DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injection: Single-dose vial containing 500 mg of ganciclovir as sterile solution for intravenous use For injection: Single dose vial containing 500 mg of ganciclovir as sterile solution for intravenous use. The concentration of ganciclovir in the solution is 50 mg/mL [see Dosage and Administration (2.6)] . For injection: 500 mg of ganciclovir as clear sterile solution in single-dose vial. 3) For injection: 500 mg of ganciclovir as clear sterile solution in single-dose vial. 3).

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION. Ganciclovir Injection is administered only intravenously.2.1Dosage in Adult Patients with Normal Renal FunctionTreatment of CMV retinitis 2.3) Induction: mg/kg (given intravenously at constant rate over hour) every 12 hours for 14 to 21 days. Maintenance: mg/kg (given intravenously at constant rate over hour) once daily for days per week, or mg/kg once daily for days per week. Prevention of CMV disease in transplant recipients 2.4) Induction: mg/kg (given intravenously at constant rate over hour) every 12 hours for to 14 days. Maintenance: mg/kg (given intravenously at constant rate over hour) once daily, days per week, or mg/kg once daily, days per week until 100 to 120 days post-transplantation. Adults with renal impairment: Adjust dosage based on creatinine clearance. 2.5) 2.1Important Dosing and Administration Information. To avoid phlebitis/pain at the infusion site, Ganciclovir Injection must only be administered by intravenous infusion over hour, preferably via plastic cannula, into vein with adequate blood flow to permit rapid dilution and distribution. only be administered by intravenous infusion over hour, preferably via plastic cannula, into vein with adequate blood flow to permit rapid dilution and distribution.Do not administer Ganciclovir Injection by rapid or bolus intravenous injection which may increase toxicity as result of excessive plasma levels.The recommended dosage and infusion rate for Ganciclovir Injection should not be exceeded.Do not administer the reconstituted Ganciclovir Injection solution intramuscularly or subcutaneously because it may result in severe tissue irritation due to high pH [see Description (11)] Administration of Ganciclovir 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.. To avoid phlebitis/pain at the infusion site, Ganciclovir Injection must only be administered by intravenous infusion over hour, preferably via plastic cannula, into vein with adequate blood flow to permit rapid dilution and distribution. only be administered by intravenous infusion over hour, preferably via plastic cannula, into vein with adequate blood flow to permit rapid dilution and distribution.. Do not administer Ganciclovir Injection by rapid or bolus intravenous injection which may increase toxicity as result of excessive plasma levels.. The recommended dosage and infusion rate for Ganciclovir Injection should not be exceeded.. Do not administer the reconstituted Ganciclovir Injection solution intramuscularly or subcutaneously because it may result in severe tissue irritation due to high pH [see Description (11)] . Administration of Ganciclovir 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.. 2.2Testing Before and During Treatment. Females of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir 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 Injection or other nucleoside analogues have previously resulted in cytopenias, or in whom absolute neutrophil counts are less than 1000 cells/mcL at the beginning of treatment [see Warnings and Precautions (5.1)] .[see Warnings and Precautions (5.1)] All patients should be monitored for renal function before and during treatment with Ganciclovir 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 Injection solution to monitor disease status and for other retinal abnormalities [see Adverse Reactions (6.1)]. Females of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir 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 Injection or other nucleoside analogues have previously resulted in cytopenias, or in whom absolute neutrophil counts are less than 1000 cells/mcL at the beginning of treatment [see Warnings and Precautions (5.1)] .[see Warnings and Precautions (5.1)] . All patients should be monitored for renal function before and during treatment with Ganciclovir 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 Injection solution to monitor disease status and for other retinal abnormalities [see Adverse Reactions (6.1)]. 2.3Recommended Dosage for Treatment of CMV Retinitis in Adult Patients with Normal Renal Function. The recommended initial dosage of Ganciclovir Injection Induction Dosage: The recommended initial dosage of Ganciclovir Injection for patients with normal renal function is mg/kg (given intravenously at constant rate over hour) every 12 hours for 14 to 21 days. Following induction treatment, the recommended maintenance dosage of Ganciclovir Injection Maintenance Dosage: Following induction treatment, the recommended maintenance dosage of Ganciclovir Injection is mg/kg (given intravenously at constant rate over hour) once daily for days per week, or mg/kg once daily for days per week. 2.4Recommended Dosage for the Prevention of CMV Disease in Adult Transplant Recipients with Normal Renal Function. The recommended initial dosage of Ganciclovir Injection Induction Dosage: The recommended initial dosage of Ganciclovir Injection for patients with normal renal function is mg/kg (given intravenously at constant rate over hour) every 12 hours for to 14 days. Following induction, the recommended maintenance dosage of Ganciclovir Injection Maintenance Dosage: Following induction, the recommended maintenance dosage of Ganciclovir Injection is mg/kg (given intravenously at constant rate over hour) once daily for days per week, or mg/kg once daily for days per week until 100 to 120 days post-transplantation. 2.5Recommended Dosage in Adult Patients with Renal Impairment For patients with impairment of renal function, refer to Table for recommended doses of Ganciclovir Injection For patients with impairment of renal function, refer to Table for recommended doses of Ganciclovir 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 ImpairmentCreatinine Clearance Creatinine clearance can be related to serum creatinine by the formulas given below. (mL/min) Ganciclovir Injection Induction Dose (mg/kg) Dosing Interval (hours) for InductionGanciclovir Injection Maintenance Dose (mg/kg) Dosing Interval (hours) for MaintenanceGreater than or equal to 7051252450692.5122.52425492.5241.252410241.25240.62524Less than 101.253 times per week, following hemodialysis0.6253 times per week, following hemodialysisCreatinine clearance for males =(140 age [yrs]) (body wt [kg])(72) (serum creatinine [mg/dL])Creatinine clearance for females 0.85 male valueCreatinine clearance for females 0.85 male value. Patients Undergoing HemodialysisInduction dosing for Ganciclovir Injection in patients undergoing hemodialysis should not exceed 1.25 mg/kg times per week; and maintenance dosing should not exceed 0.625 mg/kg times per week following each hemodialysis session. Ganciclovir 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 Injection. Ganciclovir Injection solution Ganciclovir Injection solution must be diluted under the supervision of 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:Sterile Solution of Ganciclovir Injection Instructions: a) Shake the vial b) Visually inspect the solution for particulate matter and discoloration prior to proceeding with infusion. Discard the vial if particulate matter or discoloration is observed.b) Visually inspect the solution for particulate matter and discoloration prior to proceeding with infusion. Discard the vial if particulate matter or discoloration is observed. Infusion Instructions: a) Based on patient weight, the appropriate volume of the 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 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 Injection: 0.9% Sodium Chloride, 5% Dextrose, Ringers Injection and Lactated Ringers Injection, USP. a) Based on patient weight, the appropriate volume of the 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 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 Injection: 0.9% Sodium Chloride, 5% Dextrose, Ringers Injection and Lactated Ringers Injection, USP. b) Ganciclovir Injection, when 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 (2C to 8C). Do not freeze. b) Ganciclovir Injection, when 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 (2C to 8C (36 to 46F)). Do not freeze.. Sterile Solution of Ganciclovir Injection Instructions: a) Shake the vial b) Visually inspect the solution for particulate matter and discoloration prior to proceeding with infusion. Discard the vial if particulate matter or discoloration is observed.b) Visually inspect the solution for particulate matter and discoloration prior to proceeding with infusion. Discard the vial if particulate matter or discoloration is observed. Infusion Instructions:. 2.7Handling and Disposal Caution should be exercised in the handling and preparation of solutions of Ganciclovir Injection. Solutions of Ganciclovir Injection are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with Ganciclovir Injection 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 Discard any unused portion of the reconstituted solution [see How Supplied/Storage and Handling (16)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the labeling:Hematologic Toxicity [see Warnings and Precautions (5.1)] Renal Impairment [see Warnings and Precautions (5.2)] Impairment of Fertility [see Warnings and Precautions (5.3)] Fetal Toxicity [see Warnings and Precautions (5.4)] Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)] Hematologic Toxicity [see Warnings and Precautions (5.1)] Renal Impairment [see Warnings and Precautions (5.2)] Impairment of Fertility [see Warnings and Precautions (5.3)] Fetal Toxicity [see Warnings and Precautions (5.4)] Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)] Most common adverse reactions and laboratory abnormalities reported in at least 20% of patients were: pyrexia, diarrhea, leukopenia, nausea, anemia, asthenia, headache, cough, decreased appetite, dyspnea, abdominal pain, sepsis, hyperhidrosis, and blood creatinine increased. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pharmascience Inc. at 1-888-550-6060 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trial Experience in Adult Patients. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. The most common adverse reactions and laboratory abnormalities reported in at least 20% of patients were pyrexia, diarrhea, leukopenia, nausea, anemia, asthenia, headache, cough, decreased appetite, dyspnea, abdominal pain, sepsis, hyperhidrosis, and blood creatinine increased. Selected adverse reactions that occurred during clinical trials of Ganciclovir Injection are summarized below, according to the participating study patient population.. Three controlled, randomized, phase trials comparing Ganciclovir Injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Ganciclovir Injection or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table and Table 3, respectively Adverse Reactions in Patients with CMV Retinitis: Three controlled, randomized, phase trials comparing Ganciclovir Injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Ganciclovir Injection or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table and Table 3, respectively [see Clinical Studies (14.1)] Table 2. Pooled Selected Adverse Reactions Reported in >= 5% of Subjects Comparing Ganciclovir Injection to Ganciclovir Capsules for Maintenance Treatment of CMV RetinitisMaintenance Treatment StudiesAdverse ReactionGanciclovir Injection (n=179) Ganciclovir Capsules (n=326) Pyrexia48%38%Diarrhea44%41%Leukopenia41%29%Anemia25%19%Total catheter events22%6% Catheter infection9%4% Catheter sepsis8%1% Other catheter related events5%1%Sepsis15%4%Decreased appetite14%15%Vomiting13%13%Infection13%9%Hyperhidrosis12%11%Chills10%7%Neuropathy peripheral9%8%Thrombocytopenia6%6%Pruritus5%6%. 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 Ganciclovir Injection 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 Ganciclovir Injection and in 8% of patients treated with ganciclovir capsules. Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV RetinitisCMV Retinitis Treatment Pooled data from Treatment Studies: ICM 1653, ICM 1774 and AVI 034 Laboratory AbnormalitiesGanciclovir Injection Mean time on therapy 103 days, including allowed re-induction treatment periods mg/kg/day (N=175) Ganciclovir Capsules Mean time on therapy 91 days, including allowed re-induction treatment periods 3000 mg/day (N=320) Neutropenia with Absolute Neutrophil Count (ANC) per mcL: 50025%18% 500 74914%17% 750 100026%19%Anemia with Hemoglobin (g/dL): 6.5 g/dL5%2% 6.5 8.016%10% 8.0 9.526%25%Serum Creatinine (mg/dL): >= 2.52%1% >= 1.5 < 2.514%12%. There have been three controlled clinical trials of Ganciclovir Injection for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table and Table below. Adverse Reactions in Transplant Recipients: There have been three controlled clinical trials of Ganciclovir Injection for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table and Table below. Table shows the frequency of neutropenia and thrombocytopenia and Table shows the frequency of elevated serum creatinine values observed in these trials Table shows the frequency of neutropenia and thrombocytopenia and Table shows the frequency of elevated serum creatinine values observed in these trials [see Clinical Studies (14.2)] Table 4. Laboratory Abnormalities in Controlled Trials Transplant Recipients who Received Ganciclovir Injection, Placebo or ControlGanciclovir InjectionHeart Allograft Study ICM 1496. Mean duration of treatment 28 days Bone Marrow Allograft Study ICM 1570 and ICM 1689. Mean duration of treatment 45 days Ganciclovir Injection (n=76) Placebo (n=73) Ganciclovir Injection (n=57) Control (n=55) NeutropeniaAbsolute Neutrophil Count (ANC) per mcL< 5004%3%12%6%500-10003%8%29%17%Total ANC<= 1000/mcL7%11%41%23%ThrombocytopeniaPlatelet count per mcL< 25,0003%1%32%28%25,000-50,0005%3%25%37%Total Platelet Count<= 50,000/mcL8%4%57%65%Table 5. Serum Creatinine Levels in Controlled Trials Transplant Recipients who Received Ganciclovir Injection or PlaceboSerum Creatinine Levels (mg/dL) Heart Allograft ICM 1496 Bone Marrow Allograft ICM 1570 Bone Marrow Allograft ICM 1689 Ganciclovir Injection (n=76) PlaceboGanciclovir InjectionControlGanciclovir InjectionPlacebo(n=73)(n=20)(n=20)(n=37)(n=35)>= 2.5 mg/dL18%4%20%0%0%0%>= 1.5 < 2.558%69%50%35%43%44%. Other Adverse Reactions in Clinical Trials in Patients with CMV Retinitis and in Transplant Recipients Adverse drug reactions with Ganciclovir Injection or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below Adverse drug reactions with Ganciclovir Injection or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below [see Clinical Studies (14)]. All these events occurred in at least subjects. pancytopenia, bone marrow failure Blood and lymphatic disorders: pancytopenia, bone marrow failure arrhythmia Cardiac disorders: arrhythmia tinnitus, ear pain, deafness Ear and labyrinth disorders: tinnitus, ear pain, deafness visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema Eye disorders: visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth Gastrointestinal disorders: nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure General disorders and administration site conditions: fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure hypersensitivity Immune system disorders: hypersensitivity candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis Infections and infestations: candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased Investigations: blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased weight decreased Metabolism and nutrition disorders: weight decreased back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor Nervous system disorders: headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams Psychiatric disorders: depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams kidney failure, renal function abnormal, urinary frequency, hematuria Renal and urinary disorders: kidney failure, renal function abnormal, urinary frequency, hematuria cough, dyspnea Respiratory, thoracic and mediastinal disorders: cough, dyspnea dermatitis, alopecia, dry skin, urticaria, rash Skin and subcutaneous tissues disorders: dermatitis, alopecia, dry skin, urticaria, rash hypotension, hypertension, phlebitis, vasodilation Vascular disorders: hypotension, hypertension, phlebitis, vasodilation 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Ganciclovir Injection The following adverse reactions have been identified during post-approval use of Ganciclovir Injection or ganciclovir capsules. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.: hemolytic anemia, agranulocytosis, granulocytopenia Blood and lymphatic disorders: hemolytic anemia, agranulocytosis, granulocytopenia cardiac arrest, conduction disorder, torsade de pointes, ventricular tachycardia Cardiac disorders: cardiac arrest, conduction disorder, torsade de pointes, ventricular tachycardia congenital anomaly Congenital, familial and genetic disorders: congenital anomaly inappropriate antidiuretic hormone secretion Endocrine disorders: inappropriate antidiuretic hormone secretion cataracts, dry eyes Eye disorders: cataracts, dry eyes intestinal ulcer Gastrointestinal disorders: intestinal ulcer cholelithiasis, cholestasis, hepatic failure, hepatitis Hepatobiliary disorders: cholelithiasis, cholestasis, hepatic failure, hepatitis anaphylactic reaction, allergic reaction, vasculitis Immune system disorders: anaphylactic reaction, allergic reaction, vasculitis blood triglycerides increased Investigations: blood triglycerides increased acidosis, hypercalcemia, hyponatremia Metabolism and nutrition disorders: acidosis, hypercalcemia, hyponatremia arthritis, rhabdomyolysis Musculoskeletal and connective tissue disorders: arthritis, rhabdomyolysis dysesthesia, dysphasia, extrapyramidal disorder, facial paralysis, amnesia, anosmia, myelopathy, cerebrovascular accident, third cranial nerve paralysis, aphasia, encephalopathy, intracranial hypertension Nervous system disorders: dysesthesia, dysphasia, extrapyramidal disorder, facial paralysis, amnesia, anosmia, myelopathy, cerebrovascular accident, third cranial nerve paralysis, aphasia, encephalopathy, intracranial hypertension irritability, hallucinations Psychiatric disorders: irritability, hallucinations renal tubular disorder, hemolytic uremic syndrome Renal and urinary disorders: renal tubular disorder, hemolytic uremic syndrome infertility, testicular hypotrophy Reproductive system and breast disorders: infertility, testicular hypotrophy bronchospasm, pulmonary fibrosis Respiratory, thoracic and mediastinal disorders: bronchospasm, pulmonary fibrosis exfoliative dermatitis, Stevens-Johnson syndrome Skin and subcutaneous tissues disorders: exfoliative dermatitis, Stevens-Johnson syndrome peripheral ischemia Vascular disorders: peripheral ischemia.

BOXED WARNING SECTION.

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 Injection [see Warnings and Precautions (5.1)]. Impairment of Fertility: Based on animal data and limited human data, Ganciclovir Injection 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 Injection has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)]. Mutagenesis and Carcinogenesis: Based on animal data, Ganciclovir Injection has the potential to cause cancers in humans see Warnings and Precautions (5.5)]. Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia have been reported in patients treated with Ganciclovir Injection [see Warnings and Precautions (5.1)]. Impairment of Fertility: Based on animal data and limited human data, Ganciclovir Injection 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 Injection has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)]. Mutagenesis and Carcinogenesis: Based on animal data, Ganciclovir Injection has the potential to cause cancers in humans see Warnings and Precautions (5.5)]. WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESISWARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESISSee full prescribing information for complete boxed warning.Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia have been reported in patients treated with Ganciclovir Injection ( 5.1) Impairment of Fertility: Based on animal data and limited human data, Ganciclovir Injection may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females. 5.3) Fetal Toxicity: Based on animal data, Ganciclovir Injection has the potential to cause birth defects in humans. 5.4) Mutagenesis and Carcinogenesis: Based on animal data, Ganciclovir Injection has the potential to cause cancer in humans. 5.5) Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia have been reported in patients treated with Ganciclovir Injection ( 5.1) Impairment of Fertility: Based on animal data and limited human data, Ganciclovir Injection may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females. 5.3) Fetal Toxicity: Based on animal data, Ganciclovir Injection has the potential to cause birth defects in humans. 5.4) Mutagenesis and Carcinogenesis: Based on animal data, Ganciclovir Injection has the potential to cause cancer in humans. 5.5).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis, MutagenesisGanciclovir was carcinogenic in mice at the same mean drug exposure in humans as at the RHD (5 mg/kg). At the dose of 1000 mg/kg/day (1.4 times the exposure at the RHD), there was 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 (0.1 times the exposure at the RHD), 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 mg/kg/day (exposure estimated as 0.01 times the RHD). 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 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 mcg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (2.8 to 10 times the exposure at the RHD) but not at doses of 50 mg/kg (exposure approximately comparable to the RHD). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 mcg/mL. Impairment of FertilityGanciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following doses of 90 mg/kg/day (exposures approximately 1.7 times the RHD). 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 0.1 times the exposure at the RHD.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)] . 12.3 Pharmacokinetics. Absorption At the end of 1-hour intravenous infusion of mg/kg ganciclovir, total AUC ranged between 22.1 +- 3.2 (n=16) and 26.8 +- 6.1 mcghr/mL (n=16) and max ranged between 8.27 +- 1.02 (n=16) and 9.0 +- 1.4 mcg/mL (n=16). Distribution The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 +- 0.15 L/kg (n=98). Ganciclovir diffuses across the placenta. Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours post-dose in patients who received 2.5 mg/kg ganciclovir intravenously every hours or every 12 hours ranged from 0.31 to 0.68 mcg/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 mcg/mL.. EliminationWhen administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg. 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 intravenous administration.. Specific Populations. Pharmacokinetics in Patients with Renal ImpairmentThe pharmacokinetics following intravenous administration of Ganciclovir Injection solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg. Decreased renal function results in decreased clearance of ganciclovir (Table 7).Table 7. Ganciclovir Pharmacokinetics in Patients with Renal ImpairmentEstimated Creatinine Clearance (mL/min) nDoseClearance (mL/min) Mean +- SD Half-life (hours) Mean +- SD 50-7943.2-5 mg/kg128 +- 634.6 +- 1.425-4933-5 mg/kg57 +- 84.4 +- 0.4< 2531.25-5 mg/kg30 +- 1310.7 +- 5.7Plasma concentrations of ganciclovir are reduced by about 50% during 4 hour hemodialysis session . Pharmacokinetics in Geriatric PatientsThe pharmacokinetic profiles of Ganciclovir Injection in patients 65 years of age and older have not been established. As ganciclovir is mainly renally excreted and since renal clearance decreases with age, decrease in ganciclovir total body clearance and prolongation of ganciclovir half-life can be anticipated in patients 65 years of age and older [see Dosage and Administration (2.5), Use in Specific Populations (8.5)]. Drug Interaction StudiesTable and Table provide listing of established drug interaction studies with ganciclovir. Table provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.Table 8. Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic ParametersCoadministered DrugGanciclovir DosageNGanciclovir Pharmacokinetic (PK) ParameterMycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No effect on ganciclovir PK parameters observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg orally every hours12No effect on ganciclovir PK parameters observed.Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir5 mg/kg IV twice daily11No effect on ganciclovir PK parameters observed5 mg/kg IV once daily11No effect on ganciclovir PK parameters observedProbenecid 500 mg every hours1000 mg orally every hours10AUC 53 +- 91% (range: -14% to 299%) Ganciclovir renal clearance 22 +- 20% (range: -54% to -4%) Table 9. Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered DrugCoadministered DrugGanciclovir DosageNCoadministered Drug Pharmacokinetic (PK) ParameterOral cyclosporine at therapeutic doses5 mg/kg infused over hour every 12 hours93In retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations.Mycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No PK interaction observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg orally every hours12No effect on trimethoprim PK parameters observed.Didanosine 200 mg every 12 hours5 mg/kg IV twice daily11AUC 0-12 70 +- 40% (range: 3% to 121%) max49 +- 48% (range: -28% to 125%) Didanosine 200 mg every 12 hours5 mg/kg IV once daily11AUC 0-12 50 +- 26% (range: 22% to 110%) max 36 +- 36% (range: -27% to 94%) 12.4 Microbiology. Mechanism of ActionGanciclovir is synthetic analogue of 2-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the viral DNA polymerase, pUL54, by ganciclovir triphosphate. Antiviral ActivityThe quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC 50), vary greatly depending upon number of factors including the assay used. Thus the median concentration of ganciclovir that inhibits CMV replication (EC 50 value) in cell culture (laboratory strains or clinical isolates) has ranged from 0.08 to 13.6 uM (0.02 to 3.48 mcg/mL). Ganciclovir inhibits mammalian cell proliferation (CC 50 value) in cell culture at higher concentrations ranging from 118 to 2840 uM (30 to 725 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC 50 value 0.1 to 2.7 uM (0.028 to 0.7 mcg/mL)]. The relationship between the antiviral activity in cell culture and clinical response has not been established. Viral ResistanceCell Culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 and the viral DNA polymerase pUL54. In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with ganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 10. Table 10. Summary of Resistance-associated Amino Acid Substitutions Observed in the CMV of Patients Failing Ganciclovir Treatment or ProphylaxisNote: Many additional pathways to ganciclovir resistance likely existpUL97L405P, A440V, M460I/V/T/L, V466G/M, C518Y, H520Q, P521L, del 590-593, A591D/V, C592G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G/Y, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y, I610T, A613VpUL54E315D, N408D/K/S, F412C/L/S, D413A/E/N, L501F/I, T503I, K513E/N/R, D515E, L516W, I521T, P522A/L/S, V526L, C539G, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, L773V, V781I, V787L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987GCMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with Ganciclovir Injection. In controlled study of oral ganciclovir for prevention of AIDS-associated CMV disease, 364 individuals had one or more cultures performed after at least 90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last available isolate from each subject was tested for reduced sensitivity, and of 40 were found to be resistant to ganciclovir. These resistant isolates were associated with subsequent treatment failure for retinitis.The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.. Cross-ResistanceCross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region of the viral DNA polymerase. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codons 696-742) and III (codons 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 11. Table 11. Summary of pUL54 Amino Acid Substitutions with Cross-resistance between Ganciclovir, Cidofovir, and/or FoscarnetCross-resistant to cidofovirD301N, N408D/K, N410K, F412C/L/S/V, D413E/N, P488R, L501I, T503I, K513E/N, L516R/W, I521T, P522S/A, V526L, C539G/R, L545S/W, Q578H, D588N, I726T/V, E756K, L773V, V812L, T813S, A834P, G841A, del 981-982, A987GCross-resistant to foscarnetF412C, Q578H/L, D588N, V715A/M, E756K, L773V, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A/S, del 981-982.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Treatment of CMV Retinitis. In retrospective, non-randomized, single-center analysis of 41 patients with AIDS and CMV retinitis diagnosed by ophthalmologic examination between August 1983 and April 1988, treatment with Ganciclovir Injection solution resulted in delay in mean (median) time to first retinitis progression compared to untreated controls [105 (71) days from diagnosis vs 35 (29) days from diagnosis]. Patients in this series received induction treatment of Ganciclovir Injection In retrospective, non-randomized, single-center analysis of 41 patients with AIDS and CMV retinitis diagnosed by ophthalmologic examination between August 1983 and April 1988, treatment with Ganciclovir Injection solution resulted in delay in mean (median) time to first retinitis progression compared to untreated controls [105 (71) days from diagnosis vs 35 (29) days from diagnosis]. Patients in this series received induction treatment of Ganciclovir Injection mg/kg twice daily for 14 to 21 days followed by maintenance treatment with either mg/kg once daily, days per week or mg/kg once daily, days per week.In controlled, randomized study conducted between February 1989 and December 1990, immediate treatment with Ganciclovir Injection was compared to delayed treatment in 42 patients with AIDS and peripheral CMV retinitis; 35 of 42 patients (13 in the immediate-treatment group and 22 in the delayed-treatment group) were included in the analysis of time to retinitis progression. Based on masked assessment of fundus photographs, the mean [95% CI] and median [95% CI] times to progression of retinitis were 66 days [39, 94] and 50 days [40, 84], respectively, in the immediate-treatment group compared to 19 days [11, 27] and 13.5 days [8, 18], respectively, in the delayed-treatment group.In controlled, randomized study conducted between February 1989 and December 1990, immediate treatment with Ganciclovir Injection was compared to delayed treatment in 42 patients with AIDS and peripheral CMV retinitis; 35 of 42 patients (13 in the immediate-treatment group and 22 in the delayed-treatment group) were included in the analysis of time to retinitis progression. Based on masked assessment of fundus photographs, the mean [95% CI] and median [95% CI] times to progression of retinitis were 66 days [39, 94] and 50 days [40, 84], respectively, in the immediate-treatment group compared to 19 days [11, 27] and 13.5 days [8, 18], respectively, in the delayed-treatment group.Data from trials ICM 1653, ICM 1774, and AVI 034, which were performed comparing Ganciclovir Injection to oral ganciclovir for treatment of CMV retinitis in patients with AIDS, are shown in Table 12 and Figures 1, 2, and 3, and are discussed below.Data from trials ICM 1653, ICM 1774, and AVI 034, which were performed comparing Ganciclovir Injection to oral ganciclovir for treatment of CMV retinitis in patients with AIDS, are shown in Table 12 and Figures 1, 2, and 3, and are discussed below.Table 12. Population Characteristics in Studies ICM 1653, ICM 1774 and AVI 034DemographicsICM 1653 (n=121) ICM 1774 (n=225) AVI 034 (n=159) Median age (years)383739Range24-6222-5623-62SexMales116 (96%)222 (99%)148 (93%)Females5 (4%)3 (1%)10 (6%)EthnicityAsian3 (3%)5 (2%)7 (4%)Black11 (9%)9 (4%)3 (2%)Caucasian98 (81%)186 (83%)140 (88%)Other9 (7%)25 (11%)8 (5%)Median CD Count 9.57.010.0Range0-1410-800-320Mean (SD) Observation Time (days) 107.9 (43.0)97.6 (42.5)80.9 (47.0). In this randomized, open-label, parallel group trial, conducted between March 1991 and November 1992, patients with AIDS and newly diagnosed CMV retinitis received 3-week induction course of Ganciclovir Injection solution, mg/kg twice daily for 14 days followed by mg/kg once daily for additional week. Following the 21-day intravenous induction course, patients with stable CMV retinitis were randomized to receive 20 weeks of maintenance treatment with either Ganciclovir Injection solution, mg/kg once daily, or ganciclovir capsules, 500 mg times daily (3000 mg/day). The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 57 days [44, 70] and 29 days [28, 43], respectively, for patients on oral therapy compared to 62 days [50, 73] and 49 days [29, 61], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral IV) was -5 days [-22, 12]. See Figure Trial ICM 1653: In this randomized, open-label, parallel group trial, conducted between March 1991 and November 1992, patients with AIDS and newly diagnosed CMV retinitis received 3-week induction course of Ganciclovir Injection solution, mg/kg twice daily for 14 days followed by mg/kg once daily for additional week. Following the 21-day intravenous induction course, patients with stable CMV retinitis were randomized to receive 20 weeks of maintenance treatment with either Ganciclovir Injection solution, mg/kg once daily, or ganciclovir capsules, 500 mg times daily (3000 mg/day). The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 57 days [44, 70] and 29 days [28, 43], respectively, for patients on oral therapy compared to 62 days [50, 73] and 49 days [29, 61], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral IV) was -5 days [-22, 12]. See Figure for comparison of the proportion of patients remaining free of progression over time. In this three-arm, randomized, open-label, parallel group trial, conducted between June 1991 and August 1993, patients with AIDS and stable CMV retinitis following from weeks to months of treatment with Ganciclovir Injection solution were randomized to receive maintenance treatment with Ganciclovir Injection solution, mg/kg once daily, ganciclovir capsules, 500 mg times daily, or ganciclovir capsules, 1000 mg three times daily for 20 weeks. The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 54 days [48, 60] and 42 days [31, 54], respectively, for patients on oral therapy compared to 66 days [56, 76] and 54 days [41, 69], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral IV) was -12 days [-24, 0]. See Figure Trial ICM 1774: In this three-arm, randomized, open-label, parallel group trial, conducted between June 1991 and August 1993, patients with AIDS and stable CMV retinitis following from weeks to months of treatment with Ganciclovir Injection solution were randomized to receive maintenance treatment with Ganciclovir Injection solution, mg/kg once daily, ganciclovir capsules, 500 mg times daily, or ganciclovir capsules, 1000 mg three times daily for 20 weeks. The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 54 days [48, 60] and 42 days [31, 54], respectively, for patients on oral therapy compared to 66 days [56, 76] and 54 days [41, 69], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral IV) was -12 days [-24, 0]. See Figure for comparison of the proportion of patients remaining free of progression over time. In this randomized, open-label, parallel group trial, conducted between June 1991 and February 1993, patients with AIDS and newly diagnosed (81%) or previously treated (19%) CMV retinitis who had tolerated 10 to 21 days of induction treatment with Ganciclovir Injection, mg/kg twice daily, were randomized to receive 20 weeks of maintenance treatment with either ganciclovir capsules, 500 mg times daily, or Ganciclovir Injection solution, mg/kg/day. The mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 51 days [44, 57] and 41 days [31, 45], respectively, for patients on oral therapy compared to 62 days [52, 72] and 60 days [42, 83], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral IV) was -11 days [-24, 1]. See Figure Trial AVI 034: In this randomized, open-label, parallel group trial, conducted between June 1991 and February 1993, patients with AIDS and newly diagnosed (81%) or previously treated (19%) CMV retinitis who had tolerated 10 to 21 days of induction treatment with Ganciclovir Injection, mg/kg twice daily, were randomized to receive 20 weeks of maintenance treatment with either ganciclovir capsules, 500 mg times daily, or Ganciclovir Injection solution, mg/kg/day. The mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 51 days [44, 57] and 41 days [31, 45], respectively, for patients on oral therapy compared to 62 days [52, 72] and 60 days [42, 83], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral IV) was -11 days [-24, 1]. See Figure for comparison of the proportion of patients remaining free of progression over time. Comparison of other CMV retinitis outcomes between oral and intravenous formulations (development of bilateral retinitis, progression into Zone 1, and deterioration of visual acuity), while not definitive, showed no marked differences between treatment groups in these studies. Because of low event rates among these endpoints, these studies are underpowered to rule out significant differences in these endpoints.Comparison of other CMV retinitis outcomes between oral and intravenous formulations (development of bilateral retinitis, progression into Zone 1, and deterioration of visual acuity), while not definitive, showed no marked differences between treatment groups in these studies. Because of low event rates among these endpoints, these studies are underpowered to rule out significant differences in these endpoints.Figure Trial ICM 1653: Time to Progression of CMV RetinitisFigure Trial ICM 1774: Time to Progression of CMV RetinitisFigure Trial AVI 034: Time to Progression of Retinitis. Figure Trial ICM 1653: Time to Progression of CMV Retinitis. Figure Trial ICM 1774: Time to Progression of CMV Retinitis. Figure Trial AVI 034: Time to Progression of Retinitis. 14.2Prevention of CMV Disease in Transplant Recipients. Ganciclovir Injection was evaluated in three randomized, controlled trials of prevention of CMV disease in organ transplant recipients.. In randomized, double-blind, placebo-controlled study of 149 heart transplant recipients at risk for CMV infection (CMV seropositive or seronegative recipient of an organ from CMV seropositive donor), there was reduction in the overall incidence of CMV disease in patients treated with Ganciclovir Injection. Immediately post-transplant, patients received Ganciclovir Injection solution mg/kg twice daily for 14 days followed by mg/kg once daily for days/week for an additional 14 days. Twelve of the 76 (16%) patients treated with Ganciclovir Injection vs 31 of the 73 (43%) placebo-treated patients developed CMV disease during the 120-day post-transplant observation period. No significant differences in hematologic toxicities were seen between the two treatment groups Trial ICM 1496: In randomized, double-blind, placebo-controlled study of 149 heart transplant recipients at risk for CMV infection (CMV seropositive or seronegative recipient of an organ from CMV seropositive donor), there was reduction in the overall incidence of CMV disease in patients treated with Ganciclovir Injection. Immediately post-transplant, patients received Ganciclovir Injection solution mg/kg twice daily for 14 days followed by mg/kg once daily for days/week for an additional 14 days. Twelve of the 76 (16%) patients treated with Ganciclovir Injection vs 31 of the 73 (43%) placebo-treated patients developed CMV disease during the 120-day post-transplant observation period. No significant differences in hematologic toxicities were seen between the two treatment groups [see Adverse Reactions (6.1)] . In randomized, double-blind, placebo-controlled study of 72 bone marrow transplant recipients with asymptomatic CMV infection (CMV positive culture of urine, throat or blood) there was reduction in the incidence of CMV disease in patients treated with Ganciclovir Injection following successful hematopoietic engraftment. Patients with virologic evidence of CMV infection received Ganciclovir Injection solution mg/kg twice daily for days followed by mg/kg once daily through day 100 post-transplant. One of the 37 (3%) patients treated with Ganciclovir Injection vs 15 of the 35 (43%) placebo-treated patients developed CMV disease during the study. At months post-transplant, there continued to be reduction in the incidence of CMV disease in patients treated with Ganciclovir Injection. Six of 37 (16%) patients treated with Ganciclovir Injection vs 15 of the 35 (43%) placebo-treated patients developed disease through months post-transplant. The overall rate of survival was higher in the group treated with Ganciclovir Injection, both at day 100 and day 180 post-transplant. Although the differences in hematologic toxicities were not statistically significant, the incidence of neutropenia was higher in the group treated with Ganciclovir Injection see Trial ICM 1689: In randomized, double-blind, placebo-controlled study of 72 bone marrow transplant recipients with asymptomatic CMV infection (CMV positive culture of urine, throat or blood) there was reduction in the incidence of CMV disease in patients treated with Ganciclovir Injection following successful hematopoietic engraftment. Patients with virologic evidence of CMV infection received Ganciclovir Injection solution mg/kg twice daily for days followed by mg/kg once daily through day 100 post-transplant. One of the 37 (3%) patients treated with Ganciclovir Injection vs 15 of the 35 (43%) placebo-treated patients developed CMV disease during the study. At months post-transplant, there continued to be reduction in the incidence of CMV disease in patients treated with Ganciclovir Injection. Six of 37 (16%) patients treated with Ganciclovir Injection vs 15 of the 35 (43%) placebo-treated patients developed disease through months post-transplant. The overall rate of survival was higher in the group treated with Ganciclovir Injection, both at day 100 and day 180 post-transplant. Although the differences in hematologic toxicities were not statistically significant, the incidence of neutropenia was higher in the group treated with Ganciclovir Injection [see Adverse Reactions (6.1)] . This was randomized, unblinded study that evaluated 40 allogeneic bone marrow transplant recipients at risk for CMV disease. Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) on day 35 post-transplant. Patients with histologic, immunologic or virologic evidence of CMV infection in the lung were then randomized to observation or treatment with Ganciclovir Injection solution (5 mg/kg twice daily for 14 days followed by mg/kg once daily days/week until day 120). Four of 20 (20%) patients treated with Ganciclovir Injection and 14 of 20 (70%) control patients developed interstitial pneumonia. The incidence of CMV disease was lower in the group treated with Ganciclovir Injection Trial ICM 1570: This was randomized, unblinded study that evaluated 40 allogeneic bone marrow transplant recipients at risk for CMV disease. Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) on day 35 post-transplant. Patients with histologic, immunologic or virologic evidence of CMV infection in the lung were then randomized to observation or treatment with Ganciclovir Injection solution (5 mg/kg twice daily for 14 days followed by mg/kg once daily days/week until day 120). Four of 20 (20%) patients treated with Ganciclovir Injection and 14 of 20 (70%) control patients developed interstitial pneumonia. The incidence of CMV disease was lower in the group treated with Ganciclovir Injection consistent with the results observed in ICM 1689.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Ganciclovir Injection Ganciclovir Injection is contraindicated in patients who have experienced clinically significant hypersensitivity reaction (e.g., anaphylaxis) to ganciclovir, valganciclovir, or any component of the formulation.. Hypersensitivity to ganciclovir or valganciclovir. 4) Hypersensitivity to ganciclovir or valganciclovir. 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Ganciclovir Injection Ganciclovir Injection contains ganciclovir, in the form of the sodium salt for intravenous injection. Ganciclovir is synthetic guanine derivative active against cytomegalovirus (CMV).Chemically, ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine and ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine, monosodium salt. The chemical structures of ganciclovir sodium and ganciclovir are:Chemically, ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine and ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine, monosodium salt. The chemical structures of ganciclovir sodium and ganciclovir are:Ganciclovir is white to off-white crystalline powder. Ganciclovir is polar hydrophilic compound with solubility of 2.6 mg/mL in water at 25C and an n-octanol/water partition coefficient of 0.022. The pK for ganciclovir are 2.2 and 9.4. Ganciclovir is white to off-white crystalline powder. Ganciclovir is polar hydrophilic compound with solubility of 2.6 mg/mL in water at 25C and an n-octanol/water partition coefficient of 0.022. The pK as for ganciclovir are 2.2 and 9.4. Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as salt forming agent, is sterile solution. At physiological pH, ganciclovir sodium exists as the un-ionized form with solubility of approximately mg/mL at 37C.Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as salt forming agent, is sterile solution. At physiological pH, ganciclovir sodium exists as the un-ionized form with solubility of approximately mg/mL at 37C.Each vial contains 543 mg ganciclovir sodium equivalent to 500 mg ganciclovir.Each vial contains ganciclovir sodium equivalent to 500 mg ganciclovir.Inactive ingredients may include hydrochloric acid (QS) and sodium hydroxide (QS) added to adjust the pH.Inactive ingredients may include hydrochloric acid (QS) and sodium hydroxide (QS) added to adjust the pH.All doses in this package insert are specified in terms of ganciclovir.. image description.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Ganciclovir Injection Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Ganciclovir Injection and drugs excreted by the same pathway as ganciclovir. 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 . Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table [see Clinical Pharmacology (12.3)] Table 6. Established and Other Potentially Significant Drug Interactions with GanciclovirName of the Concomitant DrugChange in the Concentration of Ganciclovir or Concomitant DrugClinical CommentImipenem-cilastatinUnknownCoadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin.Cyclosporine or amphotericin BUnknownMonitor renal function when Ganciclovir Injection is coadministered with cyclosporine or amphotericin because of potential increase in serum creatinine [see Warnings and Precautions (5.2)]. Mycophenolate mofetil (MMF)<-> Ganciclovir (in patients with normal renal function) <-> MMF (in patients with normal renal function) Based on increased risk, patients should be monitored for hematological and renal toxicity.Other drugs associated with myelosuppression or nephrotoxicity (e.g., dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/ sulfamethoxazole, vinblastine, vincristine and zidovudine)UnknownBecause of potential for higher toxicity, coadministration with Ganciclovir Injection should be considered only if the potential benefits are judged to outweigh the risks.Didanosine<-> Ganciclovir Didanosine Patients should be closely monitored for didanosine toxicity (e.g., pancreatitis).Probenecid GanciclovirGanciclovir Injection dose may need to be reduced. Monitor for evidence of ganciclovir toxicity.. 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 ganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. (5.2, 7)Mycophenolate mofetil (MMF): When coadministered with ganciclovir, 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, such drugs should be considered for concomitant use with ganciclovir 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). 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 ganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. (5.2, 7). Mycophenolate mofetil (MMF): When coadministered with ganciclovir, 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, such drugs should be considered for concomitant use with ganciclovir 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).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingFemales of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir Injection Females of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir Injection [see Dosage and Administration (2.2), Use in Specific Populations (8.1)] . Contraception. FemalesBecause of the mutagenic and teratogenic potential of Ganciclovir Injection, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Ganciclovir Injection Because of the mutagenic and teratogenic potential of Ganciclovir Injection, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Ganciclovir Injection [see Dosage and Administration (2.2), Warnings and Precautions (5.4), Nonclinical Toxicology (13.1)] . MalesBecause of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir Injection [see Warnings and Precautions (5.4), Nonclinical Toxicology (13.1)]. InfertilityGanciclovir Injection at the recommended doses may cause temporary or permanent female and male infertility Ganciclovir Injection at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)] . Data. Human DataIn small, open-label, non-randomized clinical study, adult male renal transplant patients receiving valganciclovir (the prodrug of ganciclovir) for CMV prophylaxis for up to 200 days post-transplantation were compared to an untreated control group. Patients were followed-up for six months after valganciclovir discontinuation. Among 24 evaluable patients in the valganciclovir group, the mean sperm density at the end of treatment visit decreased by 11 million/mL from baseline; whereas, among 14 evaluable patients in the control group the mean sperm density increased by 33 million/mL. However, at the follow-up visit among 20 evaluable patients in the valganciclovir group, the mean sperm density was comparable to that observed among 10 evaluable patients in the untreated control group (the mean sperm density at the end of follow-up visit increased by 41 million/mL from baseline in the valganciclovir group and by 43 million/mL in the untreated group).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of Ganciclovir Injection 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. Ganciclovir Injection 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 renal clearance decreases with age, Ganciclovir Injection should be administered to elderly patients with special consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly Clinical studies of Ganciclovir Injection 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. Ganciclovir Injection 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 renal clearance decreases with age, Ganciclovir Injection should be administered to elderly patients with special consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Use in Specific Populations (8.6)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedGanciclovir Injection is supplied as follows:NDCGanciclovir Injection (50 mg per mL)Package Factor51817-171- 01500 mg per 10 ml Single-Dose Vial25 vials per carton51817-589-02500 mg per 10 ml Single-Dose Vial1 vial per cartonGanciclovir Injection is clear solution supplied in 10 mL sterile single-dose vials, each containing 543 mg ganciclovir sodium equivalent to 500 mg of ganciclovir. The concentration of ganciclovir in the solution is 50 mg/mL. 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. StorageStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Store diluted infusion solution under refrigeration at to 8C (36 to 46F) for no longer than 24 hours. Do not freeze.Discard unused portion.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Ganciclovir Injection Ganciclovir Injection is deoxynucleoside analogue cytomegalovirus (CMV) DNA polymerase inhibitor indicated for the:treatment of CMV retinitis in immunocompromised adult patients, including patients with acquired immunodeficiency syndrome (AIDS). 1.1) prevention of CMV disease in adult transplant recipients at risk for CMV disease. 1.2) treatment of CMV retinitis in immunocompromised adult patients, including patients with acquired immunodeficiency syndrome (AIDS). 1.1) prevention of CMV disease in adult transplant recipients at risk for CMV disease. 1.2) 1.1Treatment of CMV Retinitis Ganciclovir Injection 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)]. 1.2Prevention of CMV Disease in Transplant Recipients. Ganciclovir Injection is indicated for the prevention of CMV disease in adult transplant recipients at risk for CMV disease [see Clinical Studies (14.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hematologic ToxicityInform patients that Ganciclovir Injection may cause hematologic toxicity, including granulocytopenia (neutropenia), anemia, and thrombocytopenia. Inform patients that their blood counts and platelet counts should be closely monitored while on treatment [see Warnings and Precautions (5.1)]. Impairment of Renal FunctionInform patients that Ganciclovir Injection has been associated with decreased renal function and that serum creatinine or creatinine clearance should be monitored while on treatment to allow for dosage adjustment in patients with renal impairment [see Warnings and Precautions (5.2)]. Impairment of FertilityInform patients that Ganciclovir Injection may cause temporary or permanent infertility in humans [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)] . Pregnancy and ContraceptionAdvise female patients to use effective contraception during and for at least 30 days following treatment with Ganciclovir Injection. Similarly, advise men to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir Injection Advise female patients to use effective contraception during and for at least 30 days following treatment with Ganciclovir Injection. Similarly, advise men to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir Injection [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)] . CarcinogenicityInform patients that Ganciclovir Injection should be considered potential carcinogen [see Warnings and Precautions (5.5)] . Drug InteractionsInform patients that Ganciclovir Injection may interact with other drugs. Advise patients to report to their healthcare provider the use of any other medication [see Drug Interactions (7)]. Impairment of Cognitive AbilityBased on the adverse reaction profile, ganciclovir may affect cognitive abilities, including on the ability to drive and operate machinery, as seizures, dizziness, and/or confusion have been reported with the use of Ganciclovir Injection [see Adverse Reaction (6.1)] . Ophthalmological Examination in Patients with CMV RetinitisInform patients that Ganciclovir Injection is not cure for CMV retinitis, and they may continue to experience progression of retinitis during or following treatment. Advise patients to have frequent ophthalmological follow-up examinations while being treated with Ganciclovir Injection Inform patients that Ganciclovir Injection is not cure for CMV retinitis, and they may continue to experience progression of retinitis during or following treatment. Advise patients to have frequent ophthalmological follow-up examinations while being treated with Ganciclovir Injection Some patients may require more frequent ophthalmological follow-up [see Dosage and Administration (2.2), Adverse Reactions (6.1)]. LactationAdvise nursing mothers not to breastfeed if they are receiving Ganciclovir Injection because of the potential for serious adverse events in nursing infants and because HIV can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk Summary. No data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed infant, or the effects on milk production. When ganciclovir was administered to lactating rats, ganciclovir was present in milk [see Data]. Advise nursing mothers that breastfeeding is not recommended during treatment with Ganciclovir Injection because of the potential for serious adverse reactions in nursing infants [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5), Nonclinical Toxicology (13.1)] Furthermore, the Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential postnatal transmission of HIV. Data. Animal DataGanciclovir administered intravenously (at 0.13 mg/h) to lactating rats (on lactation day 15) resulted in passive transfer into milk. The milk-to-serum ratio for ganciclovir at steady state was 1.6 +- 0.33.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ganciclovir is an antiviral drug with activity against CMV [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionGanciclovir is synthetic analogue of 2-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the viral DNA polymerase, pUL54, by ganciclovir triphosphate. Antiviral ActivityThe quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC 50), vary greatly depending upon number of factors including the assay used. Thus the median concentration of ganciclovir that inhibits CMV replication (EC 50 value) in cell culture (laboratory strains or clinical isolates) has ranged from 0.08 to 13.6 uM (0.02 to 3.48 mcg/mL). Ganciclovir inhibits mammalian cell proliferation (CC 50 value) in cell culture at higher concentrations ranging from 118 to 2840 uM (30 to 725 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC 50 value 0.1 to 2.7 uM (0.028 to 0.7 mcg/mL)]. The relationship between the antiviral activity in cell culture and clinical response has not been established. Viral ResistanceCell Culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 and the viral DNA polymerase pUL54. In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with ganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 10. Table 10. Summary of Resistance-associated Amino Acid Substitutions Observed in the CMV of Patients Failing Ganciclovir Treatment or ProphylaxisNote: Many additional pathways to ganciclovir resistance likely existpUL97L405P, A440V, M460I/V/T/L, V466G/M, C518Y, H520Q, P521L, del 590-593, A591D/V, C592G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G/Y, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y, I610T, A613VpUL54E315D, N408D/K/S, F412C/L/S, D413A/E/N, L501F/I, T503I, K513E/N/R, D515E, L516W, I521T, P522A/L/S, V526L, C539G, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, L773V, V781I, V787L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987GCMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with Ganciclovir Injection. In controlled study of oral ganciclovir for prevention of AIDS-associated CMV disease, 364 individuals had one or more cultures performed after at least 90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last available isolate from each subject was tested for reduced sensitivity, and of 40 were found to be resistant to ganciclovir. These resistant isolates were associated with subsequent treatment failure for retinitis.The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.. Cross-ResistanceCross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region of the viral DNA polymerase. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codons 696-742) and III (codons 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 11. Table 11. Summary of pUL54 Amino Acid Substitutions with Cross-resistance between Ganciclovir, Cidofovir, and/or FoscarnetCross-resistant to cidofovirD301N, N408D/K, N410K, F412C/L/S/V, D413E/N, P488R, L501I, T503I, K513E/N, L516R/W, I521T, P522S/A, V526L, C539G/R, L545S/W, Q578H, D588N, I726T/V, E756K, L773V, V812L, T813S, A834P, G841A, del 981-982, A987GCross-resistant to foscarnetF412C, Q578H/L, D588N, V715A/M, E756K, L773V, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A/S, del 981-982.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis, MutagenesisGanciclovir was carcinogenic in mice at the same mean drug exposure in humans as at the RHD (5 mg/kg). At the dose of 1000 mg/kg/day (1.4 times the exposure at the RHD), there was 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 (0.1 times the exposure at the RHD), 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 mg/kg/day (exposure estimated as 0.01 times the RHD). 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 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 mcg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (2.8 to 10 times the exposure at the RHD) but not at doses of 50 mg/kg (exposure approximately comparable to the RHD). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 mcg/mL. Impairment of FertilityGanciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following doses of 90 mg/kg/day (exposures approximately 1.7 times the RHD). 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 0.1 times the exposure at the RHD.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Reports of adverse reactions after overdoses with Ganciclovir Injection Reports of adverse reactions after overdoses with Ganciclovir Injection 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: myelosuppression including pancytopenia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, bone marrow failure Hematological toxicity: myelosuppression including pancytopenia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, bone marrow failure hepatitis, liver function disorder Hepatotoxicity: hepatitis, liver function disorder worsening of hematuria in patient with pre-existing renal impairment, acute kidney injury, elevated creatinine Renal toxicity: worsening of hematuria in patient with pre-existing renal impairment, acute kidney injury, elevated creatinine abdominal pain, diarrhea, vomiting Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting seizure Neurotoxicity: seizure Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Ganciclovir Injection Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered in patients with cytopenias Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Ganciclovir Injection [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)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY 500 mg Carton Label 25 10 mL. Rx only NDC 51817-171-01Ganciclovir Injection500mg/10mL (50 mg/mL) FOR INTRAVENOUS INFUSION ONLYCAUTION: Cytotoxic AgentHandle this product with great care because it is potent cytotoxic agent and suspected carcinogen25 10 mL Single-dose vials. Ganciclovir Injection box label 25x10 mL.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and efficacy of Ganciclovir Injection Safety and efficacy of Ganciclovir Injection have not been established in pediatric patients.A total of 120 pediatric patients with serious CMV infections participated in clinical trials. Granulocytopenia and thrombocytopenia were the most common adverse reactions. The pharmacokinetic characteristics of ganciclovir after administration of Ganciclovir Injection were studied in 27 neonates (aged to 49 days) and 10 pediatric patients, aged months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of mg/kg (n=14) and mg/kg (n=13) were 5.5 +- 1.6 and 7.0 +- 1.6 mcg/mL, systemic clearance 3.14 +- 1.75 and 3.56 +- 1.27 mL/min/kg, and of 2.4 hours (harmonic mean) for both doses, respectively. total of 120 pediatric patients with serious CMV infections participated in clinical trials. Granulocytopenia and thrombocytopenia were the most common adverse reactions. The pharmacokinetic characteristics of ganciclovir after administration of Ganciclovir Injection were studied in 27 neonates (aged to 49 days) and 10 pediatric patients, aged months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of mg/kg (n=14) and mg/kg (n=13) were max 5.5 +- 1.6 and 7.0 +- 1.6 mcg/mL, systemic clearance 3.14 +- 1.75 and 3.56 +- 1.27 mL/min/kg, and 1/2 of 2.4 hours (harmonic mean) for both doses, respectively. In pediatric patients months to 12 years of age, the pharmacokinetic characteristics of ganciclovir were the same after single and multiple (every 12 hours) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 +- 0.22 L/kg, was 7.9 +- 3.9 mcg/mL, systemic clearance was 4.7 +- 2.2 mL/min/kg, and was 2.4 +- 0.7 hours. In pediatric patients months to 12 years of age, the pharmacokinetic characteristics of ganciclovir were the same after single and multiple (every 12 hours) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 +- 0.22 L/kg, max was 7.9 +- 3.9 mcg/mL, systemic clearance was 4.7 +- 2.2 mL/min/kg, and 1/2 was 2.4 +- 0.7 hours. Although the pharmacokinetics of Ganciclovir Injection in pediatric patients were similar to those observed in adults, the safety and efficacy of ganciclovir at these exposures in pediatric patients have not been established.Although the pharmacokinetics of Ganciclovir Injection in pediatric patients were similar to those observed in adults, the safety and efficacy of ganciclovir at these exposures in pediatric patients have not been established.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption At the end of 1-hour intravenous infusion of mg/kg ganciclovir, total AUC ranged between 22.1 +- 3.2 (n=16) and 26.8 +- 6.1 mcghr/mL (n=16) and max ranged between 8.27 +- 1.02 (n=16) and 9.0 +- 1.4 mcg/mL (n=16). Distribution The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 +- 0.15 L/kg (n=98). Ganciclovir diffuses across the placenta. Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours post-dose in patients who received 2.5 mg/kg ganciclovir intravenously every hours or every 12 hours ranged from 0.31 to 0.68 mcg/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 mcg/mL.. EliminationWhen administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg. 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 intravenous administration.. Specific Populations. Pharmacokinetics in Patients with Renal ImpairmentThe pharmacokinetics following intravenous administration of Ganciclovir Injection solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg. Decreased renal function results in decreased clearance of ganciclovir (Table 7).Table 7. Ganciclovir Pharmacokinetics in Patients with Renal ImpairmentEstimated Creatinine Clearance (mL/min) nDoseClearance (mL/min) Mean +- SD Half-life (hours) Mean +- SD 50-7943.2-5 mg/kg128 +- 634.6 +- 1.425-4933-5 mg/kg57 +- 84.4 +- 0.4< 2531.25-5 mg/kg30 +- 1310.7 +- 5.7Plasma concentrations of ganciclovir are reduced by about 50% during 4 hour hemodialysis session . Pharmacokinetics in Geriatric PatientsThe pharmacokinetic profiles of Ganciclovir Injection in patients 65 years of age and older have not been established. As ganciclovir is mainly renally excreted and since renal clearance decreases with age, decrease in ganciclovir total body clearance and prolongation of ganciclovir half-life can be anticipated in patients 65 years of age and older [see Dosage and Administration (2.5), Use in Specific Populations (8.5)]. Drug Interaction StudiesTable and Table provide listing of established drug interaction studies with ganciclovir. Table provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.Table 8. Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic ParametersCoadministered DrugGanciclovir DosageNGanciclovir Pharmacokinetic (PK) ParameterMycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No effect on ganciclovir PK parameters observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg orally every hours12No effect on ganciclovir PK parameters observed.Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir5 mg/kg IV twice daily11No effect on ganciclovir PK parameters observed5 mg/kg IV once daily11No effect on ganciclovir PK parameters observedProbenecid 500 mg every hours1000 mg orally every hours10AUC 53 +- 91% (range: -14% to 299%) Ganciclovir renal clearance 22 +- 20% (range: -54% to -4%) Table 9. Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered DrugCoadministered DrugGanciclovir DosageNCoadministered Drug Pharmacokinetic (PK) ParameterOral cyclosporine at therapeutic doses5 mg/kg infused over hour every 12 hours93In retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations.Mycophenolate mofetil (MMF) 1.5 single dose5 mg/kg IV single dose12No PK interaction observed (patients with normal renal function)Trimethoprim 200 mg once daily1000 mg orally every hours12No effect on trimethoprim PK parameters observed.Didanosine 200 mg every 12 hours5 mg/kg IV twice daily11AUC 0-12 70 +- 40% (range: 3% to 121%) max49 +- 48% (range: -28% to 125%) Didanosine 200 mg every 12 hours5 mg/kg IV once daily11AUC 0-12 50 +- 26% (range: 22% to 110%) max 36 +- 36% (range: -27% to 94%).

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two times the exposure at the recommended human dose (RHD) [see Data]. Although placental transfer of ganciclovir has been shown to occur based on ex vivo experiments with human placenta and in at least one case report in pregnant woman, no adequate human data are available to establish whether Ganciclovir Injection poses risk to pregnancy outcomes. The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo-fetal riskMost maternal CMV infections are asymptomatic or they may be associated with self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS), CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth. Mortality in symptomatic infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection.. Data. Animal DataDaily intravenous doses of ganciclovir were administered to pregnant mice (108 mg/kg/day) and rabbits (60 mg/kg/day), and also to female mice (90 mg/kg) prior to mating, during gestation, and during lactation. Fetal resorptions were present in at least 85% of rabbits and mice. Additional 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 pre/postnatal development studies in mice, there were maternal/fetal toxicity and embryolethality which included fetal effects of hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach. The systemic exposure (AUC) of ganciclovir during these studies was approximately times (pregnant mice and rabbits) and 1.7 times (pre/postnatal mice) the exposure in humans at the RHD [see Nonclinical Toxicology (13.1)].

REFERENCES SECTION.

15 REFERENCES. 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

1.1Treatment of CMV Retinitis Ganciclovir Injection 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)].

STORAGE AND HANDLING SECTION.

StorageStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Store diluted infusion solution under refrigeration at to 8C (36 to 46F) for no longer than 24 hours. Do not freeze.Discard unused portion.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended with use of Ganciclovir Injection. (8.2). Lactation: Breastfeeding is not recommended with use of Ganciclovir Injection. (8.2). 8.1 Pregnancy. Risk Summary. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two times the exposure at the recommended human dose (RHD) [see Data]. Although placental transfer of ganciclovir has been shown to occur based on ex vivo experiments with human placenta and in at least one case report in pregnant woman, no adequate human data are available to establish whether Ganciclovir Injection poses risk to pregnancy outcomes. The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo-fetal riskMost maternal CMV infections are asymptomatic or they may be associated with self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS), CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth. Mortality in symptomatic infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection.. Data. Animal DataDaily intravenous doses of ganciclovir were administered to pregnant mice (108 mg/kg/day) and rabbits (60 mg/kg/day), and also to female mice (90 mg/kg) prior to mating, during gestation, and during lactation. Fetal resorptions were present in at least 85% of rabbits and mice. Additional 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 pre/postnatal development studies in mice, there were maternal/fetal toxicity and embryolethality which included fetal effects of hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach. The systemic exposure (AUC) of ganciclovir during these studies was approximately times (pregnant mice and rabbits) and 1.7 times (pre/postnatal mice) the exposure in humans at the RHD [see Nonclinical Toxicology (13.1)] . 8.2 Lactation. Risk Summary. No data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed infant, or the effects on milk production. When ganciclovir was administered to lactating rats, ganciclovir was present in milk [see Data]. Advise nursing mothers that breastfeeding is not recommended during treatment with Ganciclovir Injection because of the potential for serious adverse reactions in nursing infants [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5), Nonclinical Toxicology (13.1)] Furthermore, the Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential postnatal transmission of HIV. Data. Animal DataGanciclovir administered intravenously (at 0.13 mg/h) to lactating rats (on lactation day 15) resulted in passive transfer into milk. The milk-to-serum ratio for ganciclovir at steady state was 1.6 +- 0.33.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingFemales of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir Injection Females of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir Injection [see Dosage and Administration (2.2), Use in Specific Populations (8.1)] . Contraception. FemalesBecause of the mutagenic and teratogenic potential of Ganciclovir Injection, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Ganciclovir Injection Because of the mutagenic and teratogenic potential of Ganciclovir Injection, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Ganciclovir Injection [see Dosage and Administration (2.2), Warnings and Precautions (5.4), Nonclinical Toxicology (13.1)] . MalesBecause of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir Injection [see Warnings and Precautions (5.4), Nonclinical Toxicology (13.1)]. InfertilityGanciclovir Injection at the recommended doses may cause temporary or permanent female and male infertility Ganciclovir Injection at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)] . Data. Human DataIn small, open-label, non-randomized clinical study, adult male renal transplant patients receiving valganciclovir (the prodrug of ganciclovir) for CMV prophylaxis for up to 200 days post-transplantation were compared to an untreated control group. Patients were followed-up for six months after valganciclovir discontinuation. Among 24 evaluable patients in the valganciclovir group, the mean sperm density at the end of treatment visit decreased by 11 million/mL from baseline; whereas, among 14 evaluable patients in the control group the mean sperm density increased by 33 million/mL. However, at the follow-up visit among 20 evaluable patients in the valganciclovir group, the mean sperm density was comparable to that observed among 10 evaluable patients in the untreated control group (the mean sperm density at the end of follow-up visit increased by 41 million/mL from baseline in the valganciclovir group and by 43 million/mL in the untreated group).. 8.4 Pediatric Use. Safety and efficacy of Ganciclovir Injection Safety and efficacy of Ganciclovir Injection have not been established in pediatric patients.A total of 120 pediatric patients with serious CMV infections participated in clinical trials. Granulocytopenia and thrombocytopenia were the most common adverse reactions. The pharmacokinetic characteristics of ganciclovir after administration of Ganciclovir Injection were studied in 27 neonates (aged to 49 days) and 10 pediatric patients, aged months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of mg/kg (n=14) and mg/kg (n=13) were 5.5 +- 1.6 and 7.0 +- 1.6 mcg/mL, systemic clearance 3.14 +- 1.75 and 3.56 +- 1.27 mL/min/kg, and of 2.4 hours (harmonic mean) for both doses, respectively. total of 120 pediatric patients with serious CMV infections participated in clinical trials. Granulocytopenia and thrombocytopenia were the most common adverse reactions. The pharmacokinetic characteristics of ganciclovir after administration of Ganciclovir Injection were studied in 27 neonates (aged to 49 days) and 10 pediatric patients, aged months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of mg/kg (n=14) and mg/kg (n=13) were max 5.5 +- 1.6 and 7.0 +- 1.6 mcg/mL, systemic clearance 3.14 +- 1.75 and 3.56 +- 1.27 mL/min/kg, and 1/2 of 2.4 hours (harmonic mean) for both doses, respectively. In pediatric patients months to 12 years of age, the pharmacokinetic characteristics of ganciclovir were the same after single and multiple (every 12 hours) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 +- 0.22 L/kg, was 7.9 +- 3.9 mcg/mL, systemic clearance was 4.7 +- 2.2 mL/min/kg, and was 2.4 +- 0.7 hours. In pediatric patients months to 12 years of age, the pharmacokinetic characteristics of ganciclovir were the same after single and multiple (every 12 hours) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 +- 0.22 L/kg, max was 7.9 +- 3.9 mcg/mL, systemic clearance was 4.7 +- 2.2 mL/min/kg, and 1/2 was 2.4 +- 0.7 hours. Although the pharmacokinetics of Ganciclovir Injection in pediatric patients were similar to those observed in adults, the safety and efficacy of ganciclovir at these exposures in pediatric patients have not been established.Although the pharmacokinetics of Ganciclovir Injection in pediatric patients were similar to those observed in adults, the safety and efficacy of ganciclovir at these exposures in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of Ganciclovir Injection 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. Ganciclovir Injection 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 renal clearance decreases with age, Ganciclovir Injection should be administered to elderly patients with special consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly Clinical studies of Ganciclovir Injection 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. Ganciclovir Injection 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 renal clearance decreases with age, Ganciclovir Injection should be administered to elderly patients with special consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Use in Specific Populations (8.6)] . 8.6Renal Impairment. Dose reduction is recommended when administering Ganciclovir Injection to patients with renal impairment Dose reduction is recommended when administering Ganciclovir Injection to patients with renal impairment [see Dosage and Administration (2.5), and Warnings and Precautions (5.2)] . 8.7Hepatic Impairment. The safety and efficacy of Ganciclovir Injection have not been studied in patients with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Renal Impairment: Increased serum creatinine levels have been observed with the use of Ganciclovir Injection, particularly in elderly patients and transplant recipients receiving concomitant nephrotoxic drugs. Monitor renal function during therapy with Ganciclovir Injection, particularly in elderly patients and in patients taking other nephrotoxic drugs, and reduce dosage in patients with renal impairment. 5.2)) Renal Impairment: Increased serum creatinine levels have been observed with the use of Ganciclovir Injection, particularly in elderly patients and transplant recipients receiving concomitant nephrotoxic drugs. Monitor renal function during therapy with Ganciclovir Injection, particularly in elderly patients and in patients taking other nephrotoxic drugs, and reduce dosage in patients with renal impairment. 5.2)) 5.1Hematologic Toxicity. Granulocytopenia (neutropenia), anemia, thrombocytopenia and pancytopenia have been observed in patients treated with Ganciclovir Injection. The frequency and severity of these events vary widely in different patient populations Ganciclovir Injection is not recommended if the absolute neutrophil count is less than 500 cells/mcL, hemoglobin is less than g/dL, or the platelet count is less than 25,000 cells/mcL. Ganciclovir 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 to days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving Ganciclovir Injection Granulocytopenia (neutropenia), anemia, thrombocytopenia and pancytopenia have been observed in patients treated with Ganciclovir Injection. The frequency and severity of these events vary widely in different patient populations [see Adverse Reactions (6.1)] Ganciclovir Injection is not recommended if the absolute neutrophil count is less than 500 cells/mcL, hemoglobin is less than g/dL, or the platelet count is less than 25,000 cells/mcL. Ganciclovir 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 to days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving Ganciclovir Injection solution for treatment of CMV retinitis. Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving Ganciclovir Injection 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/mcL at the beginning of treatment Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving Ganciclovir 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/mcL at the beginning of treatment [see Dosage and Administration (2.2)] . 5.2Renal Impairment. Ganciclovir 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 Ganciclovir 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 Injection is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity 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 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)] . 5.3Impairment of Fertility. Based on animal data and limited human data, Ganciclovir Injection at the recommended human dose (RHD) 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 the use of Ganciclovir Injection [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]. 5.4Fetal Toxicity. Ganciclovir Injection may cause fetal toxicity when administered to pregnant women based on findings in animal studies. Systemic exposure of ganciclovir in animals at approximately times the RHD caused fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity. Teratogenic changes in animals included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Ganciclovir Injection. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir Injection [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]. 5.5Mutagenesis and Carcinogenesis. Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered potential carcinogen in humans Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered potential carcinogen in humans [see Dosage and Administration (2.7), Nonclinical Toxicology (13.1)].