Ganciclovir

1 INDICATIONS AND USAGE Ganciclovir 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 ) 1.1 Treatment of CMV Retinitis Ganciclovir 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) ]. 1.2 Prevention of CMV Disease in Transplant Recipients Ganciclovir is indicated for the prevention of CMV disease in adult transplant recipients at risk for CMV disease [see Clinical Studies (14.2) ].

2 DOSAGE AND ADMINISTRATION Ganciclovir for injection is administered only intravenously. ( 2.1 ) Dosage in Adult Patients with Normal Renal Function Treatment of CMV retinitis ( 2.3 ) Induction: 5 mg/kg (given intravenously at a constant rate over one hour) every 12 hours for 14 to 21 days. Maintenance: 5 mg/kg (given intravenously at a constant rate over one hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week. Prevention of CMV disease in transplant recipients ( 2.4 ) Induction: 5 mg/kg (given intravenously at a constant rate over one hour) every 12 hours for 7 to 14 days. Maintenance: 5 mg/kg (given intravenously at a constant rate over one hour) once daily, 7 days per week, or 6 mg/kg once daily, 5 days per week until 100 to 120 days post-transplantation. Adults with renal impairment: Adjust dosage based on creatinine clearance. ( 2.5 ). 2.1 Important Dosing and Administration Information To avoid phlebitis/pain at the infusion site, ganciclovir for injection must only be administered by intravenous infusion over one hour, preferably via plastic cannula, into a vein with adequate blood flow to permit rapid dilution and distribution. Do not administer ganciclovir for 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 should not be exceeded. Do not administer the reconstituted ganciclovir for injection solution intramuscularly or subcutaneously because it may result in severe tissue irritation due to high pH [see Description (11) ]. Administration of ganciclovir should be accompanied by adequate hydration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Testing Before and During Treatment Females of reproductive potential should undergo pregnancy testing before initiation of treatment with ganciclovir [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 or other nucleoside analogues have previously resulted in cytopenias, or in whom absolute neutrophil counts are less than 1000 cells/μL at the beginning of treatment [see Warnings and Precautions (5.1) ]. All patients should be monitored for renal function before and during treatment with ganciclovir 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 solution to monitor disease status and for other retinal abnormalities [see Adverse Reactions (6.1) ]. 2.3 Recommended Dosage for Treatment of CMV Retinitis in Adult Patients with Normal Renal Function Induction Dosage: The recommended initial dosage of ganciclovir for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over one hour) every 12 hours for 14 to 21 days. Maintenance Dosage: Following induction treatment, the recommended maintenance dosage of ganciclovir is 5 mg/kg (given intravenously at a constant rate over one hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week. 2.4 Recommended Dosage for the Prevention of CMV Disease in Adult Transplant Recipients with Normal Renal Function Induction Dosage: The recommended initial dosage of ganciclovir for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over one hour) every 12 hours for 7 to 14 days. Maintenance Dosage: Following induction, the recommended maintenance dosage of ganciclovir is 5 mg/kg (given intravenously at a constant rate over one hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week until 100 to 120 days post-transplantation. 2.5 Recommended Dosage in Adult Patients with Renal Impairment For patients with impairment of renal function, refer to Table 1 for recommended doses of ganciclovir for induction and maintenance dosage for treatment of CMV retinitis and prevention of CMV disease in transplant recipients. Carefully monitor serum creatinine or creatinine clearance before and during treatment to allow for dosage adjustments in patients with impaired renal function. Table 1. Recommended Induction and Maintenance Dosage for Adult Patients with Renal Impairment Creatinine Clearance Creatinine clearance can be related to serum creatinine by the formulas given below. (mL/min) Ganciclovir Induction Dose (mg/kg) Dosing Interval (hours) for Induction Ganciclovir Maintenance Dose (mg/kg) Dosing Interval (hours) for Maintenance Greater than or equal to 70 5 12 5 24 50 to 69 2.5 12 2.5 24 25 to 49 2.5 24 1.25 24 10 to 24 1.25 24 0.625 24 Less than 10 1.25 3 times per week, following hemodialysis 0.625 3 times per week, following hemodialysis Creatinine clearance for males = (140 - age [yrs]) (body wt [kg]) (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 × male value Patients Undergoing Hemodialysis Induction dosing for ganciclovir in patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per week; and maintenance dosing should not exceed 0.625 mg/kg 3 times per week following each hemodialysis session. Ganciclovir 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 for Injection Ganciclovir for injection must be reconstituted and diluted under the supervision of a healthcare provider and administered as intravenous infusion. Each 10 mL clear glass vial contains 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: Reconstitution Instructions: a) Reconstitute lyophilized ganciclovir for injection by injecting 10 mL of Sterile Water for Injection, USP, into the vial. Do not use bacteriostatic water for injection containing parabens. It is incompatible with ganciclovir for injection and may cause precipitation. b) Gently swirl the vial in order to ensure complete wetting of the product. Continue swirling until a clear reconstituted solution is obtained. c) Visually inspect the reconstituted solution for particulate matter and discoloration prior to proceeding with infusion. Discard the vial if particulate matter or discoloration is observed. d) Reconstituted solution in the vial is stable at room temperature (25°C) for 12 hours. Do not refrigerate or freeze. Infusion Instructions: a) Based on patient weight, the appropriate volume of the reconstituted solution (ganciclovir concentration 50 mg/mL) should be removed from the vial and added to an acceptable infusion fluid (typically 100 mL) for delivery over the course of one 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 for injection solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's Injection, USP. b) Ganciclovir for injection, when reconstituted with Sterile Water for Injection (non-bacteriostatic) and further diluted with 0.9% sodium chloride injection or other acceptable infusion fluid as specified above, should be used within 24 hours of dilution to reduce the risk of bacterial contamination. The diluted infusion solution should be refrigerated (2°C to 8°C). Do not freeze. 2.7 Handling and Disposal Caution should be exercised in the handling and preparation of solutions of ganciclovir. Solutions of ganciclovir are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with ganciclovir 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 [see How Supplied/Storage and Handling (16) ].

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) ] 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 Endo at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience in Adult Patients 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 for injection are summarized below, according to the participating study patient population. Adverse Reactions in Patients with CMV Retinitis Three controlled, randomized, phase 3 trials comparing ganciclovir for injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, ganciclovir for 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 2 and Table 3 , respectively [see Clinical Studies (14.1) ]. Table 2. Pooled Selected Adverse Reactions Reported in ≥ 5% of Subjects Comparing Ganciclovir for Injection to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis Adverse Reaction Maintenance Treatment Studies Ganciclovir for Injection (n = 179) Ganciclovir Capsules (n = 326) Pyrexia Diarrhea Leukopenia Anemia Total catheter events Catheter infection Catheter sepsis Other catheter related events Sepsis Decreased appetite Vomiting Infection Hyperhidrosis Chills Neuropathy peripheral Thrombocytopenia Pruritus 48% 44% 41% 25% 22% 9% 8% 5% 15% 14% 13% 13% 12% 10% 9% 6% 5% 38% 41% 29% 19% 6% 4% 1% 1% 4% 15% 13% 9% 11% 7% 8% 6% 6% 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 for injection and in 8% of patients treated with ganciclovir capsules. Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis Laboratory Abnormalities CMV Retinitis Treatment Pooled data from Treatment Studies: ICM 1653, ICM 1774 and AVI 034 Ganciclovir for Injection Mean time on therapy = 103 days, including allowed re-induction treatment periods 5 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 µL: <500 500 to <749 750 to <1000 25% 14% 26% 18% 17% 19% Anemia with Hemoglobin (g/dL): <6.5 g/dL 6.5 to <8.0 8.0 to <9.5 5% 16% 26% 2% 10% 25% Serum Creatinine (mg/dL): ≥2.5 ≥1.5 to <2.5 2% 14% 1% 12% Adverse Reactions in Transplant Recipients There have been three controlled clinical trials of ganciclovir for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table 4 and Table 5 below. Table 4 shows the frequency of neutropenia and thrombocytopenia and Table 5 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, Placebo or Control Ganciclovir Heart 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 (n = 76) Placebo (n = 73) Ganciclovir (n = 57) Control (n = 55) Neutropenia Absolute Neutrophil Count (ANC) per µL <500 500 to 1000 4% 3% 3% 8% 12% 29% 6% 17% Total ANC ≤1000/µL 7% 11% 41% 23% Thrombocytopenia Platelet count per µL <25,000 25,000 to 50,000 3% 5% 1% 3% 32% 25% 28% 37% Total Platelet Count ≤50,000/µL 8% 4% 57% 65% Table 5. Serum Creatinine Levels in Controlled Trials - Transplant Recipients who Received Ganciclovir or Placebo Serum Creatinine Levels (mg/dL) Heart Allograft ICM 1496 Bone Marrow Allograft ICM 1570 Bone Marrow Allograft ICM 1689 Ganciclovir (n = 76) Placebo (n = 73) Ganciclovir (n = 20) Control (n = 20) Ganciclovir (n = 37) Placebo (n = 35) ≥2.5 mg/dL 18% 4% 20% 0% 0% 0% ≥1.5 to <2.5 58% 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 for 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 3 subjects. Blood and lymphatic disorders: pancytopenia, bone marrow failure Cardiac disorders: arrhythmia Ear and labyrinth disorders : tinnitus, ear pain, deafness Eye disorders : visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema Gastrointestinal disorders : nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth General disorders and administration site conditions : fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure Immune system disorders : hypersensitivity Infections and infestations: candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis Investigations : blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased Metabolism and nutrition disorders: weight decreased Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia Nervous system disorders: headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor Psychiatric disorders: depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams Renal and urinary disorders: kidney failure, renal function abnormal, urinary frequency, hematuria Respiratory, thoracic and mediastinal disorders: cough, dyspnea Skin and subcutaneous tissues disorders: dermatitis, alopecia, dry skin, urticaria, rash Vascular disorders : hypotension, hypertension, phlebitis, vasodilation 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ganciclovir for 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. Blood and lymphatic disorders : hemolytic anemia, agranulocytosis, granulocytopenia Cardiac disorders: cardiac arrest, conduction disorder, torsade de pointes, ventricular tachycardia Congenital, familial and genetic disorders: congenital anomaly Endocrine disorders: inappropriate antidiuretic hormone secretion Eye disorders: cataracts, dry eyes Gastrointestinal disorders: intestinal ulcer Hepatobiliary disorders: cholelithiasis, cholestasis, hepatic failure, hepatitis Immune system disorders: anaphylactic reaction, allergic reaction, vasculitis Investigations: blood triglycerides increased Metabolism and nutrition disorders: acidosis, hypercalcemia, hyponatremia Musculoskeletal and connective tissue disorders: arthritis, rhabdomyolysis Nervous system disorders: dysesthesia, dysphasia, extrapyramidal disorder, facial paralysis, amnesia, anosmia, myelopathy, cerebrovascular accident, third cranial nerve paralysis, aphasia, encephalopathy, intracranial hypertension Psychiatric disorders: irritability, hallucinations Renal and urinary disorders: renal tubular disorder, hemolytic uremic syndrome Reproductive system and breast disorders: infertility, testicular hypotrophy Respiratory, thoracic and mediastinal disorders: bronchospasm, pulmonary fibrosis Skin and subcutaneous tissues disorders : exfoliative dermatitis, Stevens-Johnson syndrome Vascular disorders: peripheral ischemia

12.3 Pharmacokinetics Absorption At the end of a one hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ± 3.2 (n = 16) and 26.8 ± 6.1 mcg·hr/mL (n = 16) and C 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 3 patients who received 2.5 mg/kg ganciclovir intravenously every 8 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. Elimination When 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 Impairment The pharmacokinetics following intravenous administration of ganciclovir for 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 Impairment Estimated Creatinine Clearance (mL/min) n Dose Clearance (mL/min) Mean ± SD Half-life (hours) Mean ± SD 50 to 79 25 to 49 <25 4 3 3 3.2 to 5 mg/kg 3 to 5 mg/kg 1.25 to 5 mg/kg 128 + 63 57 + 8 30 + 13 4.6 ± 1.4 4.4 + 0.4 10.7 + 5.7 Plasma concentrations of ganciclovir are reduced by about 50% during a 4 hour hemodialysis session. Pharmacokinetics in Geriatric Patients The pharmacokinetic profiles of ganciclovir 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, a decrease in ganciclovir total body clearance and a 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 Studies Table 8 and Table 9 provide a listing of established drug interaction studies with ganciclovir. Table 8 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 9 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 Parameters Coadministered Drug Ganciclovir Dosage N Ganciclovir Pharmacokinetic (PK) Parameter Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No effect on ganciclovir PK parameters observed (patients with normal renal function) Trimethoprim 200 mg once daily 1000 mg orally every 8 hours 12 No effect on ganciclovir PK parameters observed. Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir 5 mg/kg IV twice daily 11 No effect on ganciclovir PK parameters observed 5 mg/kg IV once daily 11 No effect on ganciclovir PK parameters observed Probenecid 500 mg every 6 hours 1000 mg orally every 8 hours 10 AUC ↑­ 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 Drug Coadministered Drug Ganciclovir Dosage N Coadministered Drug Pharmacokinetic (PK) Parameter Oral cyclosporine at therapeutic doses 5 mg/kg infused over one hour every 12 hours 93 In a retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations. Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No PK interaction observed (patients with normal renal function) Trimethoprim 200 mg once daily 1000 mg orally every 8 hours 12 No effect on trimethoprim PK parameters observed. Didanosine 200 mg every 12 hours 5 mg/kg IV twice daily 11 AUC 0-12 ­ ↑70 ± 40% (range: 3% to 121%) C max ­ ↑49 ± 48% (range: -28% to 125%) Didanosine 200 mg every 12 hours 5 mg/kg IV once daily 11 AUC 0-12­ ↑50 ± 26% (range: 22% to 110%) C max­ ↑36 ± 36% (range: -27% to 94%)