Reports of adverse reactions after overdoses with CYTOVENE-IV, some with fatal outcomes, have been received from clinical trials and during post-marketing experience. One or more of the following adverse reactions has been reported with overdoses:
Hematological toxicity: myelosuppression including pancytopenia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, bone marrow failure
Hepatotoxicity: hepatitis, liver function disorder
Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine
Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting
Neurotoxicity: seizures
Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of CYTOVENE-IV. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered in patients with cytopenias.
CYTOVENE-IV is contraindicated in patients who have experienced a clinically significant hypersensitivity reaction (e.g., anaphylaxis) to ganciclovir, valganciclovir, or any component of the formulation.
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
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 CYTOVENE-IV are summarized below, according to the participating study patient population.
Adverse Reactions In Patients With CMV RetinitisThree controlled, randomized, phase 3 trials comparing CYTOVENE-IV and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, CYTOVENE-IV 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 CYTOVENE-IV to Ganciclovir Capsules for
Maintenance Treatment of CMV Retinitis
| Adverse Reaction | Maintenance Treatment Studies | |
| CYTOVENE-IV (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 CYTOVENE-IV and in 8% of patients treated with ganciclovir capsules.
Table 3: Selected Laboratory
Abnormalities in Trials for Treatment of CMV Retinitis
| Laboratory Abnormalities | CMV Retinitis Treatment* | |
| CYTOVENE-IV† 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% |
| * 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 |
||
There have been three controlled clinical trials of CYTOVENE-IV for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Tables 4 and 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: Laboratory
Abnormalities in Controlled Trials - Transplant Recipients who Received
CYTOVENE-IV, Placebo or Control
| CYTOVENE-IV | ||||
| Heart Allograft* | Bone Marrow Allograft† | |||
| CYTOVENE-IV (n=76) |
Placebo (n=73) |
CYTOVENE-IV (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 CYTOVENE-IV or
Placebo
| Serum Creatinine Levels (mg/dL) | Heart Allograft ICM 1496 | Bone Marrow Allograft ICM 1570 | Bone Marrow Allograft ICM 1689 | |||
| CYTOVENE-IV (n=76) |
Placebo (n=73) |
CYTOVENE-IV (n=20) |
Control (n=20) |
CYTOVENE-IV (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% |
Adverse drug reactions with CYTOVENE-IV 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.
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: cough, dyspnea
Skin and subcutaneous tissues disorders: dermatitis, alopecia, dry skin, urticaria, rash
Vascular disorders: hypotension, hypertension, phlebitis, vasodilation
Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of CYTOVENE-IV 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
CYTOVENE-IV 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 RecipientsCYTOVENE-IV is indicated for the prevention of CMV disease in adult transplant recipients at risk for CMV disease.
At the end of a 1-hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ± 3.2 (n=16) and 26.8 ± 6.1 mcg•hr/mL (n=16) and Cmax ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 mcg/mL (n=16).
DistributionThe steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98). Ganciclovir diffuses across the placenta. Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours post-dose in 3 patients who received 2.5 mg/kg ganciclovir intravenously every 8 hours or every 12 hours ranged from 0.31 to 0.68 mcg/mL, representing 24% to 70% of the respective plasma concentrations. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations of 0.5 and 51 mcg/mL.
EliminationWhen administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, 91.3 ± 5.0% (n=4) of intravenously administered ganciclovir was recovered unmetabolized in the urine. Systemic clearance of intravenously administered ganciclovir was 3.52 ± 0.80 mL/min/kg (n=98) while renal clearance was 3.20 ± 0.80 mL/min/kg (n=47), accounting for 91 ± 11% of the systemic clearance (n=47). Half-life was 3.5 ± 0.9 hours (n=98) following intravenous administration.
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 CYTOVENE-IV 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 ConsiderationsDisease-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.
DataAnimal 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.
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.
Storage And HandlingCYTOVENE-IV (ganciclovir sodium) for injection is supplied in 10 mL sterile vials, each containing ganciclovir sodium equivalent to 500 mg of ganciclovir as a white to off-white powder. CYTOVENE-IV is supplied in cartons of 5 vials (NDC 0004-6940-04).
StorageStore at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Store reconstituted solution in the vial at 25°C (77°F) for no longer than 12 hours. Do not refrigerate or freeze. Store diluted infusion solution under refrigeration at 2° to 8°C (36° to 46°F) for no longer than 24 hours. Do not freeze.
REFERENCES
1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.
Distributed by: Genentech USA, Inc. A Member of the Roche Group1, DNA Way, South San Francisco, CA 94080-4990. Revised: Jul 2017
Included as part of the PRECAUTIONS section.
PRECAUTIONS Hematologic ToxicityGranulocytopenia (neutropenia), anemia, thrombocytopenia and pancytopenia, have been observed in patients treated with CYTOVENE-IV. The frequency and severity of these events vary widely in different patient populations. CYTOVENE-IV 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. CYTOVENE-IV 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 CYTOVENE-IV solution for treatment of CMV retinitis.
Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving CYTOVENE-IV, 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.
Renal ImpairmentCYTOVENE-IV 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.
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 CYTOVENE-IV is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity.
Impairment Of FertilityBased on animal data, CYTOVENE-IV 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 CYTOVENE-IV.
Fetal ToxicityCYTOVENE-IV 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 CYTOVENE-IV. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with CYTOVENE-IV.
Mutagenesis And CarcinogenesisAnimal data indicate that ganciclovir is mutagenic and carcinogenic. CYTOVENE-IV should therefore be considered a potential carcinogen in humans.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis, MutagenesisGanciclovir was carcinogenic in mice at the same mean drug exposure in humans as at the RHD (5 mg/kg). At the dose of 1000 mg/kg/day (1.4 times the exposure at the RHD), there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the dose of 20 mg/kg/day (0.1 times the exposure at the RHD), a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day (exposure estimated as 0.01 times the RHD). Except for histiocytic sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered a potential carcinogen in humans.
Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at concentrations between 50 to 500 and 250 to 2000 μg/mL, respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (2.8 to 10 times the exposure at the RHD) but not at doses of 50 mg/kg (exposure approximately comparable to the RHD). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 μg/mL.
Impairment Of FertilityGanciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following doses of 90 mg/kg/day (exposures approximately 1.7 times the RHD). Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1 times the exposure at the RHD.
Use In Specific Populations Pregnancy Risk SummaryIn 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 CYTOVENE-IV 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 ConsiderationsDisease-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.
DataAnimal 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.
Lactation Risk SummaryNo 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. Advise nursing mothers that breastfeeding is not recommended during treatment with CYTOVENE-IV because of the potential for serious adverse reactions in nursing infants. Furthermore, the Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential postnatal transmission of HIV.
DataAnimal 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.
Females And Males Of Reproductive Potential Pregnancy TestingFemales of reproductive potential should undergo pregnancy testing before initiation of treatment with CYTOVENE-IV.
ContraceptionFemales
Because of the mutagenic and teratogenic potential of CYTOVENE-IV, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with CYTOVENE-IV.
Males
Because of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following treatment with CYTOVENE-IV.
InfertilityCYTOVENE-IV at the recommended doses may cause temporary or permanent female and male infertility.
Pediatric UseSafety and efficacy of CYTOVENE IV 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 CYTOVENE-IV 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 Cmax 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 t½ 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, Cmax was 7.9 ± 3.9 mcg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t½ was 2.4 ± 0.7 hours.
Although the pharmacokinetics of CYTOVENE-IV 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.
Geriatric UseClinical studies of CYTOVENE-IV 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. CYTOVENE-IV 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. Because renal clearance decreases with age, CYTOVENE-IV should be administered to elderly patients with special consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly.
Renal ImpairmentDose reduction is recommended when administering CYTOVENE-IV to patients with renal impairment.
Hepatic ImpairmentThe safety and efficacy of CYTOVENE-IV have not been studied in patients with hepatic impairment.
Induction Dosage: The recommended initial dosage of CYTOVENE-IV 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 CYTOVENE-IV 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.
Recommended Dosage For The Prevention Of CMV Disease In Adult Transplant Recipients With Normal Renal FunctionInduction Dosage: The recommended initial dosage of CYTOVENE-IV 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 CYTOVENE-IV 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.
Recommended Dosage In Adult Patients With Renal ImpairmentFor patients with impairment of renal function, refer to Table 1 for recommended doses of CYTOVENE-IV 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
| Creatinine Clearance* (mL/min) | CYTOVENE-IV Induction Dose (mg/kg) | Dosing Interval (hours) for Induction | CYTOVENE-IV Maintenance Dose (mg/kg) | Dosing Interval (hours) for Maintenance |
| Greater than or equal to70 | 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 |
| Lessthan10 | 1.25 | 3 times per week, following hemodialysis | 0.625 | 3 times per week, following hemodialysis |
| * Creatinine clearance can be related to serum creatinine by the formulas given below. |
Creatinine clearance for males = (140 -age [yrs]) (body wt [kg])/(72) (serum creatinine [mg/dL])
Creatinine clearance for females = 0.85 x male value
Patients Undergoing HemodialysisInduction dosing for CYTOVENE-IV 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. CYTOVENE-IV should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%.
Preparation Of CYTOVENE-IVCYTOVENE-IV must be reconstituted and diluted under the supervision of a healthcare provider and administered as intravenous infusion. Each 10 mL clear glass vial contains 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:
1. Reconstitution Instructions:
2. Infusion Instructions:
Caution should be exercised in the handling and preparation of solutions of CYTOVENE-IV. Solutions of CYTOVENE-IV are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with CYTOVENE-IV 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 drugs1.
Inform patients that CYTOVENE-IV may interact with other drugs. Advise patients to report to their healthcare provider the use of any other medication .
