Valganciclovir

Pronunciation: (val-gan-SYE-kloe-vir)
Class: Antiviral agent

Trade Names

Valcyte
- Tablets 450 mg
- Powder for oral solution 50 mg/mL

Pharmacology

Valganciclovir is a prodrug of ganciclovir, which inhibits cytomegalovirus (CMV) replication by inhibition of viral DNA synthesis.

Pharmacokinetics

Absorption

Well absorbed from the GI tract. Bioavailability is approximately 60%. T _max is approximately 1 to 3 h. When administered with high-fat meal, AUC increased 30% and C _max increased 14%. Administer with food.

Distribution

Valganciclovir is metabolized to ganciclovir. Protein binding of ganciclovir is approximately 1% to 2%. Vd of ganciclovir is approximately 0.703 L/kg.

Metabolism

Rapidly metabolized in the intestinal wall and liver to ganciclovir.

Elimination

Major route of elimination is by renal excretion. The half-life is approximately 4 h (tablets).

Special Populations

Renal Function Impairment

Dosage reductions according to CrCl are required for valganciclovir.

Hepatic Function Impairment

The safety and efficacy have not been studied in patients with hepatic impairment.

Elderly

Pharmacokinetics have not been established in elderly patients.

Children

Children produce similar exposure to adult patients.

Indications and Usage

Treatment of CMV retinitis in adult patients with AIDS; prevention of CMV disease in kidney, heart, and kidney-pancreas transplant adult patients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R−]); for the prevention of CMV disease in kidney and heart transplant pediatric patients at high risk.

Contraindications

Hypersensitivity to ganciclovir or valganciclovir.

Dosage and Administration

CMV Retinitis
Adults

PO 900 mg twice daily with food for 21 days. Following this induction phase, or in patients with inactive CMV retinitis, give 900 mg every day with food.

Prevention of CMV Disease in Heart, Kidney, and Kidney-Pancreas Transplantation
Adults

PO 900 mg every day with food, starting within 10 days of transplantation until 100 days posttransplantation.

Prevention of CMV Disease in Kidney and Heart Transplantation
Children 4 mo to 16 yr of age

PO Dose is administered once daily starting within 10 days of transplantation until 100 days posttransplantation and is based on BSA and CrCl. All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. See the following equation: Dose (mg) = 7 × BSA × CrCl (calculated using a modified Schwartz formula). î€

Where k = 0.45 for patients younger than 2 yr of age (note: k value is 0.45 instead of typical value 0.55); k = 0.55 for boys 2 to younger than 13 yr of age and for girls 2 to 16 yr of age; and k = 0.7 for boys 13 to 16 yr of age.

Decreased Renal Function
Adults Induction

PO 900 mg twice daily (CrCl 60 mL/min or more); 450 mg twice daily (CrCl 40 to 59 mL/min); 450 mg every day (CrCl 25 to 39 mL/min); 450 mg every 2 days (CrCl 10 to 24 mL/min); not recommended for CrCl less than 10 mL/min on hemodialysis.

Maintenance

PO 900 mg/day (CrCl 60 mL/min or more); 450 mg every day (CrCl 40 to 59 mL/min); 450 mg every 2 days (CrCl 25 to 39 mL/min); 450 mg twice/wk (CrCl 10 to 24 mL/min); not recommended for CrCl less than 10 mL/min on hemodialysis.

General Advice

Administer with food; tablets should not be broken or crushed.
Adult patients should use the tablet doseform and not the oral solution.
The bioavailablity of ganciclovir from valganciclovir is significantly higher than from ganciclovir capsules. Therefore, valganciclovir tablets cannot be substituted for ganciclovir capsules on a 1-to-1 basis.

Storage/Stability

Store at controlled room temperature (59° to 86°F). Store constituted solution under refrigeration (36° to 46°F) for no longer than 49 days.

Drug Interactions

Interaction studies have not been conducted; however, because valganciclovir is converted to ganciclovir, interactions associated with ganciclovir are expected to occur for valganciclovir.

Didanosine

Plasma levels of didanosine may be increased, while didanosine may decrease levels of ganciclovir. Didanosine dosage adjustment may be needed.

Mycophenolate mofetil

In patients with normal renal function, no pharmacokinetic interaction was observed. However, closely monitor patients with renal function impairment because concentrations of ganciclovir and mycophenolate metabolites may be increased.

Myelosuppressive drugs, irradiation

Risk of cytopenia may be increased. Use with caution.

Nephrotoxic drugs

Risk of renal failure may be increased. Use with caution

Probenecid

May reduce ganciclovir renal Cl and increase ganciclovir serum levels.

Trimethoprim

Ganciclovir renal Cl may be decreased while the half-life may be increased.

Zidovudine

Both ganciclovir and zidovudine can cause anemia and neutropenia. Zidovudine dosage adjustment may be needed.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (18%); hypotension (at least 5% or selected serious adverse reaction).

CNS

Tremors (28%); headache (22%); insomnia (20%); peripheral neuropathy (9%); paresthesia (8%); agitation, confusion, convulsions, depression, dizziness, fatigue, hallucinations, psychosis (at least 5% or selected serious adverse reactions).

Dermatologic

Acne, dermatitis, pruritus (at least 5% or selected serious adverse reactions).

EENT

Retinal detachment (15%); pharyngitis/nasopharyngitis, rhinorrhea (at least 5% or selected serious adverse reactions).

GI

Diarrhea (41%); nausea (30%); vomiting (21%); abdominal pain (15%); abdominal distention, ascites, constipation, dyspepsia (at least 5% or selected serious adverse reactions).

Genitourinary

Decreased CrCl, dysuria, renal impairment, UTI (at least 5% selected or serious adverse reactions).

Hematologic

Anemia (1% to 31%); thrombocytopenia (0% to 22%); neutropenia (3% to 19%); aplastic anemia, bone marrow depression, pancytopenia (at least 5% or selected serious adverse reactions).

Hepatic

Abnormal hepatic function (at least 5% or selected serious adverse reactions).

Metabolic-Nutritional

Decreased appetite, dehydration, hyperglycemia, hyperkalemia, hypocalcemia, hypokalemia, hypomagnesemia, hypophosphatemia (at least 5% or selected serious adverse reactions).

Musculoskeletal

Arthralgia, back pain, limb pain, muscle cramps (at least 5% or selected serious adverse reactions).

Respiratory

Cough, dyspnea, pleural effusion, upper respiratory tract infection, (at least 5% or selected serious adverse reactions).

Miscellaneous

Pyrexia (31%); graft rejection (24%); catheter-related infections (3%); edema, hypersensitivity, increased wound drainage, local and systemic infections and sepsis, pain, peripheral edema, postoperative pain and complications, weakness, wound dehiscence, wound infection and complications (at least 5% or selected serious adverse reactions).

Precautions

Warnings

Toxicity includes anemia, granulocytopenia, and thrombocytopenia. In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis.

Monitor

Monitor CBC with differential and platelet counts frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1,000 cells/mcL at the beginning of treatment. Monitor serum creatinine or CrCl values carefully to allow for dosage adjustments in renally impaired patients.

Pregnancy

Category C .

Lactation

Undetermined; however, the CDC recommends that HIV-infected mothers not breast-feed infants to avoid risk of HIV transmission.

Children

Safety and efficacy have been established in children 4 mo to 16 yr of age for the prevention of CMV disease in kidney and heart transplant patients. Safety and efficacy have not been established in children for the prevention of CMV disease in liver transplant patients, solid organ transplants other than those indicated, or for the treatment of congenital CMV disease.

Elderly

Because elderly patients are more likely to have decreased renal function, take care in dose selection.

Renal Function

Use with caution and adjust dosage.

Hepatic Function

Safety and efficacy have not been studied in patients with hepatic impairment.

Contact with skin

If broken or crushed tablet comes in contact with skin or mucus membranes, wash thoroughly with soap and water and rinse eyes thoroughly with plain water.

Hematologic effects

Severe leukopenia, neutropenia, bone marrow depression, and aplastic anemia have been reported; therefore, use with caution in patients with preexisting cytopenias, or those who have received or are receiving myelosuppressive drugs or irradiation.

Renal effects

Acute renal failure my occur in elderly patients, patients receiving potential nephrotoxic agents, and patients without adequate hydration.

Overdosage

Symptoms

Abdominal pain, acute renal failure, bone marrow depression, convulsion, diarrhea, elevated creatinine, generalized tremor, granulocytopenia, hepatitis, leukopenia, liver function disorder, medullary aplasia, neutropenia, pancytopenia, renal toxicity, worsening of hematuria, vomiting.

Patient Information

Advise patient to read patient information leaflet before beginning therapy and with each refill.
Warn patient that valganciclovir tablets cannot be substituted for ganciclovir capsules on a 1:1 basis.
Review dosing schedule with patient.
Instruct patient to take each dose with food to maximize absorption into the body.
Advise patient not to chew, crush, break, or split tablets. If direct contact with broken or crushed tablets occurs, advise patient to wash thoroughly with soap and water and rinse eyes thoroughly with plain water.
Advise patient that this drug is not a cure for CMV retinitis and that retinitis may continue to progress during or following treatment.
Advise patient that valganciclovir is converted to ganciclovir in the body and that it may cause infertility and birth defects. Advise men to use barrier contraception during and for at least 90 days following treatment and women to use effective contraception during treatment and for at least 30 days following treatment.
Advise men that drug may cause temporary or permanent infertility.
Advise patient that drug may cause sedation, dizziness, and/or confusion, and to use caution while performing tasks requiring alertness, including driving and operating machinery.
Advise patient to immediately report any of the following to health care provider: fever or other signs of infection, sore throat, unusual bruising or bleeding.
Advise patient that diarrhea, nausea, vomiting, and headache are common side effects and to inform health care provider if they occur and are intolerable.
Advise HIV-infected mothers not to breast-feed infants to avoid risk of HIV transmission to the infant.