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    Other Systemic Antivirals

    BOXED WARNING

    Anemia, aplastic anemia, bone marrow suppression, neutropenia, radiation therapy, thrombocytopenia

    Use caution when administering valganciclovir to patients with bone marrow suppression or to those who are receiving other myelosuppressive chemotherapy or radiation therapy. Avoid use if the absolute neutrophil count (ANC) is less than 500/mm3, the platelet count is less than 25,000/mm3, or hemoglobin is less than 8 g/dL. Severe anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and bone marrow failure, including aplastic anemia, have been reported during valganciclovir therapy. Cytopenia may occur at any time during treatment and may worsen with continued dosing; typically, cell counts will begin to recover 3 to 7 days after treatment discontinuation. Frequently monitor complete blood and platelet counts, especially in patients with impaired renal function, an ANC less than 1000/mm3 at baseline, or in whom ganciclovir or other nucleoside analogs have previously caused leukopenia. Increased monitoring for bone marrow suppression may be warranted when therapy is changed from oral ganciclovir to valganciclovir, because of the increased plasma concentrations of ganciclovir after valganciclovir administration. Consider treatment with hematopoietic growth factors in patients with severe leukopenia, neutropenia, anemia, or thrombocytopenia.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, valganciclovir is considered a potential teratogen in humans because animal studies found ganciclovir to be mutagenic and teratogenic at doses recommended for human use. Because valganciclovir is a prodrug of ganciclovir, similar toxicity is expected. Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta via passive diffusion. Pregnancy should be avoided by females taking valganciclovir and by females with male partners taking valganciclovir. At doses resulting in two-times the human exposure of ganciclovir (based on human AUC after a single IV dose of 5 mg/kg of ganciclovir), maternal and embryofetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits were observed. Fetal resorptions were present in 85% or more of rabbits and mice. Increased embryofetal mortality was seen in rabbits as well as 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 toxicity was also seen in mice. At daily IV doses of approximately 1.7-times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation, hypoplasia of the testes and seminal vesicles of the male offspring, as well as pathologic changes in the nonglandular region of the stomach were observed.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Valganciclovir is associated with reproductive risk. Valganciclovir can be teratogenic if taken by the father near the time of conception (male-mediated teratogenicity) or by the mother during pregnancy. Discuss contraception requirements with the patient. Females should use effective contraception during and for at least 30 days after treatment with valganciclovir. Males must use a condom during and for at least 90 days after treatment. Females of reproductive potential should undergo pregnancy testing prior to initiation of valganciclovir. In addition, based on animal data with ganciclovir, valganciclovir may cause temporary or permanent inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses. Animal studies also indicate that suppression of fertility in females may occur.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antiviral agent; prodrug of ganciclovir
    Used for prevention and treatment of CMV
    Dose adjustment may be required for hematological toxicity (neutropenia, thrombocytopenia) and renal dysfunction

    COMMON BRAND NAMES

    Valcyte

    HOW SUPPLIED

    Valcyte/Valganciclovir/Valganciclovir Hydrochloride Oral Pwd F/Recon: 1mL, 50mg
    Valcyte/Valganciclovir/Valganciclovir Hydrochloride Oral Tab: 450mg

    DOSAGE & INDICATIONS

    For cytomegalovirus (CMV) disease prophylaxis in patients at high risk for CMV disease.
    NOTE: The FDA-approved labeling recommends that adults and adolescents older than 16 years should receive the oral tablet and not the oral solution. For pediatric patients, if the calculated dose is within 10% of the available tablet strength (450 mg), the oral tablet may be administered.
    For prophylaxis of CMV disease in kidney transplant patients.
    Oral dosage
    Adults and Adolescents 17 years

    900 mg PO once daily with food starting within 10 days of transplantation. Continue therapy until 200 days post-transplantation.

    Infants 4 months and older, Children, and Adolescents 13 to 16 years

    Dosage (mg) is calculated as 7 x BSA x CrCl and should be given PO as a single daily dose. The dosage is based on body surface area (BSA) using the Mostellar calculation and creatinine clearance (CrCl) derived from a modified Schwartz formula. Round the dose to the nearest 10 mg increment, and do not exceed 900 mg PO daily. Using the Mostellar equation, BSA (m2) = the square root of [(height (cm) x weight (kg)) / 3600]. CrCl (mL/minute/1.73 m2) = [k x height (cm)] / serum creatinine (mg/dL). A maximum value of 150 mL/minute/1.73 m2 should be used for CrCl to prevent overdosing pediatric patients with low body weight, low BSA, and low serum creatinine. The k used in the CrCl formula is based on age as follows: Infants younger than 1 year with low birth weight for gestational age: k = 0.33; Infants younger than 1 year with birth weight appropriate for gestational age: k = 0.45; Children 1 year of age: k = 0.45; Children 2 years and older: k = 0.55; Adolescent girls 13 to 16 years: k = 0.55; Adolescent boys 13 to 16 years: k = 0.7. Start within 10 days of transplantation and continue for 200 days post-transplantation. Valganciclovir has also been studied in pediatric liver transplant patients.

    For prophylaxis of CMV disease in heart transplant patients.
    Oral dosage
    Adults and Adolescents 17 years

    900 mg PO once daily with food starting within 10 days of transplantation. Continue therapy until 100 days post-transplantation.

    Infants, Children, and Adolescents 13 to 16 years

    Dosage (mg) is calculated as 7 x BSA x CrCl and should be given PO as a single daily dose. The dosage is based on body surface area (BSA) using the Mostellar calculation and creatinine clearance (CrCl) derived from a modified Schwartz formula. Round the dose to the nearest 10 mg increment, and do not exceed 900 mg PO daily. Using the Mostellar equation, BSA (m2) = the square root of [(height (cm) x weight (kg)) / 3600]. CrCl (mL/minute/1.73 m2) = [k x height (cm)] / serum creatinine (mg/dL). A maximum value of 150 mL/minute/1.73 m2 should be used for CrCl to prevent overdosing pediatric patients with low body weight, low BSA, and low serum creatinine. The k used in the CrCl formula is based on age as follows: Infants younger than 1 year with low birth weight for gestational age: k = 0.33; Infants younger than 1 year with birth weight appropriate for gestational age: k = 0.45; Children 1 year of age: k = 0.45; Children 2 years and older: k = 0.55; Adolescent girls 13 to 16 years: k = 0.55; Adolescent boys 13 to 16 years: k = 0.7. Start within 10 days of transplantation and continue until 100 days post-transplantation.

    For prophylaxis of CMV disease in kidney-pancreas transplant patients.
    Oral dosage
    Adults and Adolescents 17 years

    900 mg PO once daily with food starting within 10 days of transplantation. Continue therapy until 100 days post-transplantation.

    For primary prophylaxis of CMV disease in patients with HIV-infection†.
    Oral dosage

    NOTE: The HIV guidelines do not recommend primary prophylaxis in HIV-infected adult and adolescent patients, as end-organ disease is best prevented by using antiretroviral therapy to maintain CD4 counts greater than 100 cells/mm3. However, primary prophylaxis may be considered in HIV-infected children who are CMV antibody positive with severe immunosuppression (CD4 percentage less than 5% for children younger than 6 years and CD4 count less than 50 cells/mm3 for children 6 years and older).

    Infants and Children 4 months and older

    The mg dosage is calculated as 7 x BSA x CrCl and should be given as a single daily dose. The dosage is based on body surface area (BSA) using the Mostellar calculation and creatinine clearance (CrCl) derived from a modified Schwartz formula. Round the dose to the nearest 10 mg increment and do not exceed 900 mg PO daily. Using the Mostellar equation, BSA (m2) = the square root of [(height (cm) x weight (kg)) / 3600]. CrCl (mL/minute/1.73 m2) = [k x height (cm)] / serum creatinine (mg/dL). A maximum value of 150 mL/minute/1.73 m2 should be used for CrCl to prevent overdosing pediatric patients with low body weight, low BSA, and low serum creatinine. The k used in the CrCl formula is based on age as follows: Infants younger than 1 year with low birth weight for gestational age: k = 0.33; Infants younger than 1 year with birth weight appropriate for gestational age: k = 0.45; Children 1 year of age: k = 0.45; Children 2 years and older: k = 0.55. Primary prophylaxis may be discontinued in patients with a CD4 percentage more than 10% (children younger than 6 years) or CD4 count more than 100 cells/mm3 (children 6 years and older). Primary prophylaxis should be restarted for patients with a CD4 percentage less than 5% (children younger than 6 years) or CD4 count less than 50 cells/mm3 (children 6 years and older).

    For secondary cytomegalovirus (CMV) prophylaxis (maintenance therapy) after induction therapy in patients with HIV, including cytomegalovirus (CMV) retinitis prophylaxis and for maintenance therapy of CMV gastrointestinal disease† with relapse or neurological disease†.
    NOTE: For adults and adolescents, chronic maintenance therapy is indicated for retinitis. Chronic maintenance therapy is not routinely recommended for gastrointestinal disease, pneumonitis, or CNS disease unless there is concurrent retinitis or relapses have occurred. For infants and children, chronic maintenance therapy is indicated for retinitis, disseminated, CNS, or GI disease with relapse.
    Oral dosage
    Adults and Adolescents 17 years

    900 mg PO once daily is a preferred maintenance therapy after induction therapy. Treatment duration depends on the immune status of the patient. For HIV-infected patients who have had a sustained immune response to highly active antiretroviral therapy (i.e., CD4 counts greater than 100 cells/mm3 for 3 to 6 months), have been on CMV treatment for at least 3 to 6 months, and have no active lesions, secondary CMV retinitis prophylaxis may be discontinued after consultation with an ophthalmologist. Maintenance therapy should be restarted if subsequent CD4 counts drop to less than 100 cells/mm3, as relapse occurs most frequently in those patients whose counts decrease to less than 50 cells/mm3 after stopping treatment. However, because relapses may occur at any CD4 count, all patients who have had maintenance CMV therapy discontinued should continue to undergo regular ophthalmologic monitoring (every 3 months) for early detection of CMV relapse (as well as for immune reconstitution uveitis). For patients who experience progression of CMV retinitis while receiving maintenance therapy, re-induction treatment with the same drug used for maintenance followed by reinstitution of maintenance therapy is recommended.

    Infants 4 months and older†, Children†, and Adolescents 13 to 16 years†

    Dosage (mg) is calculated as 7 x BSA x CrCl and should be given PO as a single daily dose. The dosage is based on body surface area (BSA) using the Mostellar calculation and creatinine clearance (CrCl) derived from a modified Schwartz formula. Round the dose to the nearest 10 mg increment, and do not exceed 900 mg PO daily. Using the Mostellar equation, BSA (m2) = the square root of [(height (cm) x weight (kg)) / 3600]. CrCl (mL/minute/1.73 m2) = [k x height (cm)] / serum creatinine (mg/dL). A maximum value of 150 mL/minute/1.73 m2 should be used for CrCl to prevent overdosing pediatric patients with low body weight, low BSA, and low serum creatinine. The k used in the CrCl formula is based on age as follows: Infants younger than 1 year with low birth weight for gestational age: k = 0.33; Infants younger than 1 year with birth weight appropriate for gestational age: k = 0.45; Children 1 year of age: k = 0.45; Children 2 years and older: k = 0.55; Adolescent girls 13 to 16 years: k = 0.55; Adolescent boys 13 to 16 years: k = 0.7. Discontinuation of secondary prophylaxis may be considered in children who have received at least 6 months of highly active antiretroviral therapy with a sustained increase (more than 6 months) in CD4 percentage of at least 15% (children 1 to 5 years) or CD4 count more than 100 cells/mm3 (children 6 years and older). The decision to discontinue secondary prophylaxis should be made in consultation with an ophthalmologist. Routine follow-up (every 3 to 6 months) with an ophthalmologist is recommended. Restart maintenance therapy if CD4 percentage is less than 15% in children 1 to 5 years or if CD4 count is less than 100 cells/mm3 in children 6 years and older.

    For treatment of cytomegalovirus (CMV) infection in HIV-infected patients including cytomegalovirus (CMV) retinitis and cytomegalovirus (CMV)-associated gastrointestinal disease†, including esophagitis† and colitis†.
    NOTE: Valganciclovir tablets cannot be substituted for ganciclovir tablets on a one-to-one basis.
    Oral dosage
    Adults and Adolescents older than 16 years

    900 mg PO twice daily is the preferred systemic induction therapy. For immediate site-threatening lesions in CMV retinitis, HIV guidelines recommend adding 1 to 4 doses of intravitreal ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection) over a 7 to 10 day period. Treatment duration for CMV retinitis is 14 to 21 days; for patients with gastrointestinal disease the duration of therapy is 21 to 42 days, or until signs and symptoms have resolved. Chronic maintenance therapy (secondary prophylaxis) should start after induction therapy for retinitis; maintenance therapy is generally not required for GI disease, but should be considered in patients with relapses.

    For the treatment of CNS dysfunction or encephalitis† caused by human herpesvirus 6 (HHV-6) infection†.
    Oral dosage
    Adults

    900 mg PO twice daily for 3 weeks, followed by 900 mg PO once daily based on very limited data from case reports/case series in adults and adolescents. Duration of treatment is not well established. One case series reported a total duration of therapy of 6 months. Other case reports describe a treatment duration range as short as 6 weeks to as long as 18 months.

    Adolescents

    900 mg PO twice daily for 3 weeks, followed by 900 mg PO once daily based on very limited data from case reports/case series in adults and adolescents. Duration of treatment is not well established. One case series reported a total duration of therapy of 6 months. Other case reports describe a treatment duration range as short as 6 weeks to as long as 18 months.

    For the treatment of diseases associated with human herpesvirus 8 (HHV-8) infection† in HIV-infected patients, including multicentric Castleman disease† (MCD).
    For multicentric Castleman disease† (MCD).
    Oral dosage
    Adults and Adolescents

    900 mg PO twice daily for 3 weeks is recommended by the HIV guidelines. Additionally, a combination of valganciclovir plus high dose zidovudine for 7 to 21 days led to durable clinical remissions of the disease.

    For primary effusion lymphoma† (PEL).
    Oral dosage
    Adults and Adolescents

    The HIV guidelines suggest 900 mg PO twice daily may be useful as an adjunct to chemotherapy and antiretroviral therapy.

    For the treatment of congenital cytomegalovirus (CMV) disease†.
    Oral dosage
    Neonates and Infants

    16 mg/kg/dose PO every 12 hours for at least 6 weeks. Treatment for 6 months may result in improved audiologic and neurodevelopmental outcomes.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    900 mg/day PO for prophylaxis; 1800 mg/day PO is used off-label for treatment of CMV infection.

    Geriatric

    900 mg/day PO for prophylaxis; 1800 mg/day PO is used off-label for treatment of CMV infection.

    Adolescents

    17 years: 900 mg/day PO for prophylaxis; 1800 mg/day PO is used off-label for treatment of CMV infection.
    13 to 16 years: Dosage is based on BSA and CrCl; not to exceed 900 mg/day PO for prophylaxis; 1800 mg/day PO is used off-label for treatment of CMV infection

    Children

    Dosage is based on BSA and CrCl; not to exceed 900 mg/day PO for prophylaxis; 1800 mg/day PO is used off-label for treatment of CMV infection in children old enough to receive adult dosage.

    Infants

    Dosage is based on BSA and CrCl; alternatively, 30 to 32 mg/kg/day PO has been studied off-label for congenital CMV disease.

    Neonates

    Safety and efficacy have not been established; 30 to 32 mg/kg/day PO has been studied off-label for congenital CMV disease.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Adults and Adolescents > 16 years:
    CrCl >= 60 mL/min: No dosage adjustment is necessary.
    CrCl 40—59 mL/min: For doses of 900 mg PO twice daily, reduce dose to 450 mg PO twice daily; for doses of 900 mg PO once daily, reduce dose to 450 mg PO once daily.
    CrCl 25—39 mL/min: For doses of 900 mg PO twice daily, reduce dose to 450 mg PO once daily; for doses of 900 mg PO once daily, reduce dose to 450 mg PO every 2 days.
    CrCl 10—24 mL/min: For doses of 900 mg PO twice daily, reduce dose to 450 mg PO every 2 days; for doses of 900 mg PO once daily, reduce dose to 450 mg PO twice weekly.
    CrCl < 10 mL/min: Do not give valganciclovir tablets. In these patients, it is recommended that ganciclovir in appropriate doses be given.
     
    Pediatric patients 1 month to 16 years:
    Dosing in pediatric patients with renal impairment is included in the approved dosing recommendations as CrCl is a component of the calculation.
     
    Intermittent hemodialysis
    Valganciclovir is not recommended. In these patients, it is recommended that ganciclovir be given in appropriate doses.
     
    Peritoneal dialysis
    Valganciclovir is not recommended.

    ADMINISTRATION

    Oral Administration

    Valganciclovir should be handled carefully. Avoid direct contact of skin or mucous membranes with broken or crushed tablets or with oral solution. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.
    Consideration should be given to handling and disposal of valganciclovir according to guidelines issued for antineoplastic agents. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate for valganciclovir.
    Administer orally with food.

    Oral Solid Formulations

    Do not crush or break tablets.

    Oral Liquid Formulations

    Adult patients should use the tablet formulation; use of the oral solution is not recommended for the adult population.
    A patient package insert and 2 oral syringes should be dispensed to each patient.
    The oral solution must be prepared by the pharmacist prior to dispensing to the patient.
     
    Reconstitution of Powder for Oral Solution (50 mg/mL)
    Wear disposable gloves during reconstitution and to wipe outer surface of the bottle, cap, and table surface after reconstitution.
    Measure 91 mL of purified water in a graduated cylinder.
    Shake the bottle to loosen the powder.
    Remove the child resistant bottle cap. Add approximately half the total amount of measured water to the bottle, and shake the closed bottle for 1 minute. Add remaining amount of measured water, and shake the closed bottle well for 1 minute.
    Removed child resistant bottle cap, and push bottle adapter into the neck of the bottle. To properly seat the bottle adaptor, tightly close the bottle with the child resistant bottle cap.
    Storage: Store reconstituted solution under refrigeration at 2 to 8 degrees C (or 36 to 46 degrees F); discard any unused portion after 49 days. Do NOT freeze.
     
    Administration of Oral Solution
    Review the patient package insert for administration instructions.
    Shake the closed bottle well for 5 seconds before each use.
    Withdraw the prescribed dose using the manufacturer supplied oral syringe.
    Administer the dose directly into the patient’s mouth. For infants and small children, place the tip of the oral dispenser between the cheek and gum and slowly administer the solution in small increments. Do not mix with any liquid prior to dispensing.
    Immediately after administration, disassemble oral syringe, rinse under running tap water, and air dry prior to the next use.

    Extemporaneous Compounding-Oral

    Extemporaneous Valganciclovir Oral Suspension Preparation (60 mg/mL)
    NOTE: The extemporaneous preparation of valganciclovir is not FDA-approved. Use of the commercially available 50 mg/mL solution is preferred.
    Because of the risk of teratogenicity, avoid unnecessary exposure to valganciclovir through skin contact or inhalation of dust by taking precautionary measures such as compounding the suspension in a vertical laminar airflow hood and wearing gloves.
    A 30 mg/mL or 60 mg/mL (of the hydrochloride salt) suspension can be compounded with a 1:1 mixture of Ora-Sweet and Ora-Plus.
    For the 60 mg/mL oral suspension, place sixteen 450 mg tablets in a glass or porcelain mortar and crush with a pestle to a fine powder.
    Add 1 mL increments of Ora-Plus and triturate to a paste. Gradually add a total of 60 mL of Ora-Plus, mixing well after each addition.
    Transfer the mixture to an amber glass bottle, scraping the mortar with a spatula or rubber policeman to ensure complete collection.
    Thoroughly rinse the mortar and pestle with 10 mL of Ora-Sweet and scrape into the bottle. Repeat rinsing process 4 times.
    Add enough Ora-Sweet to the bottle to bring the total volume to 120 mL and shake well.
    Shake well before use.
    Storage: The extemporaneous compound is stable for 35 days under refrigeration (4 degrees C or 39.2 degrees F).

    STORAGE

    Valcyte:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Valganciclovir cannot be substituted for ganciclovir capsules on a one-to-one basis. The bioavailability of ganciclovir from valganciclovir tablets is significantly higher than from ganciclovir capsules. Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of valganciclovir tablets.

    Acyclovir hypersensitivity, famciclovir hypersensitivity, ganciclovir hypersensitivity, penciclovir hypersensitivity, valacyclovir hypersensitivity, valganciclovir hypersensitivity

    Valganciclovir is contraindicated in patients who have developed ganciclovir hypersensitivity or valganciclovir hypersensitivity. Hypersensitivity reactions to valganciclovir have been reported. Because of similar chemical structures and possible cross-sensitivity, valganciclovir should not be used in patients with acyclovir hypersensitivity, famciclovir hypersensitivity, penciclovir hypersensitivity, or valacyclovir hypersensitivity. Alternative agents such as foscarnet or cidofovir may be suitable since they are not structurally related to these antivirals.

    Anemia, aplastic anemia, bone marrow suppression, neutropenia, radiation therapy, thrombocytopenia

    Use caution when administering valganciclovir to patients with bone marrow suppression or to those who are receiving other myelosuppressive chemotherapy or radiation therapy. Avoid use if the absolute neutrophil count (ANC) is less than 500/mm3, the platelet count is less than 25,000/mm3, or hemoglobin is less than 8 g/dL. Severe anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and bone marrow failure, including aplastic anemia, have been reported during valganciclovir therapy. Cytopenia may occur at any time during treatment and may worsen with continued dosing; typically, cell counts will begin to recover 3 to 7 days after treatment discontinuation. Frequently monitor complete blood and platelet counts, especially in patients with impaired renal function, an ANC less than 1000/mm3 at baseline, or in whom ganciclovir or other nucleoside analogs have previously caused leukopenia. Increased monitoring for bone marrow suppression may be warranted when therapy is changed from oral ganciclovir to valganciclovir, because of the increased plasma concentrations of ganciclovir after valganciclovir administration. Consider treatment with hematopoietic growth factors in patients with severe leukopenia, neutropenia, anemia, or thrombocytopenia.

    Dehydration, dialysis, geriatric, renal failure, renal impairment

    Monitor serum creatinine or estimated creatinine clearance closely during valganciclovir therapy. Increased serum creatinine concentrations have been observed during clinical trials. Adequate fluid intake should be maintained; avoid dehydration during therapy. Valganciclovir dosage adjustment is required for patients with renal impairment. For patients with renal failure or receiving hemodialysis (dialysis), use of valganciclovir is not recommended because the daily dose of valganciclovir required is less than 450 mg; ganciclovir, in appropriate doses, should be given in place of valganciclovir in these patients. Although clinical studies did not include sufficient numbers of geriatric patients, dose selection for these patients should be cautious, reflecting the greater frequency of decreased renal function and of concomitant disease or drug therapy. In addition, use caution in patients receiving concurrent treatment with nephrotoxic drugs, as use of these medications together may increase the risk for adverse events.

    Accidental exposure, ocular exposure, secondary malignancy

    Valganciclovir tablets should be handled carefully and should not be broken or crushed. In animal studies, ganciclovir was found to be mutagenic and carcinogenic. Although human data are not available, the development of a secondary malignancy is a potential risk to consider during valganciclovir therapy based on animal carcinogenicity data. Avoid accidental exposure of broken or crushed tablets, the powder for oral solution, and the constituted oral solution directly with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and if ocular exposure occurs, rinse eyes thoroughly with plain water.

    Antimicrobial resistance

    Antimicrobial resistance to ganciclovir may be seen following prolonged treatment with valganciclovir; however, it has also been reported in individuals who have never received ganciclovir. The possibility of viral resistance should be considered in patients who show poor clinical response or experience viral excretion during therapy.

    Children, infants, neonates

    Because of the potential for long-term carcinogenicity and reproductive toxicity, carefully consider the risks and benefits of using valganciclovir therapy in neonates, infants, children, and adolescents. Carcinogenicity and impaired fertility have occurred in animal models at doses similar to those used in humans; the precise risk in human patients is not known. Although specific human data are not available, it is considered probable in humans that valganciclovir at recommended doses may cause temporary or permanent inhibition of spermatogenesis.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, valganciclovir is considered a potential teratogen in humans because animal studies found ganciclovir to be mutagenic and teratogenic at doses recommended for human use. Because valganciclovir is a prodrug of ganciclovir, similar toxicity is expected. Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta via passive diffusion. Pregnancy should be avoided by females taking valganciclovir and by females with male partners taking valganciclovir. At doses resulting in two-times the human exposure of ganciclovir (based on human AUC after a single IV dose of 5 mg/kg of ganciclovir), maternal and embryofetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits were observed. Fetal resorptions were present in 85% or more of rabbits and mice. Increased embryofetal mortality was seen in rabbits as well as 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 toxicity was also seen in mice. At daily IV doses of approximately 1.7-times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation, hypoplasia of the testes and seminal vesicles of the male offspring, as well as pathologic changes in the nonglandular region of the stomach were observed.

    Breast-feeding

    There are no data regarding the presence of valganciclovir in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Ganciclovir is excreted in rat milk. Due to the potential for serious adverse reactions in nursing infants, breast-feeding is not recommended during treatment with valganciclovir. Additionally, valganciclovir may be used to treat infections in patients with HIV, and the Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. 

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Valganciclovir is associated with reproductive risk. Valganciclovir can be teratogenic if taken by the father near the time of conception (male-mediated teratogenicity) or by the mother during pregnancy. Discuss contraception requirements with the patient. Females should use effective contraception during and for at least 30 days after treatment with valganciclovir. Males must use a condom during and for at least 90 days after treatment. Females of reproductive potential should undergo pregnancy testing prior to initiation of valganciclovir. In addition, based on animal data with ganciclovir, valganciclovir may cause temporary or permanent inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses. Animal studies also indicate that suppression of fertility in females may occur.

    ADVERSE REACTIONS

    Severe

    retinal detachment / Delayed / 15.0-15.0
    aplastic anemia / Delayed / 0-5.0
    pancytopenia / Delayed / 0-5.0
    pancreatitis / Delayed / 0-5.0
    seizures / Delayed / 0-5.0
    hearing loss / Delayed / 0-5.0
    macular edema / Delayed / 0-5.0
    anaphylactic shock / Rapid / 0-1.0
    hyperkalemia / Delayed / 5.0
    agranulocytosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    wound dehiscence / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 1.0-31.0
    thrombocytopenia / Delayed / 1.0-22.0
    neutropenia / Delayed / 3.0-19.0
    peripheral neuropathy / Delayed / 9.0-9.0
    bleeding / Early / 0-5.0
    hallucinations / Early / 0-5.0
    confusion / Early / 0-5.0
    psychosis / Early / 0-5.0
    elevated hepatic enzymes / Delayed / 0-5.0
    leukopenia / Delayed / 20.0
    constipation / Delayed / 5.0
    oral ulceration / Delayed / 5.0
    hematuria / Delayed / 5.0
    candidiasis / Delayed / 5.0
    peripheral edema / Delayed / 5.0
    depression / Delayed / 5.0
    dyspnea / Early / 5.0
    hypotension / Rapid / 5.0
    hypophosphatemia / Delayed / 5.0
    clastogenesis / Delayed / Incidence not known
    infertility / Delayed / Incidence not known

    Mild

    diarrhea / Early / 16.0-41.0
    fever / Early / 12.0-31.0
    nausea / Early / 8.0-30.0
    tremor / Early / 12.0-28.0
    headache / Early / 9.0-22.0
    vomiting / Early / 3.0-21.0
    insomnia / Early / 7.0-20.0
    abdominal pain / Early / 15.0-15.0
    paresthesias / Delayed / 8.0-8.0
    dysgeusia / Early / 0-5.0
    agitation / Early / 0-5.0
    dyspepsia / Early / 5.0
    influenza / Delayed / 5.0
    infection / Delayed / 5.0
    pharyngitis / Delayed / 5.0
    chills / Rapid / 5.0
    night sweats / Early / 5.0
    malaise / Early / 5.0
    asthenia / Delayed / 5.0
    fatigue / Early / 5.0
    dizziness / Early / 5.0
    anxiety / Delayed / 5.0
    muscle cramps / Delayed / 5.0
    back pain / Delayed / 5.0
    arthralgia / Delayed / 5.0
    myalgia / Early / 5.0
    cough / Delayed / 5.0
    ocular pain / Early / 5.0
    pruritus / Rapid / Incidence not known
    weight loss / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Zidovudine should be used cautiously with other drugs that can cause bone marrow suppression, such as valganciclovir, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted. Occasionally, discontinuation of therapy or the addition of a hematopoietic colony stimulating factor may be necessary.
    Amikacin: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Aminoglycosides: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Use caution and monitor renal function when valganciclovir is coadministered with amphotericin B because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Amphotericin B lipid complex (ABLC): (Moderate) Use caution and monitor renal function when valganciclovir is coadministered with amphotericin B because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Amphotericin B liposomal (LAmB): (Moderate) Use caution and monitor renal function when valganciclovir is coadministered with amphotericin B because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Amphotericin B: (Moderate) Use caution and monitor renal function when valganciclovir is coadministered with amphotericin B because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Aprotinin: (Moderate) The manufacturer recommends using aprotinin cautiously in patients that are receiving drugs that can affect renal function, such as valganciclovir, as the risk of renal impairment may be increased.
    Bacitracin: (Minor) Concurrent use of nephrotoxic agents, such as systemic bacitracin, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Cisplatin: (Major) Concurrent use of nephrotoxic agents with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valganciclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Cyclosporine: (Moderate) Use caution and monitor renal function when valganciclovir is coadministered with cyclosporine because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Dapsone: (Moderate) Use valganciclovir and dapsone together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Didanosine, ddI: (Moderate) Valganciclovir may increase the concentration of didanosine, ddI, when given concurrently. Patients should be monitored closely for didanosine toxicity (e.g., pancreatitis) when receiving valganciclovir concurrently.
    Doxorubicin: (Moderate) Use valganciclovir and doxorubicin together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Efavirenz; Emtricitabine; Tenofovir: (Minor) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valganciclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Minor) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valganciclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Emtricitabine; Tenofovir disoproxil fumarate: (Minor) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valganciclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Entecavir: (Moderate) Entecavir may affect renal function and should be used cautiously in combination with other drugs that may also affect renal function including valganciclovir.
    Flucytosine: (Moderate) Use valganciclovir and flucytosine together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Gentamicin: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like valganciclovir. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Hydroxyurea: (Moderate) Use valganciclovir and hydroxyurea together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Imipenem; Cilastatin: (Major) Concomitant use of imipenem; cilastatin and valganciclovir is not recommended due to the increased risk of seizures. Generalized seizures have occurred in patients who were receiving imipenem; cilastatin concomitantly with ganciclovir. The mechanism of this interaction is not known. According to the manufacturer, imipenem and ganciclovir should not be used concomitantly unless the potential benefits outweigh the risks.
    Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like valganciclovir. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
    Kanamycin: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Lamivudine, 3TC; Zidovudine, ZDV: (Major) Zidovudine should be used cautiously with other drugs that can cause bone marrow suppression, such as valganciclovir, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted. Occasionally, discontinuation of therapy or the addition of a hematopoietic colony stimulating factor may be necessary.
    Mycophenolate: (Moderate) Because the glucuronide metabolite of mycophenolate and ganciclovir concentrations are increased in the presence of renal impairment, the potential exists for the two drugs to compete for tubular secretion, further increasing the concentration of both drugs.
    Nonsteroidal antiinflammatory drugs: (Minor) Concurrent use of nephrotoxic agents, such as NSAIDs, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Paromomycin: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Pentamidine: (Moderate) Use valganciclovir with pentamidine only if the potential benefits are judged to outweigh the risks. Concurrent use of agents that inhibit rapidly dividing cell populations (i.e., bone marrow, spermatogonia, germinal layers of the skin, gastrointestinal mucosa) with valganciclovir should be done cautiously, in order to avoid additive toxicity. Additive nephrotoxicity may be seen with the combination of pentamidine and other agents that cause nephrotoxicity, including valganciclovir.
    Polymyxin B: (Minor) Concurrent use of nephrotoxic agents, such as polymyxin b, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Probenecid: (Moderate) Probenecid may inhibit renal tubular secretion of valganciclovir, possibly potentiating valganciclovir toxicity. Patients should be monitored for increased valganciclovir toxicity when taking probenecid.
    Streptomycin: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Use valganciclovir and sulfamethoxazole; trimethoprim together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Tacrolimus: (Moderate) Use valganciclovir and tacrolimus together only if the potential benefits outweigh the risks. Monitor renal function when valganciclovir is coadministered with tacrolimus because of the potential increase in serum creatinine. Acute renal failure may occur in patients concomitantly receiving potential nephrotoxic drugs.
    Talimogene Laherparepvec: (Major) Consider the risks and benefits of treatment with talimogene laherparepvec before administering acyclovir or other antivirals to prevent or manage herpetic infection. Talimogene laherparepvec is a live, attenuated herpes simplex virus that is sensitive to acyclovir; coadministration with antiviral agents may cause a decrease in efficacy.
    Telbivudine: (Moderate) Drugs that alter renal function such as valganciclovir may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Tenofovir Alafenamide: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as valganciclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir, PMPA: (Minor) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valganciclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    Tobramycin: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Trimethoprim: (Moderate) Use valganciclovir and sulfamethoxazole; trimethoprim together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Vancomycin: (Moderate) Concurrent use of nephrotoxic agents, such as vancomycin, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
    Vinblastine: (Moderate) Use valganciclovir and vinca alkaloids together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Vinca alkaloids: (Moderate) Use valganciclovir and vinca alkaloids together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Vincristine Liposomal: (Moderate) Use valganciclovir and vinca alkaloids together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Vincristine: (Moderate) Use valganciclovir and vinca alkaloids together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Vinorelbine: (Moderate) Use valganciclovir and vinca alkaloids together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.
    Zidovudine, ZDV: (Major) Zidovudine should be used cautiously with other drugs that can cause bone marrow suppression, such as valganciclovir, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted. Occasionally, discontinuation of therapy or the addition of a hematopoietic colony stimulating factor may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, valganciclovir is considered a potential teratogen in humans because animal studies found ganciclovir to be mutagenic and teratogenic at doses recommended for human use. Because valganciclovir is a prodrug of ganciclovir, similar toxicity is expected. Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta via passive diffusion. Pregnancy should be avoided by females taking valganciclovir and by females with male partners taking valganciclovir. At doses resulting in two-times the human exposure of ganciclovir (based on human AUC after a single IV dose of 5 mg/kg of ganciclovir), maternal and embryofetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits were observed. Fetal resorptions were present in 85% or more of rabbits and mice. Increased embryofetal mortality was seen in rabbits as well as 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 toxicity was also seen in mice. At daily IV doses of approximately 1.7-times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation, hypoplasia of the testes and seminal vesicles of the male offspring, as well as pathologic changes in the nonglandular region of the stomach were observed.

    There are no data regarding the presence of valganciclovir in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Ganciclovir is excreted in rat milk. Due to the potential for serious adverse reactions in nursing infants, breast-feeding is not recommended during treatment with valganciclovir. Additionally, valganciclovir may be used to treat infections in patients with HIV, and the Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. 

    MECHANISM OF ACTION

    The activity of valganciclovir is due to the conversion to ganciclovir. Ganciclovir is a synthetic analog of 2'-deoxyguanosine and inhibits the replication of human cytomegalovirus (CMV). In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase pUL97. Further phosphorylation by protein kinases produces ganciclovir triphosphate. Ganciclovir triphosphate acts as a virustatic agent by inhibiting viral DNA synthesis by competing for a position in the viral DNA and terminating DNA synthesis once incorporated. Since phosphorylation is dependent upon viral protein kinases, ganciclovir is preferentially metabolized in virus-infected cells. As sensitivity tests vary due to many factors, the concentration of ganciclovir to inhibit the growth of virus in cell culture by 50% (CIC50) ranges from 0.02—5.75 mcg/ml. Ganciclovir inhibits mammalian cell proliferation (CIC50) in vitro at higher concentrations ranging from 10.21 to > 250 mcg/ml; however, bone marrow cells are more sensitive (CIC50 0.69—3.06 mcg/ml).
     
    Resistance to ganciclovir may occur after prolonged treatment with valganciclovir by selection of mutations in either the viral protein kinase (UL97) and/or in the viral polymerase gene (UL54). Virus with mutations in the UL97 gene is resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene may show cross-resistance to other antiviral agents with a similar mechanism of action. The current definition of CMV resistance to ganciclovir in vitro is IC50 >= 1.5 mcg/ml. CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy.

    PHARMACOKINETICS

    Valganciclovir is administered orally. Systemic exposure to valganciclovir is transient and low; AUC24 and Cmax values are about 1% and 3% of those of ganciclovir, respectively. Due to the high ganciclovir bioavailability from valganciclovir tablet, ganciclovir capsules and valganciclovir tablets cannot be substituted on a one-to-one basis. Protein binding of valganciclovir has not been determined due to rapid conversion to ganciclovir; the protein binding of ganciclovir is 1 to 2%. The pharmacokinetic parameters (e.g., AUC, half-life, and renal clearance) of valganciclovir 900 mg PO once daily and ganciclovir 5 mg/kg IV once daily are similar; the Cmax of IV ganciclovir is higher than that of valganciclovir (9.46 +/- 2.02 mcg/ml vs. 5.61 +/- 1.52 mcg/ml, respectively). No further metabolites are noted after valganciclovir is hydrolyzed to ganciclovir. Intracellularly, ganciclovir undergoes phosphorylation; ganciclovir triphosphate is metabolized slowly intracellularly with a half-life of 18 hours. Systemically, ganciclovir is eliminated renally through glomerular filtration and active tubular secretion.

    Oral Route

    Following oral administration both valganciclovir diastereomers are rapidly and completely converted to ganciclovir by intestinal and hepatic esterases. When valganciclovir tablets were administered with a high-fat meal, the steady-state ganciclovir AUC increased by 30% and the Cmax by 14% without increasing the Tmax. Therefore, it is recommended that valganciclovir tablets be given with food. The absolute bioavailability of ganciclovir from valganciclovir tablets when administered with food is about 60%. Due to the high ganciclovir bioavailability from valganciclovir tablet, ganciclovir capsules and valganciclovir tablets cannot be substituted on a one-to-one basis.