Valganciclovir Solution
Name: Valganciclovir Solution
- Valganciclovir Solution tablet
- Valganciclovir Solution drug
- Valganciclovir Solution 5 mg
- Valganciclovir Solution dosage
- Valganciclovir Solution 50 mg
- Valganciclovir Solution 900 mg
- Valganciclovir Solution oral dose
- Valganciclovir Solution action
- Valganciclovir Solution effects of
- Valganciclovir Solution the effects of
Indications and usage
1.2 Pediatric Patients
Prevention of CMV Disease: Valganciclovir hydrochloride is indicated for the prevention of CMV disease in heart transplant patients (4 months to 16 years of age) at high risk [see Clinical Studies (14.2)].
Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Drug interactions
In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for valganciclovir. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.
| Name of the | Change in the Concentration of Ganciclovir or Concomitant Drug | Clinical Comment |
| Zidovudine | ↓ Ganciclovir ↑ Zidovudine | Zidovudine and Valganciclovir each have the potential to cause neutropenia and anemia |
| Probenecid | ↑ Ganciclovir | Patients taking probenecid and Valganciclovir should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) | ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) | Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine | ↓ Ganciclovir ↑ Didanosine | Patients should be closely monitored for didanosine toxicity |
Use in specific populations
8.1 Pregnancy
Risk Summary
After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, valganciclovir 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 valganciclovir 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 (5.3), Use in Specific Populations (8.3)].
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.
8.2 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 valganciclovir 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 (5.1, 5.2, 5.3, 5.4), Nonclinical Toxicology (13.1)].
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Females of reproductive potential should undergo pregnancy testing before initiation of valganciclovir [see Use in Specific Populations (8.1)].
Contraception
Females
Because of the mutagenic and teratogenic potential of valganciclovir, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir [see Dosage and Administration (2.6), Warnings and Precautions (5.3, 5.4), Nonclinical Toxicology (13.1)].
Males
Because of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following, treatment with valganciclovir [see Dosage and Administration (2.6), Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)].
Infertility
Valganciclovir at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
Valganciclovir hydrochloride for oral solution and tablets are indicated for the prevention of CMV disease in pediatric heart transplant patients 4 months to 16 years of age at risk for developing CMV disease [see Indications and Usage (1.2), Dosage and Administration (2.3)].
Study 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). Valganciclovir was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation.
The use of valganciclovir hydrochloride for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 4 months 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 (12.3), Clinical Studies (14.2)]. Study 3 was a pharmacokinetic and safety study of valganciclovir hydrochloride for oral solution in pediatric heart transplant patients less than 4 months of age who received a single dose of valganciclovir hydrochloride for 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, valganciclovir hydrochloride for oral solution is not indicated for prophylaxis in this age group.
The safety and efficacy of valganciclovir hydrochloride 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 valganciclovir hydrochloride 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 valganciclovir hydrochloride 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 valganciclovir hydrochloride 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 valganciclovir hydrochloride tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of valganciclovir hydrochloride for oral solution 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.
Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
8.5 Geriatric Use
Studies of valganciclovir hydrochloride for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of valganciclovir 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. Valganciclovir hydrochloride 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 (2.5), Warnings and Precautions (5.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
8.6 Renal Impairment
Dose reduction is recommended when administering Valganciclovir to patients with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].
For adult patients on hemodialysis (CrCl less than 10 mL/min) valganciclovir hydrochloride 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 (2.5) and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
The safety and efficacy of valganciclovir have not been studied in patients with hepatic impairment.
Description
Valganciclovir hydrochloride for oral solution contains valganciclovir hydrochloride (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.
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 sodium benzoate, sucralose, tartaric acid, mannitol and tutti-frutti flavoring.
Valganciclovir HCl is a white to almost white 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.
Clinical pharmacology
12.1 Mechanism of Action
Valganciclovir is an antiviral drug [see Microbiology (12.4)].
12.3 Pharmacokinetics
Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for valganciclovir hydrochloride for oral solution [see Dosage and Administration (2.5)].
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 valganciclovir hydrochloride 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.
| Formulation | Valganciclovir Hydrochloride 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 (mcg·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 (mcg/mL) | 5.61 ± 1.52 (3 studies, n=58) | 9.46 ± 2.02 (4 studies, n=68) | Range of means |
| 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 valganciclovir hydrochloride 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 valganciclovir hydrochloride 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 valganciclovir hydrochloride and intravenous ganciclovir. The ganciclovir Cmin following intravenous ganciclovir and valganciclovir hydrochloride administration are less than the ganciclovir Cmin following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics after administration of valganciclovir hydrochloride 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 valganciclovir hydrochloride 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).
| Parameter | Ganciclovir Capsules | Valganciclovir Hydrochloride Tablets |
| Dosage | 1000 mg three times daily with food Mean ± SD | 900 mg once daily with food Mean ± SD |
| Heart Transplant Recipients AUC0-24h (mcg·h/mL) Cmax (mcg/mL) Elimination half-life (hr) | N=13 26.6 ± 11.6 1.4 ± 0.5 8.47 ± 2.84 | N=17 40.2 ± 11.8 4.9 ± 1.1 6.58 ± 1.50 |
| Liver Transplant Recipients AUC0-24h (mcg·h/mL) Cmax (mcg/mL) Elimination half-life (hr) | N=33 24.9 ± 10.2 1.3 ± 0.4 7.68 ± 2.74 | N=75 46.0 ± 16.1 5.4 ± 1.5 6.18 ± 1.42 |
| Kidney Transplant Recipients* AUC0-24h (mcg·h/mL) Cmax (mcg/mL) Elimination half-life (hr) | N=36 31.3 ± 10.3 1.5 ± 0.5 9.44 ± 4.37 | N=68 48.2 ± 14.6 5.3 ± 1.5 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 previously reported in solid organ transplant patients who received valganciclovir 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).
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 valganciclovir hydrochloride 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 valganciclovir hydrochloride tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir hydrochloride 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 valganciclovir hydrochloride 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). Valganciclovir hydrochloride should be administered with food [see Dosage and Administration (2.1)].
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 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 valganciclovir hydrochloride tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of valganciclovir hydrochloride 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 valganciclovir hydrochloride 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 valganciclovir was 6.48 ± 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 ± 3.62 hours.
Specific Populations:
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.
| Estimated | Apparent Clearance | AUClast | Half-life | |
| Creatinine Clearance | (mL/min) | (mcg·h/mL) | (hours) | |
| (mL/min) | N | Mean ± SD | Mean ± SD | 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 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 Dosage and Administration (2.5) and 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. 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)].
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 (2.5 )]. 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.
| Organ | PK Parameter mean (SD) | Age Group | ||
| 4 months to ≤ 2 years | > 2 to < 12 years | ≥ 12 years | ||
| Heart (N=26) | N AUC0-24h Cmax (mcg/mL) t1/2 (h) | 6 55.4 (22.8) 8.2 (2.5) 3.8 (1.7) | 2 59.6 (21.0) 12.5 (1.2) 2.8 (0.9) | 4 60.6 (25.0) 9.5 (3.3) 4.9 (0.8) |
| Kidney (N=31) | N AUC0-24h Cmax (mcg/mL) t1/2 (h) | 2 67.6 (13.0) 10.4 (0.4) 4.5 (1.5) | 10d,e 55.9 (12.1) 8.7 (2.1) 4.8 (1.0) | 19 47.8 (12.4) 7.7 (2.1) 6.0 (1.3) |
| Liver (N=17) | N AUC0-24h (mcg∙h/mL) Cmax (mcg/mL) t1/2 (h) | 9 69.9 (37.0) 11.9 (3.7) 2.8 (1.5) | 6 59.4 (8.1) 9.5 (2.3) 3.8 (0.7) | 2 35.4 (2.8) 5.5 (1.1) 4.4 (0.2) |
N= number of patients
aPharmacokinetic parameters were estimated by using population pharmacokinetic modeling
d There 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.
e The 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 valganciclovir 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 valganciclovir [see Dosage and Administration (2.5), Use in Specific Populations (8.5)].
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)].
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 valganciclovir 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.
| Coadministered Drug | Ganciclovir | 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% |
| 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% Cmax ↑ 49 ± 48% |
| Didanosine 200 mg every 12 hours | IV ganciclovir 5 mg/kg once daily | 11 | AUC0-12 ↑ 50 ± 26% Cmax ↑ 36 ± 36% |
| 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 (12.3)], 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.
Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
12.4 Microbiology
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.
Antiviral Activity: 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)].
Viral Resistance:
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.
| 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 (14.1)]. 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.
| 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 |
How supplied/storage and handling
Valganciclovir hydrochloride for Oral Solution: Supplied as a white to off-white powder blend for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution. Each bottle can deliver up to a total of 88 mL of solution. Each bottle is supplied with a bottle adapter and 2 oral dispensers (NDC 0591-2579-20)
Prior to dispensing to the patient, valganciclovir hydrochloride for oral solution must be prepared by the pharmacist [see Dosage and Administration (2.4)].
Store dry powder at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].
Store constituted solution under refrigeration at 2° to 8°C (36° to 46°F) for no longer than 49 days. Do not freeze.