Ganciclovir Sodium

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

For injection: Single-dose vial containing 500 mg of ganciclovir as a sterile lyophilized white to off-white powder for reconstitution with 10 mL of preservative-free sterile water for injection, USP for intravenous use. The concentration of ganciclovir in the reconstituted solution is 50 mg/mL [see Dosage and Administration ( 2.6 )].

• For injection: 500 mg of ganciclovir as lyophilized powder in a single-dose vial for reconstitution. ( 3 )

Ganciclovir for 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. ( 4 )

• Renal Impairment: Increased serum creatinine levels have been observed with the use of Ganciclovir for Injection, particularly in elderly patients and transplant recipients receiving concomitant nephrotoxic drugs. Monitor renal function during therapy with Ganciclovir for 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 for Injection. The frequency and severity of these events vary widely in different patient populations [see Adverse Reactions ( 6.1 )] . Ganciclovir for Injection is not recommended if the absolute neutrophil count is less than 500 cells/μL, hemoglobin is less than 8 g/dL, or the platelet count is less than 25,000 cells/μL. Ganciclovir for 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 for Injection solution for treatment of CMV retinitis. Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving Ganciclovir for 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/μL at the beginning of treatment [see Dosage and Administration ( 2.2 )] .

5.2 Renal Impairment Ganciclovir for 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 for 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 for 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 for Injection [see Use in Specific Populations ( 8.1 , 8.3 ), Nonclinical Toxicology ( 13.1 )].

5.4 Fetal Toxicity Ganciclovir for 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 for Injection. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir for 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 for Injection should therefore be considered a potential carcinogen in humans [see Dosage and Administration ( 2.7 ), Nonclinical Toxicology ( 13.1 )] .

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 Fresenius Kabi USA, LLC at 1-800-5517176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 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 Ganciclovir for Injection and in 8% of patients treated with ganciclovir capsules. Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis * Pooled data from Treatment Studies: ICM 1653, ICM 1774 and AVI 034 Mean time on therapy = 103 days, including allowed re-induction treatment periods Mean time on therapy = 91 days, including allowed re-induction treatment periods Laboratory Abnormalities CMV Retinitis Treatment* Ganciclovir for Injection† 5 mg/kg/day (N=175) % Ganciclovir Capsules‡ 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/dL): ≥2.5 2 1 ≥1.5 – <2.5 14 12 Adverse Reactions in Transplant Recipients: There have been three controlled clinical trials of Ganciclovir for 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 [see Clinical Studies ( 14.2 )] . Table 4. Laboratory Abnormalities in Controlled Trials-Transplant Recipients who Received Ganciclovir for Injection, Placebo, or Control * Study ICM 1496. Mean duration of treatment = 28 days † Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days Ganciclovir for Injection Heart Allograft* Bone Marrow Allograft† Ganciclovir for Injection (n=76) Placebo (n=73) Ganciclovir for Injection (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 Ganciclovir for Injection or Placebo Serum Creatinine Levels (mg/dL) Heart Allograft ICM 1496 Bone Marrow Allograft ICM 1570 Bone Marrow Allograft ICM 1689 Ganciclovir for Injection (n=76) Placebo (n=73) Ganciclovir for Injection (n=20) Control (n=20) Ganciclovir for Injection (n=37) Placebo (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 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. […]

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 for Injection 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 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 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. ( 7 )

• Lactation: Breastfeeding is not recommended with use of Ganciclovir for Injection. ( 8.2 )

8.1 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) [see Data ] . 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 for 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 [see Nonclinical Toxicology ( 13.1 )] .

8.2 Lactation Risk Summary No data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed infant, or the effects on milk production. When ganciclovir was administered to lactating rats, ganciclovir was present in milk [see Data ]. Advise nursing mothers that breastfeeding is not recommended during treatment with Ganciclovir because of the potential for serious adverse reactions in nursing infants [see Warnings and Precautions ( 5.1 , 5.3 , 5.4 , 5.5 ), Nonclinical Toxicology ( 13.1 )] . Furthermore, the Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential postnatal transmission of HIV. Data Animal Data Ganciclovir administered intravenously (at 0.13 mg/h) to lactating rats (on lactation day 15) resulted in passive transfer into milk. The milk-to-serum ratio for ganciclovir at steady state was 1.6 ± 0.33.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of treatment with Ganciclovir [see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.1 )] . Contraception Females Because of the mutagenic and teratogenic potential of Ganciclovir, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Ganciclovir [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 ), Nonclinical Toxicology ( 13.1 )] . Males Because of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir [see Warnings and Precautions ( 5.4 ), Nonclinical Toxicology ( 13.1 )]. Infertility Ganciclovir at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions ( 5.3 ), Nonclinical Toxicology ( 13.1 )] . Data Human Data In a small, open-label, non-randomized clinical study, adult male renal transplant patients receiving valganciclovir (the prodrug of ganciclovir) for CMV prophylaxis for up to 200 days post-transplantation were compared to an untreated control group. Patients were followed-up for six months after valganciclovir discontinuation. Among 24 evaluable patients in the valganciclovir group, the mean sperm density at the end of treatment visit decreased by 11 million/mL from baseline; whereas, among 14 evaluable patients in the control group the mean sperm density increased by 33 million/mL. However, at the follow-up visit among 20 evaluable patients in the valganciclovir group, the mean sperm density was comparable to that observed among 10 evaluable patients in the untreated control group (the mean sperm density at the end of follow-up visit increased by 41 million/mL from baseline in the valganciclovir group and by 43 million/mL in the untreated group).

8.4 Pediatric Use Safety and efficacy of Ganciclovir 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. The pharmacokinetic characteristics of ganciclovir after administration of Ganciclovir were studied in 27 neonates (aged 2 to 49 days) and 10 pediatric patients, aged 9 months to 12 years. In neonates, the pharmacokinetic parameters after ganciclovir intravenous doses of 4 mg/kg (n=14) and 6 mg/kg (n=13) were C max 5.5 ± 1.6 and 7.0 ± 1.6 mcg/mL, systemic clearance 3.14 ± 1.75 and 3.56 ± 1.27 mL/min/kg, and t 1/2 of 2.4 hours (harmonic mean) for both doses, respectively. In pediatric patients 9 months to 12 years of age, the pharmacokinetic characteristics of ganciclovir were the same after single and multiple (every 12 hours) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 ± 0.22 L/kg, C max was 7.9 ± 3.9 mcg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t 1/2 was 2.4 ± 0.7 hours. Although the pharmacokinetics of Ganciclovir in pediatric patients were similar to those observed in adults, the safety and efficacy of ganciclovir at these exposures in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of Ganciclovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Ganciclovir is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. […]

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