PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL


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DESCRIPTION SECTION

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 C14H22N6O5·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:

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

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INDICATIONS & USAGE SECTION

1 INDICATIONS & USAGE

1.1 Adult Patients

Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir hydrochloride is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].

Prevention of CMV Disease: Valganciclovir hydrochloride is 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 hydrochloride is 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)].

DOSAGE & ADMINISTRATION SECTION

2 DOSAGE & ADMINISTRATION

2.1 General Dosing Information

• Adult patients should use Valganciclovir hydrochloride tablets, not Valganciclovir hydrochloride for oral solution.
• Valganciclovir hydrochloride for oral solution should be taken with food [see Clinical Pharmacology (12.3)].
• Valganciclovir hydrochloride for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)].

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

*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 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. Valganciclovir hydrochloride for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Valganciclovir hydrochloride 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 hydrochloride tablets, pediatric patients should be assessed for the ability to swallow tablets.

2.4 Preparation of Valganciclovir hydrochloride 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 hydrochloride for oral solution must be prepared by the pharmacist as follows[see How Supplied/Storage and Handling (16)]:
• 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 [see Patient Counseling Information (17)].

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

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.

DOSAGE FORMS & STRENGTHS SECTION

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.

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CONTRAINDICATIONS SECTION

Highlight: Hypersensitivity to valganciclovir or ganciclovir.(4)

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)].

BOXED WARNING SECTION

BOXED WARNING

WARNINGS AND PRECAUTIONS SECTION

Highlight: * Acute renal failure: Acute renal failure may occur in elderly patients (with or without reduced renal function), patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients or those taking nephrotoxic drugs, reduce dosage in patients with renal impairment, and monitor renal function. (2.5,5.2,8.5,8.6)

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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DRUG INTERACTIONS SECTION

Highlight: * Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks.(7)

• Cyclosporine or amphotericin B: When coadministered with valganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function.(5.2,7)
• Mycophenolate mofetil (MMF): When coadministered with valganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity.(7)
• Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, consider for concomitant use with valganciclovir only if the potential benefits are judged to outweigh the risks. (7)
• Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis)(7).
• Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity. (7)

7 DRUG INTERACTIONS

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 Valganciclovir. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of valganciclovir 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

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SPL PATIENT PACKAGE INSERT SECTION

SPL PATIENT PACKAGE INSERT SECTION

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SPL UNCLASSIFIED SECTION

Instructions for Use

Valganciclovir (val-gan-SYE-kloe-ver) Hydrochloride for Oral Solution

Be sure that you read, and that you understand and follow these instructions carefully to ensure proper dosing of the oral solution.

Important:

• Avoid contact with your skin or eyes. If you come in contact with the contents of the oral solution, wash your skin well with soap and water or rinse your eyes well with plain water.
• Do not use valganciclovir hydrochloride for oral solution after the discard date on the bottle.
• Always use the oral dispenser provided to give or take a dose of valganciclovir hydrochloride for oral solution.
• Call your pharmacist if your oral dispenser is lost or damaged, and they will tell you how to continue to give or take a dose of valganciclovir hydrochloride for oral solution.
• Ask your healthcare provider or pharmacist to show you how to measure your prescribed dose.

To take a dose of valganciclovir hydrochloride for oral solution, you will need the bottle of medicine and an oral dispenser provided with the medicine (seeFigure 1). Your pharmacist inserts the bottle adapter in the valganciclovirhydrochloride for oral solution bottle.

How should I store****valganciclovir hydrochloride for oral solution?

• Store solution in the refrigerator at 36°to 46°F (2°to 8°C) for no longer than 49 days.
• Do not freeze.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Brands listed are the trademarks of their respective owners.

Manufactured by: Manufactured for:

**Granules Pharmaceuticals Inc.**Somerset Therapeutics, LLC

Chantilly, VA 20151 Hollywood, FL 33024

Rev. 01/2022

For more information about valganciclovir hydrochloride, please contact Granules Pharmaceuticals Inc. at 1-877-770-3183.

REFERENCES SECTION

15 REFERENCES

1. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J of Ped 1986: 109(4): 698­ 707.

2. NIOSH [2014]. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. By Connor TH, MacKenzie BA, DeBord DG, Trout DB, O’Callaghan JP, Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-138 (Supersedes 2012-150).

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