Ganciclovir
Antiviral / antiretroviral
What it is used for
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) ].
Warnings
5 WARNINGS AND PRECAUTIONS Renal Impairment: Increased serum creatinine levels have been observed with the use of Ganciclovir Injection, particularly in elderly patients and transplant recipients receiving concomitant nephrotoxic drugs. Monitor renal function during therapy with Ganciclovir Injection, particularly in elderly patients and in patients taking other nephrotoxic drugs, and reduce dosage in patients with renal impairment. ( 5.2 )) 5.1 Hematologic Toxicity Granulocytopenia (neutropenia), anemia, thrombocytopenia and pancytopenia have been observed in patients treated with Ganciclovir Injection. The frequency and severity of these events vary widely in different patient populations . Ganciclovir Injection is not recommended if the absolute neutrophil count is less than 500 cells/mcL, hemoglobin is less than 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) ] . 5.2 Renal Impairment Ganciclovir Injection should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance. If renal function is impaired, dosage adjustments are recommended Ganciclovir Injection should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance. If renal function is impaired, dosage adjustments are recommended [see Dosage and Administration (2.5) , Use in Specific Populations (8.5 , 8.6) ] . Increased serum creatinine levels have been reported in elderly patients and in transplant recipients receiving concomitant nephrotoxic medications (i.e., cyclosporine and amphotericin B). Monitoring renal function during therapy with Ganciclovir Injection is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity . Increased serum creatinine levels have been reported in elderly patients and in transplant recipients receiving concomitant nephrotoxic medications (i.e., cyclosporine and amphotericin B). Monitoring renal function during therapy with Ganciclovir Injection is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity [see Dosage and Administration (2.5) , Drug Interactions (7) , Use in Specific Populations (8.5) ] . 5.3 Impairment of Fertility Based on animal data and limited human data, Ganciclovir Injection at the recommended human dose (RHD) may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with the use of Ganciclovir Injection [see Use in Specific Populations (8.1 , 8.3 ), Nonclinical Toxicology (13.1 )]. 5.4 Fetal Toxicity Ganciclovir Injection may cause fetal toxicity when administered to pregnant women based on findings in animal studies. Systemic exposure of ganciclovir in animals at approximately 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) ]. 5.5 Mutagenesis and Carcinogenesis 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) ] .
Possible side effects
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 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 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 Injection, Placebo or Control Ganciclovir Injection 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 Injection (n=76) Placebo (n=73) Ganciclovir Injection (n=57) Control (n=55) Neutropenia Absolute Neutrophil Count (ANC) per mcL < 500 4% 3% 12% 6% 500-1000 3% 8% 29% 17% Total ANC ≤ 1000/mcL 7% 11% 41% 23% Thrombocytopenia Platelet count per mcL < 25,000 3% 1% 32% 28% 25,000-50,000 5% 3% 25% 37% Total Platelet Count ≤ 50,000/mcL 8% 4% 57% 65% Table 5. Serum Creatinine Levels in Controlled Trials - Transplant Recipients who Received Ganciclovir Injection or Placebo Serum Creatinine Levels (mg/dL) Heart Allograft ICM 1496 Bone Marrow Allograft ICM 1570 Bone Marrow Allograft ICM 1689 Ganciclovir Injection (n=76) Placebo Ganciclovir Injection Control Ganciclovir Injection Placebo (n=73) (n=20) (n=20) (n=37) (n=35) ≥ 2.5 mg/dL 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 Ganciclovir Injection or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below Adverse drug reactions with Ganciclovir Injection or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below [see Clinical Studies (14) ]. All these events occurred in at least 3 subjects. pancytopenia, bone marrow failure Blood and lymphatic disorders: pancytopenia, bone marrow failure arrhythmia Cardiac disorders: arrhythmia : tinnitus, ear pain, deafness Ear and labyrinth disorders : tinnitus, ear pain, deafness : visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema Eye disorders : visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema : nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth Gastrointestinal disorders : nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth : fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure General disorders and administration site conditions : fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure : hypersensitivity Immune system disorders : hypersensitivity candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis Infections and infestations: candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis : blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased Investigations : blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased weight decreased Metabolism and nutrition disorders: weight decreased back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor Nervous system disorders: headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams Psychiatric disorders: depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams kidney failure, renal function abnormal, urinary frequency, hematuria Renal and urinary disorders: kidney failure, renal function abnormal, urinary frequency, hematuria cough, dyspnea Respiratory, thoracic and mediastinal disorders: cough, dyspnea dermatitis, alopecia, dry skin, urticaria, rash Skin and subcutaneous tissues disorders: dermatitis, alopecia, dry skin, urticaria, rash : hypotension, hypertension, phlebitis, vasodilation Vascular disorders : hypotension, hypertension, phlebitis, vasodilation 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ganciclovir Injection The following adverse reactions have been identified during post-approval use of Ganciclovir Injection or ganciclovir capsules. Because these reactions are reported voluntarily from 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…
Storage
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Ganciclovir Injection is supplied as follows: NDC Ganciclovir Injection (50 mg per mL) Package Factor 51817-171- 01 500 mg per 10 ml Single-Dose Vial 25 vials per carton 51817-589-02 500 mg per 10 ml Single-Dose Vial 1 vial per carton Ganciclovir Injection is a clear solution supplied in 10 mL sterile single-dose vials, each containing 543 mg ganciclovir sodium equivalent to 500 mg of ganciclovir. The concentration of ganciclovir in the solution is 50 mg/mL. Because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. 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.
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