VALGANCICLOVIR HCL (Generic for VALCYTE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.
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.

Route-Specific 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.
-Administer orally with food.
Oral Solid Formulations
-Do not crush or break tablets.

Oral Liquid Formulations
-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 Compounding-Oral
Extemporaneous 60 mg/mL Valganciclovir Oral Suspension Preparation
NOTE: The extemporaneous preparation of valganciclovir is not approved by the FDA. 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.
-The extemporaneous compound is stable for 35 days under refrigeration (4 degrees C or 39.2 degrees F).

The overall safety profile of valganciclovir in pediatric patients is similar to that of adult patients.

Since valganciclovir is rapidly converted to ganciclovir after administration, adverse reactions known to be associated with ganciclovir can be expected with the use of valganciclovir.

Hypersensitivity reactions, including dermatitis, pruritus, and anaphylaxis (anaphylactic shock), have been reported with valganciclovir treatment.

Bone marrow suppression resulting in neutropenia, leukopenia, and anemia (all more than 10%) has occurred in pediatric solid organ transplant patients receiving valganciclovir in clinical studies. Both neutropenia and anemia occurred with a higher frequency in pediatric patients overall compared to adult patients; however, there was no correlation between neutropenia and infections observed in pediatric patients. The overall safety profile of valganciclovir was similar with the extension of prophylaxis until day 200 post-transplant in high-risk pediatric kidney transplant patients; however, the frequency of severe neutropenia (ANC less than 500 cells/mm3) was higher in patients treated with valganciclovir until day 200 (30%) compared to patients treated until day 100 (5%). There were no differences in the incidence of severe (Grade 4) anemia or thrombocytopenia in patients treated with 100 or 200 days of valganciclovir treatment. Thrombocytopenia has also been reported in 1% to 22% of adult patients. Potentially life-threatening bleeding associated with valganciclovir-induced thrombocytopenia has been reported. Other serious hematologic adverse reactions reported in patients receiving valganciclovir include agranulocytosis, granulocytopenia, pancytopenia, bone marrow suppression, and aplastic anemia. Fatal bone marrow suppression (medullary aplasia) occurred in a patient who received a valganciclovir dose that was 10-fold greater than recommended for the patient's estimated renal function.

Gastrointestinal adverse reactions reported in more than 10% of pediatric solid organ transplant patients during clinical studies with valganciclovir include diarrhea, constipation, abdominal pain, nausea, and vomiting. Abdominal pain was reported with a higher frequency in pediatric patients compared with adult patients. Dyspepsia, abdominal distention, oral ulceration, decreased appetite, and decreased weight (weight loss) were reported in at least 5% of adult patients receiving valganciclovir in clinical trials. Dysgeusia and pancreatitis were reported in less than 5% of patients.

Local and systemic infection has been reported in patients treated with valganciclovir. Upper respiratory tract infection and urinary tract infection have been reported in more than 10% of pediatric solid organ transplant patients receiving valganciclovir in clinical studies. Upper respiratory tract infections, including pharyngitis/nasopharyngitis, were reported with a higher frequency in pediatric patients compared with adult patients. Other infections reported in at least 5% of adult patients receiving valganciclovir in clinical trials include candidiasis, influenza, and post-operative wound infection. Cellulitis and sepsis were reported in less than 5% of patients.

Increased serum creatinine, hematuria, and urinary tract infection were reported in more than 10% of pediatric solid organ transplant patients receiving valganciclovir in clinical studies. Decreased creatinine clearance and renal impairment were also reported in at least 5% of adult patients receiving valganciclovir in clinical trials. Acute renal failure (unspecified) may occur in patients with predisposing conditions. In adult CMV retinitis patients, serum creatinine concentrations of more than 1.5 to 2.5 mg/dL occurred in 12% of patients and 3% of patients developed a serum creatinine concentration more than 2.5 mg/dL. In adult solid organ transplant patients (including heart, kidney, kidney-pancreas, and liver transplants), serum creatinine concentrations of more than 1.5 to 2.5 mg/dL occurred in 45% to 50% of patients and 14% to 17% of patients had a concentration more than 2.5 mg/dL.

Pyrexia (fever), tremor, and headache have occurred in more than 10% of pediatric solid organ transplant patients receiving valganciclovir in clinical studies. Fever occurred with a higher frequency in pediatric patients compared with adult patients. Fatigue, pain, malaise, asthenia, chills, night sweats, and peripheral edema were reported in at least 5% of adult patients receiving valganciclovir in clinical trials.

Insomnia (7% to 20%), peripheral neuropathy (9%), and paresthesias (8%) were reported with valganciclovir in adult clinical trials. Dizziness, depression, and anxiety were also reported in at least 5% of adult patients receiving valganciclovir in clinical trials. Seizures, confusion, agitation, psychosis, and hallucinations were reported in less than 5% of patients.

Back pain, arthralgia, myalgia, and muscle cramps were reported in at least 5% of adult patients receiving valganciclovir in clinical trials. Limb pain was reported in less than 5% of patients.

Cough and dyspnea were reported in at least 5% of adult patients receiving valganciclovir in clinical trials.

Hypotension was reported in at least 5% of adult patients receiving valganciclovir in clinical trials. Arrhythmias were reported in less than 5% of patients.

Postoperative complications and pain as well as increased wound drainage and wound dehiscence have occurred with valganciclovir therapy.

Hyperkalemia and hypophosphatemia were reported in at least 5% of adult patients receiving valganciclovir in clinical trials.

During treatment of CMV retinitis in adults, retinal detachment was reported in 15% of patients receiving valganciclovir. Ocular pain was reported in at least 5% of adult patients receiving valganciclovir in clinical trials; macular edema was reported in less than 5% of patients. Deafness (hearing loss) was also reported in less than 5% of adult patients receiving valganciclovir in clinical trials.

Ganciclovir is considered a potential carcinogen in humans; the same effects may be associated with valganciclovir. It has been associated with clastogenesis during in vitro testing at doses 2.8- to 10-times the normal human dose but not with doses comparable to human exposure. Tumors have developed in mice treated with approximately one-tenth to 1.4 times the human dose. Most tumors were of epithelial or vascular origin, although histiocytic sarcoma of the liver was reported. Tumors appeared in some tissues for which there is no human counterpart. Based on animal carcinogenicity data, the development of a new primary malignancy is a potential risk to consider during valganciclovir therapy.

Animal and limited human data indicate that valganciclovir may cause temporary or permanent spermatogenesis inhibition and subsequent infertility in males and suppression of fertility in females. Effects on spermatogenesis were reversible at lower doses and irreversible at higher doses. In addition, valganciclovir causes teratogenesis in animals and should not be used during pregnancy. Counsel male patients (if age appropriate) and caregivers about the potential long-term risks of valganciclovir use. In addition, counsel adolescents, both male and female, about the necessity of using effective contraception during treatment. Females should use effective contraception during and for at least 30 days after treatment with valganciclovir. Males must practice barrier contraception during and for at least 90 days after treatment with valganciclovir.

Abnormal liver function was reported in at least 5% of adult patients receiving valganciclovir in clinical trials. Elevated hepatic enzymes (increased aspartate and alanine aminotransferase) were reported in less than 5% of patients.

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.

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.

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. In addition, use caution in patients receiving concurrent treatment with nephrotoxic drugs, as use of these medications together may increase the risk for adverse reactions.

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.

Counsel adolescents, both male and female, about the reproductive risk and contraception requirements during treatment. Valganciclovir can be teratogenic if taken by the father near the time of conception (male-mediated teratogenicity) or by the mother during pregnancy. Females should use effective contraception during and for at least 30 days after treatment with valganciclovir. Males must use condoms 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 in males and suppression of fertility in females. These effects were reversible at lower doses and irreversible at higher doses.

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.

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.

Description: Valganciclovir is the L-valyl ester of ganciclovir (i.e., a prodrug), which exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir. Ganciclovir is a synthetic purine nucleoside analog used for the treatment and prevention of cytomegalovirus (CMV). The advantage of valganciclovir is the ability to attain in vivo exposure that is similar to IV ganciclovir and higher than oral ganciclovir capsules. Hematologic toxicity is common with systemic valganciclovir administration; dosage adjustments for neutropenia or thrombocytopenia may be required. Toxicity is more common in patients with renal insufficiency. Valganciclovir is FDA-approved in pediatric patients as young as 1 month of age.

NOTE: Valganciclovir tablets cannot be substituted for ganciclovir tablets on a one-to-one basis.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: cytomegalovirus (CMV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Epstein-Barr virus, herpes simplex virus type 1, herpes simplex virus type 2, human herpesvirus 6 (HHV-6), human herpesvirus 8 (HHV-8), varicella-zoster virus
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of symptomatic congenital cytomegalovirus (CMV) disease*:
Oral dosage:
Neonates: 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.
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.

For cytomegalovirus (CMV) disease prophylaxis in patients at high risk for CMV disease:
NOTE: If the calculated dose is within 10% of the available tablet strength (450 mg), the oral tablet may be administered. Adolescent patients older than 16 years are considered adults per the FDA-approved labeling and therefore should receive valganciclovir tablets, not the oral solution.
-for prophylaxis of CMV disease in kidney transplant patients:
Oral dosage:
Infants, Children, and Adolescents 4 months 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 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 200 days post-transplantation. Valganciclovir has also been studied in pediatric liver transplant patients.
Adolescents 17 years: 900 mg PO once daily starting within 10 days of transplantation. Continue therapy until 200 days post-transplantation.
-for prophylaxis of CMV disease in heart transplant patients:
Oral dosage:
Infants, Children, and Adolescents 1 month 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 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.
Adolescents 17 years : 900 mg PO once daily starting within 10 days of transplantation. Continue therapy until 100 days post-transplantation.
-for prophylaxis of CMV disease in kidney-pancreas transplant patients:
Oral dosage:
Adolescents 17 years : 900 mg PO once daily starting within 10 days of transplantation. Continue therapy until 100 days post-transplantation.
-for primary prophylaxis of CMV disease in persons living with HIV*:
NOTE: Guidelines do not recommend primary prophylaxis in adolescents older than 16 years living with HIV, 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 pediatric patients 4 months to 16 years living with HIV 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).
Oral dosage:
Infants, Children, and Adolescents 4 months to 16 years: 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; Adolescent girls 13 to 16 years: k = 0.55; Adolescent boys 13 to 16 years: k = 0.7. 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 induction treatment of cytomegalovirus (CMV) retinitis* in persons with HIV:
Oral dosage:
Children: Although an exact age or weight range is not specified, 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. Induction therapy should be followed-up with chronic maintenance therapy (secondary prophylaxis).
Adolescents: 900 mg PO every 12 hours for 14 to 21 days is recommended by 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).

For the treatment of cytomegalovirus (CMV)-associated gastrointestinal disease*, including esophagitis* or colitis*:
Oral dosage:
Adolescents: 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.

For the treatment of CNS dysfunction or encephalitis* caused by human herpesvirus 6 (HHV-6) infection*:
Oral dosage:
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. 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's disease (MCD)* and primary effusion lymphoma (PEL)*:
-for multicentric Castleman disease* (MCD):
Oral dosage:
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:
Adolescents: The HIV guidelines suggest 900 mg PO twice daily may be useful as an adjunct to chemotherapy and antiretroviral therapy.

For chronic suppressive therapy of cytomegalovirus (CMV) disease, including CMV retinitis (i.e., secondary cytomegalovirus (CMV) retinitis prophylaxis), gastrointestinal disease*, pneumonitis*, or neurological disease*, in persons with HIV:
NOTE: For infants and children, chronic maintenance therapy is indicated for retinitis, disseminated, CNS, or GI disease with relapse. For 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, there have already been recurrent infections, or severe disease was present initially.
Oral dosage:
Infants, Children, and Adolescents 4 months 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 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.
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 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.

Therapeutic Drug Monitoring:
Dosage adjustments for hematologic toxicity
The following dosage adjustments have been suggested for neonates with congenital CMV :

-If absolute neutrophil count (ANC) decreases to < 500 cells/mm3 and is confirmed on repeat testing, hold dose until ANC recovers to > 750 cells/mm3 and resume normal dose.
-If ANC again decreases to <= 750 cells/mm3 but is > 500 cells/mm3, reduce the dose by 50%.
-If after the dosage adjustment, ANC decreases to <= 500 cells/mm3, consider discontinuing valganciclovir.
-Administration of granulocyte colony-stimulating factor may be considered in an attempt to maintain ANC at acceptable levels.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, 32 mg/kg/day PO has been used off-label for congenital CMV disease.
-Infants
Dosage is based on BSA and CrCl; alternatively, 32 mg/kg/day PO has been used off-label for congenital CMV disease.
-Children
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.
-Adolescents
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
17 years: 900 mg/day PO for prophylaxis; 1,800 mg/day PO is used off-label for treatment of CMV infection.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.


Patients with Renal Impairment Dosing
Pediatric patients 1 month to 16 years:
Dosing in pediatric patients with renal impairment is included in the FDA-approved dosing recommendations as CrCl is a component of the calculation.

Adolescents > 16 years:
CrCl >= 60 mL/min: No dosage adjustment is necessary.
CrCl 40-59 mL/min: If the usual dose is 900 mg PO twice daily, reduce dose to 450 mg PO twice daily; if the usual dose is 900 mg PO once daily, reduce dose to 450 mg PO once daily.
CrCl 25-39 mL/min: If the usual dose is 900 mg PO twice daily, reduce dose to 450 mg PO once daily; if the usual dose is 900 mg PO once daily, reduce dose to 450 mg PO every 2 days.
CrCl 10-24 mL/min: If the usual dose is 900 mg PO twice daily, reduce dose to 450 mg PO every 2 days; if the usual dose is 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.

Intermittent hemodialysis
Valganciclovir use is not recommended. In these patients, it is recommended that ganciclovir be given in appropriate doses.

Peritoneal dialysis
Valganciclovir use is not recommended.

*non-FDA-approved indication

Monograph content under development

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).

Pharmacokinetics: Valganciclovir is administered orally. Systemic exposure to valganciclovir, a prodrug, 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.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
After 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%.


-Special Populations
Pediatrics
Neonates
An open-label pharmacokinetic/pharmacodynamic trial of 24 neonates treated for six weeks with IV ganciclovir and oral valganciclovir for congenital central nervous system cytomegalovirus (CMV) infection showed that in infants seven days to three months of age, valganciclovir 16 mg/kg PO twice daily provided systemic ganciclovir exposure similar to IV ganciclovir 6 mg/kg/dose given twice daily. There was a nonlinear relationship between clearance and both weight and BSA. The mean bioavailability in this study was 54%, which may be the result of the difference in food composition for neonates as compared to adults. Additionally, bioavailability increased by 32% during the first six weeks of life (from 48% on day 6 to 64% on day 36).

Infants, Children, and Adolescents
The pharmacokinetic parameters of valganciclovir were studied in an open-label trial of 63 pediatric solid organ transplant patients (kidney, liver, and heart) aged four months to 16 years and 16 heart transplant patients aged less than 4 months of age. Oral doses were administered to produce equivalent exposure to an adult 900 mg dose. The pharmacokinetic profile of valganciclovir was similar across age ranges and did not vary significantly by transplanted organ. Valganciclovir clearance was positively influenced by both body surface area and renal function. The following mean (SD) pharmacokinetic parameters were estimated using population pharmacokinetic modeling.

In patients less than 4 months of age, the estimates were an AUC of 66.3 (20.5) mcg x hour/mL, a Cmax of 10.8 (3.3) mcg/mL, and a half-life of 3.5 (0.87) hours.
In patients 4 months to 2 years, the estimates were an AUC of 55.4 (22.8) to 69.9 (37) mcg x hour/mL, a Cmax of 8.2 (2.5) to 11.9 (3.7) mcg/mL, and a half-life of 2.8 (1.5) to 4.5 (1.5) hours.
In patients 3 years to 11 years, the estimates were an AUC of 55.9 (12.1) to 59.6 (21) mcg x hour/mL, a Cmax of 8.7 (2.1) to 12.5 (1.2) mcg/mL, and a half-life of 2.8 (0.9) to 4.8 (1) hours.
In patients 12 years and older, the estimates were an AUC of 35.4 (2.8) to 60.6 (25) mcg x hour/mL, a Cmax of 5.5 (1.1) to 9.5 (3.3) mcg/mL, and a half-life of 4.4 (0.2) to 6 (1.3) hours.

Hepatic Impairment
In adult liver transplant patients, valganciclovir at doses of 450 and 900 mg resulted in systemic exposure to ganciclovir similar to standard oral or IV ganciclovir therapy, respectively.

Renal Impairment
Decreased renal function results in decreased ganciclovir clearance. Adult patients with an estimated creatinine clearance (CrCl) of 21 to 50 mL/min had a ganciclovir half-life of 10.2 +/- 4.4 hours; patients with a CrCl of 11 to 20 mL/min had a half-life of 21.8 +/- 5.2 hours; and patients with CrCl of greater than or equal to 10 mL/min had a half-life of 67.5 +/- 34 hours. Therefore dosage adjustments of valganciclovir are required in patients with impaired renal function. Hemodialysis reduces plasma concentrations of ganciclovir by about 50% after valganciclovir administration.