VALGANCICLOVIR HYDROCHLORIDE (Page 5 of 10)

8.4 Pediatric Use

Valganciclovir hydrochloride 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 [see Indications and Usage (1.2),Dosage and Administration (2.3)].

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 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). Valganciclovir hydrochloride was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation. Study 2 was a safety and tolerability study where valganciclovir hydrochloride 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 [see Adverse Reactions (6.1),Clinical Pharmacology (12.3),Clinical Studies (14.2)].

The use of valganciclovir hydrochloride 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 [see Clinical Pharmacology (12.3),Clinical Studies (14.2)]. Study 3 was a pharmacokinetic and safety study of valganciclovir hydrochloride in pediatric heart transplant patients less than 4 months of age who received a single dose of valganciclovir hydrochloride 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 hydrochloride is not indicated for prophylaxis in this age group.

The safety and efficacy of valganciclovir hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride for oral solution provided ganciclovir systemic exposures (median AUC0-12h =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 (AUC0-12h =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 hydrochloride tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of valganciclovir hydrochloride 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.

8.5 Geriatric Use

Studies of valganciclovir hydrochloride 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 65 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 hydrochloride 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 hydrochloride should be administered with consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5),Warnings and Precautions (5.2),Use in Specific Populations (8.6),Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Dose reduction is recommended when administering valganciclovir to patients with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

For adult patients on hemodialysis (CrCl less than 10 mL/min), valganciclovir hydrochloride tablets should not be used. Adult hemodialysis patients should use ganciclovir in accordance with the dose-reduction algorithm cited in the CYTOVENE® -IV complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

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

10 OVERDOSAGE

Experience with Valganciclovir Hydrochloride Tablets: An overdose of valganciclovir hydrochloride could possibly result in increased renal toxicity [see Dosage and Administration (2.5),Use in Specific Populations (8.6)].Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of valganciclovir hydrochloride [see Clinical Pharmacology (12.3)] . Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Reports of adverse reactions after overdoses with valganciclovir, some with fatal outcomes, have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events:
Hematological toxicity: myelosuppression including pancytopenia, bone marrow failure, leukopenia, neutropenia, granulocytopenia
Hepatotoxicity: hepatitis, liver function disorder
Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute kidney injury, elevated creatinineGastrointestinal toxicity: abdominal pain, diarrhea, vomiting

Neurotoxicity: generalized tremor, seizure

11 DESCRIPTION

Valganciclovir hydrochloride for oral solution contains valganciclovir hydrochloride (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.

Valganciclovir is available as a powder for oral solution, which when constituted with water as directed contains 50 mg/mL valganciclovir free base. The inactive ingredients of valganciclovir hydrochloride for oral solution are mannitol, sodium benzoate, sucralose, tartaric acid and tutti-frutti flavoring.

Valganciclovir HCl, USP is a white to off-white crystalline powder with a molecular formula of C14 H22 N6 O5·HCl and a molecular weight of 390.83. The chemical name for valganciclovir HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7 and an n-octanol/water partition coefficient of 0.0095 at pH 7. The pKa for valganciclovir HCl is 7.6.

The chemical structure of valganciclovir HCl is:

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All doses in this insert are specified in terms of valganciclovir.

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