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Generic Name: Valganciclovir Hydrochloride
Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: Ester with 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guaninel-valine monohydrochloride
Molecular Formula: C14H22N6O5•HCl
CAS Number: 175865-59-5

Warning(s)

  • Clinical toxicity of valganciclovir, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia.1 (See Warnings under Cautions.)

  • In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis.1 (See Warnings under Cautions.)

Introduction

Antiviral; prodrug of ganciclovir, a nucleoside derived from guanine.1

Uses for Valcyte

Cytomegalovirus (CMV) Retinitis

Initial (induction) treatment and maintenance treatment (secondary prophylaxis) of CMV retinitis in HIV-infected adults, including those with acquired immunodeficiency syndrome (AIDS).1 3 8 13

Also recommended by CDC, NIH, and IDSA for treatment and secondary prophylaxis of CMV retinitis in HIV-infected older children and adolescents who can receive adult dosage.13 14

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CMV disease is not cured with currently available antiviral agents; long-term suppressive or maintenance therapy (secondary prophylaxis) is recommended to prevent relapse in HIV-infected patients following treatment of the initial infection.13 14

Efficacy of valganciclovir for secondary prophylaxis of CMV has not been evaluated in comparative studies, but use of the drug for this indication is supported by pharmacokinetic data in adults.1

Safety and efficacy not established for treatment of congenital CMV disease.1

Prevention of CMV Disease in Transplant Recipients

Prevention of CMV disease in adult kidney, heart, and kidney-pancreas transplant recipients at high risk (CMV-seronegative recipient/CMV-seropositive donor).1

Prevention of CMV disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age at high risk.1

Not indicated for use in adult or pediatric liver transplant recipients based on poor clinical study results in adults.1 9 Safety and efficacy for prevention of CMV disease in other solid organ transplant recipients (e.g., lung recipients) not established.1

Valcyte Dosage and Administration

Administration

Oral Administration

Administer orally with food.1

Oral solution is the preferred preparation in pediatric patients;1 use tablets in pediatric patients only if the calculated dose is within 10% of the tablet strength (i.e., a single 450-mg tablet may be used if the calculated dose is 405–495 mg).1 (See Pediatric Patients under Dosage and Administration.)

Use tablets (not the oral solution) in adults.1

Reconstitution

Reconstitute powder for oral solution at time of dispensing by adding 91 mL of purified water to provide a solution containing 250 mg of valganciclovir per 5 mL.1 Add water in 2 approximately equal aliquots and shake for 1 minute after each addition.1 Reconstituted solution is colorless to brownish yellow.1

Just prior to each dose, shake solution for about 5 seconds.1 Administer using the bottle adapter and dosing dispenser provided by the manufacturer.1

Dosage

Available as valganciclovir hydrochloride;1 dosage expressed in terms of valganciclovir.1

Valganciclovir tablets and ganciclovir capsules are not bioequivalent; valganciclovir tablets cannot be substituted for ganciclovir capsules on a one-to-one basis.1

Pediatric Patients

CMV Retinitis
Oral

Initial (induction) therapy in older children and adolescents who can receive adult dosage: 900 mg twice daily for 14–21 days.13 14

Maintenance (secondary prophylaxis) in older children and adolescents who can receive adult dosage: 900 mg once daily.13 14

Prevention of CMV Disease in Transplant Recipients
Oral

Pediatric heart or kidney transplant recipients 4 months to 16 years of age at high risk: Administer once daily starting within 10 days of transplantation and continued until 100 days posttransplantation.1 Use individualized dose based on body surface area (BSA) and estimated Clcr (modified Schwartz formula) and calculated using the following pediatric dosage equation:1

Pediatric dose (in mg) = 7 × BSA (in m2) × Clcr (modified Schwartz formula)

Modified Schwartz Clcr (in mL/minute per 1.73 m2) = [k × height (in cm)]/ serum creatinine (in mg/dL)

Where k = 0.45 for patients 4 months to <2 years of age, 0.55 for girls 2–16 years of age, 0.55 for boys 2 to <13 years of age, and 0.7 for boys 13–16 years of age.

To prevent overdosage, estimated Clcr used to calculate pediatric dose should not exceed 150 mL/minute per 1.73 m2, regardless of value calculated using the modified Schwartz formula.1 11 If estimated Clcr is >150 mL/minute per 1.73 m2, use the value of 150 mL/minute per 1.73 m2 to calculate the dose.1 11 Round calculated dose to nearest 25-mg increment.1 Maximum dose is 900 mg.1 11

Adults

CMV Retinitis
Oral

Initial (induction) therapy: 900 mg twice daily for 21 days.1 8 13 CDC, NIH, and IDSA recommend a duration of 14–21 days.13

After completion of induction therapy or in patients with inactive CMV retinitis, use a maintenance dosage of 900 mg once daily.1 8 13

Prevention of CMV Disease in Transplant Recipients
Oral

Heart or kidney-pancreas transplant patients at high risk: 900 mg once daily starting within 10 days of transplantation and continued until 100 days posttransplantation.1

Kidney transplant patients at high risk: 900 mg once daily starting within 10 days of transplantation and continued until 200 days posttransplantation.1

Prescribing Limits

Pediatric Patients

Prevention of CMV Disease in Transplant Recipients
Oral

Maximum 900 mg daily.1 11 To avoid overdosage, Clcr used to calculate pediatric dosage should not exceed 150 mL/minute per 1.73 m2.1 11 If patient's estimated Clcr exceeds 150 mL/minute per 1.73 m2, use 150 mL/minute per 1.73 m2 in the pediatric dosage equation.1 11 (See Pediatric Patients under Dosage and Administration.)

Special Populations

Renal Impairment

Adjust adult dosage if Clcr is <60 mL/minute.1

Dosage for Treatment of CMV Retinitis in Adults with Renal Impairment1

Clcr (mL/min)

Induction Dosage

Maintenance Dosage

40–59

450 mg twice daily

450 mg once daily

25–39

450 mg once daily

450 mg every 2 days

10–24

450 mg every 2 days

450 mg twice weekly

Do not use in adults undergoing hemodialysis (Clcr <10 mL/minute).1 (See Renal Impairment under Cautions.)

Calculate dosage for pediatric patients with renal impairment using the usually recommended pediatric dosage equation.1 (See Pediatric Dosage under Dosage and Administration.)

Cautions for Valcyte

Contraindications

  • Known hypersensitivity to valganciclovir, ganciclovir, or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hematologic Effects

Toxicity of valganciclovir, following metabolism to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia.1

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported with valganciclovir or ganciclovir.1

Cytopenia may occur at any time during therapy;1 degree of cytopenia may increase with continued valganciclovir therapy.1 Cell counts usually begin to return to baseline 3–7 days after discontinuance of the drug.1

Perform CBCs and platelet counts frequently, especially in those with baseline neutrophil counts <1000/mm3 or in those who previously developed leukopenia while receiving ganciclovir or other nucleoside analogs.1

Do not use in those with absolute neutrophil count <500/mm3, platelet count <25,000/mm3, or hemoglobin concentration <8 g/dL.1

Use with caution in those with preexisting cytopenias and those receiving myelosuppressive drugs or irradiation.1

More frequent monitoring for cytopenias may be warranted if therapy is changed from oral ganciclovir to valganciclovir.1

Teratogenicity and Impairment of Fertility

In animals, ganciclovir is teratogenic, suppresses fertility in females, and inhibits spermatogenesis with subsequent infertility in males.1

Since valganciclovir is metabolized to ganciclovir, consider valganciclovir a potential teratogen and expect the drug to have adverse effects on fertility.1 (See Pregnancy under Cautions.)

Mutagenicity and Carcinogenicity

In animals, ganciclovir is mutagenic and carcinogenic.1

Since valganciclovir is metabolized to ganciclovir, consider valganciclovir a potential carcinogen or mutagen in humans.1

Other Warnings/Precautions

Renal Effects

Acute renal failure may occur in geriatric patients (with or without impaired renal function), patients receiving potentially nephrotoxic drugs, and inadequately hydrated patients.1

Maintain adequate hydration in all patients.1

Use caution and adjust dosage based on Clcr.1 (See Renal Impairment under Dosage and Administration.)

Use caution in patients receiving concomitant therapy with potentially nephrotoxic drugs.1

Adherence to Dosage Regimen

Adherence to recommended dosage regimens is essential to avoid overdosage.1 In pediatric patients, adhere to recommended pediatric dosage equation, maximum estimated Clcr, and maximum daily dosage.1 11 (See Pediatric Dosage under Dosage and Administration.)

Bioavailability of ganciclovir from valganciclovir tablets is substantially higher than from ganciclovir capsules, and the tablets and capsules cannot be substituted on a one-to-one basis.1

Handling and Disposal

Because valganciclovir is considered a potential teratogen and carcinogen, observe caution when handling the drug.1 Do not break or crush valganciclovir tablets.1 Avoid direct contact of broken or crushed tablets, powder for oral solution, or reconstituted oral solution with skin or mucous membranes.1 If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with water.1

Specific Populations

Pregnancy

Category C.1

Expected to have reproductive toxicity similar to ganciclovir.1 Likely to produce temporary or permanent inhibition of spermatogenesis and also may suppress fertility in females.1 (See Teratogenicity and Impairment of Fertility under Cautions.)

Advise women of childbearing potential to use an effective method of contraception during and for at least 30 days after valganciclovir therapy.1

Advise men to use a reliable method of barrier contraception during and for at least 90 days after valganciclovir therapy.1

Lactation

Not known if distributed into human milk.1

Because of potential for serious adverse effects in the infant, women should not breast-feed infants while receiving valganciclovir.1

Instruct HIV-infected women not to breast-feed because of the risk of HIV transmission.1

Pediatric Use

Safety and efficacy not established in pediatric patients <4 months of age.1

Use for prevention of CMV disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age at high risk is based on pharmacokinetic, safety, and efficacy data from an open-label study in this age group and efficacy extrapolated from a study in adults.1 Safety and efficacy not established for prevention of CMV disease in any other pediatric solid organ transplant recipients.1

Safety and efficacy not established for treatment of congenital CMV disease.1 7

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Assess renal function before and during therapy; make appropriate dosage adjustments as necessary.1 (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Safety and efficacy not established.1

Renal Impairment

Dosage adjustment necessary in adults if Clcr <60 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Do not use in adults undergoing hemodialysis;1 use ganciclovir (with appropriate dosage adjustment) instead.1

Common Adverse Effects

Abdominal pain, anemia, diarrhea, graft rejection, increased serum creatinine, headache, insomnia, leukopenia, nausea, neutropenia, paresthesia, peripheral neuropathy, pyrexia, retinal detachment, thrombocytopenia, tremors, vomiting.1

Upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and neutropenia reported more frequently in children than adults.1

Interactions for Valcyte

No formal drug interaction studies have been performed using valganciclovir.1 Interactions associated with ganciclovir are expected to occur in patients receiving valganciclovir.1

Specific Drugs

Drug

Interaction

Comments

Didanosine

Potential increased AUC and peak plasma concentration of didanosine1

Monitor closely for didanosine toxicity1

Mycophenolate

Potential increased metabolite concentrations of both drugs1

Monitor closely in patients with renal impairment1

Myelosuppressive agents or irradiation

Potential additive hematologic toxicity1

Use with caution1

Probenecid

Potential increased AUC of ganciclovir1

Monitor closely for ganciclovir toxicity1

Zidovudine

Potential increased AUC of zidovudine and decreased AUC of ganciclovir1

Potential additive hematologic toxicity1

Valcyte Pharmacokinetics

Absorption

Bioavailability

Valganciclovir, a prodrug of ganciclovir, is well absorbed from GI tract1 2 3 and metabolized by intestinal and hepatic esterases to ganciclovir.1 Systemic exposure to prodrug is transient and low.1 3

GI absorption of valganciclovir substantially greater than absorption of oral ganciclovir resulting in plasma ganciclovir concentrations comparable to those achieved with IV ganciclovir.1 2 4 6

Absolute bioavailability of ganciclovir approximately 60% when oral valganciclovir given with food.1 2 Time to peak ganciclovir concentrations 1–3 hours.1

Food

Administration of valganciclovir with a high-fat meal (approximately 600 calories, 31 g fat) increases AUC and peak plasma concentrations of ganciclovir at steady-state by 30 and 14%, respectively.1

Distribution

Extent

Ganciclovir crosses the placenta (based on an ex vivo human placental model).1 Not known whether ganciclovir or valganciclovir distributed into human milk.1

Plasma Protein Binding

Ganciclovir plasma protein binding 1–2%;1 protein binding of valganciclovir not determined because of rapid conversion to ganciclovir.1

Elimination

Metabolism

Valganciclovir rapidly hydrolyzed to ganciclovir; no other metabolites detected.1 Ganciclovir phosphorylated to ganciclovir phosphate in CMV-infected cells.1

Elimination Route

Major route of elimination of valganciclovir is renal excretion as ganciclovir by glomerular filtration and active tubular secretion.1

Half-life

Adults: Mean half-life of ganciclovir after oral administration of valganciclovir is approximately 4 hours in healthy or HIV-positive/CMV-positive adults (with or without retinitis) and 6.6–6.8 hours in adult heart, kidney, and kidney-pancreas transplant recipients.1

Children: Mean half-life of ganciclovir after oral administration of valganciclovir is 2.8–4.8 hours in pediatric solid organ transplant recipients 4 months through 11 years of age and 4.4–6 hours in pediatric solid organ transplant recipients ≥12 years of age.1 Clearance is influenced by BSA and renal function.1

Special Populations

Pharmacokinetics not evaluated in hepatic impairment.1

Half-life increased in renal impairment.1 2 Data from otherwise healthy adults with renal impairment indicate the mean half-life is about 22 hours if Clcr is 11–20 mL/minute and about 68 hours if Clcr is ≤10 mL/minute.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

For Solution

25°C (may be exposed to 15–30°C).1 After reconstitution, refrigerate at 2–8°C for up to 49 days.1 Do not freeze.1

Actions and Spectrum

  • Valganciclovir is the l-valyl ester of ganciclovir.1 Prodrug with no antiviral activity until converted in vivo to ganciclovir and subsequently to the active ganciclovir triphosphate.1 2

  • Rapidly converted to ganciclovir by intestinal and hepatic esterases and then phosphorylated within CMV-infected cells to ganciclovir triphosphate, which has in vitro and in vivo inhibitory activity against CMV.1

  • Ganciclovir triphosphate exerts its antiviral activity on CMV by interfering with DNA synthesis.1

  • Resistance to ganciclovir reported after prolonged treatment with valganciclovir;1 ganciclovir resistance also reported in patients not previously treated with the drug.1

Advice to Patients

  • Importance of not substituting valganciclovir tablets for ganciclovir capsules on a one-to-one basis.1

  • Risk of adverse effects, including hematologic adverse effects.1 Necessity of monitoring blood counts and serum creatinine concentration.1 Necessity of dosage adjustment or discontinuance of valganciclovir if toxicity occurs.1

  • Importance of taking with food for optimum absorption.1

  • Risk of CNS adverse effects (e.g., seizures, sedation, dizziness, ataxia and/or confusion), which may affect tasks requiring alertness.1

  • Advise patients that valganciclovir is not a cure for CMV retinitis and that regular ophthalmologic examinations during therapy (at least every 4–6 weeks) are important.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or nonprescription drugs.1

  • Advise patients that ganciclovir is a potential carcinogen.1

  • Importance of both women and men using effective contraception during valganciclovir therapy.1 Advise women to use effective barrier contraception while receiving and for at least 30 days after therapy with the drug.1 Advise men to use effective barrier contraception while receiving and for at least 90 days after therapy with the drug.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women to avoid pregnancy and to not breast-feed infants.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Valganciclovir Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

For solution

250 mg (of valganciclovir) per 5 mL

Valcyte

Roche

Tablets, film-coated

450 mg (of valganciclovir)

Valcyte

Roche

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Valcyte 450MG Tablets (GENENTECH): 60/$2,829.85 or 180/$8,427.78

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Roche. Valcyte (valganciclovir hydrochloride) tablets prescribing information. South San Francisco, CA; 2010 Aug.

2. Brown F, Banken L, Saywell K et al. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin Pharmacokinet. 1999; 37:167-76. [PubMed 10496303]

3. Martin DF, Sierra-Madero J, Walmsley S et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med. 2002; 346:1119-26. [IDIS 479425] [PubMed 11948271]

4. Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J Clin Pharmacol. 1999; 39:800-4. [IDIS 430317] [PubMed 10434231]

6. Pescovitz MD, Rabkin J, Merion RM et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother. 2000; 44:2811-5. [IDIS 453059] [PubMed 10991864]

7. Roche, Nutley, NJ: Personal communication.

8. . Drugs for Non-HIV Viral Infections. Treat Guidel Med Lett. 2010; 8:71-82. [PubMed 20864902]

9. Lange WR. Dear healthcare provider letter: 2003 safety alert: valcyte (valganciclovir HCL tablets). Nutley, NJ; 2003 Sept 30. From FDA website ().

10. Vaudry W, Ettenger R, Jara P et al. Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients. Am J Transplant. 2009; 9:636-43. [PubMed 19260840]

11. US Food and Drug Administration (FDA). FDA drug safety communication: New dosing recommendations to prevent potential Valcyte (valganciclovir) overdose in pediatric transplant patients. 2010 Sep 15. From FDA website.

12. Humar A, Lebranchu Y, Vincenti F et al. The efficacy and safety of 200 days of valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010; 10:1228-37. [PubMed 20353469]

13. Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009; 58(RR-4):1-207; quiz CE1-4.

14. Mofenson LM, Brady MT, Danner SP et al. Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep. 2009; 58(RR-11):1-166. [PubMed 19730409]

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