VALGANCICLOVIR HYDROCHLORIDE (Page 2 of 10)

2.5 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 Valganciclovir hydrochloride tablets cannot be given [see Use in Specific Populations (8.5,8.6),Clinical Pharmacology (12.3)].

Table 2 Dosage Recommendations for Adult Patients with Impaired Renal Function
*An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas: For males = (140 – age [years]) x (body weight [kg]) ———————————————— (72) x (serum creatinine [mg/dL])For females = 0.85 x male value
Valganciclovir hydrochloride 450 mg Tablets
CrCl* (mL/min) Induction Dose Maintenance/ Prevention Dose
≥ 60 900 mg twice daily 900 mg once daily
40 to 59 450 mg twice daily 450 mg once daily
25 to 39 450 mg once daily 450 mg every 2 days
10 to 24 450 mg every 2 days 450 mg twice weekly
< 10(on hemodialysis) not recommended not recommended

Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation [see Dosage and Administration (2.3)].

2.6 Handling and Disposal

Caution should be exercised in the handling of valganciclovir hydrochloride tablets and valganciclovir 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 [see Warnings and Precautions (5.4,5.5)]. 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 valganciclovir hydrochloride according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity)2.

3 DOSAGE FORMS & STRENGTHS

Valganciclovir hydrochloride for oral solution: 50 mg per mL, supplied as a white to off-white powder blend for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution. Available in amber colored glass bottles containing approximately 100 mL of solution after constitution.

4 CONTRAINDICATIONS

Valganciclovir hydrochloride 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 [see Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with valganciclovir or ganciclovir. Valganciclovir hydrochloride for oral solution should be avoided if the absolute neutrophil count is less than 500 cells/μL, the platelet count is less than 25,000/μL, or the hemoglobin is less than 8 g/dL. Valganciclovir hydrochloride should also be used with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.
Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving valganciclovir [see Adverse Reactions (6.1)], complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment, and in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/μL at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to valganciclovir, because of increased plasma concentrations of ganciclovir after valganciclovir administration [see Clinical Pharmacology (12.3)].

5.2 Acute Renal Failure

Acute renal failure may occur in:
• Elderly patients with or without reduced renal function. Caution should be exercised when administering valganciclovir to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.5),Use in Specific Populations (8.5,8.6)].
• Patients receiving potential nephrotoxic drugs. Caution should be exercised when administering valganciclovir to patients receiving potential nephrotoxic drugs.
• Patients without adequate hydration. Adequate hydration should be maintained for all patients.

5.3 Impairment of Fertility

Based on animal data and limited human data, valganciclovir at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of valganciclovir [see Use in Specific Populations (8.1,8.3),Nonclinical Toxicology (13.1)].

5.4 Fetal Toxicity

Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2 times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, valganciclovir has the potential to cause birth defects. Pregnancy should be avoided in female patients taking valganciclovir and in females with male partners taking valganciclovir. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir because of the potential risk to the fetus. Similarly, males should be advised to use condoms during and for at least 90 days following treatment with valganciclovir [see Dosage and Administration (2.6),Use in Specific Populations (8.1,8.3),Nonclinical Toxicology (13.1)].

5.5 Mutagenesis and Carcinogenesis

Animal data indicate that ganciclovir is mutagenic and carcinogenic. Valganciclovir should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.6),Nonclinical Toxicology (13.1)].

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