Valcyte (valganciclovir hydrochloride)

WARNING

HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS

• Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with Valcyte.
• Impairment of Fertility: Based on animal data and limited human data, Valcyte may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females.
• Fetal Toxicity: Based on animal data, Valcyte has the potential to cause birth defects in humans.
• Mutagenesis and Carcinogenesis: Based on animal data, Valcyte has the potential to cause cancers in humans.

The most common side effects of Valcyte in adults include:

• diarrhea
• fever
• fatigue
• nausea
• shaky movements (tremors)
• low white cell, red cell and platelet cell counts in blood tests
• headache
• sleeplessness
• urinary tract infection
• vomiting

The most common side effects of Valcyte in children include:

• diarrhea
• fever
• upper respiratory tract infection
• urinary tract infection
• vomiting
• low white blood cell counts in blood tests
• headache

These are not all the possible side effects of Valcyte.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General Dosing Information

• Adult patients should use Valcyte tablets, not Valcyte for oral solution.
• Valcyte for oral solution and tablets should be taken with food.
• Valcyte for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient.

Recommended Dosage In Adult Patients With Normal Renal Function

For dosage recommendations in adult patients with renal impairment.

Treatment Of CMV Retinitis

• Induction: The recommended dosage is 900 mg (two 450 mg tablets) taken orally twice a day for 21 days.
• Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day.

Prevention Of CMV Disease

• For adult patients who have received a heart or kidney-pancreas transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 100 days post-transplantation.
• For adult patients who have received a kidney transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 200 days post-transplantation.

Recommended Dosage In Pediatric Patients

Prevention Of CMV Disease In Pediatric Kidney Transplant Patients

• For pediatric kidney transplant patients 4 months to 16 years of age, the recommended once daily mg dose (7 x BSA x CrCl) should start within 10 days of post-transplantation until 200 days post-transplantation.

Prevention Of CMV Disease In Pediatric Heart Transplant Patients:

• For pediatric heart transplant patients 1 month to 16 years of age, the recommended once daily mg dose (7 x BSA x CrCl) should start within 10 days of transplantation until 100 days post-transplantation.
• The recommended once daily dosage of Valcyte is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below:
• Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m², then a maximum value of 150 mL/min/1.73m² should be used in the equation. The k values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 1.

Table 1 : k Values According to Pediatric Patient Age*

• Monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.
• All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose.
• The oral dispenser is graduated in 0.5 mL increments. A 50 mg dose is equivalent to 1 mL.
• If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. Valcyte for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Valcyte tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg). For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken.
• Before prescribing Valcyte tablets, pediatric patients should be assessed for the ability to swallow tablets.

Preparation Of Valcyte For Oral Solution

Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Prior to dispensing to the patient, Valcyte for oral solution must be prepared by the pharmacist as follows:

• Measure 91 mL of purified water in a graduated cylinder.
• Shake the Valcyte bottle to loosen the powder. Remove the child resistant bottle cap and add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about 1 minute. Add the remainder of water and shake the closed bottle well for about 1 minute. This prepared solution contains 50 mg of valganciclovir free base per 1 mL.
• Remove the child resistant bottle cap and push the bottle adapter into the neck of the bottle.
• Close bottle with child resistant bottle cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.
• Store constituted oral solution under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze.
• Write the discard date of the constituted oral solution on the bottle label.

The patient package insert, which includes the dosing instructions for patients, and 2 oral dispensers should be dispensed to the patient.

Dosage Recommendation For Adult Patients With Renal Impairment

Serum creatinine levels or estimated creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis  (CrCl less than 10 mL/min), a dose recommendation for Valcyte cannot be given.

Table 2 : Dosage Recommendations for Adult Patients with Impaired Renal Function

Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation.

Handling And Disposal

Caution should be exercised in the handling of Valcyte tablets and Valcyte for oral solution. Tablets should not be broken or crushed. Because valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets, the powder for oral solution, and the constituted oral solution. Avoid direct contact with broken or crushed tablets, the powder for oral solution, and the constituted oral solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.

Handle and dispose Valcyte according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity).

• In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for Valcyte.
• Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function.
• Following concomitant administration of Valcyte and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.
• Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.

Table 9 : Established and Other Potentially Significant Drug Interactions with Ganciclovir

• After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, Valcyte is expected to have reproductive toxicity effects similar to ganciclovir.
• No data are available regarding the presence of valganciclovir (prodrug) or ganciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production.