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All about: Valcyte

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Generic Name: valganciclovir hydrochloride
Dosage Form: Tablets

Warning

THE CLINICAL TOXICITY OF Valcyte, WHICH IS METABOLIZED TO GANCICLOVIR, INCLUDES GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED ASPERMATOGENESIS.

Valcyte Description

Valcyte (valganciclovir HCl tablets) 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 cytomegalovirus (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®.

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.

VIROLOGY

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 cytomegalovirus in vitro 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 viral DNA synthesis by ganciclovir triphosphate.

Antiviral Activity

The quantitative relationship between the in vitro susceptibility of human herpesviruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (IC50), vary greatly depending upon a number of factors. Thus the IC50 of ganciclovir that inhibits human CMV replication in vitro (laboratory and clinical isolates) has ranged from 0.02 to 5.75 µg/mL (0.08 to 22.94 µM). Ganciclovir inhibits mammalian cell proliferation (IC50) in vitro at higher concentrations ranging from 10.21 to >250 µg/mL (40 to >1000 µM). Bone marrow-derived colony-forming cells are more sensitive (IC50 = 0.69 to 3.06 µg/mL: 2.7 to 12 µM).

Viral Resistance

Viruses resistant to ganciclovir can arise after prolonged treatment with valganciclovir by selection of mutations in either the viral protein kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or in the viral DNA polymerase gene (UL54). Virus with mutations in the UL97 gene is resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene may show cross-resistance to other antivirals that target the same sites on viral DNA polymerase.

The current working definition of CMV resistance to ganciclovir in in vitro assays is IC50≥ 1.5 µg/mL (≥ 6.0 µM). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with ganciclovir. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Valcyte - Clinical Pharmacology

Pharmacokinetics

BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR Valcyte TABLETS. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

The ganciclovir pharmacokinetic measures following administration of 900 mg Valcyte and 5 mg/kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in Table 1.

Table 1 Mean Ganciclovir Pharmacokinetic* Measures in Healthy Volunteers and HIV-positive/CMV-positive Adults at Maintenance Dosage
Formulation Valcyte Tablets Cytovene®-IV Ganciclovir Capsules
*
Data were obtained from single and multiple dose studies in healthy volunteers, HIV-positive patients, and HIV-positive/CMV-positive patients with and without retinitis. Patients with CMV retinitis tended to have higher ganciclovir plasma concentrations than patients without CMV retinitis.
Dosage 900 mg once daily with food 5 mg/kg once daily 1000 mg three times daily with food
AUC0-24 hr (µg∙h/mL) 29.1 ± 9.7
(3 studies, n=57)
26.5 ± 5.9
(4 studies, n=68)
Range of means
12.3 to 19.2
(6 studies, n=94)
Cmax (µg/mL) 5.61 ± 1.52
(3 studies, n=58)
9.46 ± 2.02
(4 studies, n=68)
Range of means
0.955 to 1.40
(6 studies, n=94)
Absolute oral bioavailability (%) 59.4 ± 6.1
(2 studies, n=32)
Not Applicable Range of means
6.22 ± 1.29 to 8.53 ± 1.53
(2 studies, n=32)
Elimination half-life (hr) 4.08 ± 0.76
(4 studies, n=73)
3.81 ± 0.71
(4 studies, n=69)
Range of means
3.86 to 5.03
(4 studies, n=61)
Renal clearance (mL/min/kg) 3.21 ± 0.75
(1 study, n=20)
2.99 ± 0.67
(1 study, n=16)
Range of means
2.67 to 3.98
(3 studies, n=30)

The area under the plasma concentration-time curve (AUC) for ganciclovir administered as Valcyte tablets is comparable to the ganciclovir AUC for intravenous ganciclovir. Ganciclovir Cmax following Valcyte administration is 40% lower than following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC0-24 hr and Cmax following oral ganciclovir administration (1000 mg three times daily) are lower relative to Valcyte and intravenous ganciclovir. The ganciclovir Cmin following intravenous ganciclovir and Valcyte administration are less than the ganciclovir Cmin following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics for these three ganciclovir delivery systems is unknown.

Figure 1 Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients*

*Plasma concentration-time profiles for ganciclovir (GCV) from Valcyte (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (WV15376 n=21 and n=18, respectively) in HIV-positive/CMV-positive patients with CMV retinitis. The plasma concentration-time profile for oral ganciclovir was obtained from a multiple dose study (GAN2230 n=24) in HIV-positive/CMV-positive patients without CMV retinitis.

In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7 × higher following administration of 900 mg Valcyte tablets once daily versus 1000 mg ganciclovir capsules three times daily, when both drugs were administered according to their renal function dosing algorithms. The systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetics evaluation (see Table 2).

Table 2 Mean Ganciclovir Pharmacokinetic Measures by Organ Type (Study PV16000)
Parameter Ganciclovir Capsules Valcyte Tablets
*
Includes kidney-pancreas
Dosage 1000 mg three times daily with food 900 mg once daily with food
Heart Transplant Recipients N=13 N=17
AUC0-24 hr (µg∙h/mL) 26.6 ± 11.6 40.2 ± 11.8
Cmax (µg/mL) 1.4 ± 0.5 4.9 ± 1.1
Elimination half-life (hr) 8.47 ± 2.84 6.58 ± 1.50
Liver Transplant Recipients N=33 N=75
AUC0-24 hr (µg∙h/mL) 24.9 ± 10.2 46.0 ± 16.1
Cmax (µg/mL) 1.3 ± 0.4 5.4 ± 1.5
Elimination half-life (hr) 7.68 ± 2.74 6.18 ± 1.42
Kidney Transplant Recipients* N=36 N=68
AUC0-24 hr (µg∙h/mL) 31.3 ± 10.3 48.2 ± 14.6
Cmax (µg/mL) 1.5 ± 0.5 5.3 ± 1.5
Elimination half-life (hr) 9.44 ± 4.37 6.77 ± 1.25

In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC0-24 hr achieved with 900 mg valganciclovir was 41.7 ± 9.9 µg∙h/mL (n=28) and the AUC0-24 hr achieved with the approved dosage of 5 mg/kg intravenous ganciclovir was 48.2 ± 17.3 µg∙h/mL (n=27).

Absorption

Valganciclovir, a prodrug of ganciclovir, is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from Valcyte tablets following administration with food was approximately 60% (3 studies, n=18; n=16; n=28). Ganciclovir median Tmax following administration of 450 mg to 2625 mg Valcyte tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of Valcyte tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, is transient and low, and the AUC24 and Cmax values are approximately 1% and 3% of those of ganciclovir, respectively.

Food Effects

When Valcyte tablets were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) at a dose of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% CI 12% to 51%), and the Cmax increased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (Tmax). Valcyte tablets should be administered with food (see DOSAGE AND ADMINISTRATION).

Distribution

Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 µg/mL. When ganciclovir was administered intravenously, the steady-state volume of distribution of ganciclovir was 0.703 ± 0.134 L/kg (n=69).

After administration of Valcyte tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of Valcyte tablets according to weight is not required.

Metabolism

Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabeled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the feces or urine.

Elimination

The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of intravenously administered ganciclovir was 3.07 ± 0.64 mL/min/kg (n=68) while renal clearance was 2.99 ± 0.67 mL/min/kg (n=16).

The terminal half-life (t½) of ganciclovir following oral administration of Valcyte tablets to either healthy or HIV-positive/CMV-positive subjects was 4.08 ± 0.76 hours (n=73), and that following administration of intravenous ganciclovir was 3.81 ± 0.71 hours (n=69). In  heart, kidney, kidney-pancreas, and liver transplant patients, the terminal elimination half-life of ganciclovir following oral administration of Valcyte was 6.48 ± 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 ± 3.62.

Special Populations

Renal Impairment

The pharmacokinetics of ganciclovir from a single oral dose of 900 mg Valcyte tablets were evaluated in 24 otherwise healthy individuals with renal impairment.

Table 3 Pharmacokinetics of Ganciclovir From a Single Oral Dose of 900 mg Valcyte Tablets
Estimated Creatinine Clearance
(mL/min)
N Apparent Clearance
(mL/min)
Mean ± SD
AUClast
(µg∙h/mL)
Mean ± SD
Half-life
(hours)
Mean ± SD
51-70 6 249 ± 99 49.5 ± 22.4 4.85 ± 1.4
21-50 6 136 ± 64 91.9 ± 43.9 10.2 ± 4.4
11-20 6 45 ± 11 223 ± 46 21.8 ± 5.2
≤10 6 12.8 ± 8 366 ± 66 67.5 ± 34

Decreased renal function results in decreased clearance of ganciclovir from valganciclovir, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for patients with impaired renal function (see PRECAUTIONS: General).

Hemodialysis

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following Valcyte administration. Patients receiving hemodialysis (CrCl <10 mL/min) cannot use Valcyte tablets because the daily dose of Valcyte tablets required for these patients is less than 450 mg (see PRECAUTIONS: General and DOSAGE AND ADMINISTRATION: Hemodialysis Patients).

Patients With Hepatic Impairment

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

Race/Ethnicity and Gender

Insufficient data are available to demonstrate any effect of race or gender on the pharmacokinetics of valganciclovir.

Pediatrics

Valcyte tablets have not been studied in pediatric patients; the pharmacokinetic characteristics of Valcyte tablets in these patients have not been established (see PRECAUTIONS: Pediatric Use).

Geriatrics

No studies of Valcyte tablets have been conducted in adults older than 65 years of age (see PRECAUTIONS: Geriatric Use).

Indications and Usage for Valcyte

Valcyte tablets are indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) (see CLINICAL TRIALS).

Valcyte is indicated for the prevention of cytomegalovirus (CMV) disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [(D+/R-)]).

Valcyte is not indicated for use in liver transplant patients (see CLINICAL TRIALS and WARNINGS).

The safety and efficacy of Valcyte for the prevention of CMV disease in other solid organ transplant patients such as lung transplant patients have not been established.

Clinical Trials

Induction Therapy of CMV Retinitis

Study WV15376

In a randomized, open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either Valcyte tablets (900 mg twice daily for 21 days, then 900 mg once daily for 7 days) or with intravenous ganciclovir solution (5 mg/kg twice daily for 21 days, then 5 mg/kg once daily for 7 days). Study participants were: male (91%), White (53%), Hispanic (31%), and Black (11%). The median age was 39 years, the median baseline HIV-1 RNA was 4.9 log10, and the median CD4 cell count was 23 cells/mm3. A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and week 4 was the primary outcome measurement of the 3-week induction therapy. Table 4 provides the outcomes at 4 weeks.

Table 4 Week 4 Masked Review of Retinal Photographs in Study WV15376
Cytovene-IV Valcyte
Determination of CMV retinitis progression at Week 4 N=80 N=80
Progressor 7 7
Non-progressor 63 64
Death 2 1
Discontinuations due to Adverse Events 1 2
Failed to return 1 1
CMV not confirmed at baseline or no interpretable baseline photos 6 5

Maintenance Therapy of CMV Retinitis

No comparative clinical data are available on the efficacy of Valcyte for the maintenance therapy of CMV retinitis because all patients in study WV15376 received open-label Valcyte after week 4. However, the AUC for ganciclovir is similar following administration of 900 mg Valcyte tablets once daily and 5 mg/kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following Valcyte administration compared to intravenous ganciclovir, it is higher than the Cmax obtained following oral ganciclovir administration (see Figure 1 in CLINICAL PHARMACOLOGY). Therefore, use of Valcyte as maintenance therapy is supported by a plasma concentration-time profile similar to that of two approved products for maintenance therapy of CMV retinitis.

Prevention of CMV Disease in Heart, Kidney, Kidney-Pancreas, and Liver Transplantation

A double-blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, and kidney-pancreas transplant patients at high-risk for CMV disease (D+/R-). Patients were randomized (2 Valcyte: 1 oral ganciclovir) to receive either Valcyte (900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 posttransplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue-invasive disease during the first 6 months posttransplant was similar between the Valcyte arm (12.1%, N=239) and the oral ganciclovir arm (15.2%, N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the Valcyte group compared with the ganciclovir group. These results are summarized in Table 5.

Mortality at six months was 3.7% (9/244) in the Valcyte group and 1.6% (2/126) in the oral ganciclovir group. 

Table 5 Percentage of Patients With CMV Disease and Tissue-Invasive CMV Disease by Organ Type: Endpoint Committee, 6 Month ITT Population
CMV Disease* Tissue-Invasive CMV Disease CMV Syndrome
GCV = oral ganciclovir; VGCV = Valcyte
*
Number of Patients with CMV Disease = Number of Patients with Tissue-Invasive CMV Disease + Number of Patients with CMV Syndrome. 
Organ VGCV
(N=239)
GCV
(N=125)
VGCV
(N=239)
GCV
(N=125)
VGCV
(N=239)
GCV
(N=125)
Liver (n=177) 19%
(22 / 118)
12%
(7 / 59)
14%
(16 / 118)
3%
(2 / 59)
5%
(6 / 118)
9%
(5 / 59)
Kidney (n=120) 6%
(5 / 81)
23%
(9 / 39)
1%
(1 / 81)
5%
(2 / 39)
5%
(4 / 81)
18%
(7 / 39)
Heart (n=56) 6%
(2 / 35)
10%
(2 / 21)
0%
(0 / 35)
5%
(1 / 21)
6%
(2 / 35)
5%
(1 / 21)
Kidney / Pancreas (n=11) 0%
(0 / 5)
17%
(1 / 6)
0%
(0 / 5)
17%
(1 / 6)
0%
(0 / 5)
0%
(0 / 6)

Contraindications

Valcyte tablets are contraindicated in patients with hypersensitivity to valganciclovir or ganciclovir.

Warnings

THE CLINICAL TOXICITY OF Valcyte, WHICH IS METABOLIZED TO GANCICLOVIR, INCLUDES GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED ASPERMATOGENESIS.

Hematologic

Valcyte tablets 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. 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.

Impairment of Fertility

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 Fertility1). 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.

1
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.

Teratogenesis, Carcinogenesis and Mutagenesis

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 Fertility1, and Pregnancy: Category C1).

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).

Tissue Invasive CMV Disease in Liver Transplant Patients

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).

Precautions

General

Strict adherence to dosage recommendations is essential to avoid overdose.

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).

Information for Patients

(see Patient Information)

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 patient'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.

Laboratory Testing

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/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).

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.

Drug Interactions

Drug Interaction Studies Conducted With Valcyte

No in vivo drug-drug interaction studies were conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for Valcyte tablets.

Drug Interaction Studies Conducted With Ganciclovir

Binding of ganciclovir to plasma proteins is only about 1% to 2%, and drug interactions involving binding site displacement are not anticipated.

Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Valcyte tablets and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.

Table 6 Results of Drug Interaction Studies With Ganciclovir: Effects of Coadministered Drug on Ganciclovir Plasma AUC and Cmax Values
Coadministered Drug Ganciclovir Dosage n Ganciclovir Pharmacokinetic (PK) Parameter Clinical Comment
Zidovudine 100 mg every 4 hours 1000 mg every 8 hours 12 AUC ↓ 17 ± 25%
(range: -52% to 23%)
Zidovudine and Valcyte each have the potential to cause neutropenia and anemia. Some patients may not tolerate concomitant therapy at full dosage.
Didanosine 200 mg every 12 hours administered 2 hours before ganciclovir 1000 mg every 8 hours 12 AUC ↓ 21 ± 17%
(range: -44% to 5%)
Effect not likely to be clinically significant.
Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir 1000 mg every 8 hours 12 No effect on ganciclovir PK parameters observed No effect expected.
IV ganciclovir 5 mg/kg twice daily 11 No effect on ganciclovir PK parameters observed No effect expected.
IV ganciclovir 5 mg/kg once daily 11 No effect on ganciclovir PK parameters observed No effect expected.
Probenecid 500 mg every 6 hours 1000 mg every 8 hours 10 AUC ↑ 53 ± 91%
(range: -14% to 299%)
Ganciclovir renal clearance ↓ 22 ± 20%
(range: -54% to -4%)
Patients taking probenecid and Valcyte should be monitored for evidence of ganciclovir toxicity.
Zalcitabine 0.75 mg every 8 hours administered 2 hours before ganciclovir 1000 mg every 8 hours 10 AUC ↑13% Effect not likely to be clinically significant.
Trimethoprim 200 mg once daily 1000 mg every 8 hours 12 Ganciclovir renal clearance ↓ 16.3%
Half-life ↑15%
Effect not likely to be clinically significant.
Mycophenolate Mofetil 1.5 g single dose IV ganciclovir 5 mg/kg single dose 12 No effect on ganciclovir PK parameters observed (patients with normal renal function) Patients with renal impairment should be monitored carefully as levels of metabolites of both drugs may increase.
Table 7 Results of Drug Interaction Studies With Ganciclovir: Effects of Ganciclovir on Plasma AUC and Cmax Values of Coadministered Drug
Coadministered Drug Ganciclovir Dosage N Coadministered Drug Pharmacokinetic (PK) Parameter Clinical Comment
Zidovudine 100 mg every 4 hours 1000 mg every 8 hours 12 AUC0-4↑ 19 ± 27%
(range: -11% to 74%)
Zidovudine and Valcyte each have the potential to cause neutropenia and anemia. Some patients may not tolerate concomitant therapy at full dosage.
Didanosine 200 mg every 12 hours when administered 2 hours prior to or concurrent with ganciclovir 1000 mg every 8 hours 12 AUC0-12↑111 ± 114%
(range: 10% to 493%)
Patients should be closely monitored for didanosine toxicity.
Didanosine 200 mg every 12 hours IV ganciclovir 5 mg/kg twice daily 11 AUC0-12↑70 ± 40%
(range: 3% to 121%)

Cmax↑49 ± 48%
(range: -28% to 125%)
Patients should be closely monitored for didanosine toxicity.
Didanosine 200 mg every 12 hours IV ganciclovir 5 mg/kg once daily 11 AUC0-12↑50 ± 26%
(range: 22% to 110%)

Cmax↑36 ± 36%
(range: -27% to 94%)
Patients should be closely monitored for didanosine toxicity.
Zalcitabine 0.75 mg every 8 hours administered 2 hours before ganciclovir 1000 mg every 8 hours 10 No clinically relevant PK parameter changes No effect expected.
Trimethoprim 200 mg once daily 1000 mg every 8 hours 12 Increase (12%) in Cmin Effect not likely to be clinically significant.
Mycophenolate Mofetil (MMF) 1.5 g single dose IV ganciclovir 5 mg/kg single dose 12 No PK interaction observed (patients with normal renal function) Patients with renal impairment should be monitored carefully as levels of metabolites of both drugs may increase.

Carcinogenesis, Mutagenesis and Impairment of Fertility1

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 0.1× 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: 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 1.7× 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 0.1× 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.

Pregnancy

Category C1

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 2× 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 1.7× 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.

Nursing Mothers

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.

Pediatric Use

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

Geriatric Use

The pharmacokinetic characteristics of Valcyte in eld

Recent Drug Updates at DrugIndexOnline:





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