Valganciclovir Hydrochloride for Oral Solution contains valganciclovir hydrochloride, USP (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.
Valganciclovir is available as a powder blend for oral solution, which when constituted with water as directed contains 50 mg/mL valganciclovir free base. The inactive ingredients of valganciclovir hydrochloride for oral solution are mannitol, sodium benzoate, sucralose, tartaric acid and tutti-frutti flavoring.
Valganciclovir HCl, USP is a white to almost white powder. The chemical name for valganciclovir HCl, USP is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl, USP 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, USP is 7.6.
The chemical structure of valganciclovir HCl, USP is:
C14 H22 N6 O5 ·HCl M.W.390.83
All doses in this insert are specified in terms of valganciclovir.
Valganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)].
Valganciclovir is a prodrug of ganciclovir. Valganciclovir Cmax and AUC are approximately 1% and 3% of those of ganciclovir, respectively.
Pharmacokinetics in Adults: The pharmacokinetics of 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 (Table 10).
|PK parameter||N||Value (Mean ± SD)|
|AUC0-24h (mcg∙ h/mL)||57||29.1 ± 9.7|
|Cmax (mcg/mL)||58||5.61 ± 1.52|
|Absolute oral bioavailability (%)||32||59.4 ± 6.1|
|Elimination half-life (hr)||73||4.08 ± 0.76|
|Renal clearance (mL/min/kg)||20|| |
3.21 ± 0.75
*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 systemic ganciclovir exposures attained following administration of 900 mg valganciclovir tablets once daily were comparable across kidney, heart and liver transplant recipients (Table 11).
|Value (Mean ± SD)|
Heart Transplant Recipients(N=17)
|Liver Transplant Recipients (N=75)|| |
Kidney Transplant Recipients*(N=68)
|AUC0-24h (mcg· h/mL)||40.2 ± 11.8||46.0 ± 16.1||48.2 ± 14.6|
|Cmax (mcg/mL)||4.9 ± 1.1||5.4 ± 1.5||5.3 ± 1.5|
|Elimination half-life (hr)||6.58 ± 1.50||6.18 ± 1.42||6.77 ± 1.25|
* Includes kidney-pancreas
The pharmacokinetic parameters of ganciclovir following 200 days of valganciclovir administration in high-risk kidney transplant patients were similar to those in solid organ transplant patients who received valganciclovir for 100 days.
Absorption, Distribution, Metabolism, and Excretion
The pharmacokinetic (PK) properties of valganciclovir hydrochloride are provided in Table 12.
|Tmax (h) median (min-max) (fed conditions)||2.18 1.7h to 3.0h|
|Food effect (high fat meal/fasting): PK parameter ratio and 90% confidence intervala|| Cmax :1.14 (0.95, 1.36) |
AUC:1.30 (1.07, 1.51)amax : ↔
|% Bound to human plasma proteins (ex vivo)||Unknown||1 to 2% over 0.5-51 mcg/mL|
Cerebrospinal fluid penetration
|Hydrolyzed by intestinal and liver esterases||No significant metabolism|
|AUC was dose proportional under fed conditions across a valganciclovir dose range of 450 to 2625 mg|
|Major route of elimination||Metabolism to ganciclovir||Glomerular filtration and active tubular secretion|
|t1/2 (h)||See Tables 10 and 11|
|% Of dose excreted in urine||Unknown|
|% Of dose excreted in feces||Unknown|
a Steady state ganciclovir PK was assessed after administration of valganciclovir tablets (875 mg once daily) with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) to 16 HIV-positive subjects.
Renal Impairment: The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir hydrochloride tablets were evaluated in 24 otherwise healthy individuals with renal impairment. Decreased renal function results in decreased clearance of ganciclovir and increased terminal half-life (Table 13).
|Estimated||Apparent Clearance||AUC last||Half-life|
|Creatinine Clearance*||(mL/m i n)||(mcg · h/mL)||(hours)|
|(mL/min)||N||Mean ± SD||Mean ± SD||Mean ± S D|
|51 to 70||6||249 ± 99||49.5 ± 22.4||4.85 ± 1.4|
|21 to 50||6||136 ± 64||91.9 ± 43.9||10.2 ± 4.4|
|11 to 20||6||45 ± 11||223 ± 46||21.8 ± 5.2|
|≤10||6||12.8 ± 8||366 ± 66||67.5 ± 34|
*Creatinine clearance calculated from 24-hour urine collection.
Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following valganciclovir administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use valganciclovir hydrochloride tablets because the daily dose of valganciclovir hydrochloride tablets required for these patients is less than 450 mg [see Use in Specific Populations (8.6)].
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 valganciclovir hydrochloride for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration (2.3), Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Studies (14.2)].
In studies using the pediatric valganciclovir dosing algorithm, the pharmacokinetics of ganciclovir were similar across organ types and age ranges (Table 14). 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.
PK Parameter mean (SD)
< 4 months
4 months to ≤ 2 years
> 2 to < 12 years
≥ 12 years
AUC0-24h (mcg∙ h/mL)
| 9 |
N= number of patients, NA=not applicablea Ages ranged from 26 to 124 days.
Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of valganciclovir in elderly patients have not been established.
Drug Interactions: 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 valganciclovir [see Drug Interactions (7)].
Table 15 and Table 16 provide a listing of established drug interaction studies with ganciclovir. Table 15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.
|Ganciclovir Dosage||N|| |
Ganciclovir Pharmacokinetic (PK) Parameter
Mycophenolate mofetil (MMF) 1.5 g single dose
|5 mg/kg IV single dose||12||No effect on ganciclovir PK parameters observed (patients with normal renal function)|
|Trimethoprim 200 mg once daily||1000 mg every 8 hours||12||No effect on ganciclovir PK parameters observed|
|Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir||5 mg/kg IV twice daily||11||No effect on ganciclovir PK parameters observed|
|5 mg/kg IV once daily||11||No effect on ganciclovir PK parameters observed|
Probenecid 500 mg every 6 hours
|1000 mg every 8 hours||10|| |
AUC ↑ 53 ± 91%
(range: -14% to 299%)
Ganciclovir renal clearance ↓
22 ± 20%
|Ganciclovir Dosage||N|| |
Coadministered Drug Pharmacokinetic (PK) Parameter
Oral cyclosporine at therapeutic doses
|5 mg/kg infused over 1 hour every 12 hours||93||In a retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations.|
|Mycophenolate mofetil (MMF) 1.5 g single dose||5 mg/kg IV single dose||12||No PK interaction observed (patients with normal renal function)|
|Trimethoprim 200 mg once daily||1000 mg every 8 hours||12||No effect on trimethoprim PK parameters observed|
Didanosine 200 mg every 12 hours
|5 mg/kg IV twice daily||11|| |
AUC0-12 ↑70 ± 40% (range: 3% to 121%) Cmax ↑49 ± 48% (range: -28% to 125%)
|Didanosine 200 mg every 12 hours||5 mg/kg IV once daily||11||AUC0-12 ↑50 ± 26% (range: 22% to 110%) Cmax ↑36 ± 36% (range: -27% to 94%)|
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