GANCICLOVIR SODIUM

Ganciclovir for 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: 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 a s for ganciclovir are 2.2 and 9.4. Ganciclovir for injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as a salt forming agent, is a sterile white to off-white lyophilized powder. The lyophilized powder has an aqueous solubility of greater than 50 mg/mL at 25°C. At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C. Each vial contains 543 mg ganciclovir sodium equivalent to 500 mg ganciclovir. 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 T:\SPL Documents\Ganciclovir Injection-spl\Chemical Structures.jpg

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

Ganciclovir for Injection, USP 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 1 hour) every 12 hours for 14 to 21 days. Maintenance: 5 mg/kg (given intravenously at a constant rate over 1 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 1 hour) every 12 hours for 7 to 14 days. Maintenance: 5 mg/kg (given intravenously at a constant rate over 1 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. 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 1 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 for injection 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 for injection should be accompanied by adequate hydration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Testing Before and During Treatment Females of reproductive potential should undergo pregnancy testing before initiation of treatment with ganciclovir for 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 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 for 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 for injection 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 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. Maintenance Dosage Following induction treatment, the recommended maintenance dosage of ganciclovir for injection is 5 mg/kg (given intravenously at a constant rate over 1 hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week. 2.4 Recommended Dosage for Prevention of CMV Disease in Adult Transplant Recipients with Normal Renal Function Induction Dosage The recommended initial dosage of ganciclovir for injection for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days. Maintenance Dosage Following induction, the recommended maintenance dosage of ganciclovir for injection is 5 mg/kg (given intravenously at a constant rate over 1 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 injection for induction and maintenance dosage for treatment of CMV retinitis and prevention of CMV disease in 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 in Adult Patients with Renal Impairment Creatinine Clearance Creatinine clearance can be related to serum creatinine by the formulas given below. (mL/min) Ganciclovir for Injection Induction Dose (mg/kg) Dosing Interval (hours) for Induction Ganciclovir for Injection Maintenance Dose (mg/kg) Dosing Interval (hours) for Maintenance Greater than or equal to 70 5 12 5 24 50-69 2.5 12 2.5 24 25-49 2.5 24 1.25 24 10-24 1.25 24 0.625 24 Less than 10 1.25 3 times per week, following hemodialysis 0.625 3 times per week, following hemodialysis Patients Undergoing Hemodialysis Induction dosing for ganciclovir for injection 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 for injection should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50% [see Clinical Pharmacology (12.3) ]. 2.6 Preparation of Ganciclovir Injection, USP Ganciclovir for Injection, USP must be reconstituted and 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: Reconstitution Instructions: Reconstitute lyophilized Ganciclovir for Injection, USP 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, USP and may cause precipitation. Gently swirl the vial in order to ensure complete wetting of the product. Continue swirling until a clear reconstituted solution is obtained. 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. Reconstituted solution in the vial is stable at room temperature (25°C (77°F)) for 12 hours. Do not refrigerate or freeze. Discard any unused portion of the reconstituted solution. Infusion Instructions: Based on patient weight, the appropriate volume of the reconstituted solution (ganciclovir concentration 50 mg/mL) should be removed from the vial and added to an acceptable infusion fluid (typically 100 mL) for delivery over the course of 1 hour. Infusion concentrations greater than 10 mg/mL are not recommended. The following infusion fluids have been determined to be chemically and physically compatible with Ganciclovir for Injection, USP solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer’s Injection and Lactated Ringer’s Injection, USP. Ganciclovir for Injection, USP, 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 (36° to 46°F)). Do not freeze. 2.7 Handling and Disposal Caution should be exercised in the handling and preparation of solutions of Ganciclovir for Injection, USP. Solutions of Ganciclovir for Injection, USP are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with Ganciclovir for Injection, USP 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) ].

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

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 Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 the 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 are summarized below, according to the participating study patient population. Adverse Reactions in Patients with CMV Retinitis Three controlled, randomized, phase 3 trials comparing intravenous ganciclovir and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, intravenous ganciclovir 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 Intravenous Ganciclovir to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis Maintenance Treatment Studies Adverse Reaction Intravenous Ganciclovir (n=179) Ganciclovir Capsules (n=326) Pyrexia 48% 38% Diarrhea 44% 41% Leukopenia 41% 29% Anemia 25% 19% Total Catheter Events: 22% 6% Catheter Infection 9% 4% Catheter Sepsis 8% 1% Other Catheter Related Events 5% 1% Sepsis 15% 4% Decreased Appetite 14% 15% Vomiting 13% 13% Infection 13% 9% Hyperhidrosis 12% 11% Chills 10% 7% Neuropathy Peripheral 9% 8% Thrombocytopenia 6% 6% Pruritus 5% 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 intravenous ganciclovir and in 8% of patients treated with ganciclovir capsules. Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis CMV Retinitis Treatment Pooled data from Treatment Studies ICM 1653, ICM 1774, and AVI 034 Laboratory Abnormalities Intravenous Ganciclovir Mean time on therapy = 103 days, including allowed re-introduction treatment periods 5 mg/kg/day (N=175) % Ganciclovir Capsules Mean time on therapy = 91 days, including allowed re-introduction treatment periods 3000 mg/day (N=320) % Neutropenia with Absolute Neutrophil Count (ANC) per μL: <500 25% 18% 500-<749 14% 17% 750-<1000 26% 19% Anemia with Hemoglobin g/dL: <6.5 g/dL 5% 2% 6.5-8.0 16% 10% 8.0-<9.5 26% 25% Serum Creatinine mg/mL: ≥2.5 2% 1% ≥1.5-<2.5 14% 12% Adverse Reactions in Transplant Recipients There have been three controlled clinical trials of intravenous ganciclovir for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Tables 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 Intravenous Ganciclovir, Placebo or Control Laboratory Abnormalities Heart Allograft 1. Study ICM 1496. Mean duration of treatment = 28 days Bone Marrow Allograft Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days Intravenous Ganciclovir (n=76) Placebo (n=73) Intravenous Ganciclovir (n=57) Control (n=55) Neutropenia Absolute Neutrophil Count (ANC) per μL: <500 4% 3% 12% 6% 500-1000 3% 8% 29% 17% TOTAL ANC ≤1000/μL 7% 11% 41% 23% Thrombocytopenia Platelet count per μL: <25,000 3% 1% 32% 28% 25,000-50,000 5% 3% 25% 37% TOTAL Platelet Count ≤50,000 μL 8% 4% 57% 65% Table 5. Serum Creatinine Levels in Controlled Trials - Transplant Recipients who Received Intravenous Ganciclovir or Placebo Serum Creatinine Levels (mg/dL) Heart Allograft ICM 1496 Bone Marrow Allograft ICM 1570 Bone Marrow Allograft ICM 1689 Intravenous Ganciclovir (n=76) Placebo (n=73) Intravenous Ganciclovir (n=20) Control (n=20) Intravenous Ganciclovir (n=37) Placebo (n=35) ≥2.5 18% 4% 20% 0% 0% 0% ≥1.5-<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 intravenous ganciclovir 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: arrhythmias 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 infections, 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, hypoaesthesia, seizures, 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: increased 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 intravenous ganciclovir 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

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 for 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 [see Clinical Pharmacology (12.3) ]. Table 6. Established and Other Potentially Significant Drug Interactions with Ganciclovir Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment Imipenem-cilastatin Unknown Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. Cyclosporine or amphotericin B Unknown Monitor renal function when ganciclovir for injection is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions (5.2) ]. Mycophenolate mofetil (MMF) ↔Ganciclovir (in patients with normal renal function) ↔MMF (in patients with normal renal function) Based on increased risk, patients should be monitored for hematological and renal toxicity. Other drugs associated with myelosuppresion or nephrotoxicity (e.g., dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/sulfamethoxazole, vinblastine, vincristine and zidovudine) Unknown Because of potential for higher toxicity, coadministration with ganciclovir for injection should be considered only if the potential benefits are judged to outweigh the risks. Didanosine ↔ Ganciclovir ↑ Didanosine Patients should be closely monitored for didanosine toxicity (e.g., pancreatitis). Probenecid ↑ Ganciclovir Ganciclovir for injection dose may need to be reduced. Monitor for evidence of ganciclovir toxicity. Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks. ( 7 ) Cyclosporine or amphotericin B: When coadministered with ganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. ( 5.2 , 7 ) Mycophenolate mofetil (MMF): When coadministered with ganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. ( 7 ) Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, such drugs should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks. ( 7 ) Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). ( 7 ) Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity.