Valganciclovir: Package Insert and Label Information

VALGANCICLOVIR- valganciclovir hydrochloride tablet, film coated
Major Pharmaceuticals

BOXED WARNING

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 valganciclovir tablets [see Warnings and Precautions (5.1)].
• Impairment of Fertility: Based on animal data and limited human data, valganciclovir tablets may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions (5.3)].
• Fetal Toxicity: Based on animal data, valganciclovir tablets have the potential to cause birth defects in humans [see Warnings and Precautions (5.4)].
• Mutagenesis and Carcinogenesis: Based on animal data, valganciclovir tablets have the potential to cause cancers in humans [see Warnings and Precautions (5.5)].

1 INDICATIONS & USAGE

1.1 Adult Patients

Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].
Prevention of CMV Disease: Valganciclovir tablets are indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)].

1.2 Pediatric Patients

Prevention of CMV Disease: Valganciclovir tablets are indicated for the prevention of CMV disease in kidney transplant patients (4 months to 16 years of age) and heart transplant patients (1 month to 16 years of age) at high risk [see Clinical Studies (14.2)].

2 DOSAGE & ADMINISTRATION

2.1 General Dosing Information

• Adult patients should use valganciclovir tablets, not valganciclovir for oral solution.
• Valganciclovir tablets should be taken with food [see Clinical Pharmacology (12.3)].

2.2 Recommended Dosage in Adult Patients with Normal Renal Function

For dosage recommendations in adult patients with renal impairment [see Dosage and Administration (2.5)].
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.

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 (7x BSA x CrCl) should start within 10 days of transplantation until 100 days post-transplantation.
The recommended once daily dosage of valganciclovir tablets 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.

Formula
formula2
(click image for full-size original)

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 1 to less than 2 years

0.55

Boys aged 2 to less than 13 years Girls aged 2 to less than 16 years

0.7

Boys aged 13 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 used1.
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. 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; however, valganciclovir 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 valganciclovir tablets, pediatric patients should be assessed for the ability to swallow tablets.

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 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

Valganciclovir Tablets 450 mg

CrCl* (mL/min)

Induction Dose

Maintenance/Prevention Dose

≥ 60

900 mg twice daily

900 mg once daily

40 – 59

450 mg twice daily

450 mg once daily

25 – 39

450 mg once daily

450 mg every 2 days

10 – 24

450 mg every 2 days

450 mg twice weekly

< 10(on hemodialysis)

not recommended

not recommended

*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
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 tablets. 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 [see Warnings and Precautions (5.4, 5.5)]. Avoid direct contact with broken or crushed tablets 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 tablets 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 tablets USP: 450 mg, pink, oval, biconvex, film-coated tablets, debossed with ‘J’ on one side and ‘156’ on the other side.

4 CONTRAINDICATIONS

Valganciclovir tablets are 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 tablets or ganciclovir. Valganciclovir tablets 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 tablets 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 tablets [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 tablets, because of increased plasma concentrations of ganciclovir after valganciclovir tablets 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 tablets 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 tablets 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 tablets 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 tablets [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 tablets have the potential to cause birth defects. Pregnancy should be avoided in female patients taking valganciclovir tablets and in females with male partners taking valganciclovir tablets. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir tablets 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 tablets [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 tablets should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.7), Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
• Hematologic Toxicity [see Warnings and Precautions (5.1)].
• Acute Renal Failure [see Warnings and Precautions (5.2)].
• Impairment of Fertility [see Warnings and Precautions (5.3)].
• Fetal Toxicity [see Warnings and Precautions (5.4)].
• Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)].
The most common adverse reactions and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with valganciclovir tablets are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. The most common reported adverse reactions and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with valganciclovir tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.

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