Cytovene IV

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Medicines like ganciclovir can sometimes cause serious side effects such as blood problems; these are described below. Discuss these possible effects with your doctor.

Check with your doctor immediately if any of the following side effects occur:

• Sore throat and fever
• unusual bleeding or bruising

• Mood or other mental changes
• nervousness
• pain at place of injection
• skin rash
• tremor
• unusual tiredness and weakness

• Decreased vision or any change in vision

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain
• loss of appetite
• nausea and vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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.

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)].

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.

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.

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.

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)].

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:

1. 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.
2. 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.

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)].

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 [see Dosage and Administration (2.6)].

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)].

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.

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)].

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.

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)].

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)].

Hepatic Impairment

The safety and efficacy of Cytovene-IV have not been studied in patients with hepatic impairment.

Treatment of CMV Retinitis

In a retrospective, non-randomized, single-center analysis of 41 patients with AIDS and CMV retinitis diagnosed by ophthalmologic examination between August 1983 and April 1988, treatment with Cytovene-IV solution resulted in a delay in mean (median) time to first retinitis progression compared to untreated controls [105 (71) days from diagnosis vs 35 (29) days from diagnosis]. Patients in this series received induction treatment of Cytovene-IV 5 mg/kg twice daily for 14 to 21 days followed by maintenance treatment with either 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

In a controlled, randomized study conducted between February 1989 and December 1990, immediate treatment with Cytovene-IV was compared to delayed treatment in 42 patients with AIDS and peripheral CMV retinitis; 35 of 42 patients (13 in the immediate-treatment group and 22 in the delayed-treatment group) were included in the analysis of time to retinitis progression. Based on masked assessment of fundus photographs, the mean [95% CI] and median [95% CI] times to progression of retinitis were 66 days [39, 94] and 50 days [40, 84], respectively, in the immediate-treatment group compared to 19 days [11, 27] and 13.5 days [8, 18], respectively, in the delayed-treatment group.

Data from trials ICM 1653, ICM 1774, and AVI034, which were performed comparing Cytovene-IV to oral ganciclovir for treatment of CMV retinitis in patients with AIDS, are shown in Table 12, and Figures 1, 2, and 3, and are discussed below.

Trial ICM 1653: In this randomized, open-label, parallel group trial, conducted between March 1991 and November 1992, patients with AIDS and newly diagnosed CMV retinitis received a 3-week induction course of Cytovene-IV solution, 5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily for 1 additional week. Following the 21-day intravenous induction course, patients with stable CMV retinitis were randomized to receive 20 weeks of maintenance treatment with either Cytovene-IV solution, 5 mg/kg once daily, or ganciclovir capsules, 500 mg 6 times daily (3000 mg/day). The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 57 days [44, 70] and 29 days [28, 43], respectively, for patients on oral therapy compared to 62 days [50, 73] and 49 days [29, 61], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral - IV) was -5 days [-22, 12]. See Figure 1 for comparison of the proportion of patients remaining free of progression over time.

Trial ICM 1774: In this three-arm, randomized, open-label, parallel group trial, conducted between June 1991 and August 1993, patients with AIDS and stable CMV retinitis following from 4 weeks to 4 months of treatment with Cytovene-IV solution were randomized to receive maintenance treatment with Cytovene-IV solution, 5 mg/kg once daily, ganciclovir capsules, 500 mg 6 times daily, or ganciclovir capsules, 1000 mg three times daily for 20 weeks. The study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 54 days [48, 60] and 42 days [31, 54], respectively, for patients on oral therapy compared to 66 days [56, 76] and 54 days [41, 69], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral - IV) was -12 days [-24, 0]. See Figure 2 for comparison of the proportion of patients remaining free of progression over time.

Trial AVI 034: In this randomized, open-label, parallel group trial, conducted between June 1991 and February 1993, patients with AIDS and newly diagnosed (81%) or previously treated (19%) CMV retinitis who had tolerated 10 to 21 days of induction treatment with Cytovene-IV, 5 mg/kg twice daily, were randomized to receive 20 weeks of maintenance treatment with either ganciclovir capsules, 500 mg 6 times daily or Cytovene-IV solution, 5 mg/kg/day. The mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 51 days [44, 57] and 41 days [31, 45], respectively, for patients on oral therapy compared to 62 days [52, 72] and 60 days [42, 83], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to progression between the oral and intravenous therapies (oral - IV) was -11 days [-24, 1]. See Figure 3 for comparison of the proportion of patients remaining free of progression over time.

Comparison of other CMV retinitis outcomes between oral and IV formulations (development of bilateral retinitis, progression into Zone 1, and deterioration of visual acuity), while not definitive, showed no marked differences between treatment groups in these studies. Because of low event rates among these endpoints, these studies are underpowered to rule out significant differences in these endpoints.

Figure 1 Trial ICM 1653: Time to Progression of CMV Retinitis

Figure 2 Trial ICM 1774: Time to Progression of CMV Retinitis

Figure 3 Trial AVI 034: Time to Progression of Retinitis

Prevention of CMV Disease in Transplant Recipients

Cytovene-IV was evaluated in three randomized, controlled trials of prevention of CMV disease in organ transplant recipients.

Trial ICM 1496: In a randomized, double-blind, placebo-controlled study of 149 heart transplant recipients at risk for CMV infection (CMV seropositive or a seronegative recipient of an organ from a CMV seropositive donor), there was a reduction in the overall incidence of CMV disease in patients treated with Cytovene-IV. Immediately post-transplant, patients received Cytovene-IV solution 5 mg/kg twice daily for 14 days followed by 6 mg/kg once daily for 5 days/week for an additional 14 days. Twelve of the 76 (16%) patients treated with Cytovene-IV vs 31 of the 73 (43%) placebo-treated patients developed CMV disease during the 120-day post-transplant observation period. No significant differences in hematologic toxicities were seen between the two treatment groups [see Adverse Reactions (6.1)].

Trial ICM 1689: In a randomized, double-blind, placebo-controlled study of 72 bone marrow transplant recipients with asymptomatic CMV infection (CMV positive culture of urine, throat or blood) there was a reduction in the incidence of CMV disease in patients treated with Cytovene-IV following successful hematopoietic engraftment. Patients with virologic evidence of CMV infection received Cytovene-IV solution 5 mg/kg twice daily for 7 days followed by 5 mg/kg once daily through day 100 post-transplant. One of the 37 (3%) patients treated with Cytovene-IV vs 15 of the 35 (43%) placebo-treated patients developed CMV disease during the study. At 6 months post-transplant, there continued to be a reduction in the incidence of CMV disease in patients treated with Cytovene-IV. Six of 37 (16%) patients treated with Cytovene-IV vs 15 of the 35 (43%) placebo-treated patients developed disease through 6 months post-transplant. The overall rate of survival was higher in the group treated with Cytovene-IV, both at day 100 and day 180 post-transplant. Although the differences in hematologic toxicities were not statistically significant, the incidence of neutropenia was higher in the group treated with Cytovene-IV [see Adverse Reactions (6.1)].

Trial ICM 1570: This was a randomized, unblinded study evaluated 40 allogeneic bone marrow transplant recipients at risk for CMV disease. Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) on day 35 post-transplant. Patients with histologic, immunologic or virologic evidence of CMV infection in the lung were then randomized to observation or treatment with Cytovene-IV solution (5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily 5 days/week until day 120). Four of 20 (20%) patients treated with Cytovene-IV and 14 of 20 (70%) control patients developed interstitial pneumonia. The incidence of CMV disease was lower in the group treated with Cytovene-IV, consistent with the results observed in ICM 1689.