These Highlights Do Not Include All The Information Needed To Use Ganciclovir Injection Safely And Effectively. See Full Prescribing Information For Ganciclovir Injection.

Human Data

In a 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).

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

Mechanism of Action

Ganciclovir is a 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.

Storage

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

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

Discard unused portion.

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 a pregnant woman, no adequate human data are available to establish whether Ganciclovir Injection poses a 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.

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

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

Ganciclovir Injection Ganciclovir Injection contains ganciclovir, in the form of the sodium salt for intravenous injection. Ganciclovir is a 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 a white to off-white crystalline powder.  Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022.  The pK s for ganciclovir are 2.2 and 9.4. Ganciclovir is a white to off-white crystalline powder.  Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022.  The pK _as for ganciclovir are 2.2 and 9.4.

Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as a salt forming agent, is a sterile solution.  At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as a salt forming agent, is a sterile solution.  At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.

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.

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 2 to 49 days) and 10 pediatric patients, aged 9 months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of 4 mg/kg (n=14) and 6 mg/kg (n=13) were C 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 t of 2.4 hours (harmonic mean) for both doses, respectively. 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 2 to 49 days) and 10 pediatric patients, aged 9 months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of 4 mg/kg (n=14) and 6 mg/kg (n=13) were C _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 t _1/2 of 2.4 hours (harmonic mean) for both doses, respectively.

In pediatric patients 9 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, C was 7.9 ± 3.9 mcg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t was 2.4 ± 0.7 hours. In pediatric patients 9 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, C _max was 7.9 ± 3.9 mcg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t _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.

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)] .

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 2 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)].

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

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)]

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 6  . Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 6  [see Clinical Pharmacology (12.3)] .

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)] .

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)] .

The safety and efficacy of Ganciclovir Injection have not been studied in patients with hepatic impairment.

Ganciclovir Injection Ganciclovir Injection is a 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)

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

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 8 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 3 to 7 days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving Ganciclovir 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 8 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 3 to 7 days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving Ganciclovir 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)] .

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 ¹ Discard any unused portion of the reconstituted solution [see How Supplied/Storage and Handling (16)].

• 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))

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)].

Ganciclovir Injection is administered only intravenously.

Adults with renal impairment: Adjust dosage based on creatinine clearance. ( 2.5)

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

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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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

• Lactation: Breastfeeding is not recommended with use of Ganciclovir Injection. (8.2)

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)].

In a 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 a 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 a 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 a 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 5 mg/kg twice daily for 14 to 21 days followed by maintenance treatment with either 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

In a 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 a 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.

Rx only             NDC 51817-171-01

Ganciclovir Injection

500mg/10mL (50 mg/mL)

Sterile solution equivalent to 500mg ganciclovir

Sterile, Nonpyrogenic, Preservative-Free.

The container closure is not made with natural rubber latex.

FOR INTRAVENOUS INFUSION ONLY.

10 mL Single-dose vial

CAUTION: Cytotoxic Agent

Handle this product with great care because it is a potent cytotoxic agent and suspected carcinogen

Usual dosage: See package insert

Store at 25°C (77°F): excursions permitted to 15°C-30°C (59°-86°F)

Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered a potential carcinogen in humans Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.7), Nonclinical Toxicology (13.1)] .

• 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)].

Ganciclovir Injection solution Ganciclovir Injection solution must be diluted under the supervision of a healthcare provider and administered as intravenous infusion. Each 10 mL clear glass vial contains 543 mg ganciclovir sodium equivalent to 500 mg of ganciclovir. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the vial and the table after reconstitution. The contents of the vial should be prepared for administration in the following manner:

• 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 1 hour. Infusion concentrations greater than 10 mg/mL are not recommended. The following infusion fluids have been determined to be chemically and physically compatible with Ganciclovir Injection: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's 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 1 hour. Infusion concentrations greater than 10 mg/mL are not recommended. The following infusion fluids have been determined to be chemically and physically compatible with Ganciclovir Injection: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's 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 (2°C to 8°C). 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 (2°C to 8°C (36° to 46°F)). Do not freeze.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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.

• To avoid phlebitis/pain at the infusion site, Ganciclovir Injection must  only be administered by intravenous infusion over 1 hour, preferably via plastic cannula, into a vein with adequate blood flow to permit rapid dilution and distribution. only be administered by intravenous infusion over 1 hour, preferably via plastic cannula, into a vein with adequate blood flow to permit rapid dilution and distribution.
• Do not administer Ganciclovir Injection by rapid or bolus intravenous injection which may increase toxicity as a result of excessive plasma levels.
• The recommended dosage and infusion rate for Ganciclovir 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.

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

Ganciclovir Injection was evaluated in three randomized, controlled trials of prevention of CMV disease in organ transplant recipients.

For patients with impairment of renal function, refer to Table 1 for recommended doses of Ganciclovir Injection For patients with impairment of renal function, refer to Table 1 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.

Creatinine clearance for females = 0.85 × male valueCreatinine clearance for females = 0.85 × male value

Rx only        NDC 51817-589-02

Ganciclovir Injection

500mg/10mL (50 mg/mL)

FOR INTRAVENOUS INFUSION ONLY

CAUTION: Cytotoxic Agent

Handle this product with great care because it is a potent cytotoxic agent and suspected carcinogen

Sterile, Nonpyrogenic, Preservative-Free.

The container closure is not made with natural rubber latex.

1 x 10 mL Single-dose vial

Rx only                        NDC 51817-171-01

Ganciclovir Injection

500mg/10mL (50 mg/mL)

FOR INTRAVENOUS INFUSION ONLY

CAUTION: Cytotoxic Agent

Handle this product with great care because it is a potent cytotoxic agent and suspected carcinogen

25 x 10 mL Single-dose vials

• 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)].

Human Data

In a 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).

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

Mechanism of Action

Ganciclovir is a 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.

Storage

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

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

Discard unused portion.

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 a pregnant woman, no adequate human data are available to establish whether Ganciclovir Injection poses a 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.

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

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

Ganciclovir Injection Ganciclovir Injection contains ganciclovir, in the form of the sodium salt for intravenous injection. Ganciclovir is a 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 a white to off-white crystalline powder.  Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022.  The pK s for ganciclovir are 2.2 and 9.4. Ganciclovir is a white to off-white crystalline powder.  Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022.  The pK _as for ganciclovir are 2.2 and 9.4.

Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as a salt forming agent, is a sterile solution.  At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as a salt forming agent, is a sterile solution.  At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.

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.

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 2 to 49 days) and 10 pediatric patients, aged 9 months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of 4 mg/kg (n=14) and 6 mg/kg (n=13) were C 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 t of 2.4 hours (harmonic mean) for both doses, respectively. 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 2 to 49 days) and 10 pediatric patients, aged 9 months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of 4 mg/kg (n=14) and 6 mg/kg (n=13) were C _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 t _1/2 of 2.4 hours (harmonic mean) for both doses, respectively.

In pediatric patients 9 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, C was 7.9 ± 3.9 mcg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t was 2.4 ± 0.7 hours. In pediatric patients 9 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, C _max was 7.9 ± 3.9 mcg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t _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.

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)] .

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 2 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)].

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

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)]

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 6  . Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 6  [see Clinical Pharmacology (12.3)] .

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)] .

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)] .

The safety and efficacy of Ganciclovir Injection have not been studied in patients with hepatic impairment.

Ganciclovir Injection Ganciclovir Injection is a 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)

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

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 8 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 3 to 7 days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving Ganciclovir 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 8 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 3 to 7 days after discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving Ganciclovir 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)] .

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 ¹ Discard any unused portion of the reconstituted solution [see How Supplied/Storage and Handling (16)].

• 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))

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)].

Ganciclovir Injection is administered only intravenously.

Adults with renal impairment: Adjust dosage based on creatinine clearance. ( 2.5)

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

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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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

• Lactation: Breastfeeding is not recommended with use of Ganciclovir Injection. (8.2)

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)].

In a 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 a 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 a 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 a 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 5 mg/kg twice daily for 14 to 21 days followed by maintenance treatment with either 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

In a 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 a 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.

Rx only             NDC 51817-171-01

Ganciclovir Injection

500mg/10mL (50 mg/mL)

Sterile solution equivalent to 500mg ganciclovir

Sterile, Nonpyrogenic, Preservative-Free.

The container closure is not made with natural rubber latex.

FOR INTRAVENOUS INFUSION ONLY.

10 mL Single-dose vial

CAUTION: Cytotoxic Agent

Handle this product with great care because it is a potent cytotoxic agent and suspected carcinogen

Usual dosage: See package insert

Store at 25°C (77°F): excursions permitted to 15°C-30°C (59°-86°F)

Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered a potential carcinogen in humans Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.7), Nonclinical Toxicology (13.1)] .

• 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)].

Ganciclovir Injection solution Ganciclovir Injection solution must be diluted under the supervision of a healthcare provider and administered as intravenous infusion. Each 10 mL clear glass vial contains 543 mg ganciclovir sodium equivalent to 500 mg of ganciclovir. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the vial and the table after reconstitution. The contents of the vial should be prepared for administration in the following manner:

• 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 1 hour. Infusion concentrations greater than 10 mg/mL are not recommended. The following infusion fluids have been determined to be chemically and physically compatible with Ganciclovir Injection: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's 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 1 hour. Infusion concentrations greater than 10 mg/mL are not recommended. The following infusion fluids have been determined to be chemically and physically compatible with Ganciclovir Injection: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's 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 (2°C to 8°C). 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 (2°C to 8°C (36° to 46°F)). Do not freeze.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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.

• To avoid phlebitis/pain at the infusion site, Ganciclovir Injection must  only be administered by intravenous infusion over 1 hour, preferably via plastic cannula, into a vein with adequate blood flow to permit rapid dilution and distribution. only be administered by intravenous infusion over 1 hour, preferably via plastic cannula, into a vein with adequate blood flow to permit rapid dilution and distribution.
• Do not administer Ganciclovir Injection by rapid or bolus intravenous injection which may increase toxicity as a result of excessive plasma levels.
• The recommended dosage and infusion rate for Ganciclovir 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.

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

Ganciclovir Injection was evaluated in three randomized, controlled trials of prevention of CMV disease in organ transplant recipients.

For patients with impairment of renal function, refer to Table 1 for recommended doses of Ganciclovir Injection For patients with impairment of renal function, refer to Table 1 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.

Creatinine clearance for females = 0.85 × male valueCreatinine clearance for females = 0.85 × male value

Rx only        NDC 51817-589-02

Ganciclovir Injection

500mg/10mL (50 mg/mL)

FOR INTRAVENOUS INFUSION ONLY

CAUTION: Cytotoxic Agent

Handle this product with great care because it is a potent cytotoxic agent and suspected carcinogen

Sterile, Nonpyrogenic, Preservative-Free.

The container closure is not made with natural rubber latex.

1 x 10 mL Single-dose vial

Rx only                        NDC 51817-171-01

Ganciclovir Injection

500mg/10mL (50 mg/mL)

FOR INTRAVENOUS INFUSION ONLY

CAUTION: Cytotoxic Agent

Handle this product with great care because it is a potent cytotoxic agent and suspected carcinogen

25 x 10 mL Single-dose vials

• 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)].