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Cytovene

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Cytovene

CLINICAL PHARMACOLOGY

Virology

Mechanism of Action

Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses. Ganciclovir has been shown to be active against cytomegalovirus (CMV) and herpes simplex virus (HSV) in human clinical studies.

To achieve anti-CMV activity, ganciclovir is phosphorylated first to the monophosphate form by a CMV-encoded (UL97 gene) protein kinase homologue, then to the di- and triphosphate forms by cellular kinases. Ganciclovir triphosphate concentrations may be 100-fold greater in CMV-infected than in uninfected cells, indicating preferential phosphorylation in infected cells. Ganciclovir triphosphate, once formed, persists for days in the CMV-infected cell. Ganciclovir triphosphate is believed to inhibit viral DNA synthesis by (1) competitive inhibition of viral DNA polymerases; and (2) incorporation into viral DNA, resulting in eventual termination of viral DNA elongation.

Antiviral Activity

The median concentration of ganciclovir that inhibits CMV replication (IC50) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.48 g/mL. Ganciclovir inhibits mammalian cell proliferation (CIC50) in vitro at higher concentrations ranging from 30 to 725 g/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC50 0.028 to 0.7 g/mL). The relationship of in vitrosensitivity of CMV to ganciclovir and clinical response has not been established.

Clinical Antiviral Effect of CYTOVENE-IV and Ganciclovir Capsules

CYTOVENE (ganciclovir) -IV

In a study of CYTOVENE (ganciclovir) -IV treatment of life- or sight-threatening CMV disease in immunocompromised patients, 121 of 314 patients had CMV cultured within 7 days prior to treatment and sequential posttreatment viral cultures of urine, blood, throat and/or semen. As judged by conversion to culture negativity, or a greater than 100-fold decrease in in vitro CMV titer, at least 83% of patients had a virologic response with a median response time of 7 to 15 days.

Antiviral activity of CYTOVENE (ganciclovir) -IV was demonstrated in two randomized studies for the prevention of CMV disease in transplant recipients (see Table 1).

Table 1: Patients With Positive CMV Cultures

  Heart Allograft* (n = 147) Bone Marrow Allograft (n = 72)
Time CYTOVENE-IV Placebo CYTOVENE-IV Placebo
Pretreatment 1/67 (2%) 5/64 (8%) 37/37 (100%) 35/35 (100%)
Week 2 2/75 (3%) 11/67 (16%) 2/31 (6%) 19/28 (68%)
Week 4 3/66 (5%) 28/66 (43%) 0/24 (0%) 16/20 (80%)
* CMV seropositive or receiving graft from seropositive donor
5 mg/kg bid for 14 days followed by 6 mg/kg qd for 5 days/week for 14 days
5 mg/kg bid for 7 days followed by 5 mg/kg qd until day 100 posttransplant

Ganciclovir Capsules

In trials comparing CYTOVENE-IV with Ganciclovir capsules for the maintenance treatment of CMV retinitis in patients with AIDS, serial urine cultures and other available cultures (semen, biopsy specimens, blood and others) showed that a small proportion of patients remained culture-positive during maintenance therapy with no statistically significant differences in CMV isolation rates between treatment groups.

Viral Resistance

The current working definition of CMV resistance to ganciclovir in in vitro assays is IC50 > 3.0 g/mL (12.0 M). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with CYTOVENE-IV. In a controlled study of oral ganciclovir for prevention of AIDS-associated CMV disease, 364 individuals had one or more cultures performed after at least 90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last available isolate from each subject was tested for reduced sensitivity, and 2 of 40 were found to be resistant to ganciclovir. These resistant isolates were associated with subsequent treatment failure for retinitis.

The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy. The principal mechanism of resistance to ganciclovir in CMV is the decreased ability to form the active triphosphate moiety; resistant viruses have been described that contain mutations in the UL97 gene of CMV that controls phosphorylation of ganciclovir. Mutations in the viral DNA polymerase have also been reported to confer viral resistance to ganciclovir.

Pharmacokinetics

BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR CYTOVENE (ganciclovir) -IV. FOR DOSING INSTRUCTIONS IN PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.

Absorption

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 g·hr/mL (n=16) and Cmax ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 g/mL (n=16).

Distribution

The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98). Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours postdose in 3 patients who received 2.5 mg/kg ganciclovir intravenously q8h or q12h ranged from 0.31 to 0.68 g/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 g/mL.

Elimination

When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg and when administered orally, it exhibits linear kinetics up to a total daily dose of 4 g/day. 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 IV administration and 4.8 ± 0.9 hours (n=39) following oral administration.

Special Populations

Renal Impairment

The pharmacokinetics following intravenous administration of CYTOVENE (ganciclovir) -IV solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg.

Table 2: Pharmacokinetics of Patients with Renal Impairment

Estimated Creatinine Clearance (mL/min) n Dose Clearance (mL/min) Mean ± SD Half-life (hours) Mean ± SD
50-79 4 3.2-5 mg/kg 128 + 63 4.6 ± 1.4
25-49 3 3-5 mg/kg 57 + 8 4.4 + 0.4
< 25 3 1.25-5 mg/kg 30 + 13 10.7 + 5.7

Based on these observations, it is necessary to modify the dosage of ganciclovir in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% after intravenous administration.

Race/Ethnicity and Gender

The effects of race/ethnicity and gender were studied in subjects receiving a dose regimen of 1000 mg every 8 hours. Although the numbers of blacks (16%) and Hispanics (20%) were small, there appeared to be a trend towards a lower steady-state Cmax and AUC0-8 in these subpopulations as compared to Caucasians. No definitive conclusions regarding gender differences could be made because of the small number of females (12%); however, no differences between males and females were observed.

Pediatrics

Ganciclovir pharmacokinetics were studied in 27 neonates, aged 2 to 49 days. At an intravenous dose of 4 mg/kg (n=14) or 6 mg/kg (n=13), the pharmacokinetic parameters were, respectively, Cmax of 5.5 ± 1.6 and 7.0 ± 1.6 g/mL, systemic clearance of 3.14 ± 1.75 and 3.56 ± 1.27 mL/min/kg, and t½ of 2.4 hours (harmonic mean) for both.

Ganciclovir pharmacokinetics were also studied in 10 pediatric patients, aged 9 months to 12 years. The pharmacokinetic characteristics of ganciclovir were the same after single and multiple (q12h) intravenous doses (5 mg/kg). The steady-state volume of distribution was 0.64 ± 0.22 L/kg, Cmax was 7.9 ± 3.9 g/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t½ was 2.4 ± 0.7 hours. The pharmacokinetics of intravenous ganciclovir in pediatric patients are similar to those observed in adults.

Elderly

No studies have been conducted in adults older than 65 years of age.

Clinical Trials

Treatment of CMV Retinitis

The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason it is essential that the diagnosis of CMV be established by an ophthalmologist familiar with the retinal presentation of these conditions.

The diagnosis of CMV retinitis may be supported by culture of CMV from urine, blood, throat or other sites, but a negative CMV culture does not rule out CMV retinitis.

Studies With CYTOVENE (ganciclovir) -IV

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 (ganciclovir) -IV solution resulted in a significant 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 (ganciclovir) -IV 5 mg/kg bid 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 (see DOSAGE AND ADMINISTRATION).

In a controlled, randomized study conducted between February 1989 and December 1990,1 immediate treatment with CYTOVENE (ganciclovir) -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.

Studies Comparing Ganciclovir Capsules to CYTOVENE (ganciclovir) -IV

Table 3: Population Characteristics in Studies ICM 1653, ICM 1774 and AVI 034

  ICM 1653
(n=121)
ICM 1774
(n=225)
AVI 034
(n=159)
Median age (years) Range 38 24-62 37 22-56 39 23-62
Sex Males 116 (96%) 222 (99%) 148 (93%)
Females 5 (4%) 3 (1%) 10 (6%)
Ethnicity Asian 3 (3%) 5 (2%) 7 (4%)
Black 11 (9%) 9 (4%) 3 (2%)
Caucasian 98 (81%) 186 (83%) 140 (88%)
Other 9 (7%) 25 (11%) 8 (5%)
Median CD4 Count Range 9.5 0-141 7.0 0-80 10.0 0-320
Mean (SD) Observation Time (days) 107.9 (43.0) 97.6 (42.5) 80.9 (47.0)

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 (ganciclovir) -IV solution, 5 mg/kg bid for 14 days followed by 5 mg/kg once daily for 1 additional week.2 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.

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 (ganciclovir) -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 tid 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.

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 (ganciclovir) -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 (ganciclovir) -IV solution, 5 mg/kg/day.3 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: ICM 1653

ICM 1653 - Illustration

Figure 2: ICM 1774

ICM 1774 - Illustration

Figure 3: AVI 034

AVI 034 - Illustration

Prevention of CMV Disease in Transplant Recipients

CYTOVENE (ganciclovir) -IV was evaluated in three randomized, controlled trials of prevention of CMV disease in organ transplant recipients.

ICM 1496: In a randomized, double-blind, placebo-controlled study of 149 heart transplant recipients4 at risk for CMV infection (CMV seropositive or a seronegative recipient of an organ from a CMV seropositive donor), there was a statistically significant reduction in the overall incidence of CMV disease in patients treated with CYTOVENE (ganciclovir) -IV. Immediately posttransplant, patients received CYTOVENE (ganciclovir) -IV solution 5 mg/kg bid for 14 days followed by 6 mg/kg qd for 5 days/week for an additional 14 days. Twelve of the 76 (16%) patients treated with CYTOVENE (ganciclovir) -IV vs 31 of the 73 (43%) placebo-treated patients developed CMV disease during the 120-day posttransplant observation period. No significant differences in hematologic toxicities were seen between the two treatment groups (refer to Table 6 in ADVERSE EVENTS).

ICM 1689: In a randomized, double-blind, placebo-controlled study of 72 bone marrow transplant recipients5 with asymptomatic CMV infection (CMV positive culture of urine, throat or blood) there was a statistically significant reduction in the incidence of CMV disease in patients treated with CYTOVENE (ganciclovir) -IV following successful hematopoietic engraftment. Patients with virologic evidence of CMV infection received CYTOVENE (ganciclovir) -IV solution 5 mg/kg bid for 7 days followed by 5 mg/kg qd through day 100 posttransplant. One of the 37 (3%) patients treated with CYTOVENE (ganciclovir) -IV vs 15 of the 35 (43%) placebo-treated patients developed CMV disease during the study. At 6 months posttransplant, there continued to be a statistically significant reduction in the incidence of CMV disease in patients treated with CYTOVENE (ganciclovir) -IV. Six of 37 (16%) patients treated with CYTOVENE (ganciclovir) -IV vs 15 of the 35 (43%) placebo-treated patients developed disease through 6 months posttransplant. The overall rate of survival was statistically significantly higher in the group treated with CYTOVENE (ganciclovir) -IV, both at day 100 and day 180 posttransplant. Although the differences in hematologic toxicities were not statistically significant, the incidence of neutropenia was higher in the group treated with CYTOVENE-IV (refer to Table 6 in ADVERSE EVENTS).

ICM 1570: A second, randomized, unblinded study evaluated 40 allogeneic bone marrow transplant recipients at risk for CMV disease.6 Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) on day 35 posttransplant. Patients with histologic, immunologic or virologic evidence of CMV infection in the lung were then randomized to observation or treatment with CYTOVENE (ganciclovir) -IV solution (5 mg/kg bid for 14 days followed by 5 mg/kg qd 5 days/week until day 120). Four of 20 (20%) patients treated with CYTOVENE (ganciclovir) -IV and 14 of 20 (70%) control patients developed interstitial pneumonia. The incidence of CMV disease was significantly lower in the group treated with CYTOVENE (ganciclovir) -IV, consistent with the results observed in ICM 1689.

REFERENCES

1. Spector SA, Weingeis T, Pollard R, et al. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J Inf Dis. 1993; 168:557-563.

2. Drew WL, Ives D, Lalezari JP, et al. Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. New Engl J Med. 1995; 333:615-620.

3. The Oral Ganciclovir European and Australian Cooperative Study Group. Intravenous vs oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS. 1995; 9:471-477.

4. Merigan TC, Renlund DG, Keay S, et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. New Engl J Med. 1992; 326:1182-1186.

5. Goodrich JM, Mori M, Gleaves CA, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. New Engl J Med. 1991; 325:1601-1607.

6. Schmidt GM, Horak DA, Niland JC, et al. The City of Hope-Stanford-Syntex CMV Study Group. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. New Engl J Med. 1991; 15:1005-1011.

Last reviewed on RxList: 4/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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