Valcyte Information
Valcyte () Indications And Usage
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:
Valcyte () Dosage And Administration
For dosage recommendations in adult patients with renal impairment see .
Prevention of CMV Disease:
Pediatric Dose (mg) = 7 × BSA × CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m, then a maximum value of 150 mL/min/1.73m should be used in the equation.
where k =
0.45 for patients aged 4 months to
0.45 for patients aged 1 to
0.55 for boys aged 2 to
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.
Prior to dispensing to the patient, Valcyte () for oral solution must be prepared by the pharmacist as follows :
The patient package insert, which includes the dosing instructions for patients, and 2 oral dispensers should be dispensed to the patient .
Dosage recommendations for adult patients with reduced renal function are provided in . For adult patients on hemodialysis (CrCl
Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation .
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 . 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 .
Valcyte () Dosage Forms And Strengths
Valcyte () Tablets:
Valcyte () for Oral Solution:
Valcyte () 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
Valcyte () Warnings And Precautions
Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with Valcyte () or ganciclovir. 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 () , 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 .
Valcyte () Adverse Reactions
The following serious adverse events are discussed in greater detail in other sections of the labeling:
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.
Valcyte () 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 .
Valcyte () Use In Specific Populations
Pregnancy Category C
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 .
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
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 .
The safety and efficacy of Valcyte () for oral solution and tablets have not been established in children for:
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 .
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 = 23.6 [range 16.8 – 35.5] µgh/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 = 25.3 [range 2.4 – 89.7] µgh/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.
Dose reduction is recommended when administering Valcyte () to patients with renal impairment .
For adult patients on hemodialysis (CrCl
Valcyte () Overdosage
Experience With Valcyte () Tablets:
An overdose of Valcyte () could also possibly result in increased renal toxicity .
Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Valcyte () . Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered .
Experience With Intravenous Ganciclovir:
Hematological toxicity:
Hepatotoxicity:
Renal toxicity:
Gastrointestinal toxicity:
Neurotoxicity:
Valcyte () 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 CHNO•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 () Nonclinical Toxicology
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 . 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 (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 . 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.
Valcyte () How Supplied/storage And Handling
Valcyte () Tablets:
Valcyte () for Oral Solution:
Prior to dispensing to the patient, Valcyte () for oral solution must be prepared by the pharmacist
Valcyte () Patient Counseling Information
Adult patients should use Valcyte () tablets, not Valcyte () for oral solution .
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.
Valcyte ()
Valcyte ()
Valcyte ()
