Data from FDA - Curated by EPG Health - Last updated 31 December 2017

Indication(s)

1 INDICATIONS AND USAGE CYTOVENE-IV 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 CYTOVENE-IV 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 CYTOVENE-IV is indicated for the prevention of CMV disease in adult transplant recipients at risk for CMV disease [see Clinical Studies (14.2)].

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Advisory information

contraindications
4 CONTRAINDICATIONS 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. Hypersensitivity to ganciclovir or valganciclovir. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Hematologic Toxicity [see Warnings and Precautions (5.1)] Renal Impairment [see Warnings and Precautions (5.2)] Impairment of Fertility [see Warnings and Precautions (5.3)] Fetal Toxicity [see Warnings and Precautions (5.4)] Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)] Most common adverse reactions and laboratory abnormalities reported in at least 20% of patients were: pyrexia, diarrhea, leukopenia, nausea, anemia, asthenia, headache, cough, decreased appetite, dyspnea, abdominal pain, sepsis, hyperhidrosis, and blood creatinine increased. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Roche at 1-800-526-6367 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 CYTOVENE-IV are summarized below, according to the participating study patient population. Adverse Reactions in Patients with CMV Retinitis: Three 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 [see Clinical Studies (14)]. Table 2. Pooled Selected Adverse Reactions Reported in ≥ 5% of Subjects Comparing CYTOVENE-IV to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis Maintenance Treatment Studies Adverse Reaction 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: 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 CMV Retinitis TreatmentPooled data from Treatment Studies: ICM 1653, ICM 1774 and AVI 034 Laboratory Abnormalities CYTOVENE-IVMean time on therapy = 103 days, including allowed re-induction treatment periods 5 mg/kg/day (N=175) % Ganciclovir CapsulesMean time on therapy = 91 days, including allowed re-induction treatment periods 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 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 [see Clinical Studies (14)]. Table 4. Laboratory Abnormalities in Controlled Trials – Transplant Recipients who Received CYTOVENE-IV, Placebo or Control CYTOVENE-IV Heart AllograftStudy ICM 1496. Mean duration of treatment = 28 days Bone Marrow AllograftStudy ICM 1570 and ICM 1689. Mean duration of treatment = 45 days 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 CYTOVENE-IV Control CYTOVENE-IV 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 CYTOVENE-IV 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: 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 6.2 Postmarketing Experience The 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

Usage information

Dosing and administration
2. DOSAGE AND ADMINISTRATION CYTOVENE-IV is administered only intravenously. (2.1) Dosage in Adult Patients with Normal Renal Function Treatment of CMV retinitis (2.3) Induction: 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days. Maintenance: 5 mg/kg (given intravenously at a constant-rate over 1 hour) once daily for 7 days per week, or 6 mg/kg once daily for 5 days per week. Prevention of CMV disease in transplant recipients (2.4) Induction: 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days. Maintenance: 5 mg/kg (given intravenously at a constant-rate over 1 hour) once daily, 7 days per week, or 6 mg/kg once daily, 5 days per week until 100 to 120 days post-transplantation. Adults with renal impairment: Adjust dosage based on creatinine clearance. (2.5). 2.1 Important Dosing and Administration Information To avoid phlebitis/pain at the infusion site, CYTOVENE-IV 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. Do not administer CYTOVENE-IV by rapid or bolus intravenous injection which may increase toxicity as a result of excessive plasma levels. The recommended dosage and infusion rate for CYTOVENE-IV should not be exceeded. Do not administer the reconstituted CYTOVENE-IV solution intramuscularly or subcutaneously because it may result in severe tissue irritation due to high pH (11). Administration of CYTOVENE-IV 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 CYTOVENE-IV [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)]. Complete blood counts with differential and platelet counts should be performed frequently, especially in patients in whom CYTOVENE-IV or other nucleoside analogues have previously resulted in cytopenias, or in whom absolute neutrophil counts are less than 1000 cells/μL at the beginning of treatment [see Warnings and Precautions (5.1)]. All patients should be monitored for renal function before and during treatment with CYTOVENE-IV and dose should be adjusted as needed [see Dosage and Administration (2.5), Warnings and Precautions (5.2)]. Patients with CMV retinitis should have frequent ophthalmological examinations during treatment with CYTOVENE-IV solution to monitor disease status and for other retinal abnormalities [see Adverse Reactions (6.1)]. 2.3 Recommended Dosage for Treatment of CMV Retinitis in Adult Patients with Normal Renal Function 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. 2.4 Recommended Dosage for the Prevention of CMV Disease in Adult Transplant Recipients with Normal Renal Function 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 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. 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 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 ClearanceCreatinine clearance can be related to serum creatinine by the formulas given below. (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 to 70 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 Less than 10 1.25 3 times per week, following hemodialysis 0.625 3 times per week, following hemodialysis Creatinine clearance for males = (140 - age [yrs]) (body wt [kg]) (72) (serum creatinine [mg/dL]) Creatinine clearance for females = 0.85 × male value Patients Undergoing Hemodialysis Induction 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% [see Clinical Pharmacology (12.3)]. 2.6 Preparation of CYTOVENE-IV CYTOVENE-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: Reconstitution Instructions: a)Reconstitute lyophilized CYTOVENE-IV by injecting 10 mL of Sterile Water for Injection, USP, into the vial. Do not use bacteriostatic water for injection containing parabens. It is incompatible with CYTOVENE-IV and may cause precipitation. b)Gently swirl the vial in order to ensure complete wetting of the product. Continue swirling until a clear reconstituted solution is obtained. c)Visually inspect the reconstituted solution for particulate matter and discoloration prior to proceeding with infusion. Discard the vial if particulate matter or discoloration is observed. d)Reconstituted solution in the vial is stable at room temperature (25°C) for 12 hours. Do not refrigerate or freeze. Infusion Instructions: a)Based on patient weight, the appropriate volume of the reconstituted 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 CYTOVENE-IV solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and Lactated Ringer's Injection, USP. b)CYTOVENE-IV, when reconstituted with Sterile Water for Injection (non-bacteriostatic) and 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 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 [see How Supplied/Storage and Handling (16)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended with use of CYTOVENE-IV. (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 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 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 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 [see Warnings and Precautions (5.1, 5.3, 5.5), Nonclinical Toxicology (13.1)]. 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 CYTOVENE-IV [see Dosage and Administration (2.2), Use in Specific Populations (8.1)]. Contraception Females 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 [see 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 CYTOVENE-IV [see Warnings and Precautions (5.4), Nonclinical Toxicology (13.1)]. Infertility CYTOVENE-IV at the recommended doses may cause temporary or permanent female and male infertility [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety 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 t1/2 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, Cmax was 7.9 ± 3.9 mcg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t1/2 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. 8.5 Geriatric Use Clinical 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 [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Use in Specific Populations (8.6)]. 8.6 Renal Impairment Dose reduction is recommended when administering CYTOVENE-IV to patients with renal impairment [see Dosage and Administration (2.5), and Warnings and Precautions (5.2)]. 8.7 Hepatic Impairment The safety and efficacy of CYTOVENE-IV have not been studied in patients with hepatic impairment.

Interactions

7 DRUG INTERACTIONS Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of CYOTVENE-IV 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 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 CYTOVENE IV 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 myelosuppresion 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 CYTOVENE-IV 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 CYTOVENE-IV 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)

More information

Category Value
Authorisation number NDA019661
Agency product number 02L083W284
Orphan designation No
Product NDC 0004-6940
Date Last Revised 30-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 205743
Storage and handling Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. 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.
Marketing authorisation holder Genentech, Inc.
Warnings WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia have been reported in patients treated with CYTOVENE-IV [see Warnings and Precautions (5.1)]. Impairment of Fertility: Based on animal data, CYTOVENE-IV may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions (5.3)]. Fetal Toxicity: Based on animal data, CYTOVENE-IV has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)]. Mutagenesis and Carcinogenesis: Based on animal data, CYTOVENE-IV has the potential to cause cancers in humans [see Warnings and Precautions (5.5)]. WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS See full prescribing information for complete boxed warning. Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia have been reported in patients treated with CYTOVENE-IV. (5.1) Impairment of Fertility: Based on animal data, CYTOVENE-IV may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females. (5.3) Fetal Toxicity: Based on animal data, CYTOVENE-IV has the potential to cause birth defects in humans. (5.4) Mutagenesis and Carcinogenesis: Based on animal data, CYTOVENE-IV has the potential to cause cancer in humans. (5.5)