Valganciclovir (Valcyte) is an antiviral medicine. It is a prodrug that is converted in the body to ganciclovir. It  is used to treat the following conditions:

• For the prophylaxis of cytomegalovirus infection in solid organ transplant recipients:

  • Cytomegalovirus (CMV) high-risk adult patients (the donor is CMV seropositive and the recipient is CMV seronegative) undergoing kidney, heart, or kidney/pancreas transplantation.

  • High-risk pediatric patients of Cytomegalovirus undergoing a kidney transplant (age 4 months to 16 years) or heart transplant (age 1 month to 16 years)

• For the treatment of aids-related CMV retinitis:

• Off Label Use of Valganciclovir in Adults:

  • Treatment of mild to moderate cytomegalovirus disease (solid organ transplant recipients).

  • Treatment of HIV-infected patients with CMV esophagitis or colitis

  • Preemptive therapy of CMV (hematopoietic cell transplant recipients)

Valganciclovir dose in Adults

Valganciclovir dose in the treatment of Cytomegalovirus (CMV) retinitis (AIDS-related): Oral:

• An induction dose of 900 mg twice a day for 14 to 21 days.

• Maintenance:

  • Maintenance dose of 900 mg once a day.
  • 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 discontinuation of chronic maintenance therapy may be considered.

Valganciclovir dose in the prophylaxis of CMV (solid organ transplant recipients): Oral:

• • 900 mg once a day.
  • The duration of prophylaxis is dependent on the type of transplant and donor and recipient CMV serostatus.

Note:

Based on limited data, some centers utilize a lower dose of 450 mg once a day in intermediate-risk (CMV-seropositive [CMV R+] transplant recipients). This dosing strategy has not been studied prospectively it has only been primarily described in renal transplant recipients.

Valganciclovir dose in the treatment of mild to moderate CMV disease (solid organ transplant recipients) (off-label):

• 900 mg per oral twice a day until 1 or 2 consecutive weekly undetectable CMV viral load samples are obtained and there is the clinical resolution of disease (minimum treatment course: 2 weeks) (TTS [Kotton 2018])

Dose in the treatment of CMV esophagitis or colitis in HIV-infected patients (off-label): Oral:

• Initial treatment is started with IV ganciclovir.
• Switch to oral valganciclovir 900 mg twice a day for a total duration of 21 to 42 days, or until signs and symptoms resolve once patient is able to tolerate and absorb oral therapy.

Dose in the preemptive therapy of CMV (hematopoietic cell transplant recipients) (off-label) oral:

• <100 days post-transplant:

  • 900 mg twice daily for 7 days (autologous transplant) or 7 to 14 days (allogeneic transplant), then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative (Total induction and maintenance treatment is a minimum of 2 weeks when 14 days of twice-daily course is taken and 3 weeks with a 7-day induction course)

• >100 days post-transplant:

  • 900 mg twice a day for 7 to 14 days, then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative

Valganciclovir dose in Childrens

Note:

Valganciclovir tablets and ganciclovir capsules cannot be substituted on an mg-per-mg basis because they are NOT BIOEQUIVALENT. In pediatric patients, oral valganciclovir solution is preferred for accurate dosing.

The tablets of valganciclovir can be considered if the calculated dose is within 10% of the available tablet strength (450 mg). In pediatric patients, dosage may be based on either weight (mg/kg) or BSA (mg/m²). Extra precautions must be used to verify dosage parameters during calculations.

Dose in the treatment of Congenital CMV infection (continuation from the neonatal period):

• Infants 1 to 6 months:

  • 16 mg/kg oral dose every 12 hours for 6 months.

Dose in the Prevention of CMV disease:

• Following solid organ transplantation:

  • Heart transplantation: 

    • Therapy should be started within 10 days of transplantation and should be continued until 100 days post-transplantation.
    • Doses should be rounded off to the nearest 10 mg increment.
    • The maximum daily dose is 900 mg/day

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

    • A daily dose (mg) = 7 x body surface area x creatinine clearance*

  • Adolescents ≥17 years:

    • 900 mg once daily.

  • Kidney transplantation: 

    • Therapy should begin within 10 days of transplantation.
    • Continue the therapy until 200 days post-transplantation or 100 days post-transplantation if kidney-pancreas transplant in adolescents carried out in people ≥17 years.
    • Doses should be rounded off to the nearest 10 mg increment.
    • The maximum daily dose is 900 mg/day

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

    • Once-daily dose (mg) = 7 x body surface area x creatinine clearance*

  • Adolescents ≥17 years:

    • 900 mg once daily

• Liver transplantation:

  • Infants, Children, and Adolescents 4 months to 16 years:
    • Once-daily dose (mg) = 7 x body surface area x creatinine clearance*

Note:

In adults, studies in liver transplant patients reported a higher incidence of tissue-invasive CMV with valganciclovir relative to oral ganciclovir. In trials of the pediatric population, therapy was initiated within 10 days of transplantation and was continued until 100 days post-transplantation. The maximum daily dose: 900 mg/day

Dose in the treatment of HIV-exposed or HIV-positive:

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

  • Once daily dose (mg) equal to 7 x body surface area x creatinine clearance*
  • Consider therapy initiation for children <6 years of age who are CMV seropositive and have a CD4 percentage <5% of and for children ≥6 years of age who are CMV-seropositive and have CD4 cell counts <50 cells/mm³.
  • Consider cessation of therapy when CD4 cell count is >10% in children <6 years of age and >100 cells/mm for children ≥6 years of age.
  • The maximum daily dose: 900 mg/day

• Creatinine clearance calculation (based on the modified Schwartz formula):

  • CrCl (ml/minute/1.73 m ) = [k x height (cm)] ÷ 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 a modified Schwartz formula where k =

• 33 in infants <1 year of age with low birth weight for gestational age
• 45 in infants <1 year of age with birth weight appropriate for gestational age
• 45 in children 1 year to <2 years
• 55 in boys age 2 to <13 years
• 55 in girls age 2 to <16 years
• 7 in boys age 13 to 16 years

Dose in the treatment of CMV retinitis:

• Adolescents: Oral:

  • Induction (active retinitis):

    • 900 mg twice daily for 14 to 21 days

  • Maintenance:

    • Following induction treatment or for patients with inactive CMV retinitis who require maintenance therapy: 900 mg once daily for at least 3 to 6 months

Pregnancy Risk Category: C

• [US Boxed Warning]Based on animal data, valganciclovir may cause birth defects in people.
• Ganciclovir is converted to valganciclovir by ganciclovir, which has the same reproductive toxicities. Ganciclovir crosses over the placental barrier.
• Cytomegalovirus (CMV), infection can cause adverse events.
• Several medical conditions have been noted, including hearing loss, seizures, mental retardation and microcephaly.
• CMV retinitis can be treated during pregnancy in the same way as for women who are not HIV-infected.
• Systemic therapy should not be used during the first trimester.
• Valganciclovir can be used to treat maternal infections. However, it is not recommended to be used for asymptomatic mothers' disease. It is recommended that fetus monitoring be done.
• Valganciclovir should be used in HIV-infected pregnant women. The current recommendations are based upon data from ganciclovir usage in pregnant women after transplantation or late use in pregnancy in HIV-infected women.
• [US Boxed Warning]Based on limited animal data and limited human data it is possible to cause temporary or permanent suppressions of fertility in females, and inhibitions of spermatogenesis for males.
• Manufacturer recommends that females with reproductive potential undergo pregnancy testing before starting therapy. Effective contraception should only be used during treatment, and for 30 days afterwards; males should use barrier contraception during treatment and for 90 day after.

Valganciclovir use during breastfeeding:

• It is not known if breast milk contains ganciclovir and valganciclovir.
• The manufacturer does not recommend breastfeeding due to the risk of serious adverse reactions in breastfed babies.
• To reduce the risk of HIV transmission, pregnant women with HIV should stop breastfeeding.

Valganciclovir (Valcyte) dose in kidney disease:

• Induction dose:

  • CrCl ≥60 mL/minute:

    • No dosage adjustment necessary

  • CrCl 40 to 59 mL/minute:

    • 450 mg twice daily dose

  • CrCl 25 to 39 mL/minute:

    • 450 mg once daily dose

  • CrCl 10 to 24 mL/minute:

    • 450 mg dose 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.

  • 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 valganciclovir is dialyzable and should be administered following dialysis.

• Maintenance/prevention dose:

  • CrCl greater than and equal to 60 mL/minute: No dosage adjustment necessary

  • CrCl 40 to 59 mL/minute is 450 mg once daily

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

  • CrCl 10 to 24 mL/minute is 450 mg twice weekly

  • CrCl less than 10 mL/minute:

    • Manufacturer labeling:

      • Use is 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 a week.

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

    • Manufacturer labeling:

      • Use is 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 a week. valganciclovir is dialyzable and should be administered after dialysis.

Valganciclovir dose in Liver Disease:

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

Valganciclovir Side Effects (Common):

• Cardiovascular:

  • Hypertension

• Central Nervous System:

  • Headache
  • Insomnia

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Vomiting
  • Abdominal Pain

• Hematologic & Oncologic:

  • Anemia
  • Thrombocytopenia
  • Neutropenia

• Immunologic:

  • Graft Rejection

• Neuromuscular & Skeletal:

  • Tremor

• Ophthalmic:

  • Retinal Detachment

• Renal:

  • Increased Serum Creatinine

• Miscellaneous:

  • Fever

Side Effects of Valganciclovir (Less Common):

• Cardiovascular:

  • Hypotension
  • Peripheral Edema
  • Cardiac Arrhythmia

• Central Nervous System:

  • Peripheral Neuropathy
  • Paresthesia
  • Anxiety
  • Chills
  • Depression
  • Dizziness
  • Fatigue
  • Malaise
  • Pain
  • Agitation
  • Confusion
  • Hallucination
  • Psychosis
  • Seizure

• Dermatologic:

  • Dermatitis
  • Increased Wound Secretion
  • Night Sweats
  • Pruritus
  • Cellulitis

• Endocrine & Metabolic:

  • Hyperkalemia
  • Hypophosphatemia
  • Weight Loss

• Gastrointestinal:

  • Abdominal Distention
  • Constipation
  • Decreased Appetite
  • Dyspepsia
  • Oral Mucosa Ulcer
  • Dysgeusia
  • Pancreatitis

• Genitourinary:

  • Hematuria
  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Bone Marrow Depression
  • Febrile Neutropenia
  • Hemorrhage
  • Pancytopenia

• Hepatic:

  • Hepatic Insufficiency
  • Increased Serum ALT
  • Increased Serum AST

• Hypersensitivity:

  • Hypersensitivity Reaction

• Immunologic:

  • Organ Transplant Rejection

• Infection:

  • Candidiasis
  • Influenza
  • Wound Infection
  • Sepsis

• Neuromuscular & Skeletal:

  • Arthralgia
  • Back Pain
  • Muscle Spasm
  • Myalgia
  • Weakness
  • Limb Pain

• Ophthalmic:

  • Eye Pain
  • Macular Edema

• Otic:

  • Deafness

• Renal:

  • Decreased Creatinine Clearance
  • Renal Impairment
  • Renal Failure

• Respiratory:

  • Cough
  • Dyspnea
  • Pharyngitis
  • Upper Respiratory Tract Infection

• Miscellaneous:

  • Postoperative Complication
  • Postoperative Pain
  • Wound Dehiscence

Valganciclovir side effects (rare):

• Genitourinary:

  • Reduced fertility

Contraindication to Valganciclovir Include:

• Hypersensitivity (eg anaphylactic reaction to valganciclovir), ganciclovir or any other component of the formulation

Warnings and precautions

• Acute renal failure:
  • Acute renal failure can occur.
  • Patients receiving concomitant drugs nephrotoxic should ensure adequate hydration.
• Blood dyscrasias: [US Boxed Warning]:
  • Reports of severe leukopenia and neutropenia, as well as anemia, thrombocytopenia and pancytopenia and bone marrow failure (including anemia) have been made.
  • It can occur at any stage of the treatment, and it may get worse with continued use.
  • Usually, the cell counts begin to recover within three to seven days after treatment is stopped.
  • Patients with an absolute neutrophil count below 500 cells/mm3, platelet count under 25,000/mm3 or hemoglobin lower than 3.8g/dL should not be used.
  • Patients with pre-existing bone marrow suppression or cytopenias should be cautious.
  • Monitoring of CBC and platelet counts at baseline and during treatment, particularly in patients with renal impairment and infants, as well as those with drug-induced leukopenia and those with neutrophil counts 1,000/mm3 at the beginning of therapy.
• Carcinogenic/teratogenic: [US Boxed Warning]:
  • It can cause temporary or permanent suppression of fertility and spermatogenesis inhibition.
  • It can cause birth defects and cancer in humans.
  • It is teratogenic so women should be tested for pregnancy before initiation. They should also use effective contraception throughout treatment and for the 30 days thereafter.
  • For the first 90 days of treatment, males should use barrier contraception
• Renal impairment:
  • Patients with impaired renal function should be cautious; dosage adjustments may be necessary.

Valganciclovir: Drug Interaction

Monitor:

• CBC
• Platelet count
• Serum creatinine at baseline and periodically during therapy;

CBC and platelet count monitoring should be done more frequently during therapy in infants and in patients with renal impairment, those with previous drug-induced leukopenia, and those with neutrophil counts <1,000 cells/mm³ at treatment initiation. A pregnancy test prior to initiation in females of reproductive potential. 

How to administer Valganciclovir (Valcyte)?

• Oral: Valganciclovir should be administered with meals. Do not break or crush tablets. 

Mechanism of action of Valganciclovir (Valcyte):

• In the body, ganciclovir can be converted to valganciclovir quickly.
• Ganciclovir is phosphorylated to a substrate, which competely inhibits DNA polymerase's binding of deoxyguanosine triphosphate. This results in inhibition of viral DNA synthesizing.

Absorption:

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

Distribution: V :

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

Protein binding:

• Ganciclovir: 1% to 2%

Metabolism:

• Converted to ganciclovir by intestinal mucosal cells and hepatocytes

Bioavailability:

• With food: 60%; similar in pediatric patients 4 months to 16 years; neonates: Initial data: 54% (Acosta 2007)

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 eliminated in 4.08 hours; it is prolonged with renal impairment; Severe renal impairment: Up to 68 hours Heart, kidney, kidney-pancreas, or liver transplant patients: Mean range of elimination is 6.18 to 6.77 hours

Time to peak:

• Ganciclovir peaks in 1.7 to 3 hours

Excretion:

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

International Brands of Valganciclovir:

• APO-ValGANciclovir
• Auro-Valganciclovir
• TEVA-ValGANciclovir
• Valcyte
• Ganzos
• Rovalcyte
• RoValcyte
• Vagacyte
• Valcyte
• Valixa

Valganciclovir brands in Paksitan: