Ganciclovir

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

1 INDICATIONS AND USAGE 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 ) 1.1 Treatment of CMV Retinitis Ganciclovir Injection is indicated for the treatment of cytomegalovirus (CMV) retinitis in immunocompromised adult patients, including patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1 )]. 1.2 Prevention of CMV Disease in Transplant Recipients Ganciclovir Injection is indicated for the prevention of CMV disease in adult transplant recipients at risk for CMV disease [see Clinical Studies (14.2) ].

2. DOSAGE AND ADMINISTRATION Ganciclovir 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 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, 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 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. 2.2 Testing Before and During Treatment Females of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir Injection [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1 , 8.3 )]. Complete blood counts with differential and platelet counts should be performed frequently, especially in patients in whom Ganciclovir Injection or other nucleoside analogues have previously resulted in cytopenias, or in whom absolute neutrophil counts are less than 1000 cells/mcL at the beginning of treatment [see Warnings and Precautions (5.1) ] .[see Warnings and Precautions (5.1) ] . All patients should be monitored for renal function before and during treatment with Ganciclovir Injection and dose should be adjusted as needed [see Dosage and Administration (2.5) , Warnings and Precautions (5.2) ]. Patients with CMV retinitis should have frequent ophthalmological examinations during treatment with Ganciclovir Injection solution to monitor disease status and for other retinal abnormalities [see Adverse Reactions (6.1) ]. 2.3 Recommended Dosage for Treatment of CMV Retinitis in Adult Patients with Normal Renal Function The recommended initial dosage of Ganciclovir Injection Induction Dosage: The recommended initial dosage of Ganciclovir Injection for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days. Following induction treatment, the recommended maintenance dosage of Ganciclovir Injection Maintenance Dosage: Following induction treatment, the recommended maintenance dosage of Ganciclovir Injection is 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 the Prevention of CMV Disease in Adult Transplant Recipients with Normal Renal Function The recommended initial dosage of Ganciclovir Injection Induction Dosage: The recommended initial dosage of Ganciclovir Injection for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days. Following induction, the recommended maintenance dosage of Ganciclovir Injection Maintenance Dosage: Following induction, the recommended maintenance dosage of Ganciclovir 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 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 creatinin

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 Pharmascience Inc. at 1-888-550-6060 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 Injection are summarized below, according to the participating study patient population. Three controlled, randomized, phase 3 trials comparing Ganciclovir Injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Ganciclovir Injection or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table 2 and Table 3, respectively Adverse Reactions in Patients with CMV Retinitis: Three controlled, randomized, phase 3 trials comparing Ganciclovir Injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Ganciclovir Injection or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table 2 and Table 3, respectively [see Clinical Studies (14.1) ] . Table 2. Pooled Selected Adverse Reactions Reported in ≥ 5% of Subjects Comparing Ganciclovir Injection to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis Maintenance Treatment Studies Adverse Reaction Ganciclovir Injection (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 has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal detachment occurred in 11% of patients treated with Ganciclovir Injection Retinal Detachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal detachment occurred in 11% of patients treated with Ganciclovir Injection and in 8% of patients treated with ganciclovir capsules. Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis CMV Retinitis Treatment Pooled data from Treatment Studies: ICM 1653, ICM 1774 and AVI 034 Laboratory Abnormalities Ganciclovir 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 mcL: < 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/dL): ≥ 2.5 2% 1% ≥ 1.5 – < 2.5 14% 12% There have been three controlled clinical trials of Ganciclovir Injection for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table 4 and Table 5 below. Adverse Reactions in Transplant Recipients: There have been three controlled clinical trials of Ganciclovir Injection for the prevention of CMV disease in transplant recipients. Selected laboratory abnormal

7 DRUG INTERACTIONS Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Ganciclovir Injection Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Ganciclovir Injection and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 6 . 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 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 myelosuppression 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 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 Injection dose may need to be reduced. Monitor for evidence of ganciclovir toxicity. Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks. (7) Cyclosporine or amphotericin B: When coadministered with ganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. (5.2, 7) Mycophenolate mofetil (MMF): When coadministered with ganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. (7) Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, such drugs should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks. (7) Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). (7) Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity. (7)