Drug: Cytovene

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

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Adverse events that occurred during clinical trials of CYTOVENE (ganciclovir) -IV solution are summarized below, according to the participating study subject population. Subjects With AIDS 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. Laboratory Data Table 4: Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis
  CMV Retinitis Treatment* Treatment Ganciclovir Capsules†
3000 mg/day CYTOVENE-IV‡
5 mg/kg/day Subjects, number 320 175 Neutropenia:    < 500 ANC/µL 18% 25%   500 – < 749 17% 14%   750 – < 1000 19% 26% Anemia Hemoglobin:    < 6.5 g/dL 2% 5%   6.5 – < 8.0 10% 16%   8.0 – < 9.5 25% 26% Maximum Serum Creatinine:    ≥ 2.5 mg/dL 1% 2%    ≥ 1.5 – < 2.5 12% 14% * Pooled data from Treatment Studies, ICM 1653, Study ICM 1774 and Study AVI 034
† Mean time on therapy = 91 days, including allowed reinduction treatment periods
‡ Mean time on therapy = 103 days, including allowed reinduction treatment periods (See Clinical Trials.) Adverse Events The following table shows selected adverse events reported in 5% or more of the subjects in three controlled clinical trials during treatment with either CYTOVENE-IV solution (5 mg/kg/day) or ganciclovir capsules (3000 mg/day), and in one controlled clinical trial with CYTOVENE (ganciclovir) capsules (3000 mg/day). Table 5: Selected Adverse Events Reported in ≥ 5% of Subjects in Three Randomized Phase 3 Studies Comparing Ganciclovir Capsules to CYTOVENE (ganciclovir) -IV Solution for Maintenance Treatment of CMV Retinitis
Body System Adverse Event Maintenance Treatment Studies Capsules
(n=326) IV
(n=179) Body as a Whole Fever 38% 48% Infection 9% 13% Chills 7% 10% Sepsis 4% 15% Digestive System Diarrhea 41% 44% Anorexia 15% 14% Vomiting 13% 13% Hemic and Lymphatic System Leukopenia 29% 41% Anemia 19% 25% Thrombocytopenia 6% 6% Nervous System Neuropathy 8% 9% Other Sweating 11% 12% Pruritus 6% 5% Catheter Related* Total Catheter Events 6% 22% Catheter Infection 4% 9% Catheter Sepsis 1% 8% *Some of these events also appear under other body systems. The following events were frequently observed in clinical trials but occurred with equal or greater frequency in placebo-treated subjects: abdominal pain, nausea, flatulence, pneumonia, paresthesia, rash. Retinal Detachment Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal detachment occurred in 11% of patients treated with CYTOVENE-IV solution and in 8% of patients treated with ganciclovir capsules. Patients with CMV retinitis should have frequent ophthalmologic evaluations to monitor the status of their retinitis and to detect any other retinal pathology. Transplant Recipients There have been three controlled clinical trials of CYTOVENE (ganciclovir) -IV solution for the prevention of CMV disease in transplant recipients. Laboratory data and adverse events reported during these trials are summarized below. Laboratory Data The following table shows the frequency of granulocytopenia (neutropenia) and thrombocytopenia observed: Table 6: Controlled Trials – Transplant Recipients
  CYTOVENE-IV Heart Allograft* Bone Marrow Allograft† CYTOVENE-IV
(n=76) Placebo
(n=73) CYTOVENE-IV
(n=57) Control
(n=55) Neutropenia   Minimum ANC < 500/µL 4% 3% 12% 6%   Minimum ANC 500-1000/µL 3% 8% 29% 17%   TOTAL ANC ≤ 1000/µL 7% 11% 41% 23% Thrombocytopenia   Platelet count < 25,000/µL 3% 1% 32% 28%   Platelet count25,000-50,000/µL 5% 3% 25% 37%   TOTAL Platelet ≤ 50,000/µL 8% 4% 57% 65% * Study ICM 1496. Mean duration of treatment = 28 days
†Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days (See Clinical Trials.) The following table shows the frequency of elevated serum creatinine values in these controlled clinical trials: Table 7: Controlled Trials - Transplant Recipients
  CYTOVENE-IV Heart Allograft
ICM 1496 Bone Marrow Allograft
ICM 1570 Bone Marrow Allograft
ICM 1689 Maximum Serum Creatinine Levels CYTOVENE-IV
(n=76) Placebo
(n=73) CYTOVENE-IV
(n=20) Control
(n=20) CYTOVENE-IV
(n=37) Placebo
(n=35) Serum Creatinine ≥ 2.5 mg/dL 18% 4% 20% 0% 0% 0% Serum Creatinine ≥ 1.5 - < 2.5 mg/dL 58% 69% 50% 35% 43% 44% In these three trials, patients receiving CYTOVENE (ganciclovir) -IV solution had elevated serum creatinine levels when compared to those receiving placebo. Most patients in these studies also received cyclosporine. The mechanism of impairment of renal function is not known. However, careful monitoring of renal function during therapy with CYTOVENE (ganciclovir) -IV solution is essential, especially for those patients receiving concomitant agents that may cause nephrotoxicity. General 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 listed 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. Adverse Events Reported During Postmarketing Experience With CYTOVENE-IV and Ganciclovir Capsules 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 Read the Cytovene (ganciclovir) Side Effects Center for a complete guide to possible side effectsLearn More »

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CAUTION - DO NOT ADMINISTER CYTOVENE (ganciclovir) -IV SOLUTION BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF CYTOVENE (ganciclovir) -IV MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS. CAUTION - INTRAMUSCULAR OR SUBCUTANEOUS INJECTION OF RECONSTITUTED CYTOVENE (ganciclovir) -IV SOLUTION MAY RESULT IN SEVERE TISSUE IRRITATION DUE TO HIGH pH (11). Dosage THE RECOMMENDED DOSE FOR CYTOVENE (ganciclovir) -IV SOLUTION SHOULD NOT BE EXCEEDED. THE RECOMMENDED INFUSION RATE FOR CYTOVENE (ganciclovir) -IV SOLUTION SHOULD NOT BE EXCEEDED. For Treatment of CMV Retinitis in Patients With Normal Renal Function Induction Treatment The recommended initial dosage 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 Treatment Following induction treatment, the recommended maintenance dosage of CYTOVENE (ganciclovir) -IV solution is 5 mg/kg given as a constant-rate intravenous infusion over 1 hour once daily, 7 days per week, or 6 mg/kg once daily, 5 days per week. For patients who experience progression of CMV retinitis while receiving maintenance treatment with CYTOVENE (ganciclovir) -IV, reinduction treatment is recommended. For the Prevention of CMV Disease in Transplant Recipients With Normal Renal Function The recommended initial dosage of CYTOVENE (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -IV was continued until day 100 to 120 posttransplantation. CMV disease occurred in several patients who discontinued treatment with CYTOVENE (ganciclovir) -IV solution prematurely. In heart allograft recipients, the onset of newly diagnosed CMV disease occurred after treatment with CYTOVENE (ganciclovir) -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 section for a more detailed discussion). Renal Impairment For patients with impairment of renal function, refer to Table 8 for recommended doses of CYTOVENE (ganciclovir) -IV solution and adjust the dosing interval as indicated: Table 8: Dosing for Patients with Renal Impairment
Creatinine Clearance* (mL/min) CYTOVENE-IV Induction Dose (mg/kg) Dosing Interval (hours) CYTOVENE-IV Maintenance Dose (mg/kg) Dosing Interval (hours) ≥ 70 5.0 12 5.0 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 < 10 1.25 3 times per week, following hemodialysis 0.625 3 times per week, following hemodialysis * 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 x male value Dosing for patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per week, following each hemodialysis session. CYTOVENE (ganciclovir) -IV should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%. Patient Monitoring 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). Reduction of Dose Dosage reductions in renally impaired patients are required for CYTOVENE (ganciclovir) -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). Method of Preparation of CYTOVENE (ganciclovir) -IV Solution Each 10 mL clear glass vial contains ganciclovir sodium equivalent to 500 mg of ganciclovir and 46 mg of sodium. The contents of the vial should be prepared for administration in the following manner:
  1. Reconstituted Solution:
    1. Reconstitute lyophilized CYTOVENE (ganciclovir) -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 (ganciclovir) -IV AND MAY CAUSE PRECIPITATION.
    2. Shake the vial to dissolve the drug.
    3. 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.
    4. Reconstituted solution in the vial is stable at room temperature for 12 hours. It should not be refrigerated.
  2. 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 (ganciclovir) -IV solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's Injection, USP
    CYTOVENE (ganciclovir) -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 (ganciclovir) -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.
Handling and Disposal Caution should be exercised in the handling and preparation of solutions of CYTOVENE (ganciclovir) -IV. Solutions of CYTOVENE (ganciclovir) -IV are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with CYTOVENE (ganciclovir) -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.

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Didanosine When the standard intravenous ganciclovir induction dose (5 mg/kg infused over 1 hour every 12 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, the steady-state didanosine AUC0-12 increased 70 ± 40% (range: 3% to 121%, n=11) and Cmax increased 49 ± 48% (range: -28% to 125%). In a separate study, when the standard intravenous ganciclovir maintenance dose (5 mg/kg infused over 1 hour every 24 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, didanosine AUC0-12 increased 50 ± 26% (range: 22% to 110%, n=11) and Cmax increased 36 ± 36% (range: -27% to 94%) over the first didanosine dosing interval. Didanosine plasma concentrations (AUC12-24) were unchanged during the dosing intervals when ganciclovir was not coadministered. Ganciclovir pharmacokinetics were not affected by didanosine. In neither study were there significant changes in the renal clearance of either drug. Zidovudine At an oral dose of 1000 mg of ganciclovir every 8 hours, mean steady-state ganciclovir AUC0-8 decreased 17 ± 25% (range: -52% to 23%) in the presence of zidovudine, 100 mg every 4 hours (n=12). Steady-state zidovudine AUC0-4 increased 19 ± 27% (range: -11% to 74%) in the presence of ganciclovir. No drug-drug interaction studies have been conducted with IV ganciclovir and zidovudine. Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, some patients may not tolerate concomitant therapy with these drugs at full dosage. Probenecid At an oral dose of 1000 mg of ganciclovir every 8 hours (n=10), ganciclovir AUC0-8 increased 53 ± 91% (range: -14% to 299%) in the presence of probenecid, 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22 ± 20% (range: -54% to -4%), which is consistent with an interaction involving competition for renal tubular secretion. No drug-drug interaction studies have been conducted with IV ganciclovir and probenecid. Imipenem-cilastatin Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. These drugs should not be used concomitantly unless the potential benefits outweigh the risks. Other Medications It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. Therefore, drugs such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks. No formal drug interaction studies of CYTOVENE (ganciclovir) -IV and drugs commonly used in transplant recipients have been conducted. Increases in serum creatinine were observed in patients treated with CYTOVENE (ganciclovir) -IV plus either cyclosporine or amphotericin B, drugs with known potential for nephrotoxicity (see ADVERSE EVENTS). In a retrospective analysis of 93 liver allograft recipients receiving ganciclovir (5 mg/kg infused over 1 hour every 12 hours) and oral cyclosporine (at therapeutic doses), there was no evidence of an effect on cyclosporine whole blood concentrations. Last reviewed on RxList: 4/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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CYTOVENE (ganciclovir) -IV is indicated for the treatment of CMV retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). CYTOVENE (ganciclovir) -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 (ganciclovir) -IV HAVE 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.

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CYTOVENE (ganciclovir) -IV is contraindicated in patients with hypersensitivity to ganciclovir or acyclovir. Last reviewed on RxList: 4/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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Overdosage with CYTOVENE (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -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).

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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). Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. REFERENCES 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. Distributed by: Roche Laboratories Inc. 340 Kingsland Street. Nutley, New Jersey 07110-1199. Revised August 2008. Last reviewed on RxList: 4/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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General In clinical studies with CYTOVENE (ganciclovir) -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 (ganciclovir) -IV solution should be accompanied by adequate hydration. Initially reconstituted solutions of CYTOVENE (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -IV. Such adjustments should be based on measured or estimated creatinine clearance values (see DOSAGE AND ADMINISTRATION). Laboratory Testing 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 CYTOVENE (ganciclovir) -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). Carcinogenesis, Mutagenesis‡ 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. Impairment of Fertility‡ 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. Pregnancy‡ Category C Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2x the human exposure based on AUC comparisons), respectively. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality. Daily intravenous doses of 90 mg/kg administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach (see Carcinogenesis, Mutagenesis‡). The drug exposure in mice as estimated by the AUC was approximately 1.7x the human AUC. Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. There are no adequate and well-controlled studies in pregnant women. CYTOVENE (ganciclovir) -IV should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Nursing Mothers 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 (ganciclovir) -IV. The minimum interval before nursing can safely be resumed after the last dose of CYTOVENE (ganciclovir) -IV is unknown. Pediatric Use SAFETY AND EFFICACY OF CYTOVENE (ganciclovir) -IV IN PEDIATRIC PATIENTS HAVE NOT BEEN ESTABLISHED. THE USE OF CYTOVENE (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -IV and 6 with placebo). Five of the pediatric patients treated with CYTOVENE (ganciclovir) -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 (ganciclovir) -IV. Two of the 6 placebo-treated pediatric patients developed CMV pneumonia vs none of the 5 patients treated with CYTOVENE (ganciclovir) -IV. The spectrum of adverse events in the pediatric group was similar to that observed in the adult patients. Geriatric Use The pharmacokinetic profiles of CYTOVENE (ganciclovir) -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 (ganciclovir) -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 (ganciclovir) -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). Use in Patients With Renal Impairment CYTOVENE (ganciclovir) -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%. ‡Footnote: All dose comparisons presented in the Carcinogenesis, Mutagenesis‡, Impairment of Fertility‡, and Pregnancy‡ subsections are based on the human AUC following administration of a single 5 mg/kg intravenous infusion of CYTOVENE (ganciclovir) -IV as used during the maintenance phase of treatment. Compared with the single 5 mg/kg intravenous infusion, human exposure is doubled during the intravenous induction phase (5 mg/kg bid). The cross-species dose comparisons should be divided by 2 for intravenous induction treatment with CYTOVENE (ganciclovir) -IV. Last reviewed on RxList: 4/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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