These Highlights Do Not Include All The Information Needed To Use Valcyte®

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)].

Table 15 and Table 16 provide a listing of established drug interaction studies with ganciclovir. Table 15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

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

VALCYTE is a registered trademark of CHEPLAPHARM Arzneimittel GmbH.

Distributed by:

H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by:

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 24, 17489 Greifswald, Germany

Revised: 04/2023

For more information call 1-866-946-3684.

© 2023 CHEPLAPHARM Arzneimittel GmbH. All rights reserved.

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 by ganciclovir triphosphate.

Store VALCYTE tablets at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

1. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J of Ped 1986: 109(4): 698-707.

2. NIOSH [2014]. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. By Connor TH, MacKenzie BA, DeBord DG, Trout DB, O'Callaghan JP, Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-138 (Supersedes 2012-150).

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.

VALCYTE for oral solution and tablets are indicated for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age and in pediatric heart transplant patients 1 month 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 kidney transplant patients 4 months to 16 years of age is based on two single-arm, open-label, non-comparative studies in patients 4 months to 16 years of age. Study 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). VALCYTE was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation. Study 2 was a safety and tolerability study where VALCYTE was administered once daily within 10 days of transplantation for a maximum of 200 days post-transplantation in pediatric kidney transplant patients. The results of these studies were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 1 month to 16 years of age is based on two studies (Study 1 described above and Study 3) and was supported by previous demonstration of efficacy in adult patients [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Study 3 was a pharmacokinetic and safety study of VALCYTE in pediatric heart transplant patients less than 4 months of age who received a single dose of VALCYTE oral solution on each of two consecutive days. A physiologically based pharmacokinetic (PBPK) model was developed based on the available pharmacokinetic data from pediatric and adult patients to support dosing in heart transplant patients less than 1 month of age. However, due to uncertainty in model predictions for neonates, VALCYTE is not indicated for prophylaxis in this age group.

The safety and efficacy of VALCYTE for oral solution and tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 4 months of age, in heart transplant patients less than 1 month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.

A pharmacokinetic and pharmacodynamic evaluation of VALCYTE for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system. All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg per kg twice daily or VALCYTE for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily. The pharmacokinetic results showed that in infants greater than 7 days to 3 months of age, a dose of 16 mg per kg twice daily of VALCYTE for oral solution provided ganciclovir systemic exposures (median AUC_0-12h=23.6 [range 16.8–35.5] mcg∙h/mL; n=6) comparable to those obtained in infants up to 3 months of age from a 6 mg per kg dose of intravenous ganciclovir twice daily (AUC_0-12h=25.3 [range 2.4–89.7] mcg∙h/mL; n=18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of VALCYTE tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of VALCYTE 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.

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 renal clearance decreases with age, VALCYTE should be administered with consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2 times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, VALCYTE has the potential to cause birth defects. Pregnancy should be avoided in female patients taking VALCYTE and in females with male partners taking VALCYTE. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE because of the potential risk to the fetus. Similarly, males should be advised to use condoms during and for at least 90 days following treatment with VALCYTE [see Dosage and Administration (2.6), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

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)].

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

• Hematologic Toxicity [see Warnings and Precautions (5.1)].
• Acute Renal Failure [see Warnings and Precautions (5.2)].
• Impairment of Fertility [see Warnings and Precautions (5.3)].
• Fetal Toxicity [see Warnings and Precautions (5.4)].
• Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)].

The most common adverse reactions and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with VALCYTE tablets are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. The most common reported adverse reactions and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with VALCYTE for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.

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

Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.

Dose reduction is recommended when administering VALCYTE to patients with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

For adult patients on hemodialysis (CrCl less than 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 complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Be sure that you read, and that you understand and follow these instructions carefully to ensure proper dosing of the oral solution.

Important:

• Avoid contact with your skin or eyes. If you come in contact with the contents of the oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.
• Do not use VALCYTE for oral solution after the discard date on the bottle.
• Always use the oral dispenser provided to give or take a dose of VALCYTE for oral solution.
• Call your pharmacist if your oral dispenser is lost or damaged, and they will tell you how to continue to give or take a dose of VALCYTE for oral solution.
• Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose.

To take a dose of VALCYTE for oral solution, you will need the bottle of medicine and an oral dispenser provided with the medicine (see Figure 1). Your pharmacist inserts the bottle adapter in the VALCYTE for oral solution bottle.

How should I store VALCYTE for oral solution?

• Store solution in the refrigerator at 36°F to 46°F (2°C to 8°C) for no longer than 49 days.
• Do not freeze.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

VALCYTE is a registered trademark of CHEPLAPHARM Arzneimittel GmbH.

Distributed by:

H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by:

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 24, 17489 Greifswald, Germany

Revised: 04/2023

For more information call 1-866-946-3684.

© 2023 CHEPLAPHARM Arzneimittel GmbH. All rights reserved.

Valganciclovir is a prodrug of ganciclovir. Valganciclovir C_max and AUC are approximately 1% and 3% of those of ganciclovir, respectively.

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

VALCYTE is a deoxynucleoside analogue cytomegalovirus (CMV) 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, and kidney-pancreas transplant patients at high risk.

Pediatric Patients (1.2)

• Prevention of CMV disease in kidney and heart transplant patients at high risk.

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.

Valganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)].

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE or ganciclovir. VALCYTE should be avoided 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 and in patients 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. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.

Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving VALCYTE [see Adverse Reactions (6.1)], complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment, and 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)].

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 (5.4, 5.5)]. 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.

Handle and dispose VALCYTE according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity).²

• 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, 5.2, 8.5, 8.6)

• VALCYTE for oral solution and tablets should be taken with food. (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)

Based on animal data and limited human data, VALCYTE at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of VALCYTE [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

• VALCYTE tablets: 450 mg, pink, film-coated convex oval tablets with "VGC" on one side and "450" on the other side.
• VALCYTE for oral solution: 50 mg per 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.

The following adverse reactions have been identified during post-approval use of VALCYTE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. As VALCYTE is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir.

• –
  Anaphylactic reaction
• –
  Agranulocytosis
• –
  Granulocytopenia

In general, the adverse reactions reported during the postmarketing use of VALCYTE were similar to those identified during the clinical trials.

• Lactation: Breastfeeding is not recommended with use of VALCYTE. (8.2)

• Adult patients should use VALCYTE tablets, not VALCYTE for oral solution.
• 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)].

Because clinical trials are conducted under widely varying conditions, adverse reaction 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.

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

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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

Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. 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 discard date 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)].

NDC 61269-485-10

Valcyte^®

(valganciclovir)

for oral solution

50 mg/mL

Each mL of constituted oral

solution contains 50 mg

valganciclovir free base.

100 mL (3.4 fl oz)

Rx only

CHEPLAPHARM

NDC 61269-480-60

Valcyte^®

(valganciclovir)

tablets

450 mg

DO NOT BREAK OR CRUSH TABLETS

CAUTION: Strict adherence to dosage

recommendations is essential to avoid

overdose.

60 tablets

Rx only

CHEPLAPHARM

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 0.1× and 1.4×, 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 (5.3)]. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7× the mean drug exposure in humans following the dose of 5 mg per 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 0.1× the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. These effects were reversible at lower doses but irreversible at higher doses. It is considered likely that ganciclovir (and valganciclovir) could cause temporary or permanent inhibition of human spermatogenesis.

Serum creatinine levels or estimated creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis (CrCl less than 10 mL/min), a dose recommendation for VALCYTE cannot be given [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)].

*An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas:

For females = 0.85 × male value

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)].

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

• Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE [see Warnings and Precautions (5.1)].
• Impairment of Fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions (5.3)].
• Fetal Toxicity: Based on animal data, VALCYTE has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)].
• Mutagenesis and Carcinogenesis: Based on animal data, VALCYTE has the potential to cause cancers in humans [see Warnings and Precautions (5.5)].

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)].

Table 15 and Table 16 provide a listing of established drug interaction studies with ganciclovir. Table 15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

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

VALCYTE is a registered trademark of CHEPLAPHARM Arzneimittel GmbH.

Distributed by:

H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by:

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 24, 17489 Greifswald, Germany

Revised: 04/2023

For more information call 1-866-946-3684.

© 2023 CHEPLAPHARM Arzneimittel GmbH. All rights reserved.

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 by ganciclovir triphosphate.

Store VALCYTE tablets at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

1. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J of Ped 1986: 109(4): 698-707.

2. NIOSH [2014]. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. By Connor TH, MacKenzie BA, DeBord DG, Trout DB, O'Callaghan JP, Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-138 (Supersedes 2012-150).

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.

VALCYTE for oral solution and tablets are indicated for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age and in pediatric heart transplant patients 1 month 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 kidney transplant patients 4 months to 16 years of age is based on two single-arm, open-label, non-comparative studies in patients 4 months to 16 years of age. Study 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). VALCYTE was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation. Study 2 was a safety and tolerability study where VALCYTE was administered once daily within 10 days of transplantation for a maximum of 200 days post-transplantation in pediatric kidney transplant patients. The results of these studies were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

The use of VALCYTE for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 1 month to 16 years of age is based on two studies (Study 1 described above and Study 3) and was supported by previous demonstration of efficacy in adult patients [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Study 3 was a pharmacokinetic and safety study of VALCYTE in pediatric heart transplant patients less than 4 months of age who received a single dose of VALCYTE oral solution on each of two consecutive days. A physiologically based pharmacokinetic (PBPK) model was developed based on the available pharmacokinetic data from pediatric and adult patients to support dosing in heart transplant patients less than 1 month of age. However, due to uncertainty in model predictions for neonates, VALCYTE is not indicated for prophylaxis in this age group.

The safety and efficacy of VALCYTE for oral solution and tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 4 months of age, in heart transplant patients less than 1 month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.

A pharmacokinetic and pharmacodynamic evaluation of VALCYTE for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system. All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg per kg twice daily or VALCYTE for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily. The pharmacokinetic results showed that in infants greater than 7 days to 3 months of age, a dose of 16 mg per kg twice daily of VALCYTE for oral solution provided ganciclovir systemic exposures (median AUC_0-12h=23.6 [range 16.8–35.5] mcg∙h/mL; n=6) comparable to those obtained in infants up to 3 months of age from a 6 mg per kg dose of intravenous ganciclovir twice daily (AUC_0-12h=25.3 [range 2.4–89.7] mcg∙h/mL; n=18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of VALCYTE tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of VALCYTE 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.

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 renal clearance decreases with age, VALCYTE should be administered with consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2 times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, VALCYTE has the potential to cause birth defects. Pregnancy should be avoided in female patients taking VALCYTE and in females with male partners taking VALCYTE. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE because of the potential risk to the fetus. Similarly, males should be advised to use condoms during and for at least 90 days following treatment with VALCYTE [see Dosage and Administration (2.6), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

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)].

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

• Hematologic Toxicity [see Warnings and Precautions (5.1)].
• Acute Renal Failure [see Warnings and Precautions (5.2)].
• Impairment of Fertility [see Warnings and Precautions (5.3)].
• Fetal Toxicity [see Warnings and Precautions (5.4)].
• Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)].

The most common adverse reactions and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with VALCYTE tablets are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. The most common reported adverse reactions and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with VALCYTE for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.

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

Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.

Dose reduction is recommended when administering VALCYTE to patients with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

For adult patients on hemodialysis (CrCl less than 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 complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Be sure that you read, and that you understand and follow these instructions carefully to ensure proper dosing of the oral solution.

Important:

• Avoid contact with your skin or eyes. If you come in contact with the contents of the oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.
• Do not use VALCYTE for oral solution after the discard date on the bottle.
• Always use the oral dispenser provided to give or take a dose of VALCYTE for oral solution.
• Call your pharmacist if your oral dispenser is lost or damaged, and they will tell you how to continue to give or take a dose of VALCYTE for oral solution.
• Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose.

To take a dose of VALCYTE for oral solution, you will need the bottle of medicine and an oral dispenser provided with the medicine (see Figure 1). Your pharmacist inserts the bottle adapter in the VALCYTE for oral solution bottle.

How should I store VALCYTE for oral solution?

• Store solution in the refrigerator at 36°F to 46°F (2°C to 8°C) for no longer than 49 days.
• Do not freeze.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

VALCYTE is a registered trademark of CHEPLAPHARM Arzneimittel GmbH.

Distributed by:

H2-Pharma, LLC

Montgomery, AL 36117, USA

Licensed by:

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 24, 17489 Greifswald, Germany

Revised: 04/2023

For more information call 1-866-946-3684.

© 2023 CHEPLAPHARM Arzneimittel GmbH. All rights reserved.

Valganciclovir is a prodrug of ganciclovir. Valganciclovir C_max and AUC are approximately 1% and 3% of those of ganciclovir, respectively.

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

VALCYTE is a deoxynucleoside analogue cytomegalovirus (CMV) 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, and kidney-pancreas transplant patients at high risk.

Pediatric Patients (1.2)

• Prevention of CMV disease in kidney and heart transplant patients at high risk.

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.

Valganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)].

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE or ganciclovir. VALCYTE should be avoided 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 and in patients 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. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.

Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving VALCYTE [see Adverse Reactions (6.1)], complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment, and 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)].

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 (5.4, 5.5)]. 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.

Handle and dispose VALCYTE according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity).²

• 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, 5.2, 8.5, 8.6)

• VALCYTE for oral solution and tablets should be taken with food. (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)

Based on animal data and limited human data, VALCYTE at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of VALCYTE [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

• VALCYTE tablets: 450 mg, pink, film-coated convex oval tablets with "VGC" on one side and "450" on the other side.
• VALCYTE for oral solution: 50 mg per 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.

The following adverse reactions have been identified during post-approval use of VALCYTE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. As VALCYTE is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir.

• –
  Anaphylactic reaction
• –
  Agranulocytosis
• –
  Granulocytopenia

In general, the adverse reactions reported during the postmarketing use of VALCYTE were similar to those identified during the clinical trials.

• Lactation: Breastfeeding is not recommended with use of VALCYTE. (8.2)

• Adult patients should use VALCYTE tablets, not VALCYTE for oral solution.
• 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)].

Because clinical trials are conducted under widely varying conditions, adverse reaction 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.

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

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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

Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. 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 discard date 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)].

NDC 61269-485-10

Valcyte^®

(valganciclovir)

for oral solution

50 mg/mL

Each mL of constituted oral

solution contains 50 mg

valganciclovir free base.

100 mL (3.4 fl oz)

Rx only

CHEPLAPHARM

NDC 61269-480-60

Valcyte^®

(valganciclovir)

tablets

450 mg

DO NOT BREAK OR CRUSH TABLETS

CAUTION: Strict adherence to dosage

recommendations is essential to avoid

overdose.

60 tablets

Rx only

CHEPLAPHARM

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 0.1× and 1.4×, 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 (5.3)]. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7× the mean drug exposure in humans following the dose of 5 mg per 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 0.1× the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. These effects were reversible at lower doses but irreversible at higher doses. It is considered likely that ganciclovir (and valganciclovir) could cause temporary or permanent inhibition of human spermatogenesis.

Serum creatinine levels or estimated creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis (CrCl less than 10 mL/min), a dose recommendation for VALCYTE cannot be given [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)].

*An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas:

For females = 0.85 × male value

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)].

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

• Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE [see Warnings and Precautions (5.1)].
• Impairment of Fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions (5.3)].
• Fetal Toxicity: Based on animal data, VALCYTE has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)].
• Mutagenesis and Carcinogenesis: Based on animal data, VALCYTE has the potential to cause cancers in humans [see Warnings and Precautions (5.5)].