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Included as part of the PRECAUTIONS section.

Hematologic Effects

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with Valcyte (valganciclovir hcl) or ganciclovir. Valcyte (valganciclovir hcl) 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 (valganciclovir hcl) 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], 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 (valganciclovir hcl) , because of increased plasma concentrations of ganciclovir after Valcyte administration [see CLINICAL PHARMACOLOGY].

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]. In men, Valcyte (valganciclovir hcl) at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Animal data also indicate suppression of fertility in females may occur.

Teratogenesis and Mutagenesis

Animal data indicate ganciclovir is teratogenic and mutagenic. Therefore, Valcyte (valganciclovir hcl) 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 (valganciclovir hcl) . Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Valcyte [see DOSAGE AND ADMINISTRATION, Use in Specific Populations, Nonclinical Toxicology].

Carcinogenesis

Animal data indicate that administration of ganciclovir is carcinogenic. Valcyte (valganciclovir hcl) should therefore be considered a potential carcinogen in humans [see DOSAGE AND ADMINISTRATION, Nonclinical Toxicology].

Acute Renal Failure

Acute renal failure may occur in:

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

Patient Counseling Information

See FDA-Approved Patient Labeling

Valcyte (valganciclovir hcl) 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, OVERDOSAGE].

Adult patients should use Valcyte (valganciclovir hcl) tablets, not Valcyte for oral solution [see DOSAGE AND ADMINISTRATION].

Valcyte (valganciclovir hcl) 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 (valganciclovir hcl) 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 (valganciclovir hcl) . Advise women of childbearing potential to use effective contraception during and for at least 30 days following treatment with Valcyte (valganciclovir hcl) . Similarly, advise men to practice barrier contraception during and for at least 90 days following treatment with Valcyte (valganciclovir hcl) .

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 (valganciclovir hcl) 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 (valganciclovir hcl) . Some patients will require more frequent follow-up.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted with Valcyte (valganciclovir hcl) . 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]. 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.

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]. 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.

Use In Specific Populations

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].

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]. 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.

Pediatric Use

Valcyte (valganciclovir hcl) 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, DOSAGE AND ADMINISTRATION].

The use of Valcyte (valganciclovir hcl) 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 (valganciclovir hcl) (Valcyte (valganciclovir hcl) 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, CLINICAL PHARMACOLOGY, Clinical Studies].

The safety and efficacy of Valcyte (valganciclovir hcl) 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 (valganciclovir hcl) for oral solution in children were studied in two open-label studies.

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

Study 2 was a pharmacokinetic and pharmacodynamic evaluation of Valcyte (valganciclovir hcl) 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 (valganciclovir hcl) 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 (valganciclovir hcl) for oral solution provided ganciclovir systemic exposures (median AUC0-12h = 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 (AUC0-12h = 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 (valganciclovir hcl) 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.

Geriatric Use

Studies of Valcyte (valganciclovir hcl) for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of Valcyte (valganciclovir hcl) 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 (valganciclovir hcl) 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, WARNINGS AND PRECAUTIONS, Use in Specific Populations, CLINICAL PHARMACOLOGY].

Renal Impairment

Dose reduction is recommended when administering Valcyte (valganciclovir hcl) to patients with renal impairment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

For adult patients on hemodialysis (CrCl < 10 mL/min) Valcyte (valganciclovir hcl) 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 and CLINICAL PHARMACOLOGY].

Hepatic Impairment

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

Last reviewed on RxList: 9/8/2010
This monograph has been modified to include the generic and brand name in many instances.