Valcyte

Nucleoside and Nucleotide DNA Polymerase Inhibitor Antivirals

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and 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.
Administer orally with food.

Do not crush or break tablets.

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 adapter, tightly close the bottle with the child resistant bottle cap.
Storage: Store reconstituted solution under refrigeration at 2 to 8 degrees C (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 supplied oral syringe; the oral dispenser is graduated in 0.5 mL increments.
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 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).

retinal detachment / Delayed / 15.0-15.0
pancytopenia / Delayed / 0-5.0
aplastic anemia / 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
new primary malignancy / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

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
bone marrow suppression / Delayed / Incidence not known
clastogenesis / Delayed / Incidence not known
infertility / Delayed / Incidence not known

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

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.

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 new primary 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.

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.

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 and limited human data, valganciclovir may cause temporary or permanent inhibition of spermatogenesis and subsequent infertility. Animal studies also indicate that suppression of fertility in females may occur.

Valcyte, Valcyte Powder

Rx

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

900 mg PO every 12 hours for 14 to 21 days as an initial therapy. For immediate sight-threatening lesions (i.e., within 1,500 microns of the fovea), may give in combination with intravitreal ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection). Induction therapy should be followed-up with chronic maintenance therapy (secondary prophylaxis).

900 mg PO every 12 hours for 14 to 21 days is recommended in the HIV guidelines as an initial therapy. For immediate sight-threatening lesions (i.e., within 1,500 microns of the fovea), may give in combination with intravitreal ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection). Induction therapy should be followed-up with chronic maintenance therapy (secondary prophylaxis).

Although an exact age or weight range is not specified, the HIV guidelines recommend valganciclovir 900 mg PO twice daily for 14 to 21 days as an alternative therapy for patients old enough to receive adult dosing. Although there are limited dosing data for valganciclovir in young children with retinitis, the guidelines also state that consideration may be given to transitioning from IV ganciclovir to oral valganciclovir after improvement in retinitis. Chronic maintenance therapy (secondary prophylaxis) should start after induction therapy.

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

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

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 25 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)) / 3,600]. 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.

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

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

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 25 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)) / 3,600]. 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.

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

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

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).

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 25 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)) / 3,600]. 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).

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.

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.

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 25 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)) / 3,600]. 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.

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.

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.

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.

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.

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

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

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.

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.

900 mg PO twice daily for 21 to 42 days or until symptoms have resolved in patients with mild disease who are able to tolerate oral therapy. Chronic maintenance therapy (secondary prophylaxis) may be considered in GI disease in patients with relapse.

900 mg PO twice daily for 21 to 42 days or until symptoms have resolved in patients with mild disease who are able to tolerate oral therapy. Chronic maintenance therapy (secondary prophylaxis) may be considered in GI disease in patients with relapse.

†Indicates off-label use

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

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.

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 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.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
Cisplatin: (Moderate) Concomitant use of cisplatin and valganciclovir should be considered only if the potential benefits outweigh the risks of increased treatment-related toxicities. If coadministration is necessary, closely monitor for treatment-related adverse reactions. Valganciclovir is rapidly and extensively converted to ganciclovir. Ganciclovir is eliminated renally and cisplatin can cause nephrotoxicity, which may result in increased plasma concentrations of ganciclovir. Side effects such as nephrotoxicity and myelosuppression may be additive.
Clindamycin: (Moderate) Concomitant use of valganciclovir and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
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.
Doravirine; Lamivudine; 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.
Doxorubicin Liposomal: (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.
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 Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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.
Efavirenz; Lamivudine; 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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 alafenamide: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as valganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and valganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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) Avoid concomitant use of imipenem; cilastatin and valganciclovir unless the potential benefits outweigh the risks. Generalized seizures have occurred in patients who were receiving imipenem; cilastatin concomitantly with ganciclovir.
Imipenem; Cilastatin; Relebactam: (Major) Avoid concomitant use of imipenem; cilastatin and valganciclovir unless the potential benefits outweigh the risks. Generalized seizures have occurred in patients who were receiving imipenem; cilastatin concomitantly with ganciclovir.
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.
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.
Lamivudine; 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.
Maribavir: (Major) Avoid concomitant use of maribavir and valganciclovir. Maribavir may antagonize the antiviral activity of valganciclovir by inhibiting human CMV pUL97 kinase, which is required for activation of valganciclovir.
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.
Plazomicin: (Major) Concurrent use of nephrotoxic agents, such as aminoglycosides, with valganciclovir should be done cautiously to avoid additive nephrotoxicity.
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.
Probenecid; Colchicine: (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.
Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with a nephrotoxic agent, such as valganciclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse reactions.
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.
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.
Voclosporin: (Moderate) Concomitant use of voclosporin and valganciclovir may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
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.

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

900 mg/day PO for prophylaxis; 1,800 mg/day PO is used off-label for treatment of CMV infection.

900 mg/day PO for prophylaxis; 1,800 mg/day PO is used off-label for treatment of CMV infection.

17 years: 900 mg/day PO for prophylaxis; 1,800 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; 1,800 mg/day PO is used off-label for treatment of CMV infection

Dosage is based on BSA and CrCl; not to exceed 900 mg/day PO for prophylaxis; 1,800 mg/day PO is used off-label for treatment of CMV infection in children old enough to receive adult dosage.

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

Safety and efficacy have not been established; however, 32 mg/kg/day PO has been used off-label for congenital CMV disease.

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.

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.

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.

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.

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 and limited human data, valganciclovir may cause temporary or permanent inhibition of spermatogenesis and subsequent infertility. Animal studies also indicate that suppression of fertility in females may occur.