CYTOVENE-IV Solution for injection Ref.[10800] Active ingredients: Ganciclovir

2.1 Important Dosing and Administration Information

• To avoid phlebitis/pain at the infusion site, CYTOVENE-IV 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 CYTOVENE-IV by rapid or bolus intravenous injection which may increase toxicity as a result of excessive plasma levels.
• The recommended dosage and infusion rate for CYTOVENE-IV should not be exceeded.
• Do not administer the reconstituted CYTOVENE-IV solution intramuscularly or subcutaneously because it may result in severe tissue irritation due to high pH [see Description 11].
• Administration of CYTOVENE-IV 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 CYTOVENE-IV [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 CYTOVENE-IV 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 CYTOVENE-IV 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 CYTOVENE-IV 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 CYTOVENE-IV 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 CYTOVENE-IV 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 CYTOVENE-IV 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 CYTOVENE-IV 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 CYTOVENE-IV 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

Patients Undergoing Hemodialysis

Induction dosing for CYTOVENE-IV 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. CYTOVENE-IV 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 CYTOVENE-IV

CYTOVENE-IV must be reconstituted and diluted under the supervision of a healthcare provider and administered as intravenous infusion. Each 10 mL clear glass vial contains 543 mg 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:

a) Reconstitute lyophilized CYTOVENE-IV 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 CYTOVENE-IV and may cause precipitation.

b) Gently swirl the vial in order to ensure complete wetting of the product. Continue swirling until a clear reconstituted solution is obtained.

c) 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.

d) Reconstituted solution in the vial is stable at room temperature (25°C (77°F)) for 12 hours. Do not refrigerate or freeze. Discard any unused portion of the reconstituted solution.

2. Infusion Instructions:

a) 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 CYTOVENE-IV solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer’s Injection and Lactated Ringer’s Injection, USP.

b) CYTOVENE-IV, 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° to 8°C (36° to 46°F)). Do not freeze.

2.7 Handling and Disposal

Caution should be exercised in the handling and preparation of solutions of CYTOVENE-IV. Solutions of CYTOVENE-IV are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with CYTOVENE-IV 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 drugs¹. Discard any unused portion of the reconstituted solution [see How Supplied/Storage and Handling (16)].

Reports of adverse reactions after overdoses with CYTOVENE-IV, some with fatal outcomes, have been received from clinical trials and during postmarketing experience. One or more of the following adverse reactions has been reported with overdoses:

Hematological toxicity: myelosuppression including pancytopenia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, bone marrow failure

Hepatotoxicity: hepatitis, liver function disorder

Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute kidney injury, elevated creatinine

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting

Neurotoxicity: seizure

Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of CYTOVENE-IV [see Clinical Pharmacology (12.3)]. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered in patients with cytopenias [see Warnings and Precautions (5.1)].

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Store reconstituted solution in the vial at 25°C (77°F) for no longer than 12 hours. Do not refrigerate or freeze. Discard any unused portion of the reconstituted solution.

Store diluted infusion solution under refrigeration at 2° to 8°C (36° to 46°F) for no longer than 24 hours. Do not freeze.