Valcyte tablets should not be administered if the absolute neutrophil count is less than 500 cells/mL, the platelet count is less than 25,000/ mL, or the hemoglobin is less than 8 g/dL. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with Valcyte tablets (and ganciclovir) (see PRECAUTIONS: Laboratory Testing and ADVERSE EVENTS ).

Valcyte tablets should, therefore, 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 increase with continued dosing. Cell counts usually begin to recover within 3 to 7 days of discontinuing drug.

Animal data indicate that administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses (see PRECAUTIONS: Carcinogenesis, Mutagenesis and Impairment of Fertility‡). It is considered probable that in humans, Valcyte at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Animal data also indicate that suppression of fertility in females may occur.

Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing potential should be advised to use effective contraception during treatment. Similarly, men should be advised to practice barrier contraception during, and for at least 90 days following, treatment with Valcyte tablets (see PRECAUTIONS: Carcinogenesis, Mutagenesis and Impairment of Fertility_‡, and Pregnancy: Category C^‡ ). In animal studies, ganciclovir was found to be mutagenic and carcinogenic. Valcyte should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see DOSAGE AND ADMINISTRATION: Handling and Disposal ).

In liver transplant patients, there was a significantly higher incidence of tissue-invasive CMV disease in the Valcyte-treated group compared with the oral ganciclovir group (see CLINICAL TRIALS ).

The bioavailability of ganciclovir from Valcyte tablets is significantly higher than from ganciclovir capsules. Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of Valcyte tablets. Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis (see DOSAGE AND ADMINISTRATION ).

Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS ARE REQUIRED FOR VALCYTE TABLETS. Such adjustments should be based on measured or estimated creatinine clearance values (see DOSAGE AND ADMINISTRATION: Renal Impairment ).

For patients on hemodialysis (CrCl <10 mL/min) it is recommended that ganciclovir be used (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) rather than Valcyte tablets (see DOSAGE AND ADMINISTRATION: Hemodialysis Patients and CLINICAL PHARMACOLOGY: Special Populations: Hemodialysis ).

Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis. Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of Valcyte tablets (see OVERDOSAGE and DOSAGE AND ADMINISTRATION ).

Valcyte is changed to ganciclovir once it is absorbed into the body. All patients should be informed 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. Patients should be informed that ganciclovir has been associated with elevations in serum creatinine.

Patients should be instructed to take Valcyte tablets with food to maximize bioavailability.

Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause decreased fertility in humans. Women of childbearing potential should be advised 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, mothers should be instructed not to breast-feed if they are receiving Valcyte tablets. Women of childbearing potential should be advised to use effective contraception during treatment with Valcyte tablets. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Valcyte tablets.

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

Convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of Valcyte tablets and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness including the patientβ†β†s ability to drive and operate machinery. Patients should be told that ganciclovir is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during or following treatment.

Patients should be advised to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with Valcyte tablets. Some patients will require more frequent follow-up.

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving Valcyte tablets (see ADVERSE EVENTS ), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/mL at the beginning of treatment. 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 ).

Increased serum creatinine levels have been observed in trials evaluating Valcyte tablets. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION: Renal Impairment ). The mechanism of impairment of renal function is not known.

No long-term carcinogenicity studies have 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: Impairment of Fertility ). 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.

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. 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: Teratogenesis, Carcinogenesis and Mutagenesis ). The drug exposure in mice as estimated by the AUC was approximately 1.7x the human AUC.

Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/mL and occurred by passive diffusion.

Valganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. There are no adequate and well-controlled studies in pregnant women. Valcyte tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

^β†β†Footnote: All dose comparisons presented in the Carcinogenesis, Mutagenesis and Impairment of Fertility, and Pregnancy subsections are based on the human AUC following administration of a single 5 mg/kg infusion of intravenous ganciclovir.

It is not known whether ganciclovir or valganciclovir is excreted in human milk. Because valganciclovir caused granulocytopenia, anemia and thrombocytopenia in clinical trials and ganciclovir was mutagenic and carcinogenic in animal studies, the possibility of serious adverse events from ganciclovir in nursing infants is possible (see WARNINGS ). Because of potential for serious adverse events in nursing infants, mothers should be instructed not to breast-feed if they are receiving Valcyte tablets. In addition, the Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.

Safety and effectiveness of Valcyte tablets in pediatric patients have not been established.

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

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

Bookmark this page: