Drug Interactions
It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. In addition, toxicity may be enhanced when ganciclovir is coadministered with other drugs known to be associated with renal impairment. Therefore, drugs known to be myelosuppressive or associated with renal impairment, such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, doxorubicin, amphotericin B, trimethoprim/sulfamethoxazole combinations, other nucleoside analogues, or hydroxyurea, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.
There was no evidence that introduction of ganciclovir affects the pharmacokinetics of cyclosporine based on the comparison of cyclosporine trough concentrations. However, there was some evidence of increases in the maximum serum creatinine value observed following initiation of ganciclovir therapy.
No statistically significant pharmacokinetic interaction was observed when stavudine and oral ganciclovir were given in combination.
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 and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.
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 | I.V. 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 | I.V. 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 | I.V. 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. |
Didanosine has been associated with pancreatitis. In three controlled trials, pancreatitis was reported in 2% of patients taking didanosine and CYTOVENE (ganciclovir sodium for injection) or ganciclovir capsules. The rates of pancreatitis were similar in the intravenous solution and capsule groups.
Other than laboratory abnormalities, concomitant treatment with zidovudine, didanosine, or zalcitabine did not appear to affect the type or frequency of reported adverse events, with the exception of moderately increased rates of diarrhea. Among patients taking CYTOVENE as ganciclovir sodium for injection or ganciclovir capsules, the diarrhea rates were 51% and 49% respectively with didanosine versus 39% and 35% respectively, without didanosine.
Valganciclovir is rapidly and extensively converted to ganciclovir; therefore interactions associated with ganciclovir will be expected for VALCYTE (valganciclovir hydrochloride). In a rat in situ model of intestinal permeability, there was no interaction of valacyclovir, didanosine, nelfinavir, cyclosporine, omeprazole and mycophenolate mofetil with valganciclovir.
Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. VALCYTE should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks.
Information for the Patient
Valcyte
Special Handling Instructions
Caution should be exercised in the handling of VALCYTE (valganciclovir hydrochloride) tablets or powder for oral solution. Tablets should not be broken or crushed. Since valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets (see Warnings and Precautions, Sexual Function/Reproduction). Avoid direct contact of broken or crushed tablets, powder or reconstituted solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with sterile water or plain water if sterile water is not available.
Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g. CSHP, 1997). Disposal of VALCYTE should follow provincial, municipal, and local hospital guidelines or requirements.
Dosage and Administration
For patients with active CMV retinitis, the recommended dosage is 900 mg twice a day (with food) for 21 days. Prolonged induction treatment may increase the risk of bone marrow toxicity (see Warnings and Precautions, Hematologic).
VALCYTE should be administered orally, and should be taken with food (see Action and Clinical Pharmacology, Absorption).
The missed dose should be taken as soon as remembered, then the regular dosing schedule should be continued. Two doses of VALCYTE should not be taken at the same time.
Dosage reductions in renally impaired patients are required for VALCYTE (see Renal Impairment). Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see Adverse Reactions). VALCYTE should not be administered in patients with severe neutropenia (ANC less than 500/μL), severe thrombocytopenia (platelets less than 25 000/μL), or severe anemia (hemoglobin less than 80 g/L).
Valcyte Oral Solution Dose for Patients with Impaired Renal Function
| CrCla (mL/min) | Treatment of CMV Retinitis | Prophylaxis of CMV Disease in Solid Organ Transplantation
VALCYTE Oral Solution |
Induction Dose
VALCYTE Oral Solution | Maintenance Dose
VALCYTE Oral Solution |
| ≥60 | 900 mg twice daily | 900 mg once daily | 900 mg once daily |
| 40–59 | 450 mg twice daily | 450 mg once daily | 450 mg once daily |
| 25–39 | 450 mg once daily | 225 mg once daily | 225 mg once daily |
| 10–24 | 225 mg once daily | 125 mg once daily | 125 mg once daily |
| <10 | 200 mg (three times a week after dialysis) | 100 mg (three times a week after dialysis) | 100 mg (three times a week after dialysis) |
a. An estimated creatinine clearance can be related to serum creatinine by the following formulas.
| For males | = | (140−age [years])×(body weight [kg]) |
| (72)×(0.011×serum creatinine [micromol/L]) |
| For females | = | 0.85×male value |
Measure 91 mL of purified water in a graduated cylinder.
Remove the child resistant cap and add the water to the bottle. Shake the closed bottle until the powder is dissolved.
Remove the child resistant cap and push the bottle adapter into the neck of the bottle.
Close bottle with child resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.
Write the date of expiration of the reconstituted solution on the bottle label. The shelf-life of the reconstituted solution is 49 days when stored at 2 to 8°C (see Storage and Stability).
Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g. CSHP, 1997) (see Special Handling Instructions).
Serum creatinine or creatinine clearance levels should be monitored carefully. Dosage adjustment is required according to creatinine clearance as shown in Table 6 and Table 7 (see Warnings and Precautions, Renal and Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency).
The dose-reduction algorithm was based on predicted ganciclovir exposures. The range of exposures in renally impaired patients may be greater than in renally sufficient patients. Thus, increased monitoring for cytopenias may be warranted in patients with renal impairment (see Warnings and Precautions, Monitoring and Laboratory Tests).
VALCYTE powder for oral solution requires reconstitution prior to oral administration. An oral dosing dispenser with 25 mg graduations up to 500 mg is provided with the powder for oral solution. It is recommended that this dispenser is used to measure and administer the dose.
Since VALCYTE is considered a potential teratogen and carcinogen in humans, caution should be observed in handling the powder and the reconstituted solution. Avoid direct contact of the powder and solution with skin and mucous membranes. If such contact occurs, wash thoroughly with soap and water. If the powder or solution gets into the eyes, rinse eyes thoroughly with sterile water or plain water if sterile water is not available (see Special Handling Instructions).
It is recommended that VALCYTE powder for oral solution be reconstituted by the pharmacist prior to dispensing to the patient.
Adverse Reactions
hematuria present, impotence, renal failure, urinary frequency.
Adverse reactions from post-marketing spontaneous reports with intravenous and oral ganciclovir not mentioned in any section above, and for which a causal relationship cannot be excluded are listed below. As VALCYTE is rapidly and extensively converted to ganciclovir, such adverse events might also occur with VALCYTE.
Adverse events that have been reported during the post-marketing period are consistent with those seen in clinical trials with VALCYTE and ganciclovir. For a full listing of ganciclovir post-marketing adverse events please refer to the current CYTOVENE product monograph.
musculoskeletal pain, myasthenic syndrome.
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
potentially life-threatening bleeding associated with thrombocytopenia.
amblyopia, blindness, earache, eye hemorrhage, eye pain, deafness, glaucoma, taste disturbance, tinnitus, vision abnormal, vitreous disorder.
blood alkaline phosphatase increased, blood creatine phosphokinase increased, blood glucose decreased, blood lactic dehydrogenase increased, diabetes mellitus, hypoproteinemia.
abnormal dreams, amnesia, ataxia, coma, dry mouth, emotional disturbance, hyperkinetic syndrome, hypertonia, libido decreased, myoclonic jerks, nervousness, somnolence, thinking abnormal.
alopecia, dry skin, sweating increased, urticaria.
valganciclovir hypersensitivity.
arrhythmia (including ventricular arrhythmia), migraine, phlebitis, tachycardia, thrombophlebitis deep, vasodilatation.
convulsion, psychotic disorder, hallucinations, confusion, agitation.
cholangitis, dysphagia, eructation, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal disorder, gastrointestinal hemorrhage, mouth ulceration, pancreatitis, tongue disorder.
decreased creatinine clearance.
VALCYTE is rapidly converted to ganciclovir. Key adverse events reported with ganciclovir, and not mentioned above, are listed below. However, for a full listing of ganciclovir adverse reactions please refer to the current CYTOVENE product monograph.
Valganciclovir is a prodrug of ganciclovir, and is rapidly converted to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir usage can therefore be expected to occur with VALCYTE (valganciclovir hydrochloride). All of the adverse events observed in clinical studies of VALCYTE have been previously observed with ganciclovir.
Severe neutropenia (<500 ANC/µL) is seen more frequently in CMV retinitis patients (19%) undergoing treatment with valganciclovir than in solid organ transplant patients receiving valganciclovir (5%) or oral ganciclovir (3%). There was a greater increase in serum creatinine seen in solid organ transplant patients with both valganciclovir and oral ganciclovir when compared to CMV retinitis patients. Impaired renal function is a feature common to solid organ transplantation patients.
eosinophilia, leukocytosis, splenomegaly.
asthenia, bacterial, fungal and viral infections, hemorrhage, malaise, mucous membrane disorder, photosensitivity reaction, rigors, sepsis.
pancytopenia, bone marrow depression, aplastic anemia.
Indications and Clinical Use
VALCYTE (valganciclovir hydrochloride) is indicated for:
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the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).
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the prevention of cytomegalovirus (CMV) disease in solid organ transplant patients at risk. This indication is based on a double-blind, double-dummy, active comparator study in heart, liver, kidney and kidney-pancreas transplant patients at high risk for CMV disease (donor CMV seropositive/recipient seronegative [D+/R-] (see Warnings and Precautions for information on specific solid organ transplant subgroups).
Overdosage
worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine.
Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. In some of these cases no adverse reactions were reported. The majority of patients experienced one or more of the following adverse reactions:
generalized tremor, convulsion.
hepatitis, liver function disorder.
pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia.
abdominal pain, diarrhea, vomiting.
Dosage Forms, Composition and Packaging
Each bottle of white to slightly yellow powder (granulate) contains: valganciclovir HCl 5.5 g (corresponding to valganciclovir 5 g), in 12 g powder for oral solution. Following reconstitution, 1 mL solution contains: valganciclovir HCl 55 mg corresponding to valganciclovir 50 mg (free base). Nonmedicinal ingredients: fumaric acid, mannitol, povidone K30, sodium benzoate, sodium saccharin and tutti-frutti flavour (maltodextrins (maize), propylene glycol, arabic gum and natural identical flavouring substances mainly consisting of banana, pineapple, and peach flavour). Cartons containing an amber glass bottle with child-resistant plastic screw cap, a bottle adapter and a sealed bag containing 2 oral dispensers. Each bottle contains 12 g of powder for oral solution. When reconstituted, the volume of the solution is 100 mL, providing a minimal usable volume of 88 mL.
Each pink, convex, oval, film-coated tablet with “VGC” on one side and “450” on the other side contains: valganciclovir HCl 496.3 mg (corresponding to valganciclovir 450 mg). Nonmedicinal ingredients: crospovidone, microcrystalline cellulose, povidone K-30 and stearic acid powder; Opadry Pink film-coat: hydroxypropyl methylcellulose, polyethylene glycol 400/macrogol, polysorbate 80, synthetic red iron oxide and titanium dioxide. Plastic bottles of 60.
Warnings and Precautions
Dosage adjustment is necessary for patients on hemodialysis (CrCl <10 mL/min) (see Dosage and Administration, Dosing Considerations, Recommended Dose and Dosage Adjustment and Action and Clinical Pharmacology, Special Populations and Conditions, Hemodialysis).
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. Such adjustments should be based on measured or estimated creatinine clearance values (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).
The pharmacokinetic profiles of VALCYTE in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of VALCYTE (see Dosage and Administration).
Clinical studies of VALCYTE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. VALCYTE is known to be substantially excreted by the kidney, 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 Warnings and Precautions and Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency and Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).
VALCYTE 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 80 g/L. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with VALCYTE tablets (and ganciclovir) (see Warnings and Precautions, Monitoring and Laboratory Tests, Adverse Reactions and Dosage and Administration, Dosing Considerations).
VALCYTE should, therefore, be used with caution in patients with pre-existing cytopenias, or who have received or 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. Colony-stimulating factors have been shown to increase neutrophil counts in patients receiving ganciclovir for treatment of CMV retinitis.
No long-term carcinogenicity studies have been conducted with valganciclovir. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, valganciclovir is a potential carcinogen.
The clinical toxicity of VALCYTE (valganciclovir hydrochloride) includes granulocytopenia, anemia and thrombocytopenia. In animal and in-vitro studies ganciclovir was mutagenic, carcinogenic, teratogenic and caused aspermatogenesis. Therefore it should be considered a potential teratogen and carcinogen in humans. VALCYTE is indicated for use only in immunocompromised patients, where the potential benefit outweighs the risks. Safety and efficacy of VALCYTE have not been established for congenital or neonatal CMV disease; nor for the treatment of established CMV disease other than retinitis; nor for use in non-immunocompromised individuals.
Strict adherence to dosage recommendations is essential to avoid overdose.
Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving VALCYTE (see Adverse Reactions), 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. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, it is recommended that treatment with hematopoietic growth factors and/or dose interruption be considered. 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, Recommended Dose and Dosage Adjustment, Renal Impairment).
The safety and efficacy of VALCYTE for the prevention of CMV disease in other SOT patients not mentioned in the Indications and Clinical Use section, such as lung transplant patients, have not been established.
In an unpowered subanalysis of the SOT study, PV16000, there was a higher incidence of tissue-invasive CMV disease in liver transplant patients treated with VALCYTE compared with the oral ganciclovir group. The clinical significance of this is unknown.
Safety and efficacy of VALCYTE in children have not been established. The use of VALCYTE in children warrants extreme caution due to the probability of long-term carcinogenicity and reproductive toxicity. Administration to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh these considerable risks.
VALCYTE has not been studied in pediatric patients, and the pharmacokinetic characteristics of VALCYTE in this population are not known.
There are no adequate and well-controlled studies in pregnant women. VALCYTE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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. It is considered probable that in humans, valganciclovir at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Animal data also indicate that suppression of fertility in females may occur.
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.
In animal studies, ganciclovir was found to be mutagenic and carcinogenic. Valganciclovir should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see Special Handling Instructions).
It is not known whether ganciclovir or valganciclovir is excreted in human milk. However, many drugs are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely. Mothers should be instructed to discontinue the drug or discontinue nursing if they are receiving VALCYTE.
Storage and Stability
Do not store dry powder above 30°C. Store reconstituted solution in a refrigerator at 2 to 8°C. After reconstitution with purified water the solution should not be used for longer than 49 days. For preparation of the reconstituted medicinal product see Dosage and Administration, Reconstitution of Oral Solution.
Store in tightly closed container between temperatures of 15 and 30°C.
Action and Clinical Pharmacology
No studies of VALCYTE have been conducted in adults older than 65 years of age (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).
Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir was 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 0.680±0.161 L/kg (n=114).
After administration of VALCYTE tablets, no correlation was observed between ganciclovir AUC and weight; oral dosing of VALCYTE according to weight is not required.
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 food was approximately 60% (3 studies, n=18; n=16; n=28). Dose proportionality with respect to ganciclovir AUC following administration of VALCYTE tablets in the dose range 450 to 2625 mg was demonstrated only under fed conditions. Systemic exposure to the prodrug, valganciclovir, was transient and low, and the AUC24 and Cmax values were approximately 1% and 3% of those of ganciclovir, respectively.
When VALCYTE tablets were administered with food at a dose of 900 mg, the area under the plasma concentration time curve (AUC) over 24 hours was 28.0±8.9 μg·h/mL (n=75), and the maximum plasma concentration (Cmax) was 5.37±1.53 μg/mL (n=76).
Following the administration of valganciclovir as an oral solution, equivalent systemic ganciclovir exposures were obtained compared to the tablet formulation.
Valganciclovir is an L-valyl ester salt (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 herpes viruses in vitro and in vivo.
In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, UL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly. This has been shown to occur in CMV-infected cells (half-life 18 hours) and HSV-infected cells (half-life between 6 and 24 hours) after removal of extracellular ganciclovir. 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: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.
The median concentration of ganciclovir that inhibits CMV replication (IC50) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.58 μg/mL (0.08 to 14.32 μM). Ganciclovir inhibits mammalian cell proliferation (CIC50) 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 (CIC50 0.69 to 3.06 μg/mL; 2.7 to 12 μM). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.
Insufficient data are available to demonstrate any effect of race on the pharmacokinetics of valganciclovir.
When VALCYTE tablets were administered with a meal containing 569 calories (31.1 g fat, 51.6 g carbohydrates, and 22.2 g protein) at a dosage 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). Therefore it is recommended that VALCYTE be administered with food (see Dosage and Administration).
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 3.05±0.81 mL/min/kg (n=86) while renal clearance was 2.40±0.93 mL/min/kg (n=46).
The terminal half-life (t½) of ganciclovir following oral administration of VALCYTE tablets to either healthy or HIV-positive/CMV-positive subjects was 4.18±0.80 hours (n=244), and that following administration of intravenous ganciclovir was 3.85±0.74 hours (n=87). In liver transplant recipients, the t½ of ganciclovir after oral administration of VALCYTE tablets (900 mg dose) was 5.10±1.10 hours (n=28), compared to 5.17±1.39 hours (n=27) after intravenous administration of ganciclovir.
Insufficient data are available to demonstrate any effect of gender on the pharmacokinetics of valganciclovir.
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.
For patients receiving hemodialysis (CrCl <10 mL/min) VALCYTE powder for oral solution is recommended to provide an individualized dose (see Warnings and Precautions, Patients Undergoing Hemodialysis and Dosage and Administration, Dosing Considerations and Recommended Dose and Dosage Adjustment).
Decreased renal function resulted in decreased clearance of ganciclovir from valganciclovir, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients (see Warnings and Precautions, Renal and Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).
The pharmacokinetic characteristics of VALCYTE in pediatric patients have not been established (see Warnings and Precautions, Special Populations, Pediatrics).
Contraindications
VALCYTE (valganciclovir hydrochloride) is contraindicated in patients with known hypersensitivity to valganciclovir, ganciclovir or to any component of the product (see Dosage Forms, Composition and Packaging).
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Due to the similarity of the chemical structure of valganciclovir and that of acyclovir and valacyclovir, a cross-hypersensitivity reaction between these drugs is possible.
