July 2, 2015
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Valcyte

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Valcyte




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hematologic Toxicity

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and 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, 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, because of increased plasma concentrations of ganciclovir after VALCYTE administration [see CLINICAL PHARMACOLOGY].

Impairment Of Fertility

Based on animal data with ganciclovir, 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, Nonclinical Toxicology].

Fetal Toxicity

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. Similarly, males 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].

Mutagenesis And Carcinogenesis

Animal data indicate that ganciclovir is mutagenic and carcinogenic. VALCYTE 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 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 to patients receiving potential nephrotoxic drugs.
  • Patients without adequate hydration. Adequate hydration should be maintained for all patients.

Patient Counseling Information

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

Serious Adverse Reactions

Inform patients that VALCYTE may cause granulocytopenia (neutropenia), anemia, thrombocytopenia and elevated creatinine levels and that dose modification or discontinuation of dosing may be required. Complete blood counts, platelet counts, and creatinine levels should be performed frequently during treatment [see WARNINGS AND PRECAUTIONS].

Pregnancy and Contraception

Inform females of reproductive potential that VALCYTE causes birth defects in animals. Advise them to use effective contraception during and for at least 30 days following treatment with VALCYTE. Similarly, advise males to practice barrier contraception during and for at least 90 days following treatment with VALCYTE [see Use In Specific Populations].

Carcinogenicity

Advise patients that VALCYTE is considered a potential carcinogen [see Nonclinical Toxicity].

Lactation

Advise mothers not to breast-feed if they are receiving VALCYTE because of the potential for hematologic toxicity and cancer in nursing infants, and because HIV can be passed to the baby in breast milk [see Use in Specific Populations].

Infertility

Advise patients that VALCYTE may cause temporary or permanent female and male infertility [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].

Impairment of Cognitive Ability

Inform patients that tasks requiring alertness may be affected including the patient's ability to drive and operate machinery as convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of VALCYTE [see ADVERSE REACTIONS].

Use in Patients with CMV Retinitis

Inform patients that VALCYTE 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.

Administration

Inform adult patients that they should use VALCYTE tablets, not VALCYTE for oral solution [see DOSAGE AND ADMINISTRATION].

Inform patients to take VALCYTE with food to maximize bioavailability.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons. At the higher dose there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans.

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

Valganciclovir is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir [see WARNINGS AND PRECAUTIONS]. 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 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 0.1x 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.

Use In Specific Populations

Pregnancy

Risk Summary

After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, VALCYTE is expected to have reproductive toxicity effects similar to ganciclovir. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two-times the human exposure. There are no available human data on use of VALCYTE or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and the risk of miscarriage is 15-20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to the fetus [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Most maternal CMV infections are asymptomatic or they may be associated with a self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS) CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is a result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth. Mortality in these infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection.

Data

Animal Data

At doses resulting in two-times the human exposure of ganciclovir (all dose comparisons presented are based on the human AUC following a single intravenous infusion of 5 mg per kg of ganciclovir) resulted in maternal and embryofetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits. Fetal resorptions were present in at least 85% of rabbits and mice. Rabbits showed increased embryofetal mortality, growth retardation of the fetuses and structural abnormalities of multiple organs of the fetuses including the palate (cleft palate), eyes (anophthalmia/microphthalmia), brain (hydrocephalus), jaw (brachygnathia), kidneys and pancreas (aplastic organs). Increased embryofetal mortality was also seen in mice. Daily intravenous doses of approximately 1.7-times 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 the 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.

Lactation

Risk Summary

No data are available regarding the presence of valganciclovir (prodrug) or ganciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Advise nursing mothers that breastfeeding is not recommended during treatment with VALCYTE because of the potential for serious adverse events in nursing infants and because of the potential for transmission of HIV [see BOXED WARNING, WARNINGS AND PRECAUTIONS, Nonclinical Toxicology].

Females And Males Of Reproductive Potential

Pregnancy Testing

Females of reproductive potential should undergo pregnancy testing before initiation of VALCYTE [see Use in Specific Populations].

Contraception

Females

Because of the mutagenic and teratogenic potential of VALCYTE, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Nonclinical Toxicology].

Males

Because of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following, treatment with VALCYTE [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Nonclinical Toxicology].

Infertility

VALCYTE at the recommended doses may cause temporary or permanent female and male infertility [see WARNINGS AND PRECAUTIONS, Nonclinical Toxicology].

Pediatric Use

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, DOSAGE AND ADMINISTRATION].

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, CLINICAL PHARMACOLOGY, Clinical Studies].

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, Clinical Studies]. 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 AUC0-12h = 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 (AUC0-12h = 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.

Geriatric Use

Studies of VALCYTE for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of VALCYTE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. VALCYTE is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Use in Specific Populations, CLINICAL PHARMACOLOGY].

Renal Impairment

Dose reduction is recommended when administering VALCYTE to patients with renal impairment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

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 and CLINICAL PHARMACOLOGY].

Hepatic Impairment

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

Last reviewed on RxList: 5/13/2015
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions

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