"Infants exposed in the womb to a drug used to treat HIV and reduce the transmission of HIV from mother to child, may have lower bone mineral content than those exposed to other anti-HIV drugs, according to a National Institutes of Health study"...
Mechanism Of Action
Valganciclovir is an antiviral drug [see Microbiology].
Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for VALCYTE tablets and VALCYTE for oral solution [see DOSAGE AND ADMINISTRATION].
Pharmacokinetics in Adults
The pharmacokinetics of valganciclovir and ganciclovir after administration of valganciclovir tablets have been evaluated in HIV-and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients.
The ganciclovir pharmacokinetic parameters following administration of 900 mg VALCYTE tablets and 5 mg per kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in Table 10.
Table 10 : Mean Ganciclovir Pharmacokinetic* Measures
in Healthy Volunteers and HIV-positive/CMV-positive Adults at Maintenance
|Formulation||VALCYTE Tablets||Intravenous Ganciclovir||Ganciclovir Capsules|
|Dosage||900 mg once daily with food||5 mg/kg once daily||1000 mg three times daily with food|
|AUC0-24h (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•h/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)|
|*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.|
The area under the plasma concentration-time curve (AUC) of ganciclovir administered as VALCYTE tablets (900 mg once daily) is comparable to the AUC of ganciclovir after administration of intravenous ganciclovir (5 mg per kg once daily). The Cmax of ganciclovir following VALCYTE administration is 40% lower than the Cmax following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC0-24h 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 after administration of VALCYTE tablets, ganciclovir capsules, and intravenous ganciclovir is unknown.
Figure 1 : Ganciclovir
Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients*
*Plasma concentration-time profiles for ganciclovir (GCV) from valganciclovir (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (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 (n=24) in HIV-positive/CMV-positive patients without CMV retinitis.
In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7x 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 pharmacokinetic evaluation (see Table 11).
Table 11 : Mean Ganciclovir Pharmacokinetic Measures
by Organ Transplant Type
|Parameter||Ganciclovir Capsules||VALCYTE Tablets|
|Dosage||1000 mg three times daily with food Mean ± SD||900 mg once daily with food Mean ± SD|
|Heart Transplant Recipients||N=13||N=17|
|AUC0-24h (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|
|AUC0-24h (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|
|AUC0-24h (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|
|* Includes kidney-pancreas|
The pharmacokinetic parameters of ganciclovir following 200 days of VALCYTE administration in high-risk kidney transplant patients were similar to those previously reported in solid organ transplant patients who received VALCYTE for 100 days.
In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC0-24h achieved with 900 mg valganciclovir was 41.7 ± 9.9 mcg•h/mL (n=28) and the AUC0-24h achieved with the approved dosage of 5 mg per kg intravenous ganciclovir was 48.2 ± 17.3 mcg•h/mL (n=27).
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.
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 should be administered with food [see DOSAGE AND ADMINISTRATION].
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 mcg/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.
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.
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 hours.
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 12 : 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 (^gh/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.
Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following VALCYTE administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use VALCYTE tablets because the daily dose of VALCYTE tablets required for these patients is less than 450 mg [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in 63 pediatric solid organ transplant patients aged 4 months to 16 years, and in 16 pediatric heart transplant patients less than 4 months of age. In these studies, patients received oral doses of valganciclovir (either VALCYTE for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Use In Specific Populations, Clinical Studies].
The pharmacokinetics of ganciclovir were similar across organ types and age ranges. Based on a population pharmacokinetic evaluation, clearance is influenced by both body weight and renal function, while the central and peripheral volumes of distribution were influenced by weight [see DOSAGE AND ADMINISTRATION]. The mean total clearance was 5.3 L/hr (88.3 mL/min) for a patient with creatinine clearance of 70.4 mL/min. The mean ganciclovir Cmax, AUC and half-life by age and organ type in studies using the pediatric valganciclovir dosing algorithm are listed in Table 13. Relative to adult transplant patients (Table 11), AUC values in pediatric patients were somewhat increased, but were within the range considered safe and effective in adults.
Table 13 : Ganciclovir
Pharmacokinetics by Age in Pediatric Solid Organ Transplant Patientsa
|Organ||PK Parameter mean (SD)||Age Group|
|< 4 months||4 months to ≤ 2 years||> 2 to < 12 years||≥ 12 years|
|AU C0-24h (μg•h/mL)||66.3 (20.5)c||55.4 (22.8)||59.6 (21.0)||60.6 (25.0)|
|Cmax(μg/mL)||10.8 (3.30)||8.2 (2.5)||12.5 (1.2)||9.5 (3.3)|
|t½ (h)||3.5 (0.87)||3.8 (1.7)||2.8 (0.9)||4.9 (0.8)|
|AUC0-24h (μg•h/mL)||67.6 (13.0)||55.9 (12.1)||47.8 (12.4)|
|Cmax (μg/mL)||NA||10.4 (0.4)||8.7 (2.1)||7.7 (2.1)|
|t½ (h)||4.5 (1.5)||4.8 (1.0)||6.0 (1.3)|
|AUC0-24h (μg•h/mL)||69.9 (37.0)||59.4 (8.1)||35.4 (2.8)|
|Cmax (μg/mL)||NA||11.9 (3.7)||9.5 (2.3)||5.5 (1.1)|
|t½ (h)||2.8 (1.5)||3.8 (0.7)||4.4 (0.2)|
|N= number of patients
aPharmacokinetic parameters were estimated by using population pharmacokinetic modeling.
b14 heart transplant patients 26 to 124 days of age were included in the population pharmacokinetic model development.
c19 observations, some patients contributed more than one value.
dThere was one subject in this age group who received both a kidney and liver transplant. The pharmacokinetic profile for this subject has not been included in this table as it is not possible to determine whether the effects observed are from the kidney/liver transplant or neither.
eThe pharmacokinetic profiles for two subjects in this age group who received kidney transplants have not been included in this table as the data were determined to be non-evaluable.
Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of VALCYTE in elderly patients have not been established. Because elderly individuals frequently have a reduced glomerular filtration rate, renal function should be assessed before and during administration of VALCYTE [see DOSAGE AND ADMINISTRATION, Use in Specific Populations].
In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for VALCYTE [see DRUG INTERACTIONS].
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 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 14 and Table 15 provide a listing of established drug interaction studies with ganciclovir. Table 14 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 15 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.
Table 14 : Results of Drug
Interaction Studies with Ganciclovir: Effects of Coadministered Drug on
Ganciclovir Pharmacokinetic Parameters
|Coadministered Drug||Ganciclovir Dosage||N||Ganciclovir Pharmacokinetic (PK) Parameter|
|Zidovudine 100 mg every 4 hours||1000 mg every 8 hours||12||AUC ↓ 17 ± 25%
(range: -52% to 23%)
|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%)
|Mycophenolate Mofetil (MMF) 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)|
|Didanosine 200 mg every 12 hours administered 2 hours before ganciclovir||1000 mg every 8 hours||12||AUC ↓ 21 ± 17%
(range: -44% to 5%)
|Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir||1000 mg every 8 hours||12||No effect on ganciclovir PK parameters observed|
|IV ganciclovir 5 mg/kg twice daily||11||No effect on ganciclovir PK parameters observed|
|IV ganciclovir 5 mg/kg once daily||11||No effect on ganciclovir PK parameters observed|
|Trimethoprim 200 mg once daily||1000 mg every 8 hours||12||Ganciclovir renal clearance ↓ 16.3% Half-life ↑15%|
Table 15 : Results of Drug Interaction Studies with
Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of
|Coadministered Drug||Ganciclovir Dosage||N||Coadministered Drug Pharmacokinetic (PK) Parameter|
|Zidovudine 100 mg every 4 hours||1000 mg every 8 hours||12||AUC0-4 ↑ 19 ± 27%
(range: -11% to 74%)
|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)|
|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%)
|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%)
|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%)
|Trimethoprim 200 mg once daily||1000 mg every 8 hours||12||Increase (12%) in Cmin|
Other Potential Drug Interactions
Since ganciclovir is excreted through the kidney via glomerular filtration and active secretion [see Pharmacokinetics], coadministration of valganciclovir with antiretroviral drugs that share the tubular secretion pathway, such as nucleos(t)ide reverse transcriptase inhibitors, may change the plasma concentrations of valganciclovir and/or the coadministered drug.
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 CMV in cell culture 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 the viral DNA polymerase, pUL54, synthesis by ganciclovir triphosphate.
The quantitative relationship between the cell culture susceptibility of human herpes viruses 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% (EC50), vary greatly depending upon a number of factors including the assay used. Thus, the reported EC50 values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 μM (0.02 to 5.75 mcg/mL). The distribution and range in susceptibility observed in one assay evaluating 130 clinical isolates was 0 to 1 μM (35%), 1.1 to 2 μM (20%), 2.1 to 3 μM (27%), 3.1 to 4 μM (13%), 4.1 to 5 μM (5%), less than 5 μM (less than 1%). Ganciclovir inhibits mammalian cell proliferation (CC50) in cell culture at higher concentrations ranging from 40 to greater than 1,000 μM (10.21 to greater than 250 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC50 value = 2.7 to 12 μM (0.69 to 3.06 mcg/mL)].
Cell culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 (M460I/V, L595S, G598D, and K599T) and the viral DNA polymerase pUL54 (D301N, N410K, F412V, P488R, L516R, C539R, L545S, F595I, V812L, P829S, L862F, D879G, and V946L).
In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with valganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 16.
Table 16 : Summary of
Resistance-associated Amino Acid Substitutions Observed in the CMV of Patients
Failing Ganciclovir Treatment or Prophylaxis
|pUL97||L405P, A440V, M460I/V/T, V466G/M, C518Y, H520Q, del 590-593, A591D/V, C592G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y, A613V|
|pUL54||E315D, N408D/K/S, F412C/L/S, D413A/E, L501F/I, T503I, K513E/N/R, I521T, P522A/L/S, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, V781I, V787L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987G|
Note: Many additional pathways to ganciclovir resistance likely exist
The presence of known ganciclovir resistance-associated amino acid substitutions was evaluated in a study that extended valganciclovir CMV prophylaxis from 100 days to 200 days post-transplant in adult kidney transplant patients at high risk for CMV disease (D+/R-) [see Clinical Studies]. Five subjects from the 100 day group and four subjects from the 200 day group meeting the resistance analysis criteria had known ganciclovir resistance-associated amino acid substitutions detected. In six subjects, the following resistance-associated amino acid substitutions were detected within pUL97: 100 day group: A440V, M460V, C592G; 200 day group: M460V, C603W. In three subjects, the following resistance-associated amino acid substitutions were detected within pUL54: 100 day group: E315D, 200 day group: E315D, P522S. Overall, the detection of known ganciclovir resistance-associated amino acid substitutions was observed more frequently in patients during prophylaxis therapy than after the completion of prophylaxis therapy (during therapy: 5/12 [42%] versus after therapy: 4/58 [7%]). The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.
Cross-Resistance: Cross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region V. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 17.
Substitutions at amino acid positions pUL97 340-400 have been found to confer resistance to ganciclovir. Resistance data based on assays that do not include this region should be interpreted cautiously.
Table 17 : Summary of pUL54
Amino Acid Substitutions with Cross-Resistance between Ganciclovir, Cidofovir,
|Cross-resistant to cidofovir||D301N, N408D/K, N410K, F412C/L/S/V, D413E, L501I, T503I, K513E/N, L516R, I521T, P522S/A, L545S/W, Q578H, D588N, I726T/V, E756K, V812L, T813S, A834P, G841A, del 981-982, A987G|
|Cross-resistant to foscarnet||F412C, Q578H/L, D588N, E756K, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A, del 981-982|
Induction Therapy of CMV Retinitis
In one 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 per kg twice daily for 21 days, then 5 mg per 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 18 provides the outcomes at 4 weeks.
Table 18 : Week 4 Masked
Review of Retinal Photographs in CMV Retinitis Study
|Intravenous Ganciclovir||VALCYTE Tablets|
|Determination of CMV retinitis progression at Week 4||N=80||N=80|
|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 tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label VALCYTE tablets after Week 4. However, the AUC for ganciclovir is similar following administration of 900 mg VALCYTE tablets once daily and 5 mg per kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following VALCYTE tablets 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 tablets 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, or Liver Transplantation
A double blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, or kidney-pancreas transplant patients at high risk for CMV disease (D+/R-). Patients were randomized (2 VALCYTE: 1 oral ganciclovir) to receive either VALCYTE tablets (900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 post-transplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue-invasive disease during the first 6 months post-transplant was similar between the VALCYTE tablets 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 19.
Mortality at six months was 3.7% (9/244) in the VALCYTE group and 1.6% (2/126) in the oral ganciclovir group.
Table 19 : Percentage of Patients with CMV Disease,
Tissue-Invasive CMV Disease or CMV syndrome by Organ Type: Endpoint Committee,
6 Month ITT Population
|Organ||CMV Disease1||Tissue-Invasive CMV Disease||CMV Syndrome2|
(22 / 118)
(7 / 59)
(16 / 118)
(2 / 59)
(6 / 118)
(5 / 59)
(5 / 81)
(9 / 39)
(1 / 81)
(2 / 39)
(4 / 81)
(7 / 39)
(2 / 35)
(2 / 21)
(0 / 35)
(1 / 21)
(2 / 35)
(1 / 21)
|Kidney / Pancreas (n=11)||0%
(0 / 5)
(1 / 6)
(0 / 5)
(1 / 6)
(0 / 5)
(0 / 6)
|GCV = oral ganciclovir; VGCV =
1Number of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome
2CMV syndrome was defined as evidence of CMV viremia accompanied with fever greater than or equal to 38°C on two or more occasions separated by at least 24 hours within a 7-day period and one or more of the following: malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases
Prevention of CMV Disease in Kidney Transplantation
A double-blind, placebo-controlled study was conducted in 326 kidney transplant patients at high risk for CMV disease (D+/R-) to assess the efficacy and safety of extending VALCYTE CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive VALCYTE tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. Extending CMV prophylaxis with VALCYTE until Day 200 post-transplant demonstrated superiority in preventing CMV disease within the first 12 months post-transplant in high risk kidney transplant patients compared to the 100 day dosing regimen (primary endpoint). These results are summarized in Table 20.
Table 20 : Percentage of
Kidney Transplant Patients with CMV Disease, Tissue-Invasive CMV Disease or CMV
Syndrome, 12 Month ITT Population
|CMV Disease1||Tissue-Invasive CMV Disease||CMV Syndrome2|
|100 Days VGCV
|200 Days VGCV
|100 Days VGCV
|200 Days VGCV
|100 Days VGCV
|200 Days VGCV
|Cases||36.8% (60/163)||16.8% (26/155)||1.8% (3/163)3||0.6% (1/155)||35. 0% (57/163)||16.1% (25/155)|
|VGCV = valganciclovir.
1Number of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome
2CMV syndrome was defined as evidence of CMV viremia accompanied with at least one of the following: fever (greater than or equal to 38°C), severe malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases
3Two patients in the 100 day group had both tissue-invasive CMV disease and CMV syndrome; however, these patients are counted as having only tissue-invasive CMV disease.
The percentage of kidney transplant patients with CMV disease at 24 months post-transplant was 38.7% (63/163) for the 100 day dosing regimen and 21.3% (33/155) for the 200 day dosing regimen.
Prevention of CMV in Pediatric Heart, Kidney, or Liver Transplantation
Sixty-three children, 4 months to 16 years of age, who had a solid organ transplant (kidney 33, liver 17, heart 12, and kidney/liver 1) and were at risk for developing CMV disease, were enrolled in an open-label, safety, and pharmacokinetic study of oral VALCYTE (VALCYTE for oral solution or tablets). Patients received VALCYTE once daily within 10 days after transplant until a maximum of 100 days post-transplant. The daily doses of VALCYTE were calculated at each study visit based on body surface area and a modified creatinine clearance [see DOSAGE AND ADMINISTRATION].
The pharmacokinetics of ganciclovir were similar across organ transplant types and age ranges. The mean daily ganciclovir exposures in pediatric patients were somewhat increased relative to those observed in adult solid organ transplant patients receiving VALCYTE 900 mg once daily, but were within the range considered safe and effective in adults [see CLINICAL PHARMACOLOGY]. No case of CMV syndrome or tissue-invasive CMV disease was reported within the first six months post-transplantation.
Prevention of CMV in Pediatric Kidney Transplantation
Fifty-seven children, 1 to 16 years of age, who had a renal transplant and were at risk for developing CMV disease, were enrolled in an open-label tolerability study of oral VALCYTE (VALCYTE for oral solution or tablets). Patients received VALCYTE once daily within 10 days after transplant until a maximum of 200 days post-transplant. The daily doses of VALCYTE were calculated at each study visit based on body surface area and a modified creatinine clearance [see DOSAGE AND ADMINISTRATION]. No case of CMV syndrome or tissue-invasive CMV disease was reported within the first 12 months post-transplantation.
1. Brion, L.P., Fleischman, A.R., McCarton, C., Schwartz, G.J. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J of Ped 1986: 109(4): 698-707.
2. NIOSH . NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. By Connor T.H., MacKenzie B.A., DeBord D.G., Trout D.B., O'Callaghan J.P., Cincinnati, O.H.: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-138 (Supersedes 2012-150).
Last reviewed on RxList: 5/13/2015
This monograph has been modified to include the generic and brand name in many instances.
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