Ganciclovir: Package Insert and Label Information

GANCICLOVIR- ganciclovir sodium injection, powder, lyophilized, for solution
Hainan Poly Pharm. Co., Ltd.

WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS

  • Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia have been reported in patients treated with ganciclovir [see Warnings and Precautions ( 5.1)] .
  • Impairment of Fertility: Based on animal data and limited human data, Ganciclovir for Injection, USP may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions ( 5.3)] . Impairment of Fertility: Based on animal data and limited human data, Ganciclovir for Injection, USP 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, Ganciclovir for Injection, USP has the potential to cause birth defects in humans [see Warnings and Precautions ( 5.4)] .
  • Mutagenesis and Carcinogenesis: Based on animal data, Ganciclovir for Injection, USP has the potential to cause cancers in humans [see Warnings and Precautions ( 5.5)] .

1 INDICATIONS AND USAGE

1.1 Treatment of CMV Retinitis

Ganciclovir for Injection, USP is indicated for the treatment of cytomegalovirus (CMV) retinitis in immunocompromised adult patients, including patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies ( 14.1)].

1.2 Prevention of CMV Disease in Transplant Recipients

Ganciclovir for Injection, USP is indicated for the prevention of CMV disease in adult transplant recipients at risk for CMV disease [see Clinical Studies ( 14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing and Administration Information

  • To avoid phlebitis/pain at the infusion site, ganciclovir for injection must only be administered by intravenous infusion over 1 hour, preferably via plastic cannula, into a vein with adequate blood flow to permit rapid dilution and distribution.
  • Do not administer ganciclovir for injection by rapid or bolus intravenous injection which may increase toxicity as a result of excessive plasma levels.
  • The recommended dosage and infusion rate for ganciclovir for injection should not be exceeded.
  • Do not administer the reconstituted ganciclovir for injection solution intramuscularly or subcutaneously because it may result in severe tissue irritation due to high pH [see Description 11] .
  • Administration of ganciclovir for injection should be accompanied by adequate hydration.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Testing Before and During Treatment

  • Females of reproductive potential should undergo pregnancy testing before initiation of treatment with ganciclovir for injection [see Warnings and Precautions ( 5.4), Use in Specific Populations ( 8.1, 8.3)] .
  • Complete blood counts with differential and platelet counts should be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenias, or in whom absolute neutrophil counts are less than 1000 cells/μL at the beginning of treatment [see Warnings and Precautions ( 5.1)] .
  • All patients should be monitored for renal function before and during treatment with ganciclovir for injection and dose should be adjusted as needed [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.2)] .
  • Patients with CMV retinitis should have frequent ophthalmological examinations during treatment with ganciclovir for injection solution to monitor disease status and for other retinal abnormalities [see Adverse Reactions ( 6.1)] .

2.3 Recommended Dosage for Treatment of CMV Retinitis in Adult Patients with Normal Renal Function

Induction Dosage: The recommended initial dosage of ganciclovir for injection for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days.

Maintenance Dosage: Following induction treatment, the recommended maintenance dosage of ganciclovir for injection is 5 mg/kg (given intravenously at a constant rate over 1 hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week.

2.4 Recommended Dosage for the Prevention of CMV Disease in Adult Transplant Recipients with Normal Renal Function

Induction Dosage: The recommended initial dosage of ganciclovir for injection for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days.

Maintenance Dosage: Following induction, the recommended maintenance dosage of ganciclovir for injection is 5 mg/kg (given intravenously at a constant rate over 1 hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week until 100 to 120 days post-transplantation.

2.5 Recommended Dosage in Adult Patients with Renal Impairment

For patients with impairment of renal function, refer to Table 1 for recommended doses of ganciclovir for injection for induction and maintenance dosage for treatment of CMV retinitis and prevention of CMV disease in transplant recipients. Carefully monitor serum creatinine or creatinine clearance before and during treatment to allow for dosage adjustments in patients with impaired renal function.

Table 1. Recommended Induction and Maintenance Dosage for Adult Patients with Renal Impairment
*
Creatinine clearance can be related to serum creatinine by the formulas given below. Creatinine clearance for males = (140 – age[yrs])(body wt[kg]) / (72)(serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 × male value

Creatinine Clearance * (mL/min)

Ganciclovir for Injection Induction Dose (mg/kg)

Dosing Interval (hours) for Induction

Ganciclovir for Injection Maintenance Dose (mg/kg)

Dosing Interval (hours) for Maintenance

Greater than or equal to 70

5

12

5

24

50–69

2.5

12

2.5

24

25–49

2.5

24

1.25

24

10–24

1.25

24

0.625

24

Less than 10

1.25

3 times per week, following hemodialysis

0.625

3 times per week, following hemodialysis

Patients Undergoing Hemodialysis

Induction dosing for ganciclovir for injection in patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per week; and maintenance dosing should not exceed 0.625 mg/kg 3 times per week following each hemodialysis session. Ganciclovir for injection should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50% [see Clinical Pharmacology ( 12.3)] .

2.6 Preparation of Ganciclovir for Injection, USP

Ganciclovir for Injection, USP must be reconstituted and diluted under the supervision of a healthcare provider and administered as intravenous infusion. Each 10 mL clear glass vial contains ganciclovir sodium equivalent to 500 mg of ganciclovir. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the vial and the table after reconstitution. The contents of the vial should be prepared for administration in the following manner:

  1. Reconstitution Instructions:
    1. Reconstitute lyophilized Ganciclovir for Injection, USP by injecting 10 mL of Sterile Water for Injection, USP, into the vial. Do not use bacteriostatic water for injection containing parabens. It is incompatible with Ganciclovir for Injection, USP and may cause precipitation.
    2. Gently swirl the vial in order to ensure complete wetting of the product. Continue swirling until a clear reconstituted solution is obtained.
    3. Visually inspect the reconstituted solution for particulate matter and discoloration prior to proceeding with infusion. Discard the vial if particulate matter or discoloration is observed.
    4. Reconstituted solution in the vial is stable at room temperature (25°C) for 12 hours. Do not refrigerate or freeze.
  2. Infusion Instructions:
    1. Based on patient weight, the appropriate volume of the reconstituted solution (ganciclovir concentration 50 mg/mL) should be removed from the vial and added to an acceptable infusion fluid (typically 100 mL) for delivery over the course of 1 hour. Infusion concentrations greater than 10 mg/mL are not recommended. The following infusion fluids have been determined to be chemically and physically compatible with Ganciclovir for Injection, USP solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer’s Injection and Lactated Ringer’s Injection, USP.
    2. Ganciclovir for Injection, USP, when reconstituted with Sterile Water for Injection (non-bacteriostatic) and further diluted with 0.9% sodium chloride injection or other acceptable infusion fluid as specified above, should be used within 24 hours of dilution to reduce the risk of bacterial contamination. The diluted infusion solution should be refrigerated (2°C to 8°C). Do not freeze.

2.7 Handling and Disposal

Caution should be exercised in the handling and preparation of solutions of Ganciclovir for Injection, USP. Solutions of Ganciclovir for Injection, USP are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with Ganciclovir for Injection, USP solution. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Wearing disposable gloves is recommended.

Because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs 1 [see How Supplied/Storage and Handling ( 16)] .

3 DOSAGE FORMS AND STRENGTHS

For injection: Single dose vial containing 500 mg of ganciclovir as a sterile lyophilized white to off-white powder for reconstitution with 10 mL of preservative-free Sterile Water for Injection, USP for intravenous use [see Dosage and Administration ( 2.6)] .

4 CONTRAINDICATIONS

Ganciclovir for Injection, USP is contraindicated in patients who have experienced a clinically significant hypersensitivity reaction (e.g., anaphylaxis) to ganciclovir, valganciclovir or any component of the formulation.

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

Granulocytopenia (neutropenia), anemia, thrombocytopenia and pancytopenia, have been observed in patients treated with ganciclovir. The frequency and severity of these events vary widely in different patient populations [see Adverse Reactions ( 6.1)] . Ganciclovir for injection is not recommended if the absolute neutrophil count is less than 500 cells/μL, hemoglobin is less than 8 g/dL, or the platelet count is less than 25,000 cells/μL. Ganciclovir for injection should also be used with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation. Granulocytopenia (neutropenia) usually occurs during the first or second week of treatment but may occur at any time during treatment. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving ganciclovir solution for treatment of CMV retinitis.

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving ganciclovir for injection [see Adverse Reactions ( 6.1)] , complete blood counts with differential and platelet counts should be performed frequently in all patients, especially 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 [see Dosage and Administration ( 2.2)] .

5.2 Renal Impairment

Ganciclovir for injection should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance. If renal function is impaired, dosage adjustments are recommended [see Dosage and Administration ( 2.5), Use in Specific Populations ( 8.5, 8.6)] .

Increased serum creatinine levels have been reported in elderly patients and in transplant recipients receiving concomitant nephrotoxic medications (i.e., cyclosporine and amphotericin B). Monitoring renal function during therapy with ganciclovir for injection is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity [see Dosage and Administration ( 2.5), Drug Interactions ( 7), Use in Specific Populations ( 8.5)] .

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