VALGANCICLOVIR TABLETS USP

Valganciclovir hydrochloride (Valcyte, As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir.

After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases.

Valganciclovir is an antiviral medication used for the treatment of cytomegalovirus infections.

Valganciclovir is an antiviral medication used to treat cytomegalovirus infections.

As the

L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir.

After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases.

After this, it (being an analogue of guanosine) gets incorporated into DNA and thus cannot be properly read by DNA polymerase.

This results in the termination of the elongation of viral DNA.

Valganciclovir is well absorbed from the gastrointestinal tract and the absolute bioavailability from valganciclovir tablets (following administration with food) is approximately 60%.

Rapidly hydrolyzed in the intestinal wall and liver to ganciclovir.

No other metabolites have been detected.

The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion.

Approximately 4.08 hours.

Increased in patients with renal function impairment.

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It is expected that an overdose of valganciclovir could also possibly result in increased renal toxicity.

Valganciclovir for oral solution is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation.

Hypersensitivity to valganciclovir or ganciclovir.

Pediatric Dosage Prevention of

CMV disease in kidney transplant patients 4 months to 16 years of age Dose once a day within 10 days of transplantation until 200 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children) Prevention of CMV disease in heart transplant patients 1 month to 16 years of age Dose once a day within 10 days of transplantation until 100 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children) Valganciclovir for oral solution should be taken with food. 2.1 General Dosing Information Valganciclovir for oral solution should be taken with food.

Valganciclovir for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient. 2.3 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 valganciclovir for oral solution 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/1.73m 2, then a maximum value of 150 mL/min/1.73m 2 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 k value Pediatric Patient Age 0.33 Infants less than 1 year of age with low birth weight for gestational age 0.45 Infants less than 1 year of age with birth weight appropriate for gestational age 0.45 Children aged to less than 2 years 0.55 Boys aged to less than 13 years Girls aged to less than 16 years 0.7 Boys aged to 16 years The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used 1.

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 10 mg increment for the actual deliverable dose.

The oral dispenser is graduated in 0.2 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.

Valganciclovir for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above. modified Schwartz formula 2.4 Preparation of Valganciclovir 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, valganciclovir for oral solution must be prepared by the pharmacist as follows: Measure 91 mL of purified water in a graduated cylinder.

Shake the valganciclovir 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. 2.6 Handling and Disposal Caution should be exercised in the handling of valganciclovir for oral solution.

Because valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling, the powder for oral solution, and the constituted oral solution.

Avoid direct contact with 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 valganciclovir for oral solution according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity).

Valganciclovir for oral solution

Supplied as a white to off-white powder blend for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution.

Available in glass bottles containing approximately 100 mL of solution after constitution.

Each bottle can deliver up to a total of 88 mL of solution.Each bottle is supplied with a bottle adapter and 2 oral dispensers (NDC 42291-972-01).

Prior to dispensing to the patient, valganciclovir for oral solution must be prepared by the pharmacist.

Store dry powder at 20° to 25°C (68° to 77°F) .

Store constituted solution under refrigeration at 2° to 8°C (36° to 46°F) for no longer than 49 days.

Do not freeze.

Valganciclovir for oral solution and tablets are indicated for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age and in pediatric heart transplant patients 1 month to 16 years of age at risk for developing CMV disease.

The use of valganciclovir hydrochloride for oral solution and tablets for the prevention of CMV disease in pediatric kidney transplant patients 4 months to 16 years of age is based on two single-arm, open-label, non-comparative studies in patients 4 months to 16 years of age.

Study was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas).

Valganciclovir was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation.

Study was a safety and tolerability study where valganciclovir was administered once daily within 10 days of transplantation for a maximum of 200 days post-transplantation in pediatric kidney transplant patients.

The results of these studies were supported by previous demonstration of efficacy in adult patients.

The use of valganciclovir for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 1 month to 16 years of age is based on two studies (Study 1 described above and Study 3) and was supported by previous demonstration of efficacy in adult patients.

Study was a pharmacokinetic and safety study of valganciclovir for oral solution in pediatric heart transplant patients less than 4 months of age who received a single dose of valganciclovir for oral solution on each of two consecutive days.

A physiologically based pharmacokinetic (PBPK) model was developed based on the available pharmacokinetic data from pediatric and adult patients to support dosing in heart transplant patients less than 1 month of age.

However, due to uncertainty in model predictions for neonates, valganciclovir for oral solution is not indicated for prophylaxis in this.

The safety and efficacy of valganciclovir for oral solution and tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 4 months of age, in heart transplant patients less than 1 month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.

A pharmacokinetic and pharmacodynamic evaluation of valganciclovir for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system.

All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg per kg twice daily or valganciclovir for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily.

The pharmacokinetic results showed that in infants greater than 7 days to 3 months of age, a dose of 16 mg per kg twice daily of valganciclovir for oral solution provided ganciclovir systemic exposures (median AUC 0-12h = 23.6 [range 16.8 to 35.5] mcg ∙ h/mL; n = 6) comparable to those obtained in infants up to 3 months of age from a 6 mg per kg dose of intravenous ganciclovir twice daily (AUC 0-12h = 25.3 [range 2.4 to 89.7] mcg ∙ h/mL; n = 18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of valganciclovir tablets twice daily.

However, the efficacy and safety of intravenous ganciclovir and of valganciclovir for oral solution have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.

Studies of valganciclovir for oral solution or tablets have not been conducted in adults older than 65 years of age.

Clinical studies of valganciclovir did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Valganciclovir is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because renal clearance decreases with age, valganciclovir should be administered with consideration of their renal status.

Renal function should be monitored and dosage adjustments should be made accordingly.