28.0 ± 10.9 µg•h/mL, respectively. The systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetics evaluation.

Table 11: Mean Ganciclovir Pharmacokinetic Measures by Organ Type (Study

PV16000)

* Includes kidney-pancreas

The pharmacokinetics of valganciclovir hydrochloride 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 valganciclovir hydrochloride tablets under fed conditions was approximately 60%, in agreement with the estimates obtained in other patient populations.

Ganciclovir AUC_0-24h, achieved following a single dose of 900 mg valganciclovir hydrochloride tablets under fed conditions, was 41.7 ± 9.9 μg•h/mL (n=28), compared to 48.2 ± 17.3 μg•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 valganciclovir hydrochloride (valganciclovir hydrochloride) tablets for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS), the antiviral effect of valganciclovir hydrochloride tablets was demonstrated by a decrease in CMV shedding (see Table 12).

Table 12: Antiviral Effect of valganciclovir hydrochloride 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 valganciclovir hydrochloride 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 μg/mL (6.0 μM). 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. MYLAN-VALGANCICLOVIR (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 13: 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 14: 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 M ouse 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 15: Mutagenicity Studies

REFERENCES

1. 1. Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV - seropositive volunteers. Clin Pharmacokinet 1999;37(2):167-176.
2. 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
3. 3.

   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.

4. 4.

   CYTOVENE (ganciclovir capsules and ganciclovir sodium for injection) Product

   Monograph. Mississauga, ON: Hoffmann-La Roche Limited; May 29, 2008.

5. 5.

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

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

6. 6.

   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.

7. 7.

   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.

8. 8. 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.
9. 9.

   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.

10. 10.

    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.

11. 11. Jung D, Dorr A. Single dose pharmacokinetics of valganciclovir in HIV- and CMV- seropositive subjects. J Clin Pharmacol 1999;39(8):800-804.
12. 12.

    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.

13. 13.

    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.

14. 14. 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.
15. 15. 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.
16. 16.

    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.

17. 17. Sorbera LA, Castaner R, Castaner J. Valganciclovir hydrochloride. Anti-cytomegalovirus drug. Drugs Fut 2000;25(5):474-480.
18. 18. Sugawara M, Huang W, Fei YJ, Leibach FH, Ganapathy V, Ganapathy ME. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci 2000;89(6):781-789.
19. 19. Walter E, Kissel T, Amidon GL. The intestinal peptide carrier: A potential transport system for small peptide derived drugs. Adv Drug Deliv Rev 1996;20:33-58.
20. 20. Product Monograph for ^PrVALCYTE®, Hoffman La-Roche Ltd., Mississauga, Ontario, dated July 21, 2014, Control No. 174614.