Valcyte

Genentech, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Valcyte safely and effectively. See full prescribing information for Valcyte. Valcyte (valganciclovir hydrochloride) tablets, for oral useValcyte (valganciclovir hydrochloride) for oral solutionInitial U.S. Approval: 2001BOXED WARNING WARNING: HEMATOLOGIC TOXICITY, CARCINOGENICITY, TERATOGENICITY, AND IMPAIRMENT OF FERTILITY See full prescribing information for complete boxed warning . Clinical toxicity of Valcyte, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia (5.1) In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis (5.2, 5.3, 5.4) INDICATIONS AND USAGEValcyte is a cytomegalovirus (CMV) nucleoside analogue DNA polymerase inhibitor indicated for: Adult Patients (1.1) Treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Prevention of CMV disease in kidney, heart, or kidney-pancreas transplant patients at high risk. Pediatric Patients (1.2) Prevention of CMV disease in kidney or heart transplant patients at high risk. Limitations of Use (1.3) Valcyte is not indicated for use in either adult or pediatric liver transplant patients. The safety and efficacy of Valcyte have not been established for: - Prevention of CMV disease in solid organ transplants other than those indicated. - Prevention of CMV disease in pediatric solid organ transplant patients < 4 months of age. - Treatment of congenital CMV disease. DOSAGE AND ADMINISTRATION Adult Dosage (2.2) Treatment of CMV retinitis Induction: 900 mg (two 450 mg tablets) twice a day for 21 daysMaintenance: 900 mg (two 450 mg tablets) once a day Prevention of CMV disease in heart or kidney-pancreas transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 100 days post-transplantation Prevention of CMV disease in kidney transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 200 days post-transplantation Pediatric Dosage (2.3) Prevention of CMV disease in kidney or heart transplant patients 4 months to 16 years of age Dose once a day within 10 days of transplantation until 100 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children 1 to < 2 years of age) Valcyte for oral solution and tablets should be taken with food (2.1, 12.3). Valcyte for oral solution and tablets cannot be substituted for ganciclovir capsules on a one-to-one basis (2.1, 12.3). Valcyte tablets should not be broken or crushed (2.6). Adult patients should use Valcyte tablets, not Valcyte for oral solution (2.1). Adults with renal impairment: Adjust dose based on creatinine clearance. For adult patients receiving hemodialysis a dose recommendation cannot be given (2.5, 8.6, 12.3). DOSAGE FORMS AND STRENGTHS Tablets: 450 mg (3) Valcyte for Oral Solution: 50 mg/mL (3) CONTRAINDICATIONSHypersensitivity to valganciclovir or ganciclovir (4)WARNINGS AND PRECAUTIONS Hematologic effects: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia have occurred with the use of Valcyte or ganciclovir. Do not administer Valcyte if absolute neutrophil count is < 500 cells/µL, platelet count is < 25,000/µL, or hemoglobin is < 8 g/dL. Use with caution in pre-existing cytopenias and when receiving myelosuppressive drugs or irradiation. Monitor with frequent testing of platelet and complete blood counts (5.1). Impairment of fertility: Based on animal studies, Valcyte may cause temporary or permanent inhibition of spermatogenesis (5.2). Teratogenesis and mutagenesis: Based on animal studies, Valcyte is potentially teratogenic and mutagenic. Women of childbearing potential should use contraception during and following treatment and men should practice barrier contraception during and following treatment (5.3). Acute renal failure: Acute renal failure may occur in elderly patients (with or without reduced renal function), patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients or those taking nephrotoxic drugs, reduce dosage in patients with renal impairment, and monitor renal function (2.5, 5.5, 8.5, 8.6, 12.3). Side Effects Adult patients: Most common adverse events and laboratory abnormalities (reported in at least one indication by ≥ 20% of patients) are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting (6.1). Pediatric patients: Most common adverse events and laboratory abnormalities (reported in > 10% of pediatric solid organ transplant recipients) are diarrhea, pyrexia, hypertension, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation, nausea, and cough (6.2). To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Zidovudine: Potential to cause neutropenia and anemia. Monitor with frequent tests of white blood cell counts with differential and hemoglobin levels (7). Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity (7). Mycophenolate mofetil (MMF): May increase ganciclovir concentrations and levels of MMF metabolites in patients with renal impairment. Monitor for ganciclovir and MMF toxicity (7). Didanosine: May increase didanosine concentrations. Monitor for didanosine toxicity (7). USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, Valcyte may cause fetal harm (8.1). Nursing mothers: May cause adverse events in nursing infants. Discontinue drug or nursing, taking into consideration the importance of drug to mother (8.3).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 VALCYTE INDICATIONS AND USAGE
  • 1.1 Adult Patients
  • 1.2 Pediatric Patients
  • 1.3 Limitations of Use
• 2 VALCYTE DOSAGE AND ADMINISTRATION
  • 2.1 General Dosing Information
  • 2.2 Adult Patients With Normal Renal Function
  • 2.3 Pediatric Patients
  • 2.4 Preparation of Valcyte for Oral Solution
  • 2.5 Renal Impairment
  • 2.6 Handling and Disposal
• 3 DOSAGE FORMS AND STRENGTHS
• 4 VALCYTE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hematologic Effects
  • 5.2 Impairment of Fertility
  • 5.3 Teratogenesis and Mutagenesis
  • 5.4 Carcinogenesis
  • 5.5 Acute Renal Failure
• 6 VALCYTE ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience in Adult Patients
  • 6.2 Clinical Trial Experience in Pediatric Patients
  • 6.3 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10 OVERDOSAGE
• 11 VALCYTE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.3 Reproductive and Developmental Toxicology
• 14 CLINICAL STUDIES
  • 14.1 Adult Patients
  • 14.2 Pediatric Patients
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Adult Patients

Treatment of Cytomegalovirus (CMV) Retinitis : Valcyte tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].

Prevention of CMV Disease : Valcyte tablets are indicated for the prevention of CMV disease in kidney, heart, or kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)].

1.2 Pediatric Patients

Prevention of CMV Disease: Valcyte for oral solution and tablets are indicated for the prevention of CMV disease in kidney or heart transplant patients (4 months to 16 years of age) at high risk [see Clinical Studies (14.2)].

1.3 Limitations of Use

Valcyte is not indicated for use in either adult or pediatric liver transplant patients [see Clinical Studies (14.1, 14.2)].

The safety and efficacy of Valcyte have not been established for:

• Prevention of CMV disease in solid organ transplants other than those indicated [see Clinical Studies (14.1, 14.2)].
• Prevention of CMV disease in pediatric solid organ transplant patients < 4 months of age [see Clinical Studies (14.2)].
• Treatment of congenital CMV disease [see Use in Specific Populations (8.4)]

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

• Valcyte for oral solution and tablets should be taken with food [see Clinical Pharmacology (12.3)].
• Valcyte for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)].
• The bioavailability of ganciclovir from Valcyte is significantly higher than from ganciclovir capsules. Therefore, Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis [see Clinical Pharmacology (12.3)].
• Adult patients should use Valcyte tablets, not Valcyte for oral solution.

2.2 Adult Patients With Normal Renal Function

For dosage recommendations in adult patients with renal impairment see Dosage and Administration (2.5) .

Treatment of CMV Retinitis:

• Induction: The recommended dose is 900 mg (two 450 mg tablets) twice a day for 21 days.
• Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dose is 900 mg (two 450 mg tablets) once a day.

Prevention of CMV Disease:

• For adult patients who have received a heart or kidney-pancreas transplant, the recommended dose is 900 mg (two 450 mg tablets) once a day starting within 10 days of transplantation until 100 days post-transplantation.
• For adult patients who have received a kidney transplant, the recommended dose is 900 mg (two 450 mg tablets) once a day starting within 10 days of transplantation until 200 days post-transplantation.

2.3 Pediatric Patients

Prevention of CMV Disease: For pediatric patients 4 months to 16 years of age who have received a kidney or heart transplant, the recommended once daily dose of Valcyte starting within 10 days of transplantation until 100 days post-transplantation is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below:

Pediatric Dose (mg) = 7 × BSA × CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m², then a maximum value of 150 mL/min/1.73m² should be used in the equation.

where k =

0.45 for patients aged 4 months to < 1 year,

0.45 for patients aged 1 to < 2 years (note k value is 0.45 instead of the typical value of 0.55),

0.55 for boys aged 2 to < 13 years and girls aged 2 to 16 years, and

0.7 for boys aged 13 to 16 years.

All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. Valcyte for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Valcyte tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg). For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken.

2.4 Preparation of Valcyte for Oral Solution

Prior to dispensing to the patient, Valcyte for oral solution must be prepared by the pharmacist as follows [see How Supplied/Storage and Handling (16)]:

• Measure 91 mL of purified water in a graduated cylinder.
• Shake the Valcyte bottle to loosen the powder. Remove the child resistant bottle cap and add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about 1 minute. Add the remainder of water and shake the closed bottle well for about 1 minute. This prepared solution contains 50 mg of valganciclovir free base per 1 mL.
• Remove the child resistant bottle cap and push the bottle adapter into the neck of the bottle.
• Close bottle with child resistant bottle cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.
• Store constituted oral solution under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze.
• Write the date of expiration of the constituted oral solution on the bottle label.

The patient package insert, which includes the dosing instructions for patients, and 2 oral dispensers should be dispensed to the patient [see Patient Counseling Information (17)].

2.5 Renal Impairment

Dosage recommendations for adult patients with reduced renal function are provided in Table 1 . For adult patients on hemodialysis (CrCl <10 mL/min), a dose recommendation for Valcyte cannot be given [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)].

Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation [see Dosage and Administration (2.3)].

2.6 Handling and Disposal

Caution should be exercised in the handling of Valcyte tablets and Valcyte for oral solution. Tablets should not be broken or crushed. Because valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets, the powder for oral solution, and the constituted oral solution [see Warnings and Precautions (5.3, 5.4)]. Avoid direct contact with broken or crushed tablets, the powder for oral solution, and the constituted oral solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.

Because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. Several guidelines on this subject have been published. However, there is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate [see References (15)].

3 DOSAGE FORMS AND STRENGTHS

Valcyte Tablets:

• 450 mg, pink, convex oval tablets with "VGC" on one side and "450" on the other side.

Valcyte for Oral Solution:

• 50 mg/mL, supplied as a white to slightly yellow powder for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution. Valcyte for oral solution must be constituted by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)].

4 CONTRAINDICATIONS

Valcyte is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [see Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Effects

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with Valcyte or ganciclovir. Valcyte 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 8 g/dL. Valcyte should also be used with caution in patients with pre-existing cytopenias, or who have received or who are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug.

Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving Valcyte [see Adverse Reactions (6.1, 6.2)], complete blood counts with differential and platelet counts should 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. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to Valcyte, because of increased plasma concentrations of ganciclovir after Valcyte administration [see Clinical Pharmacology (12.3)].

5.2 Impairment of Fertility

Animal data indicate administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses but irreversible at higher doses [see Nonclinical Toxicology (13.1)]. In men, Valcyte at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Animal data also indicate suppression of fertility in females may occur.

5.3 Teratogenesis and Mutagenesis

Animal data indicate ganciclovir is teratogenic and mutagenic. Therefore, Valcyte should be considered to have the potential to cause birth defects and cancers in humans. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Valcyte. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Valcyte [see Dosage and Administration (2.6), Use in Specific Populations (8.1), Nonclinical Toxicology (13.1, 13.3)].

5.4 Carcinogenesis

Animal data indicate that administration of ganciclovir is carcinogenic. Valcyte should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.6), Nonclinical Toxicology (13.1)].

5.5 Acute Renal Failure

Acute renal failure may occur in:

• Elderly patients with or without reduced renal function. Caution should be exercised when administering Valcyte to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.5), Use in Specific Populations (8.5, 8.6)].
• Patients receiving potential nephrotoxic drugs. Caution should be exercised when administering Valcyte to patients receiving potential nephrotoxic drugs.
• Patients without adequate hydration. Adequate hydration should be maintained for all patients.

6 ADVERSE REACTIONS

The following serious adverse events are discussed in greater detail in other sections of the labeling:

• Hematologic adverse events [see Boxed Warning, Warnings and Precautions (5.1)].
• Acute renal failure [see Warnings and Precautions (5.5)].

The most common adverse events and laboratory abnormalities reported in at least one indication by ≥ 20% of adult patients treated with Valcyte tablets are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting. The most common reported adverse events and laboratory abnormalities reported in > 10% of pediatric solid organ transplant recipients treated with Valcyte for oral solution or tablets are diarrhea, pyrexia, hypertension, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation, nausea, and cough.

6.1 Clinical Trial Experience in Adult Patients

Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse events known to be associated with ganciclovir usage can therefore be expected to occur with Valcyte.

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Treatment of CMV Retinitis in AIDS Patients : In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse events reported by patients receiving Valcyte tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), headache (9%, 5%), and catheter-related infections (3%, 11%). The incidence of adverse events was similar between the group who received Valcyte tablets and the group who received intravenous ganciclovir, with the exception of catheter-related infections, which occurred with greater frequency in patients randomized to receive intravenous ganciclovir. The frequencies of neutropenia (ANC < 500/µL) were 11% for patients receiving Valcyte tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb < 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.

Adverse events and abnormal laboratory values data are available for 370 patients who received maintenance therapy with Valcyte tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received Valcyte tablets for more than nine months (maximum duration was 36 months). Table 2 and Table 3 show the pooled adverse event data and abnormal laboratory values from these patients.

Prevention of CMV Disease in Selected Solid Organ Transplantation: Table 4 shows selected adverse events regardless of severity and drug relationship with an incidence of ≥ 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received Valcyte tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant. The majority of the adverse events were of mild or moderate intensity.

The overall safety profile of Valcyte did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients (see Table 5 ).

Adverse events not included in Table 4 and Table 5 , which either occurred at a frequency of ≥ 5% in clinical studies with solid organ transplant patients, or were selected serious adverse events reported in studies with patients with CMV retinitis or in studies with solid organ transplant patients with a frequency of < 5% are listed below.

Allergic reactions: valganciclovir hypersensitivity

Bleeding complications: potentially life-threatening bleeding associated with thrombocytopenia

Central and peripheral nervous system: paresthesia, dizziness (excluding vertigo), convulsion

Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, abdominal distention, ascites

General disorders and administration site disorders: fatigue, pain, edema, peripheral edema, weakness

Hemic system: anemia, neutropenia, thrombocytopenia, pancytopenia, bone marrow depression, aplastic anemia

Hepatobiliary disorders: abnormal hepatic function

Infections and infestations: pharyngitis/nasopharyngitis, upper respiratory tract infection, urinary tract infection, local and systemic infections and sepsis, postoperative wound infection

Injury, poisoning, and procedural complications: postoperative complications, postoperative pain, increased wound drainage, wound dehiscence

Metabolism and nutrition disorders: hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, appetite decreased, dehydration, hypophosphatemia, hypocalcemia

Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle cramps, limb pain

Psychiatric disorders: depression, psychosis, hallucinations, confusion, agitation

Renal and urinary disorders: renal impairment, dysuria, decreased creatinine clearance

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, pleural effusion

Skin and subcutaneous tissue disorders: dermatitis, pruritus, acne

Vascular disorders: hypotension

Laboratory abnormalities reported with Valcyte tablets in two studies in solid organ transplant patients are listed in Table 6 and Table 7.

6.2 Clinical Trial Experience in Pediatric Patients

Valcyte for oral solution and tablets have been studied in 109 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 4 months to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged 8 to 34 days), with duration of ganciclovir exposure ranging from 2 to 100 days. The overall safety profile was similar in pediatric patients as compared to adult patients. However, the rates of certain adverse events and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and neutropenia, were reported more frequently in pediatric patients than in adults [see Use in Specific Populations (8.4), Clinical Studies (14.2)].

6.3 Postmarketing Experience

In general, the adverse events reported during the postmarketing use of Valcyte were similar to those identified during the clinical trials and to those reported during the postmarketing use of ganciclovir. Please also refer to the intravenous ganciclovir product information and ganciclovir capsule product information for more information on postmarketing adverse events associated with ganciclovir.

7 DRUG INTERACTIONS

In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for Valcyte. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 8 .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, is expected to have reproductive toxicity effects similar to ganciclovir. There are no adequate and well-controlled studies of valganciclovir or ganciclovir use in pregnant women. In animal studies of ganciclovir, embryo-fetal toxicity and structural malformations occurred. Valganciclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In animal studies, pregnant mice and rabbits received ganciclovir at doses that produced 2x the human exposure (based on AUC comparison). Treated rabbits had increased rates of fetal resorption, fetal growth retardation, embryolethality, maternal toxicity, cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, increased fetal resorptions and embryolethality occurred in the presence of maternal/fetal toxicity.

Daily intravenous doses of approximately 1.7x the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach.

Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL [see Nonclinical Toxicology (13.3)].

8.3 Nursing Mothers

It is not known whether valganciclovir (prodrug) or ganciclovir (active drug) are excreted in human milk. Because valganciclovir caused granulocytopenia, anemia and thrombocytopenia in clinical trials and ganciclovir was mutagenic and carcinogenic in animal studies, serious adverse events may occur from ganciclovir exposure in nursing infants [see Boxed Warning, Warnings and Precautions (5.1, 5.3, 5.4)]. Because of the potential for serious adverse events in nursing infants, a decision should be made whether to discontinue nursing or discontinue drug, taking into consideration the importance of the drug to the mother. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.

8.4 Pediatric Use

Valcyte for oral solution and tablets are indicated for the prevention of CMV disease in kidney or heart transplant pediatric patients 4 months to 16 years of age at risk for developing CMV disease [see Indications and Usage (1.2), Dosage and Administration (2.3)].

The use of Valcyte for oral solution and tablets for the prevention of CMV disease in pediatric patients 4 months to 16 years of age with kidney or heart transplant is based on pharmacokinetic, safety, and efficacy data from an open-label trial with oral Valcyte (Valcyte for oral solution or tablets) in pediatric solid organ transplant recipients at risk for developing CMV disease. The results of this study were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

The safety and efficacy of Valcyte for oral solution and tablets have not been established in children for:

• Prevention of CMV disease in liver transplant patients
• Prevention of CMV disease in solid organ transplants other than those indicated
• Prevention of CMV disease in pediatric solid organ transplant patients < 4 months of age
• Treatment of congenital CMV disease

The pharmacokinetic profile and safety of Valcyte for oral solution in children were studied in two open-label studies.

Study 1 was an open-label trial with oral Valcyte (Valcyte for oral solution or tablets) in pediatric solid organ transplant recipients at risk for developing CMV disease [see Clinical Pharmacology (12.3), Clinical Studies (14.2)].

Study 2 was a pharmacokinetic and pharmacodynamic evaluation of Valcyte for oral solution in neonates with congenital CMV infection involving the central nervous system. Twenty-four neonates were enrolled in this study. All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg/kg twice daily and Valcyte for oral solution at doses ranging from 14 mg/kg to 20 mg/kg twice daily. The pharmacokinetic results showed that in infants > 7 days to 3 months of age, a dose of 16 mg/kg twice daily of Valcyte for oral solution provided ganciclovir systemic exposures (median AUC_0-12h = 23.6 [range 16.8 – 35.5] µg∙h/mL; n = 6) comparable to those obtained in infants up to 3 months from a 6 mg/kg dose of intravenous ganciclovir twice daily (AUC_0-12h = 25.3 [range 2.4 – 89.7] µg∙h/mL; n = 18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of Valcyte tablets twice daily.

The safety and efficacy of intravenous ganciclovir have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.

8.5 Geriatric Use

Studies of Valcyte for oral solution or tablets have not been conducted in adults older than 65 years of age. 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, usually starting at the low end of the dosing range, 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 kidneys, 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 Dosage and Administration (2.5), Warnings and Precautions (5.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Dose reduction is recommended when administering Valcyte to patients with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

For adult patients on hemodialysis (CrCl <10 mL/min) Valcyte tablets should not be used. Adult hemodialysis patients should use ganciclovir in accordance with the dose-reduction algorithm cited in the Cytovene^®-IV and ganciclovir capsules complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The safety and efficacy of Valcyte have not been studied in patients with hepatic impairment.

10 OVERDOSAGE

Experience With Valcyte 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.

An overdose of Valcyte could also possibly result in increased renal toxicity [see Dosage and Administration (2.5), Use in Specific Populations (8.6)].

Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Valcyte [see Clinical Pharmacology (12.3)]. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Clinical Pharmacology (12.3)].

Experience With Intravenous Ganciclovir: Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events:

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

Hepatotoxicity: hepatitis, liver function disorder

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

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting

Neurotoxicity: generalized tremor, convulsion

11 DESCRIPTION

Valcyte contains valganciclovir hydrochloride (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.

Valcyte is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crospovidone and stearic acid. The film-coat applied to the tablets contains Opadry Pink^®.

Valcyte is also available as a powder for oral solution, which when constituted with water as directed contains 50 mg/mL valganciclovir free base. The inactive ingredients of Valcyte for oral solution are sodium benzoate, fumaric acid, povidone K-30, sodium saccharin, mannitol and tutti-frutti flavoring.

Valganciclovir HCl is a white to off-white crystalline powder with a molecular formula of C₁₄H₂₂N₆O₅•HCl and a molecular weight of 390.83. The chemical name for valganciclovir HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for valganciclovir HCl is 7.6.

The chemical structure of valganciclovir HCl is:

All doses in this insert are specified in terms of valganciclovir.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Valganciclovir is an antiviral drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for Valcyte tablets and Valcyte for oral solution [see Dosage and Administration (2.5)].

Pharmacokinetics in Adults: The pharmacokinetics of valganciclovir and ganciclovir after administration of valganciclovir tablets have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients.

The ganciclovir pharmacokinetic parameters following administration of 900 mg Valcyte tablets and 5 mg/kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in Table 9 .

The area under the plasma concentration-time curve (AUC) of ganciclovir administered as Valcyte tablets (900 mg once daily) is comparable to the AUC of ganciclovir after administration of intravenous ganciclovir (5 mg/kg once daily). The C_max of ganciclovir following Valcyte administration is 40% lower than the C_max 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 Valcyte and intravenous ganciclovir. The ganciclovir C_min following intravenous ganciclovir and Valcyte administration are less than the ganciclovir C_min following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics after administration of Valcyte tablets, ganciclovir capsules, and intravenous ganciclovir is unknown.

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

*Plasma concentration-time profiles for ganciclovir (GCV) from valganciclovir (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (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 (n=24) in HIV-positive/CMV-positive patients without CMV retinitis.

In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7x 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 systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetics evaluation (see Table 10 ).

The pharmacokinetic parameters of ganciclovir following 200 days of Valcyte administration in high-risk kidney transplant patients were similar to those previously reported in solid organ transplant patients who received Valcyte for 100 days.

In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC_0-24h achieved with 900 mg valganciclovir was 41.7 ± 9.9 µg∙h/mL (n=28) and the AUC_0-24h achieved with the approved dosage of 5 mg/kg intravenous ganciclovir was 48.2 ± 17.3 µg∙h/mL (n=27).

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 administration with food was approximately 60% (3 studies, n=18; n=16; n=28). Ganciclovir median T_max following administration of 450 mg to 2625 mg Valcyte tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of Valcyte tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, is transient and low, and the AUC₂₄ and C_max values are approximately 1% and 3% of those of ganciclovir, respectively.

Food Effects: When Valcyte tablets were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) at a dose 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). Valcyte should be administered with food [see Dosage and Administration (2.1)].

Distribution: Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir is 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 0.703 ± 0.134 L/kg (n=69).

After administration of Valcyte tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of Valcyte tablets 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.

Elimination: 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 3.07 ± 0.64 mL/min/kg (n=68) while renal clearance was 2.99 ± 0.67 mL/min/kg (n=16).

The terminal half-life (t_½) of ganciclovir following oral administration of Valcyte tablets to either healthy or HIV-positive/CMV-positive subjects was 4.08 ± 0.76 hours (n=73), and that following administration of intravenous ganciclovir was 3.81 ± 0.71 hours (n=69). In heart, kidney, kidney-pancreas, and liver transplant patients, the terminal elimination half-life of ganciclovir following oral administration of Valcyte was 6.48 ± 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 ± 3.62 hours.

Specific Populations:

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

Decreased renal function results in decreased clearance of ganciclovir from valganciclovir, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for patients with impaired renal function.

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following Valcyte administration. Adult patients receiving hemodialysis (CrCl <10 mL/min) cannot use Valcyte tablets because the daily dose of Valcyte tablets required for these patients is less than 450 mg [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].

Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in 63 pediatric solid organ transplant patients aged 4 months to 16 years. In this study, patients received oral doses of valganciclovir (either Valcyte for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration (2.3), Adverse Reactions (6.2), Use in Specific Populations (8.4), Clinical Studies (14.2)].

The pharmacokinetics of ganciclovir were similar across organ types and age ranges. Population pharmacokinetic modeling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function. The mean total clearance was 5.3 L/hr (88.3 mL/min) for a patient with creatinine clearance of 70.4 mL/min. The mean C_max and AUC by age and organ type are listed in Table 12 .

Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of Valcyte in elderly patients have not been established. Because elderly individuals frequently have a reduced glomerular filtration rate, renal function should be assessed before and during administration of Valcyte [see Dosage and Administration (2.5), Use in Specific Populations (8.5)].

Drug Interactions: In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for Valcyte [see Drug Interactions (7)].

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.

Table 13 and Table 14 provide a listing of established drug interaction studies with ganciclovir. Table 13 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 14 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

12.4 Microbiology

Mechanism of Action: Valganciclovir is an L-valyl ester (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 human CMV in cell culture and in vivo.

In CMV-infected cells ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly (half-life 18 hours). 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 the viral DNA polymerase, pUL54, synthesis by ganciclovir triphosphate.

Antiviral Activity: The quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC₅₀), vary greatly depending upon a number of factors including the assay used. Thus, the reported EC₅₀ values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 µM (0.02 to 5.75 µg/mL). The distribution and range in susceptibility observed in one assay evaluating 130 clinical isolates was 0 to 1 µM (35%), 1.1 to 2 µM (20%), 2.1 to 3 µM (27%), 3.1 to 4 µM (13%), 4.1 to 5 µM (5%), > 5 µM (<1%). Ganciclovir inhibits mammalian cell proliferation (CIC₅₀) in cell culture at higher concentrations ranging from 40 to > 1,000 µM (10.21 to > 250 µg/mL). Bone marrow-derived colony-forming cells are more sensitive [CIC₅₀ value = 2.7 to 12 µM (0.69 to 3.06 µg/mL)].

Viral Resistance:

Cell culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 (M460I/V, L595S, G598D, and K599T) and the viral DNA polymerase pUL54 (D301N, N410K, F412V, P488R, L516R, C539R, L545S, F595I, V812L, P829S, L862F, D879G, and V946L).

In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with valganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 15

The presence of known ganciclovir resistance-associated amino acid substitutions was evaluated in a study that extended valganciclovir CMV prophylaxis from 100 days to 200 days post-transplant in adult kidney transplant patients at high risk for CMV disease (D+/R-) [see Clinical Studies (14.1)]. Five subjects from the 100 day group and four subjects from the 200 day group meeting the resistance analysis criteria had known ganciclovir resistance-associated amino acid substitutions detected. In six subjects, the following resistance-associated amino acid substitutions were detected within pUL97: 100 day group: A440V, M460V, C592G; 200 day group: M460V, C603W. In three subjects, the following resistance-associated amino acid substitutions were detected within pUL54: 100 day group: E315D, 200 day group: E315D, P522S. Overall, the detection of known ganciclovir resistance-associated amino acid substitutions was observed more frequently in patients during prophylaxis therapy than after the completion of prophylaxis therapy (during therapy: 5/12 [42%] versus after therapy: 4/58 [7%]). The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Cross-Resistance: Cross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region V. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 16 .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted with Valcyte. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a potential carcinogen.

Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures 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 curve (AUC) comparisons. At the higher dose there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans.

Valganciclovir increases mutations in mouse lymphoma cells. In the mouse micronucleus assay, valganciclovir was clastogenic. Valganciclovir was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic. Ganciclovir was not mutagenic in the Ames Salmonella assay.

Valganciclovir is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir [see Warnings and Precautions (5.2)]. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure 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 and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. It is considered likely that ganciclovir (and valganciclovir) could cause inhibition of human spermatogenesis.

13.3 Reproductive and Developmental Toxicology

Valganciclovir is converted to ganciclovir and therefore is expected to have reproductive toxicity effects similar to ganciclovir. 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 doses that produced 2x the human exposure based on AUC comparisons (all dose comparisons presented are based on the human AUC following administration of a single 5 mg/kg infusion of intravenous ganciclovir). 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 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 [see Warnings and Precautions (5.3)]. 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.

14 CLINICAL STUDIES

14.1 Adult Patients

Induction Therapy of CMV Retinitis : In one randomized open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either Valcyte tablets (900 mg twice daily for 21 days, then 900 mg once daily for 7 days) or with intravenous ganciclovir solution (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 3-week induction therapy. Table 17 provides the outcomes at 4 weeks.

Maintenance Therapy of CMV Retinitis : No comparative clinical data are available on the efficacy of Valcyte tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label Valcyte tablets after Week 4. However, the AUC for ganciclovir is similar following administration of 900 mg Valcyte tablets once daily and 5 mg/kg intravenous ganciclovir once daily. Although the ganciclovir C_max is lower following Valcyte tablets administration compared to intravenous ganciclovir, it is higher than the C_max obtained following oral ganciclovir administration [see Figure 1 in Clinical Pharmacology (12.3)]. Therefore, use of Valcyte tablets 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 Heart, Kidney, Kidney-Pancreas, or Liver Transplantation : A double blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, or kidney-pancreas transplant patients at high risk for CMV disease (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 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 similar between the Valcyte tablets arm (12.1%, N=239) and the oral ganciclovir arm (15.2%, N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the Valcyte group compared with the ganciclovir group. These results are summarized in Table 18 .

Mortality at six months was 3.7% (9/244) in the Valcyte group and 1.6% (2/126) in the oral ganciclovir group.

Prevention of CMV Disease in Kidney Transplantation: A double-blind, placebo-controlled study was conducted in 326 kidney transplant patients at high risk for CMV disease (D+/R-) to assess the efficacy and safety of extending Valcyte CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Valcyte tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. Extending CMV prophylaxis with Valcyte until Day 200 post-transplant demonstrated superiority in preventing CMV disease within the first 12 months post-transplant in high risk kidney transplant patients compared to the 100 day dosing regimen (primary endpoint). These results are summarized in Table 19.

The percentage of kidney transplant patients with CMV disease at 24 months post-transplant was 38.7% (63/163) for the 100 day dosing regimen and 21.3% (33/155) for the 200 day dosing regimen.

14.2 Pediatric Patients

Prevention of CMV in Pediatric Solid Organ Transplant Recipients: Sixty-three children, 4 months to 16 years of age, who had a solid organ transplant (kidney 33, liver 17, heart 12, and kidney/liver 1) and were at risk for developing CMV disease, were enrolled in an open-label, safety, and pharmacokinetic study of oral Valcyte (Valcyte for oral solution or tablets). Patients received Valcyte once daily as soon as possible after transplant until a maximum of 100 days post-transplant. The daily doses of Valcyte were calculated at each study visit based on body surface area and a modified creatinine clearance [see Dosage and Administration (2.3)].

The pharmacokinetics of ganciclovir were similar across organ transplant types and age ranges. The mean daily ganciclovir exposures in pediatric patients were comparable to those observed in adult solid organ transplant patients receiving Valcyte 900 mg once daily [see Clinical Pharmacology (12.3)]. No case of CMV disease was reported during the study. CMV viremia was reported in 7 (11%) patients during the study; however, none of these events fulfilled the definition of CMV syndrome. Based on the pharmacokinetic, safety, and efficacy data from this study and extrapolated efficacy data from the adult study, oral Valcyte is indicated for the prevention of CMV disease in kidney and heart transplant children 4 months to 16 years of age at risk for developing CMV disease. Valcyte is not approved in adults for CMV prophylaxis in liver transplant patients; therefore, Valcyte is not recommended for CMV prophylaxis in pediatric liver transplant patients because efficacy cannot be extrapolated from adults.

15 REFERENCES

• NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
• OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
• American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
• Polovich, M., White, J. M., & Kelleher, L.O. (eds.). 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.). Pittsburgh, PA: Oncology Nursing Society.
• Drew A.L., Miner R., Saleh E. 1993. Antiviral Susceptibility Testing of Cytomegalovirus Criteria for Detecting Resistance to Antivirals. Clinical Diagnostic Virology 1:179-185.
• Hakki M., Chou, S. The biology of cytomegalovirus drug resistance. Curr Opinion in Infectious Dis. 2011; 24:605-611.
• Lurain, N.S., Chou, S. Antiviral drug resistance of humancytomegalovirus. Clin Microbiol Rev. 2010; 23(4):689-712.

16 HOW SUPPLIED/STORAGE AND HANDLING

Valcyte Tablets: Supplied as 450 mg, pink, convex oval tablets with "VGC" on one side and "450" on the other side. Each tablet contains valganciclovir HCl equivalent to 450 mg valganciclovir. Valcyte is supplied in bottles of 60 tablets (NDC 0004-0038-22).

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP controlled room temperature].

Valcyte for Oral Solution: Supplied as a white to slightly yellow powder blend for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution. Each bottle can deliver up to a total of 88 mL of solution. Each bottle is supplied with a bottle adapter and 2 oral dispensers (NDC 0004-0039-09).

Prior to dispensing to the patient, Valcyte for oral solution must be prepared by the pharmacist [see Dosage and Administration (2.4)].

Store dry powder at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP controlled room temperature].

Store constituted solution under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis. Inform patients switching from ganciclovir capsules of the risk of overdosage if they take more than the prescribed number of Valcyte tablets [see Dosage and Administration (2.1), Overdosage (10)].

Adult patients should use Valcyte tablets, not Valcyte for oral solution [see Dosage and Administration (2.1)].

Valcyte is changed to ganciclovir once it is absorbed into the body. Inform all patients that the major toxicities of ganciclovir include granulocytopenia (neutropenia), anemia, and thrombocytopenia and that dose modifications may be required, including discontinuation. The importance of close monitoring of blood counts while on therapy should be emphasized. Inform patients that ganciclovir has been associated with elevations in serum creatinine.

Instruct patients to take Valcyte with food to maximize bioavailability.

Advise patients that ganciclovir causes decreased sperm production in animals and may cause decreased fertility in humans. Advise women of childbearing potential that ganciclovir causes birth defects in animals and should not be used during pregnancy. Because of the potential for serious adverse events in nursing infants, instruct mothers not to breast-feed if they are receiving Valcyte. Advise women of childbearing potential to use effective contraception during and for at least 30 days following treatment with Valcyte. Similarly, advise men to practice barrier contraception during and for at least 90 days following treatment with Valcyte.

Although there is no information from human studies, advise patients that ganciclovir should be considered a potential carcinogen.

Convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of Valcyte and/or ganciclovir. If they occur, tasks requiring alertness may be affected including the patient's ability to drive and operate machinery.

Inform patients that ganciclovir is not a cure for CMV retinitis, and they may continue to experience progression of retinitis during or following treatment. Advise patients to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with Valcyte. Some patients will require more frequent follow-up.

FDA-Approved Patient Labeling

Read the Patient Information that comes with Valcyte before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor.

What is the most important information I should know about Valcyte?

• Valcyte can affect your blood cells and bone marrow causing serious and life-threatening problems. Valcyte can lower the amount of your white blood cells, red blood cells, and platelets. Your doctor may do regular blood tests to check your blood cells while you are taking Valcyte. Based on these tests, your doctor may change your dose or tell you to stop taking Valcyte.
• Valcyte may cause cancer. Valcyte causes cancer in animals. It is not known if Valcyte causes cancer in people.
• Valcyte may cause birth defects. Valcyte causes birth defects in animals. It is not known if Valcyte causes birth defects in people. If you are pregnant, talk to your doctor before taking Valcyte.
  • Tell your doctor right away if you become pregnant while taking Valcyte.
  • If you are a female who can become pregnant, you should use effective birth control during treatment with Valcyte and for at least 30 days after treatment.
  • Men should use a condom during treatment with Valcyte, and for at least 90 days after treatment, if their female sexual partner can become pregnant. Talk to your doctor if you have questions about birth control.
• Valcyte may lower the amount of sperm in a man's body and cause fertility problems.
• Valcyte can affect your kidney, including serious problems such as kidney failure. Your doctor may do regular blood tests to check your kidney function while you are taking Valcyte. Your doctor may adjust your dose based on these tests.
• Valcyte changes into the medicine ganciclovir once it is in your body. Ganciclovir is also the active ingredient in Cytovene^®-IV and ganciclovir capsules. Do not take ganciclovir capsules or Cytovene-IV if you are taking Valcyte. The dose of medicine in Valcyte tablets and ganciclovir capsules is different. One tablet of Valcyte has more medicine than one capsule of ganciclovir. This means that one Valcyte tablet cannot be substituted for one ganciclovir capsule. You could overdose and become very sick if Valcyte is taken with ganciclovir capsules or Cytovene-IV. Talk to your doctor or pharmacist if you have questions about your medicine.

What is Valcyte?

Valcyte is an "antiviral" medicine.

In adults, Valcyte tablets are used:

• to treat cytomegalovirus (CMV) retinitis in people who have acquired immunodeficiency syndrome (AIDS). When CMV virus infects the eyes, it is called CMV retinitis. If CMV retinitis is left untreated, it can cause blindness.
• to prevent cytomegalovirus (CMV) disease in people who have received a heart, kidney, or kidney-pancreas transplant and who have a high risk for getting CMV disease.

In children (4 months to 16 years of age) Valcyte tablets or oral solution are used:

• to prevent cytomegalovirus (CMV) disease in children who have received a heart or kidney transplant and have a high risk for getting CMV disease.

Valcyte is not for use in adults or children who have received a liver transplant.

It is not known if Valcyte is safe and effective:

• to prevent CMV disease in people who have had other types of organ transplants such as lung or intestine.
• to prevent CMV disease in children under 4 months of age who receive an organ transplant.
• to treat CMV disease that a baby might be born with (congenital CMV disease)
• in adults older than age 65.

Valcyte does not cure CMV retinitis. You may still get retinitis or worsening of retinitis during or after treatment with Valcyte. It is important to stay under a doctor's care and have your eyes checked regularly.

Who should not take Valcyte?

Do not take Valcyte tablets if you are receiving hemodialysis. The use of ganciclovir capsules rather than Valcyte tablets is recommended.

Do not take Valcyte if you are allergic to any of its ingredients or if you have ever had a serious allergic reaction to ganciclovir capsules or Cytovene-IV. Symptoms of an allergic reaction to Valcyte may include: sudden trouble breathing, wheezing, hives all over your body, swelling around your mouth, or feeling anxious.

See the end of this leaflet for a list of the ingredients in Valcyte.

What should I tell my doctor before taking Valcyte?

Before taking Valcyte, tell your doctor if you:

• have kidney problems. Your doctor may give you a lower dose of Valcyte, or check you more often if you are taking Valcyte.
• have blood cell problems
• are having radiation treatment
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if Valcyte causes birth defects in an unborn baby. Tell your doctor right away if you become pregnant while taking Valcyte. See "What is the most important information I should know about Valcyte?"
• are breast-feeding or plan to breast-feed. It is not known if Valcyte passes into your milk and if it may harm your baby. You should not breast-feed if you are HIV-positive because of the chance of passing the HIV virus to your baby through your milk.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Valcyte and other medicines may affect each other and cause serious side effects. Especially tell your doctor if you take:

• didanosine (Videx^®)
• zidovudine (Retrovir^®, Trizivir, Combivir)
• probenecid (Col-Probenecid, Probenecid and Colchicine)
• mycophenolate mofetil (CellCept^®)

How should I take Valcyte?

• Take Valcyte exactly as your doctor prescribes it. Your dose of Valcyte will depend on your medical condition.
• Adults should only take Valcyte tablets. Children may take either Valcyte tablets or oral solution.
• Take Valcyte with food.
• Do not break or crush Valcyte tablets. Avoid contact with your skin or eyes. If you come in contact with the contents of the tablet or oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.
• If your child is prescribed Valcyte for oral solution, your pharmacist will give you dosing dispensers to measure your dose of Valcyte for oral solution. To be sure you receive the prescribed dose, it is important to use the dispenser provided to you. Be sure to read, and that you understand, and follow the instructions below on how to take Valcyte for oral solution and how to use the dispenser. Ask your pharmacist if you have any questions. If you lose or damage your dispensers and cannot use them, contact your pharmacist.
• If you miss a dose of Valcyte, take the missed dose as soon as you remember. Then, take the next dose at the usual scheduled time. However, if it is almost time for your next dose, do not take the missed dose.
• 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.
• If you take too much Valcyte, call your local poison control center or emergency room right away. You may need treatment in a hospital.
• Do not substitute Valcyte tablets for ganciclovir capsules. Talk to your doctor, nurse or pharmacist if you have questions about your medicine.

What should I avoid while taking Valcyte?

• Valcyte can cause seizures, sleepiness, dizziness, unsteady movements, and confusion. You should not drive a car or operate other dangerous machinery until you know how Valcyte affects you.

What are the possible side effects of Valcyte?

Valcyte may cause serious side effects, including:

• See " What is the most important information I should know about Valcyte? "

Common side effects of Valcyte in adults and children include:

• diarrhea
• nausea, vomiting
• fever
• shaky movements (tremors)
• low white cell, red cell and platelet cell counts in blood tests
• rejection of the transplanted organ (graft)

Other common side effects in children include:

• constipation
• high blood pressure
• cough and colds

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Valcyte. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Valcyte?

• Store Valcyte tablets at room temperature between 59°F to 86°F (15°C to 30°C).
• Store Valcyte for oral solution in the refrigerator between 36°F to 46°F (2°C to 8°C), for no longer than 49 days. Do not freeze.
• Do not keep medicine that is out of date or that you no longer need.
• Keep Valcyte and all medicines out of the reach of children.

General information about Valcyte

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Valcyte for a condition for which it was not prescribed. Do not give Valcyte to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Valcyte. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Valcyte that is written for health professionals.

For more information about Valcyte go to www.VALCYTE.com or call 1-888-835-2555.

What are the ingredients in Valcyte?

Active Ingredient: valganciclovir hydrochloride

Inactive Ingredients for Tablets: microcrystalline cellulose, povidone K-30, crospovidone, and stearic acid. The film-coating applied to the tablets contains Opadry Pink^®.

Inactive Ingredients for Oral Solution: sodium benzoate, fumaric acid, povidone K-30, sodium saccharin, mannitol and tutti-frutti flavoring.

Patient Instructions for Use

How do I give Valcyte for oral solution?

Your pharmacist will mix Valcyte for oral solution for you.

Be sure that you read, and that you understand and follow these instructions carefully to ensure proper dosing of the oral solution. To take a dose of Valcyte for oral solution, you will need the bottle of medicine and an oral dispenser. See Figure 1 below.

Figure 1:

• Shake closed bottle well for about 5 seconds before each use.
• Remove the child-resistant bottle cap.
• Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.
• Insert tip firmly into opening of the bottle adapter.

Turn the entire unit (bottle and oral dispenser) upside down (see Figure 2 ).

Figure 2:

• Make sure the dosing dispenser stays connected to the bottle. Pull the plunger down slowly until the prescribed amount of medicine is withdrawn into the oral dispenser (see Figure 3 ).

Figure 3:

• Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.
• Give the dose of medicine directly into mouth and swallow. Do not mix with any liquid before giving the dose.
• Close the bottle with child-resistant bottle cap after each use.
• After taking your medicine, take apart (disassemble) the oral dispenser right away and rinse under running tap water. Then air dry before next use.

Avoid skin contact with Valcyte for oral solution. If you come in contact with Valcyte for oral solution, wash the area well with soap and water.

Do not use Valcyte for oral solution after the expiration date on the bottle.

Call your pharmacist if your oral dispenser is lost or damaged, and they will tell you how to continue to take your medicine.

VALCYTE is a registered trademark of Hoffmann-La Roche Inc.

Distributed by:

Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

VECO_1079070_PI_2013_02_N

Revised: March 2013

© 2013 Genentech, Inc. All rights reserved.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 450 mg Tablet Bottle Label

NDC 0004-0038-22

Valcyte ^®
(valganciclovir HCl tablets)

450 mg

equivalent to 450 mg valganciclovir

DO NOT BREAK OR CRUSH TABLETS

60 tablets
Rx only

Genentech

PRINCIPAL DISPLAY PANEL - 50 mg/1 mL Bottle Carton

NDC 0004-0039-09

Valcyte ^®
(valganciclovir
hydrochloride)
for oral solution

50 mg/1 mL

Each mL of constituted
oral solution contains
50 mg valganciclovir
free base.

100 mL (3.4 fl oz)
Rx only

Genentech