Ganciclovir Drug Information

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).

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.

2. Adults with renal impairment: Adjust dosage based on creatinine clearance. 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. 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. 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. All patients should be monitored for renal function before and during treatment with Ganciclovir Injection and dose should be adjusted as needed.

Patients with CMV retinitis should have frequent ophthalmological examinations during treatment with Ganciclovir Injection solution to monitor disease status and for other retinal abnormalities. 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 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 (140 - age ) (body wt ) (serum creatinine ) Creatinine clearance for females = 0.85 × male valueCreatinine clearance for females = 0.85 × male value Patients Undergoing Hemodialysis Induction dosing for Ganciclovir 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 Injection should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%. 2.6 Preparation of Ganciclovir Injection 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. 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. 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. 2.7 Handling and Disposal 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.

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.

Table 2. Pooled Selected Adverse Reactions Reported in ≥ 5% of Subjects Comparing Ganciclovir Injection to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis 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. 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 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.

Table 4. Laboratory Abnormalities in Controlled Trials Transplant Recipients who Received led Trials - Transplant Recipients who Received s 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. 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

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 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

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. Table 6. Established and Other Potentially Significant Drug Interactions with Ganciclovir Monitor renal function when Ganciclovir Injection is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine.: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin.

Concomitant use is not recommended unless the potential benefits outweigh the risks. Cyclosporine or amphotericin B: When coadministered with ganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function.

Mycophenolate mofetil (MMF): When coadministered with ganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. 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.

Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). Probenecid: May increase ganciclovir levels.

Pregnancy Risk Summary 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). 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. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Most maternal CMV infections are asymptomatic or they may be associated with a self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS), CMV infections may be symptomatic and may result in significant maternal morbidity and mortality.

The transmission of CMV to the fetus is a result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth.

Mortality in symptomatic infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection. Data Animal Data Daily intravenous doses of ganciclovir were administered to pregnant mice (108 mg/kg/day) and rabbits (60 mg/kg/day), and also to female mice (90 mg/kg) prior to mating, during gestation, and during lactation.

Fetal resorptions were present in at least 85% of rabbits and mice. Additional effects observed in rabbits included fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly, and brachygnathia.

In pre/postnatal development studies in mice, there were maternal/fetal toxicity and embryolethality which included fetal effects of hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach. The systemic exposure (AUC) of ganciclovir during these studies was approximately 2 times (pregnant mice and rabbits) and 1.7 times (pre/postnatal mice) the exposure in humans at the RHD.

Pediatric Use 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.

In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of 4 mg/kg (n=14) and 6 mg/kg (n=13) were C mcg/mL, systemic clearance mL/min/kg, and t of 2.4 hours (harmonic mean) for both doses, respectively.

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. Hypersensitivity to ganciclovir or valganciclovir.

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.