CYTOVENE^®-IV
(ganciclovir sodium for injection)
FOR INTRAVENOUS INFUSION ONLY

THE CLINICAL TOXICITY OF CYTOVENE-IV INCLUDES GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED ASPERMATOGENESIS.

CYTOVENE-IV IS INDICATED FOR USE ONLY IN THE TREATMENT OF CYTOMEGALOVIRUS (CMV) RETINITIS IN IMMUNOCOMPROMISED PATIENTS AND FOR THE PREVENTION OF CMV DISEASE IN TRANSPLANT PATIENTS AT RISK FOR CMV DISEASE (see INDICATIONS AND USAGE).

Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV). CYTOVENE-IV is the brand name for ganciclovir sodium for injection.

CYTOVENE-IV is available as sterile lyophilized powder in strength of 500 mg per vial for intravenous administration only. Each vial of CYTOVENE-IV contains the equivalent of 500 mg ganciclovir as the sodium salt (46 mg sodium). Reconstitution with 10 mL of Sterile Water for Injection, USP, yields a solution with pH 11 and a ganciclovir concentration of approximately 50 mg/mL. Further dilution in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION).

Ganciclovir is a white to off-white crystalline powder with a molecular formula of C₉H₁₃N₅0₄ and a molecular weight of 255.23. The chemical name for ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine. Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022. The pK_as for ganciclovir are 2.2 and 9.4.

Ganciclovir, when formulated as monosodium salt in the IV dosage form, is a white to off-white lyophilized powder with the molecular formula of C₉H₁₂N₅Na0₄, and a molecular weight of 277.22. The chemical name for ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine, monosodium salt. The lyophilized powder has an aqueous solubility of greater than 50 mg/mL at 25°C. At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.

The chemical structures of ganciclovir sodium and ganciclovir are:

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

Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses. Ganciclovir has been shown to be active against cytomegalovirus (CMV) and herpes simplex virus (HSV) in human clinical studies.

To achieve anti-CMV activity, ganciclovir is phosphorylated first to the monophosphate form by a CMV-encoded (UL97 gene) protein kinase homologue, then to the di- and triphosphate forms by cellular kinases. Ganciclovir triphosphate concentrations may be 100-fold greater in CMV-infected than in uninfected cells, indicating preferential phosphorylation in infected cells. Ganciclovir triphosphate, once formed, persists for days in the CMV-infected cell. Ganciclovir triphosphate is believed to inhibit viral DNA synthesis by (1) competitive inhibition of viral DNA polymerases; and (2) incorporation into viral DNA, resulting in eventual termination of viral DNA elongation.

The median concentration of ganciclovir that inhibits CMV replication (IC₅₀) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.48 µg/mL. Ganciclovir inhibits mammalian cell proliferation (CIC₅₀) in vitro at higher concentrations ranging from 30 to 725 µg/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC₅₀ 0.028 to 0.7 µg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

In a study of CYTOVENE-IV treatment of life- or sight-threatening CMV disease in immunocompromised patients, 121 of 314 patients had CMV cultured within 7 days prior to treatment and sequential posttreatment viral cultures of urine, blood, throat and/or semen. As judged by conversion to culture negativity, or a greater than 100-fold decrease in in vitro CMV titer, at least 83% of patients had a virologic response with a median response time of 7 to 15 days.

Antiviral activity of CYTOVENE-IV was demonstrated in two randomized studies for the prevention of CMV disease in transplant recipients (see Table 1).

BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR CYTOVENE-IV. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.

At the end of a 1-hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ± 3.2 (n=16) and 26.8 ± 6.1 µg∙hr/mL (n=16) and C_max ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 µg/mL (n=16).

The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98). Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours postdose in 3 patients who received 2.5 mg/kg ganciclovir intravenously q8h or q12h ranged from 0.31 to 0.68 µg/mL representing 24% to 70% of the respective plasma concentrations. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg and when administered orally, it exhibits linear kinetics up to a total daily dose of 4 g/day. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, 91.3 ± 5.0% (n=4) of intravenously administered ganciclovir was recovered unmetabolized in the urine. Systemic clearance of intravenously administered ganciclovir was 3.52 ± 0.80 mL/min/kg (n=98) while renal clearance was 3.20 ± 0.80 mL/min/kg (n=47), accounting for 91 ± 11% of the systemic clearance (n=47). Half-life was 3.5 ± 0.9 hours (n=98) following IV administration and 4.8 ± 0.9 hours (n=39) following oral administration.

CYTOVENE-IV is indicated for the treatment of CMV retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). CYTOVENE-IV is also indicated for the prevention of CMV disease in transplant recipients at risk for CMV disease (see CLINICAL TRIALS).

SAFETY AND EFFICACY OF CYTOVENE-IV HAS NOT BEEN ESTABLISHED FOR CONGENITAL OR NEONATAL CMV DISEASE; NOR FOR THE TREATMENT OF ESTABLISHED CMV DISEASE OTHER THAN RETINITIS; NOR FOR USE IN NON-IMMUNOCOMPROMISED INDIVIDUALS.

The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason it is essential that the diagnosis of CMV be established by an ophthalmologist familiar with the retinal presentation of these conditions. The diagnosis of CMV retinitis may be supported by culture of CMV from urine, blood, throat or other sites, but a negative CMV culture does not rule out CMV retinitis.

CYTOVENE-IV was evaluated in three randomized, controlled trials of prevention of CMV disease in organ transplant recipients.

CYTOVENE-IV is contraindicated in patients with hypersensitivity to ganciclovir or acyclovir.

CYTOVENE-IV should not be administered if the absolute neutrophil count is less than 500 cells/µL or the platelet count is less than 25,000 cells/µL. Granulocytopenia (neutropenia), anemia and thrombocytopenia have been observed in patients treated with CYTOVENE-IV. The frequency and severity of these events vary widely in different patient populations (see ADVERSE EVENTS).

CYTOVENE-IV should, therefore, be used with caution in patients with pre-existing cytopenias or with a history of cytopenic reactions to other drugs, chemicals or irradiation. Granulocytopenia 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 of discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving CYTOVENE-IV solution for treatment of CMV retinitis.

In clinical studies with CYTOVENE-IV, the maximum single dose administered was 6 mg/kg by intravenous infusion over 1 hour. Larger doses have resulted in increased toxicity. It is likely that more rapid infusions would also result in increased toxicity (see OVERDOSAGE). Administration of CYTOVENE-IV solution should be accompanied by adequate hydration.

Initially reconstituted solutions of CYTOVENE-IV have a high pH (pH 11). Despite further dilution in intravenous fluids, phlebitis and/or pain may occur at the site of intravenous infusion. Care must be taken to infuse solutions containing CYTOVENE-IV only into veins with adequate blood flow to permit rapid dilution and distribution (see DOSAGE AND ADMINISTRATION).

Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS ARE REQUIRED FOR CYTOVENE-IV. Such adjustments should be based on measured or estimated creatinine clearance values (see DOSAGE AND ADMINISTRATION).

All patients should be informed that the major toxicities of ganciclovir are granulocytopenia (neutropenia), anemia and thrombocytopenia and that dose modifications may be required, including discontinuation. The importance of close monitoring of blood counts while on therapy should be emphasized. Patients should be informed that ganciclovir has been associated with elevations in serum creatinine.

Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause infertility in humans. Women of childbearing potential should be advised that ganciclovir causes birth defects in animals and should not be used during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment with CYTOVENE-IV. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with CYTOVENE-IV.

Patients should be advised that ganciclovir causes tumors in animals. Although there is no information from human studies, ganciclovir should be considered a potential carcinogen.

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving CYTOVENE-IV (see ADVERSE EVENTS), it is recommended that complete blood counts and platelet counts be performed frequently, especially 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 serum creatinine levels have been observed in trials evaluating both CYTOVENE-IV. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION).

Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day (approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve [AUC] comparisons). At the dose of 1000 mg/kg/day there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the dose of 20 mg/kg/day, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day (estimated as 0.01x the human dose based on AUC comparison). Except for histiocytic sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered a potential carcinogen in humans.

Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at concentrations between 50 to 500 and 250 to 2000 µg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (IV) (2.8 to 10x human exposure based on AUC) but not 50 mg/kg (exposure approximately comparable to the human based on AUC). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 µg/mL.

Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day (approximately 1.7x the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons). Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended human intravenous dose.

It is not known whether ganciclovir is excreted in human milk. However, many drugs are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely (see Pregnancy: Category C). Mothers should be instructed to discontinue nursing if they are receiving CYTOVENE-IV.

The minimum interval before nursing can safely be resumed after the last dose of CYTOVENE-IV is unknown.

SAFETY AND EFFICACY OF CYTOVENE-IV IN PEDIATRIC PATIENTS HAVE NOT BEEN ESTABLISHED. THE USE OF CYTOVENE-IV IN THE PEDIATRIC POPULATION WARRANTS EXTREME CAUTION DUE TO THE PROBABILITY OF LONG-TERM CARCINOGENICITY AND REPRODUCTIVE TOXICITY. ADMINISTRATION TO PEDIATRIC PATIENTS SHOULD BE UNDERTAKEN ONLY AFTER CAREFUL EVALUATION AND ONLY IF THE POTENTIAL BENEFITS OF TREATMENT OUTWEIGH THE RISKS.

The spectrum of adverse events reported in 120 immunocompromised pediatric clinical trial participants with serious CMV infections receiving CYTOVENE-IV solution were similar to those reported in adults. Granulocytopenia (17%) and thrombocytopenia (10%) were the most common adverse events reported.

Sixteen pediatric patients (8 months to 15 years of age) with life- or sight-threatening CMV infections were evaluated in an open-label, CYTOVENE-IV solution, pharmacokinetics study. Adverse events reported for more than one pediatric patient were as follows: hypokalemia (4/16, 25%), abnormal kidney function (3/16, 19%), sepsis (3/16, 19%), thrombocytopenia (3/16, 19%), leukopenia (2/16, 13%), coagulation disorder (2/16, 13%), hypertension (2/16, 13%), pneumonia (2/16, 13%) and immune system disorder (2/16, 13%).

There has been very limited clinical experience using CYTOVENE-IV for the treatment of CMV retinitis in patients under the age of 12 years. Two pediatric patients (ages 9 and 5 years) showed improvement or stabilization of retinitis for 23 and 9 months, respectively. These pediatric patients received induction treatment with 2.5 mg/kg tid followed by maintenance therapy with 6 to 6.5 mg/kg once per day, 5 to 7 days per week. When retinitis progressed during once-daily maintenance therapy, both pediatric patients were treated with the 5 mg/kg bid regimen. Two other pediatric patients (ages 2.5 and 4 years) who received similar induction regimens showed only partial or no response to treatment. Another pediatric patient, a 6-year-old with T-cell dysfunction, showed stabilization of retinitis for 3 months while receiving continuous infusions of CYTOVENE-IV at doses of 2 to 5 mg/kg/24 hours. Continuous infusion treatment was discontinued due to granulocytopenia.

Eleven of the 72 patients in the placebo-controlled trial in bone marrow transplant recipients were pediatric patients, ranging in age from 3 to 10 years (5 treated with CYTOVENE-IV and 6 with placebo). Five of the pediatric patients treated with CYTOVENE-IV received 5 mg/kg intravenously bid for up to 7 days; 4 patients went on to receive 5 mg/kg qd up to day 100 posttransplant. Results were similar to those observed in adult transplant recipients treated with CYTOVENE-IV. Two of the 6 placebo-treated pediatric patients developed CMV pneumonia vs none of the 5 patients treated with CYTOVENE-IV. The spectrum of adverse events in the pediatric group was similar to that observed in the adult patients.

The pharmacokinetic profiles of CYTOVENE-IV in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of CYTOVENE-IV (see DOSAGE AND ADMINISTRATION).

Clinical studies of CYTOVENE-IV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. CYTOVENE-IV is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see Use in Patients With Renal Impairment and DOSAGE AND ADMINISTRATION).

CYTOVENE-IV 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 (see DOSAGE AND ADMINISTRATION and ADVERSE EVENTS).

Hemodialysis has been shown to reduce plasma levels of ganciclovir by approximately 50%.

Adverse events that occurred during clinical trials of CYTOVENE-IV solution are summarized below, according to the participating study subject population.

Three controlled, randomized, phase 3 trials comparing CYTOVENE-IV and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, CYTOVENE-IV or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse events. Laboratory data and adverse events reported during the conduct of these controlled trials are summarized below.

There have been three controlled clinical trials of CYTOVENE-IV solution for the prevention of CMV disease in transplant recipients. Laboratory data and adverse events reported during these trials are summarized below.

Other adverse events that were thought to be "probably" or "possibly" related to CYTOVENE-IV solution or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are uled below. These events all occurred in at least 3 subjects.

Body as a Whole: abdomen enlarged, asthenia, chest pain, edema, headache, injection site inflammation, malaise, pain

Digestive System: abnormal liver function test, aphthous stomatitis, constipation, dyspepsia, eructation

Hemic and Lymphatic System: pancytopenia

Respiratory System: cough increased, dyspnea

Nervous System:abnormal dreams, anxiety, confusion, depression, dizziness, dry mouth, insomnia, seizures, somnolence, thinking abnormal, tremor

Skin and Appendages: alopecia, dry skin

Special Senses: abnormal vision, taste perversion, tinnitus, vitreous disorder

Metabolic and Nutritional Disorders: creatinine increased, SGOT increased, SGPT increased, weight loss

Cardiovascular System: hypertension, phlebitis, vasodilatation

Urogenital System: creatinine clearance decreased, kidney failure, kidney function abnormal, urinary frequency

Musculoskeletal System: arthralgia, leg cramps, myalgia, myasthenia

The following adverse events reported in patients receiving ganciclovir may be potentially fatal: gastrointestinal perforation, multiple organ failure, pancreatitis and sepsis.

The following events have been identified during postapproval use of the drug. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either the seriousness, frequency of reporting, the apparent causal connection or a combination of these factors:

acidosis, allergic reaction, anaphylactic reaction, arthritis, bronchospasm, cardiac arrest, cardiac conduction abnormality, cataracts, cholelithiasis, cholestasis, congenital anomaly, dry eyes, dysesthesia, dysphasia, elevated triglyceride levels, encephalopathy, exfoliative dermatitis, extrapyramidal reaction, facial palsy, hallucinations, hemolytic anemia, hemolytic uremic syndrome, hepatic failure, hepatitis, hypercalcemia, hyponatremia, inappropriate serum ADH, infertility, intestinal ulceration, intracranial hypertension, irritability, loss of memory, loss of sense of smell, myelopathy, oculomotor nerve paralysis, peripheral ischemia, pulmonary fibrosis, renal tubular disorder, rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, Torsades de Pointes, vasculitis, ventricular tachycardia

Overdosage with CYTOVENE-IV has been reported in 17 patients (13 adults and 4 children under 2 years of age). Five patients experienced no adverse events following overdosage at the following doses: 7 doses of 11 mg/kg over a 3-day period (adult), single dose of 3500 mg (adult), single dose of 500 mg (72.5 mg/kg) followed by 48 hours of peritoneal dialysis (4-month-old), single dose of approximately 60 mg/kg followed by exchange transfusion (18-month-old), 2 doses of 500 mg instead of 31 mg (21-month-old).

Irreversible pancytopenia developed in 1 adult with AIDS and CMV colitis after receiving 3000 mg of CYTOVENE-IV solution on each of 2 consecutive days. He experienced worsening GI symptoms and acute renal failure that required short-term dialysis. Pancytopenia developed and persisted until his death from a malignancy several months later. Other adverse events reported following overdosage included: persistent bone marrow suppression (1 adult with neutropenia and thrombocytopenia after a single dose of 6000 mg), reversible neutropenia or granulocytopenia (4 adults, overdoses ranging from 8 mg/kg daily for 4 days to a single dose of 25 mg/kg), hepatitis (1 adult receiving 10 mg/kg daily, and one 2 kg infant after a single 40 mg dose), renal toxicity (1 adult with transient worsening of hematuria after a single 500 mg dose, and 1 adult with elevated creatinine (5.2 mg/dL) after a single 5000 to 7000 mg dose), and seizure (1 adult with known seizure disorder after 3 days of 9 mg/kg). In addition, 1 adult received 0.4 mL (instead of 0.1 mL) CYTOVENE-IV solution by intravitreal injection, and experienced temporary loss of vision and central retinal artery occlusion secondary to increased intraocular pressure related to the injected fluid volume.

Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered (see DOSAGE AND ADMINISTRATION: Renal Impairment).

CAUTION - DO NOT ADMINISTER CYTOVENE-IV SOLUTION BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF CYTOVENE-IV MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS.

CAUTION - INTRAMUSCULAR OR SUBCUTANEOUS INJECTION OF RECONSTITUTED CYTOVENE-IV SOLUTION MAY RESULT IN SEVERE TISSUE IRRITATION DUE TO HIGH pH (11).

THE RECOMMENDED DOSE FOR CYTOVENE-IV SOLUTION SHOULD NOT BE EXCEEDED. THE RECOMMENDED INFUSION RATE FOR CYTOVENE-IV SOLUTION SHOULD NOT BE EXCEEDED.

The recommended initial dosage of CYTOVENE-IV solution 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, followed by 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

The duration of treatment with CYTOVENE-IV solution in transplant recipients is dependent upon the duration and degree of immunosuppression. In controlled clinical trials in bone marrow allograft recipients, treatment with CYTOVENE-IV was continued until day 100 to 120 posttransplantation. CMV disease occurred in several patients who discontinued treatment with CYTOVENE-IV solution prematurely. In heart allograft recipients, the onset of newly diagnosed CMV disease occurred after treatment with CYTOVENE-IV was stopped at day 28 posttransplant, suggesting that continued dosing may be necessary to prevent late occurrence of CMV disease in this patient population (see INDICATIONS AND USAGE section for a more detailed discussion).

For patients with impairment of renal function, refer to Table 8 for recommended doses of CYTOVENE-IV solution and adjust the dosing interval as indicated:

                                                             (140 - age[yrs]) (body wt [kg])
Creatinine clearance for males =    (72) (serum creatinine [mg/dL])

Creatinine clearance for females = 0.85 × male value

Dosing for patients undergoing hemodialysis should not exceed 1.25 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%.

Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients receiving ganciclovir (see ADVERSE EVENTS), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION).

Dosage reductions in renally impaired patients are required for CYTOVENE-IV (see Renal Impairment). Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see ADVERSE EVENTS). Ganciclovir should not be administered in patients with severe neutropenia (ANC less than 500/µL) or severe thrombocytopenia (platelets less than 25,000/µL).

Each 10 mL clear glass vial contains ganciclovir sodium equivalent to 500 mg of ganciclovir and 46 mg of sodium. The spans of the vial should be prepared for administration in the following manner:

• Reconstituted Solution:
  • 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.

  • Shake the vial to dissolve the drug.
  • Visually inspect the reconstituted solution for particulate matter and discoloration prior to proceeding with infusion solution. Discard the vial if particulate matter or discoloration is observed.
  • Reconstituted solution in the vial is stable at room temperature for 12 hours. It should not be refrigerated.
• Infusion Solution:

  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.

  CYTOVENE-IV, when reconstituted with sterile water for injection, further diluted with 0.9% sodium chloride injection, and stored refrigerated at 5°C in polyvinyl chloride (PVC) bags, remains physically and chemically stable for 14 days.

  However, because CYTOVENE-IV is reconstituted with nonbacteriostatic sterile water, it is recommended that the infusion solution be used within 24 hours of dilution to reduce the risk of bacterial contamination. The infusion should be refrigerated. Freezing is not recommended.

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 solutions. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.

Because ganciclovir shares some of the properties of antitumor agents (ie, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. Several guidelines on this subject have been published.^7-9

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

CYTOVENE^®-IV (ganciclovir sodium for injection) is supplied in 10 mL sterile vials, each containing ganciclovir sodium equivalent to 500 mg of ganciclovir, in cartons of 25 (NDC 0004-6940-03).

Store vials at temperatures below 40°C (104°F).

• 1. Spector SA, Weingeis T, Pollard R, et al. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J Inf Dis. 1993; 168:557-563.
• 2. Drew WL, Ives D, Lalezari JP, et al. Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. New Engl J Med. 1995; 333:615-620.
• 3. The Oral Ganciclovir European and Australian Cooperative Study Group. Intravenous vs oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS. 1995; 9:471-477.
• 4. Merigan TC, Renlund DG, Keay S, et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. New Engl J Med. 1992; 326:1182-1186.
• 5. Goodrich JM, Mori M, Gleaves CA, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. New Engl J Med. 1991; 325:1601-1607.
• 6. Schmidt GM, Horak DA, Niland JC, et al. The City of Hope-Stanford-Syntex CMV Study Group. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. New Engl J Med. 1991; 15:1005-1011.
• 7. Recommendations for the Safe Handling of Cytotoxic Drugs. US Department of Health and Human Services, National Institutes of Health, Bethesda, MD, September 1992. NIH Publication No. 92-2621.
• 8. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
• 9. Controlling Occupational Exposures to Hazardous Drugs. US Department of Labor. Occupational Health and Safety Administration. OSHA Technical Manual. Section V - Chapter 3. September 22, 1995.