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ValGANciclovir

Pronunciation

(val gan SYE kloh veer)

Index Terms

  • Valganciclovir HCl
  • Valganciclovir Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Oral:

Valcyte: 50 mg/mL (88 mL) [contains saccharin sodium, sodium benzoate; tutti-frutti flavor]

Generic: 50 mg/mL (88 mL)

Tablet, Oral:

Valcyte: 450 mg

Generic: 450 mg

Brand Names: U.S.

  • Valcyte

Pharmacologic Category

  • Antiviral Agent

Pharmacology

Valganciclovir is rapidly converted to ganciclovir in the body. The bioavailability of ganciclovir from valganciclovir is increased 10-fold compared to oral ganciclovir. A dose of 900 mg achieved systemic exposure of ganciclovir comparable to that achieved with the recommended doses of intravenous ganciclovir of 5 mg/kg. Ganciclovir is phosphorylated to a substrate which competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase resulting in inhibition of viral DNA synthesis.

Absorption

Well absorbed; high-fat meal increases AUC by 30%

Distribution

Vdss: Ganciclovir: 0.7 L/kg; widely to all tissue including CSF and ocular tissue

Metabolism

Converted to ganciclovir by intestinal mucosal cells and hepatocytes

Excretion

Urine (80% to 90%; primarily as ganciclovir)

Time to Peak

Ganciclovir: 1-3 hours

Half-Life Elimination

Pediatric patients (heart, kidney, or liver transplant): Mean range:

4 months to 2 years: 2.8 to 4.5 hours

2 to 12 years: 2.8 to 3.8 hours

12 to 16 years: 4.9 to 6 hours

Adults:

Ganciclovir: 4.08 hours, prolonged with renal impairment; Severe renal impairment: Up to 68 hours

Heart, kidney, kidney-pancreas, or liver transplant patients: Mean range: 6.18 to 6.77 hours

Protein Binding

Ganciclovir: 1% to 2%

Use: Labeled Indications

Cytomegalovirus, prophylaxis (solid organ transplant recipients):

Prevention of cytomegalovirus (CMV) in high-risk adult patients (donor CMV seropositive/recipient CMV seronegative) undergoing kidney, heart, or kidney/pancreas transplantation

Prevention of CMV in high risk pediatric patients undergoing kidney transplant (age 4 months to 16 years) or heart transplant (age 1 month to 16 years)

CMV retinitis, treatment (AIDS-related): Treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS)

Off Label Uses

Cytomegalovirus disease, treatment (solid organ transplant recipients):

Based on the Transplantation Society International Cytomegalovirus (CMV) Consensus Group guidelines, valganciclovir is an effective and recommended agent in the treatment of nonsevere CMV disease in solid organ transplant recipients.

CMV esophagitis or colitis treatment in HIV-infected patients (adolescents and adults)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, valganciclovir is an effective and recommended agent for the treatment of esophagitis or colitis due to CMV disease in adolescent and adult HIV-infected patients.

CMV, preemptive therapy (hematopoietic cell transplant recipients)

Based on the American Society for Blood and Marrow Transplantation (ASBMT) Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients, ganciclovir is an effective and recommended agent in the preemptive management of CMV in bone marrow transplant recipients.

CMV, secondary prophylaxis (solid organ transplant recipients):

Based on the Transplantation Society International CMV Consensus Group guidelines, valganciclovir is an effective and recommended agent in the secondary prophylaxis of CMV in solid organ transplant recipients.

Contraindications

Hypersensitivity to valganciclovir, ganciclovir, or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to acyclovir or valacyclovir

Dosing: Adult

Cytomegalovirus (CMV) retinitis, treatment (AIDS-related): Oral:

Manufacturer's labeling:

Induction: 900 mg twice daily for 21 days

Maintenance: Following induction treatment, or for patients with inactive CMV retinitis who require maintenance therapy: 900 mg once daily

Alternate dosing (HHS [OI adult 2016]):

Induction: 900 mg twice daily for 14 to 21 days

Maintenance: 900 mg once daily; may consider discontinuation of chronic maintenance therapy in patients that have received 3 to 6 months of treatment, have inactive lesions, and CD4 count >100 cells/mm3 for 3 to 6 months in response to antiretroviral therapy

CMV, prophylaxis (solid organ transplant recipients): Oral:

Manufacturer’s labeling: 900 mg once daily beginning within 10 days of transplantation; continue therapy until 100 days (heart or kidney-pancreas transplant) or 200 days (kidney transplant) post-transplantation

Alternate dosing: 900 mg once daily; duration of prophylaxis is dependent on type of transplant, as well as donor and recipient CMV serostatus (Kotton 2013)

CMV disease (nonsevere), treatment (solid organ transplant recipients) (off-label use): Oral: 900 mg twice daily until 1 or 2 consecutive undetectable CMV viral load samples are obtained (minimum treatment course: 2 weeks) (Kotton 2013)

CMV esophagitis or colitis in HIV-infected patients (off-label use): Oral: Treat initially with ganciclovir IV; once patient is able to absorb and tolerate oral therapy, may switch to oral valganciclovir 900 mg twice daily for a total duration of 21 to 42 days, or until signs and symptoms have resolved (HHS [OI adult 2016])

CMV, preemptive therapy (hematopoietic cell transplant recipients) (off-label use) (Tomblyn 2009): Oral:

<100 days post-transplant: 900 mg twice daily for 7 days (autologous transplant) or 7 to 14 days (allogenic transplant), then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative (minimum total induction and maintenance treatment is 2 weeks when 14 days of twice daily is used and 3 weeks when a 7-day induction course is used)

>100 days post-transplant: 900 mg twice daily for 7 to 14 days, then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative

CMV, secondary prophylaxis (solid organ transplant recipients) (off-label use): Oral: 900 mg once daily for 1 to 3 months after completion of treatment for CMV disease (Kotton 2013)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Infants, Children, and Adolescents 1 month to 16 years:

CMV disease (prophylaxis) following heart transplantation: Oral: Dose (mg) = 7 x body surface area x creatinine clearance (see Calculation below) once daily beginning within 10 days of transplantation; continue therapy until 100 days post-transplantation. Doses should be rounded to the nearest 10 mg increment; maximum dose: 900 mg daily.

Infants, Children, and Adolescents 4 months to 16 years:

CMV disease (prophylaxis) following kidney transplantation: Oral: Dose (mg) = 7 x body surface area x creatinine clearance (see Calculation below) once daily beginning within 10 days of transplantation; continue therapy until 200 days post-transplantation. Doses should be rounded to the nearest 10 mg increment; maximum dose: 900 mg daily.

Calculation of creatinine clearance: CrCl (mL/minute/1.73 m2) = [k x Height (cm)] divided by serum creatinine (mg/dL)

Note: If the calculated CrCl is >150 mL/minute/1.73 m2, then a maximum value of 150 mL/minute/1.73 m2 should be used to calculate the dose.

Note: Calculated using modified Schwartz formula where k is as follows:

Infants with low birth weight for gestational age: k = 0.33

Infants with birth weight appropriate for gestational age: k = 0.45

Children 1 to <2 years: k = 0.45

Girls 2 to 16 years: k = 0.55

Boys 2 to <13 years: k = 0.55

Boys 13 to 16 years: k = 0.7

Adolescents >16 years: Oral: Refer to adult dosing

Dosing: Renal Impairment

Infants, Children, and Adolescents 1 month to 16 years: No dosage adjustment necessary; calculation for pediatric dosing adjusts for renal function.

Adolescents >16 years and Adults:

Induction dose:

CrCl ≥60 mL/minute: No dosage adjustment necessary

CrCl 40 to 59 mL/minute: 450 mg twice daily

CrCl 25 to 39 mL/minute: 450 mg once daily

CrCl 10 to 24 mL/minute: 450 mg every 2 days

CrCl <10 mL/minute:

Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir

Alternate dosing: HIV-1 infected persons: Consider valganciclovir solution 200 mg 3 times weekly (Lucas, 2014)

End stage renal disease (ESRD) on intermittent hemodialysis (IHD):

Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir.

Alternate dosing: HIV-1 infected persons: Consider valganciclovir solution 200 mg 3 times weekly (Lucas, 2014); valganciclovir is dialyzable and should be administered following dialysis.

Maintenance/prevention dose:

CrCl ≥60 mL/minute: No dosage adjustment necessary

CrCl 40 to 59 mL/minute: 450 mg once daily

CrCl 25 to 39 mL/minute: 450 mg every 2 days

CrCl 10 to 24 mL/minute: 450 mg twice weekly

CrCl <10 mL/minute:

Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir

Alternate dosing: HIV infected persons: Consider valganciclovir solution 100 mg 3 times weekly (Lucas, 2014)

End stage renal disease (ESRD) on intermittent hemodialysis (IHD):

Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir.

Alternate dosing: HIV-1 infected persons: Consider valganciclovir solution: 100 mg 3 times weekly (Lucas, 2014); valganciclovir is dialyzable and should be administered following dialysis.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer labeling (has not been studied).

Reconstitution

Oral solution: Reconstitute powder for oral solution with appropriate amount of water (in 2 equal portions) as specified in the manufacturer’s labeling. Shake well for 1 minute after each addition. Discard any unused medication after 49 days. A reconstituted 100 mL bottle will only provide 88 mL of solution for administration.

Extemporaneously Prepared

Note: Commercial preparation is available (50 mg/mL)

A 60 mg/mL oral suspension may be with tablets and a 1:1 mixture of Ora-Sweet® and Ora-Plus®. Crush sixteen 450 mg tablets and reduce to a fine powder. Add 1 mL portions of chosen vehicle (10 mL total) and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated amber glass bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well" and "refrigerate". Stable for 35 days refrigerated.

Henkin CC, Griener JC, and Ten Eick AP, "Stability of Valganciclovir in Extemporaneously Compounded Liquid Formulations," Am J Health Syst Pharm, 2003, 60(7):687-90.12701551

Administration

Oral: Valganciclovir should be taken with meals. The preferred dosage form for pediatric patients is the oral solution; however, valganciclovir tablets may be used so long as the calculated dose is within 10% of the available tablet strength (450 mg).

Due to the carcinogenic and mutagenic potential, avoid direct contact with broken or crushed tablets, powder for oral solution, and oral solution. Consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. However, there is no consensus on the need for these precautions.

Dietary Considerations

Should be taken with meals.

Storage

Oral solution: Store dry powder at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store oral solution at 2°C to 8°C (36°F to 46°F); do not freeze. Discard any unused medication after 49 days.

Tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Didanosine: Ganciclovir-Valganciclovir may increase the serum concentration of Didanosine. Monitor therapy

Imipenem: Ganciclovir-Valganciclovir may enhance the adverse/toxic effect of Imipenem. Specifically, the risk of seizures may be increased. Management: Avoid concomitant use of these agents unless the prospective benefits of therapy outweigh the risks. Consider therapy modification

Mycophenolate: May increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Mycophenolate. Monitor therapy

Probenecid: May increase the serum concentration of Ganciclovir-Valganciclovir. Monitor therapy

Tenofovir Products: May increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

Zidovudine: Ganciclovir-Valganciclovir may enhance the adverse/toxic effect of Zidovudine. Specifically, hematologic toxicity may be enhanced. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypertension (12% to 18%)

Central nervous system: Headache (6% to 22%), insomnia (6% to 20%)

Gastrointestinal: Diarrhea (16% to 41%), nausea (8% to 30%), vomiting (3% to 21%), abdominal pain (15%)

Hematologic: Anemia (≤31%), thrombocytopenia (≤22%), neutropenia (3% to 19%)

Immunologic: Graft rejection (24%)

Neuromuscular & skeletal: Tremor (12% to 28%)

Ophthalmic: Retinal detachment (15%)

Renal: Increased serum creatinine (Scr >1.5 to 2.5 mg/dL: 12% to 50%; Scr >2.5: 3% to 17%)

Miscellaneous: Fever (9% to 31%)

1% to 10%:

Cardiovascular: Edema (<5%), hypotension (<5%), peripheral edema (<5%)

Central nervous system: Peripheral neuropathy (9%), paresthesia (≤8%), agitation (<5%), confusion (<5%), depression (<5%), dizziness (<5%), fatigue (<5%), hallucination (<5%), pain (<5%), psychosis (<5%), seizure (<5%)

Dermatologic: Acne vulgaris (<5%), dermatitis (<5%), increased wound secretion (<5%), pruritus (<5%)

Endocrine & metabolic: Dehydration (<5%), hyperglycemia (<5%), hyperkalemia (<5%), hypocalcemia (<5%), hypokalemia (<5%), hypomagnesemia (<5%), hypophosphatemia (<5%)

Gastrointestinal: Abdominal distention (<5%), constipation (<5%), decreased appetite (<5%), dyspepsia (<5%)

Genitourinary: Dysuria (<5%), urinary tract infection (<5%)

Hematologic: Aplastic anemia (<5%), bone marrow depression (<5%), pancytopenia (<5%)

Hepatic: Ascites (<5%), hepatic insufficiency (<5%)

Hypersensitivity: Hypersensitivity reaction (<5%)

Immunologic: Organ transplant rejection (6% to 9%)

Infection: Localized infection (<5%), sepsis (<5%), wound infection (<5%)

Local: Catheter infection (3%)

Neuromuscular & skeletal: Arthralgia (<5%), back pain (<5%), limb pain (<5%), muscle cramps (<5%), weakness (<5%)

Renal: Decreased creatinine clearance (<5%), renal impairment (<5%)

Respiratory: Cough (<5%), dyspnea (<5%), nasopharyngitis (<5%), pharyngitis (<5%), pleural effusion (<5%), rhinorrhea (<5%), upper respiratory tract infection (<5%)

Miscellaneous: Postoperative complication (<5%), postoperative pain (<5%), wound dehiscence (<5%)

Postmarketing and/or case reports (Limited to important or life-threatening): Acute renal failure, anaphylaxis, bone marrow aplasia, reduced fertility (males)

ALERT: U.S. Boxed Warning

Hematologic toxicity:

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia and aplastic anemia have been reported in patients treated with valganciclovir.

Impairment of fertility:

Based on animal data, valganciclovir may cause temporary or permanent inhibition of spermatogenesis.

Fetal toxicity:

Based on animal data, valganciclovir has the potential to cause birth defects in humans.

Mutagenesis and carcinogenesis:

Based on animal data, valganciclovir has the potential to cause cancers in humans.

Warnings/Precautions

Concerns related to adverse effects:

• Acute renal failure: Acute renal failure may occur; ensure adequate hydration and use with caution in patients receiving concomitant nephrotoxic agents.

• Blood dyscrasias: [US Boxed Warning]: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia and aplastic anemia have been reported; do not use in patients with an absolute neutrophil count <500/mm3, platelet count <25,000/mm3, or hemoglobin <8 g/dL. Use with caution in patients with pre-existing bone marrow suppression, cytopenias, or in those receiving myelosuppressive drugs/irradiation. Monitor CBC and platelet count at baseline and periodically during therapy.

• Carcinogenic/teratogenic: [US Boxed Warning]: May cause temporary or permanent inhibition of spermatogenesis; has the potential to cause birth defects and cancers in humans. Due to its teratogenic potential, females should use effective contraception during treatment and for 30 days after; males should use barrier contraception during treatment and for 90 days after. Fertility may be temporarily or permanently impaired in males and females.

Disease-related concerns:

• Renal impairment: Use with caution in patients with impaired renal function; dosage adjustment required.

Special populations:

• Elderly: Acute renal failure may occur in elderly patients with or without pre-existing renal impairment; use with caution and adjust dose as needed based on renal function.

• Liver transplant recipients: Not indicated for use in liver transplant patients (higher incidence of tissue-invasive CMV relative to oral ganciclovir was observed in trials).

• Pediatric: The preferred dosage form for pediatric patients is the oral solution; however, valganciclovir tablets may be used so long as the calculated dose is within 10% of the available tablet strength (450 mg). Use of valganciclovir for the treatment of congenital CMV disease has not been evaluated.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

Monitoring Parameters

Retinal exam (at least every 4-6 weeks) when treating CMV retinitis, CBC, platelet count, serum creatinine at baseline and periodically during therapy

Pregnancy Considerations

[US Boxed Warning]: May cause temporary or permanent inhibition of spermatogenesis; has the potential to cause birth defects in humans. Valganciclovir is converted to ganciclovir and shares its reproductive toxicity. Ganciclovir crosses the placenta. Based on animal data, temporary or permanent impairment of fertility may occur in males and females. Ganciclovir is also teratogenic in animals. The manufacturer recommends females of reproductive potential undergo pregnancy testing prior to therapy. Females should use effective contraception during treatment and for 30 days after; males should use barrier contraception during treatment and for 90 days after.

Adverse events following congenital CMV infection may also occur. Hearing loss, mental retardation, microcephaly, seizures, and other medical problems have been observed. The indications for treating CMV retinitis during pregnancy are the same as in non-pregnant HIV infected woman; however systemic therapy should be avoided during the first trimester when possible. Use of valganciclovir is recommended to treat maternal infection, but not recommended for the treatment of asymptomatic maternal disease for the sole purpose of preventing infant infection. Monitoring of the fetus is recommended. Current recommendations for use of valganciclovir in HIV infected pregnant women are based on data from ganciclovir use in pregnant women following organ transplant or use late in pregnancy in non-HIV infected women [DHHS Adult OI, 2014].

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, abdominal pain, or insomnia. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), pale skin, confusion, loss of strength and energy, dark urine, jaundice, tremors, difficulty moving, rigidity, change in balance, hallucinations, depression, burning or numbness feeling, seizures, severe headache, severe dizziness, severe fatigue, swelling of arms or legs, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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