CYTOVENE®-IV
(ganciclovir
sodium for injection)
FOR INTRAVENOUS INFUSION ONLY
CYTOVENE®
(ganciclovir capsules)
FOR ORAL ADMINISTRATION
This
product information is intended for United States residents and on-screen
viewing only.
Before prescribing, please refer to printed complete product information.
Complete Product Information
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WARNING: THE CLINICAL TOXICITY
OF CYTOVENE AND CYTOVENE-IV INCLUDES GRANULOCYTOPENIA, ANEMIA AND
THROMBOCYTOPENIA. IN ANIMAL STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC
AND CAUSED ASPERMATOGENESIS. CYTOVENE-IV IS INDICATED
FOR USE ONLY IN THE TREATMENT OF CYTOMEGALOVIRUS (CMV) RETINITIS IN
IMMUNOCOMPROMISED PATIENTS AND FOR THE PREVENTION OF CMV DISEASE IN
TRANSPLANT PATIENTS AT RISK FOR CMV DISEASE. CYTOVENE CAPSULES ARE
INDICATED ONLY FOR PREVENTION OF CMV DISEASE IN PATIENTS WITH ADVANCED
HIV INFECTION AT RISK FOR CMV DISEASE, FOR MAINTENANCE TREATMENT OF CMV
RETINITIS IN IMMUNOCOMPROMISED PATIENTS, AND FOR PREVENTION OF CMV DISEASE IN
SOLID ORGAN TRANSPLANT RECIPIENTS (see INDICATIONS
AND USAGE). BECAUSE CYTOVENE CAPSULES
ARE ASSOCIATED WITH A RISK OF MORE RAPID RATE OF CMV RETINITIS PROGRESSION,
THEY SHOULD BE USED AS MAINTENANCE TREATMENT ONLY IN THOSE PATIENTS FOR WHOM
THIS RISK IS BALANCED BY THE BENEFIT ASSOCIATED WITH AVOIDING DAILY
INTRAVENOUS INFUSIONS. |
DESCRIPTION:
Ganciclovir is a
synthetic guanine derivative active against cytomegalovirus (CMV). CYTOVENE-IV
and CYTOVENE are the brand names for ganciclovir sodium for injection and
ganciclovir capsules, respectively.
CYTOVENE-IV
is available as sterile lyophilized powder in strength of 500 mg per vial for
intravenous administration only. Each vial of CYTOVENE-IV contains the
equivalent of 500 mg ganciclovir as the sodium salt (46 mg sodium).
Reconstitution with 10 mL of Sterile Water for Injection, USP, yields a
solution with pH 11 and a ganciclovir concentration of approximately 50 mg/mL.
Further dilution in an appropriate intravenous solution must be performed
before infusion (see DOSAGE
AND ADMINISTRATION).
CYTOVENE
is available as 250 mg and 500 mg capsules. Each capsule contains 250 mg or 500
mg ganciclovir, respectively, and inactive ingredients croscarmellose sodium,
magnesium stearate and povidone. Both hard gelatin shells consist of gelatin,
titanium dioxide, yellow iron oxide and FD&C Blue No. 2.
Ganciclovir
is a white to off-white crystalline powder with a molecular formula of C9H13N504
and a molecular weight of 255.23. The chemical name for ganciclovir is
9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine. Ganciclovir is a polar
hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C and an
n-octanol/water partition coefficient of 0.022. The pKas for
ganciclovir are 2.2 and 9.4.
Ganciclovir,
when formulated as monosodium salt in the IV dosage form, is a white to
off-white lyophilized powder with a molecular formula of C9H12N5Na04,
and a molecular weight of 277.22. The chemical name for ganciclovir sodium is
9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine, monosodium salt. The lyophilized
powder has an aqueous solubility of greater than 50 mg/mL at 25°C. At
physiological pH, ganciclovir sodium exists as the un-ionized form with a
solubility of approximately 6 mg/mL at 37°C.
The
chemical structures of ganciclovir sodium and ganciclovir are:
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ganciclovir sodium |
ganciclovir |
All
doses in this insert are specified in terms of ganciclovir.
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
µg/mL. Ganciclovir inhibits mammalian cell proliferation (CIC50) in
vitro at higher concentrations ranging from 30 to 725 µg/mL. Bone
marrow-derived colony-forming cells are more sensitive (CIC50 0.028
to 0.7 µg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir
and clinical response has not been established.
Clinical Antiviral Effect of CYTOVENE-IV and CYTOVENE
Capsules: CYTOVENE-IV:
In a study of CYTOVENE-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-IV was demonstrated in two randomized studies for the
prevention of CMV disease in transplant recipients (see table below).
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Patients
with Positive CMV Cultures |
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Heart Allograft* (n=147) |
Bone Marrow Allograft
(n=72) |
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Time |
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Placebo |
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Placebo |
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Pretreatment |
1/67 (2%) |
5/64
(8%) |
37/37 (100%) |
35/35 (100%) |
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*
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 post-transplant
CYTOVENE
Capsules: In trials
comparing CYTOVENE-IV with CYTOVENE 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.
A
study of CYTOVENE capsules (1000 mg q8h) for prevention of CMV disease in
individuals with advanced HIV infection (ICM 1654) evaluated antiviral activity
as measured by CMV isolation in culture; most cultures were from urine. At
baseline, 40% (176/436) and 44% (92/210) of ganciclovir and placebo recipients,
respectively, had positive cultures (urine or blood). After 2 months on
treatment, 10% vs 44% of ganciclovir vs placebo recipients had positive
cultures.
Viral
Resistance: The current
working definition of CMV resistance to ganciclovir in in vitro assays is IC50
>3.0 µg/mL (12.0 µM). 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.
CLINICAL
PHARMACOLOGY: Pharmacokinetics:
BECAUSE
THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS RENAL, DOSAGE REDUCTIONS
ACCORDING TO CREATININE CLEARANCE ARE REQUIRED FOR CYTOVENE-IV AND SHOULD BE
CONSIDERED FOR CYTOVENE CAPSULES. FOR DOSING INSTRUCTIONS IN PATIENTS WITH
RENAL IMPAIRMENT, REFER TO DOSAGE AND ADMINISTRATION.
Absorption:
The absolute bioavailability of oral ganciclovir under fasting conditions was
approximately 5% (n=6) and following food was 6% to 9% (n=32). When ganciclovir
was administered orally with food at a total daily dosage of 3 g/day (500 mg
q3h, 6 times daily and 1000 mg tid), the steady-state absorption as measured by
area under the serum concentration vs time curve (AUC) over 24 hours and maximum
serum concentrations (Cmax) were similar following both regimens
with an AUC0-24 of 15.9 ± 4.2 (mean ± SD) and 15.4 ± 4.3 µg.hr/mL
and Cmax of 1.02 ± 0.24 and 1.18 ± 0.36 µg/mL, respectively (n=16).
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 µg.hr/mL (n=16) and Cmax
ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 µg/mL (n=16).
Food
Effects: When CYTOVENE
capsules were given with a meal containing 602 calories and 46.5% fat at a
dosage of 1000 mg every 8 hours to 20 HIV-positive subjects, the steady-state
AUC increased by 22 ± 22% (range: -6% to 68%) and there was a significant
prolongation of time to peak serum concentrations (Tmax) from 1.8 ±
0.8 to 3.0 ± 0.6 hours and a higher Cmax (0.85 ± 0.25 vs 0.96 ± 0.27
µg/mL) (n=20).
Distribution:
The steady-state volume of distribution of ganciclovir after intravenous
administration was 0.74 ± 0.15 L/kg (n=98). For CYTOVENE capsules, no
correlation was observed between AUC and reciprocal weight (range: 55 to 128
kg); oral dosing according to weight is not required. 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 µg/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
µg/mL.
Metabolism:
Following oral administration of a single 1000 mg dose of 14C-labeled
ganciclovir, 86 ± 3% of the administered dose was recovered in the feces and 5
± 1% was recovered in the urine (n=4). No metabolite accounted for more than 1%
to 2% of the radioactivity recovered in urine or feces.
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). After oral administration of ganciclovir, steady-state is
achieved within 24 hours. Renal clearance following oral administration was 3.1
± 1.2 mL/min/kg (n=22). 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-IV
solution were evaluated in 10 immunocompromised patients with renal impairment
who received doses ranging from 1.25 to 5.0 mg/kg.
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Estimated |
n |
Dose |
Clearance |
Half-life |
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50-79 |
4 |
3.2-5 mg/kg |
128 ± 63 |
4.6 ± 1.4 |
The
pharmacokinetics of ganciclovir following oral administration of CYTOVENE
capsules were evaluated in 44 patients, who were either solid organ transplant
recipients or HIV positive. Apparent oral clearance of ganciclovir decreased
and AUC0-24h increased with diminishing renal function (as expressed
by creatinine clearance). 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 both
intravenous and oral 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 µg/mL, systemic clearance of 3.14 ± 1.75 and 3.56 ±
1.27 mL/min/kg, and t1/2 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
µg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg, and t1/2 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.
INDICATIONS
AND USAGE: CYTOVENE-IV
is indicated for the treatment of CMV retinitis in immunocompromised patients,
including patients with acquired immunodeficiency syndrome (AIDS). CYTOVENE-IV
is also indicated for the prevention of CMV disease in transplant recipients at
risk for CMV disease (see CLINICAL
TRIALS).
CYTOVENE
capsules are indicated for the prevention of CMV disease in solid organ
transplant recipients and in individuals with advanced HIV infection at risk
for developing CMV disease. CYTOVENE capsules are also indicated as an alternative
to the intravenous formulation for maintenance treatment of CMV retinitis in
immunocompromised patients, including patients with AIDS, in whom retinitis is
stable following appropriate induction therapy and for whom the risk of more
rapid progression is balanced by the benefit associated with avoiding daily IV
infusions (see CLINICAL
TRIALS).
SAFETY
AND EFFICACY OF CYTOVENE-IV AND CYTOVENE HAVE NOT BEEN
ESTABLISHED FOR CONGENITAL OR NEONATAL CMV DISEASE; NOR FOR THE TREATMENT OF
ESTABLISHED CMV DISEASE OTHER THAN RETINITIS; NOR FOR USE IN
NON-IMMUNOCOMPROMISED INDIVIDUALS. THE SAFETY AND EFFICACY OF CYTOVENE CAPSULES
HAVE NOT BEEN ESTABLISHED FOR TREATING ANY MANIFESTATION OF CMV DISEASE OTHER
THAN MAINTENANCE TREATMENT OF CMV RETINITIS.
CLINICAL TRIALS:
1.
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-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-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-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-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 CYTOVENE Capsules to CYTOVENE-IV:
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Population
Characteristics in Studies ICM 1653, ICM 1774 and AVI 034 |
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ICM 1653 |
ICM 1774 |
AVI 034 |
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Median age (years) |
38 |
37 |
39 |
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Sex |
Males |
116 (96%) |
222 (99%) |
148 (93%) |
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Females |
5 (4%) |
3 (1%) |
10 (6%) |
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Ethnicity |
Asian |
3 (3%) |
5 (2%) |
7 (4%) |
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Black |
11 (9%) |
9 (4%) |
3 (2%) |
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Caucasian |
98 (81%) |
186 (83%) |
140 (88%) |
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Other |
9 (7%) |
25 (11%) |
8 (5%) |
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Median CD4 Count |
9.5 |
7.0 |
10.0 |
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Mean (SD) |
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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 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 CYTOVENE 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-IV solution were randomized to receive
maintenance treatment with CYTOVENE-IV solution, 5 mg/kg once daily, CYTOVENE
capsules, 500 mg 6 times daily, or CYTOVENE 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-IV, 5 mg/kg twice daily, were randomized to receive 20 weeks of
maintenance treatment with either CYTOVENE capsules, 500 mg 6 times daily or
CYTOVENE-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
Figure
2 - ICM 1774
Figure
3 - AVI 034
2.
Prevention of CMV Disease in Subjects With AIDS
ICM
1654: In a double-blind
study conducted between November 1992 and July 1994, 725 subjects with AIDS,
who were CMV seropositive and/or culture positive, were randomized to receive
CYTOVENE capsules, 1000 mg, every 8 hours, or placebo.4 The study
population had a median age of 38 years (range: 21 to 69); were 99% male; were
82% Caucasian, 10% Hispanic, 7% African-American and 1% Asian; and had a median
CD4 count of 21 (range: 0 to 100). The mean observation time was 351
days (range: 5 to 621). As shown in the following table, significantly more
placebo recipients developed CMV disease.
|
Incidence of CMV Disease at 6, 12 and 18 Months After
Enrollment (Kaplan-Meier Estimates) |
|
|
Incidence (Number Still at Risk) |
|
|
|
CMV Disease |
|
|
|
Ganciclovir |
Placebo |
|
6 months |
8%
(397) |
11% (190) |
|
12 months |
14% (225) |
26%
(92) |
|
18 months |
20%
(27) |
39%
(9) |
3.
Prevention of CMV Disease in Transplant Recipients
CYTOVENE-IV:
CYTOVENE-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 recipients5
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-IV. Immediately posttransplant, patients received CYTOVENE-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-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 in ADVERSE EVENTS).
ICM
1689: In a randomized,
double-blind, placebo-controlled study of 72 bone marrow transplant recipients6
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-IV following successful hematopoietic
engraftment. Patients with virologic evidence of CMV infection received
CYTOVENE-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-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-IV. Six of 37 (16%) patients treated with CYTOVENE-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-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 in ADVERSE EVENTS).
ICM
1570: A second,
randomized, unblinded study evaluated 40 allogeneic bone marrow transplant
recipients at risk for CMV disease.7 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-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-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-IV, consistent with the
results observed in ICM 1689.
CYTOVENE Capsules: GAN040: CYTOVENE capsules were evaluated in a
randomized, double-blind, placebo-controlled study of 304 orthotopic liver
transplant recipients who were CMV seropositive or recipients of an organ from
a seropositive donor. Administration of CYTOVENE capsules (1000 mg three times
daily) or matching placebo commenced as soon as patients were able to take
medication by mouth, but no later than 10 days following transplantation, and
continued through 14 weeks after transplantation. Dosing was adjusted for
patients with an estimated creatinine clearance <50 mL/min. The incidence of
CMV disease at 6 months is summarized in the table below:
|
Incidence
of CMV Disease at 6 Months (Kaplan-Meier Estimates) |
|
CMV
Disease at 6 months |
|||
|
|
Ganciclovir (n=150) |
Placebo
(n=154) |
Relative Risk (95% Cl) |
|
CMV
Disease,* N (%) |
7 (4.8%) |
29 (18.9%) |
0.22 (0.10, 0.51) |
|
CMV
syndrome# |
6 (4.1%) |
19 (12.4%) |
|
|
CMV
hepatitis |
1 (0.7%) |
9 (5.9%) |
|
|
CMV
GI disease |
0 (0.0%) |
3 (2.0%) |
|
|
CMV
lung disease |
0 (0.0%) |
4 (2.6%) |
|
·
One or more
CMV endpoints
CMV
syndrome: CMV viremia and unexplained fever, accompanied by malaise and/or
neutropenia.
CYTOVENE
capsules significantly reduced the 6-month incidence of CMV disease in patients
at increased risk of CMV disease, including seronegative recipients of organs
from seropositive donors (15% [3/21] with CYTOVENE capsules vs 44% [11/25] with
placebo), and patients receiving antilymphocyte antibodies (5% [2/44] with
CYTOVENE capsules vs 33% [12/37] with placebo). The incidence of HSV infection
at 6 months was 4% (5/150) in ganciclovir vs 24% (36/154) in placebo recipients
(relative risk: 0.13; 95% CI: 0.05, 0.32).
CONTRAINDICATIONS:
CYTOVENE-IV and CYTOVENE
are contraindicated in patients with hypersensitivity to ganciclovir or acyclovir.
WARNINGS:
Hematologic: CYTOVENE-IV and CYTOVENE should not be administered if the
absolute neutrophil count is less than 500 cells/µL or the platelet count is
less than 25,000 cells/µL. Granulocytopenia
(neutropenia), anemia and thrombocytopenia have been observed in patients
treated with CYTOVENE-IV and CYTOVENE. The frequency and severity of these
events vary widely in different patient populations (see ADVERSE EVENTS).
CYTOVENE-IV
and CYTOVENE should, therefore, be used with caution in patients with
pre-existing cytopenias or with a history of cytopenic reactions to other
drugs, chemicals or irradiation. Granulocytopenia 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 of 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.
Impairment
of Fertility: Animal
data indicate that administration of ganciclovir causes inhibition of
spermatogenesis and subsequent infertility. These effects were reversible at
lower doses and irreversible at higher doses (see PRECAUTIONS: Carcinogenesis,
Mutagenesis and Impairment
of Fertility). Although data in humans have not been obtained regarding
this effect, it is considered probable that ganciclovir at the recommended
doses causes temporary or permanent inhibition of spermatogenesis. Animal data
also indicate that suppression of fertility in females may occur.
Teratogenesis: Because of the mutagenic and teratogenic
potential of ganciclovir, women of childbearing potential should be advised to
use effective contraception during treatment. Similarly, men should be advised
to practice barrier contraception during and for at least 90 days following
treatment with CYTOVENE-IV or CYTOVENE (see Pregnancy: Category C).
PRECAUTIONS:
General: In
clinical studies with CYTOVENE-IV, the maximum single dose administered was 6
mg/kg by intravenous infusion over 1 hour. Larger doses have resulted in increased
toxicity. It is likely that more rapid infusions would also result in increased
toxicity (see OVERDOSAGE).
Administration of CYTOVENE-IV solution should be accompanied by adequate
hydration.
Initially
reconstituted solutions of CYTOVENE-IV have a high pH (pH 11). Despite further
dilution in intravenous fluids, phlebitis and/or pain may occur at the site of
intravenous infusion. Care must be taken to infuse solutions containing
CYTOVENE-IV only into veins with adequate blood flow to permit rapid dilution
and distribution (see DOSAGE
AND ADMINISTRATION).
Since
ganciclovir is excreted by the kidneys, normal clearance depends on adequate
renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS ARE REQUIRED
FOR CYTOVENE-IV AND SHOULD BE CONSIDERED FOR CYTOVENE CAPSULES. Such
adjustments should be based on measured or estimated creatinine clearance
values (see DOSAGE
AND ADMINISTRATION).
Information for Patients: All patients should be informed that the
major toxicities of ganciclovir are granulocytopenia (neutropenia), anemia and
thrombocytopenia and that dose modifications may be required, including
discontinuation. The importance of close monitoring of blood counts while on
therapy should be emphasized. Patients should be informed that ganciclovir has
been associated with elevations in serum creatinine.
Patients
should be instructed to take CYTOVENE capsules with food to maximize
bioavailability.
Patients
should be advised that ganciclovir has caused decreased sperm production in
animals and may cause infertility in humans. Women of childbearing potential
should be advised that ganciclovir causes birth defects in animals and should
not be used during pregnancy. Women of childbearing potential should be advised
to use effective contraception during treatment with CYTOVENE-IV or CYTOVENE.
Similarly, men should be advised to practice barrier contraception during and
for at least 90 days following treatment with CYTOVENE-IV or CYTOVENE.
Patients
should be advised that ganciclovir causes tumors in animals. Although there is
no information from human studies, ganciclovir should be considered a potential
carcinogen.
All
HIV+ Patients: These
patients may be receiving zidovudine (Retrovir®*). Patients should
be counseled that treatment with both ganciclovir and zidovudine simultaneously
may not be tolerated by some patients and may result in severe granulocytopenia
(neutropenia). Patients with AIDS may be receiving didanosine (Videx®#).
Patients should be counseled that concomitant treatment with both ganciclovir
and didanosine can cause didanosine serum concentrations to be significantly
increased.
HIV+
Patients With CMV Retinitis:
Ganciclovir is not a cure for CMV retinitis, and immunocompromised patients may
continue to experience progression of retinitis during or following treatment.
Patients should be advised to have ophthalmologic follow-up examinations at a
minimum of every 4 to 6 weeks while being treated with CYTOVENE-IV or CYTOVENE.
Some patients will require more frequent follow-up.
Transplant
Recipients: Transplant
recipients should be counseled regarding the high frequency of impaired renal
function in transplant recipients who received CYTOVENE-IV solution in
controlled clinical trials, particularly in patients receiving concomitant
administration of nephrotoxic agents such as cyclosporine and amphotericin B.
Although the specific mechanism of this toxicity, which in most cases was
reversible, has not been determined, the higher rate of renal impairment in
patients receiving CYTOVENE-IV solution compared with those who received
placebo in the same trials may indicate that CYTOVENE-IV played a significant
role.
Laboratory Testing: Due to the frequency of neutropenia, anemia and
thrombocytopenia in patients receiving CYTOVENE-IV and CYTOVENE (see ADVERSE EVENTS),
it is recommended that complete blood counts and platelet counts be performed
frequently, especially 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. Increased serum
creatinine levels have been observed in trials evaluating both CYTOVENE-IV and
CYTOVENE. Patients should have serum creatinine or creatinine clearance values
monitored carefully to allow for dosage adjustments in renally impaired
patients (see DOSAGE
AND ADMINISTRATION).
Drug Interactions: Didanosine: At
an oral dose of 1000 mg of CYTOVENE every 8 hours and didanosine, 200 mg every
12 hours, the steady-state didanosine AUC0-12 increased 111 ± 114%
(range: 10% to 493%) when didanosine was administered either 2 hours prior to
or concurrent with administration of CYTOVENE (n=12 patients, 23 observations).
A decrease in steady-state ganciclovir AUC of 21 ± 17% (range: -44% to 5%) was
observed when didanosine was administered 2 hours prior to administration of
CYTOVENE, but ganciclovir AUC was not affected by the presence of didanosine
when the two drugs were administered simultaneously (n=12). There were no
significant changes in renal clearance for either drug.
When
the standard intravenous ganciclovir induction dose (5 mg/kg infused over 1
hour every 12 hours) was coadministered with didanosine at a dose of 200 mg
orally every 12 hours, the steady-state didanosine AUC0-12 increased
70 ± 40% (range: 3% to 121%, n=11) and Cmax increased 49 ± 48%
(range: -28% to 125%). In a separate study, when the standard intravenous
ganciclovir maintenance dose (5 mg/kg infused over 1 hour every 24 hours) was
coadministered with didanosine at a dose of 200 mg orally every 12 hours,
didanosine AUC0-12 increased 50 ± 26% (range: 22% to 110%, n=11) and
Cmax increased 36 ± 36% (range: -27% to 94%) over the first
didanosine dosing interval. Didanosine plasma concentrations (AUC12-24)
were unchanged during the dosing intervals when ganciclovir was not
coadministered. Ganciclovir pharmacokinetics were not affected by didanosine.
In neither study were there significant changes in the renal clearance of
either drug.
Zidovudine: At an oral dose of 1000 mg of CYTOVENE
every 8 hours, mean steady-state ganciclovir AUC0-8 decreased 17 ±
25% (range: -52% to 23%) in the presence of zidovudine, 100 mg every 4 hours
(n=12). Steady-state zidovudine AUC0-4 increased 19 ± 27% (range:
-11% to 74%) in the presence of ganciclovir.
Since
both zidovudine and ganciclovir have the potential to cause neutropenia and
anemia, some patients may not tolerate concomitant therapy with these drugs at
full dosage.
Probenecid: At an oral dose of 1000 mg of CYTOVENE
every 8 hours (n=10), ganciclovir AUC0-8 increased 53 ± 91% (range:
-14% to 299%) in the presence of probenecid, 500 mg every 6 hours. Renal
clearance of ganciclovir decreased 22 ± 20% (range: -54% to -4%), which is
consistent with an interaction involving competition for renal tubular
secretion.
Imipenem-cilastatin: Generalized seizures have been reported
in patients who received ganciclovir and imipenem-cilastatin. These drugs
should not be used concomitantly unless the potential benefits outweigh the
risks.
Other
Medications: It is
possible that drugs that inhibit replication of rapidly dividing cell
populations such as bone marrow, spermatogonia and germinal layers of skin and
gastrointestinal mucosa may have additive toxicity when administered
concomitantly with ganciclovir. Therefore, drugs such as dapsone, pentamidine,
flucytosine, vincristine, vinblastine, adriamycin, amphotericin B,
trimethoprim/sulfamethoxazole combinations or other nucleoside analogues,
should be considered for concomitant use with ganciclovir only if the potential
benefits are judged to outweigh the risks.
No
formal drug interaction studies of CYTOVENE-IV or CYTOVENE and drugs commonly
used in transplant recipients have been conducted. Increases in serum
creatinine were observed in patients treated with CYTOVENE-IV plus either
cyclosporine or amphotericin B, drugs with known potential for nephrotoxicity
(see ADVERSE
EVENTS). In a retrospective analysis of 93 liver allograft recipients
receiving ganciclovir (5 mg/kg infused over 1 hour every 12 hours) and oral
cyclosporine (at therapeutic doses), there was no evidence of an effect on
cyclosporine whole blood concentrations.
Carcinogenesis, Mutagenesis##: Ganciclovir was carcinogenic in the mouse at oral doses of
20 and 1000 mg/kg/day (approximately 0.1x and 1.4x, respectively, the mean drug
exposure in humans following the recommended intravenous dose of 5 mg/kg, based
on area under the plasma concentration curve [AUC] comparisons). At the dose of
1000 mg/kg/day 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, 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 (estimated as 0.01x the human dose based on AUC comparison). 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 (IV) (2.8 to 10x human exposure based on AUC) but not 50 mg/kg
(exposure approximately comparable to the human based on AUC). Ganciclovir was
not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000
µg/mL.
Impairment of Fertility##: Ganciclovir caused decreased mating behavior, decreased
fertility, and an increased incidence of embryolethality in female mice
following intravenous doses of 90 mg/kg/day (approximately 1.7x the mean drug
exposure in humans following the dose of 5 mg/kg, based on AUC comparisons).
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 0.1x the AUC of the
recommended human intravenous dose.
Pregnancy:
Category C##: Ganciclovir has been shown to be embryotoxic in rabbits and
mice following intravenous administration and teratogenic in rabbits. Fetal
resorptions were present in at least 85% of rabbits and mice administered 60
mg/kg/day and 108 mg/kg/day (2x the human exposure based on AUC comparisons),
respectively. 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 mice, effects observed were
maternal/fetal toxicity and embryolethality.
Daily
intravenous doses of 90 mg/kg administered to female mice prior to mating,
during gestation, and during lactation caused hypoplasia of the testes and
seminal vesicles in the month-old male offspring, as well as pathologic changes
in the nonglandular region of the stomach (see Carcinogenesis,
Mutagenesis). The drug exposure in mice as estimated by the AUC was
approximately 1.7x the human AUC.
Ganciclovir
may be teratogenic or embryotoxic at dose levels recommended for human use.
There are no adequate and well-controlled studies in pregnant women.
CYTOVENE-IV or CYTOVENE should be used during pregnancy only if the potential
benefits justify the potential risk to the fetus.
##Footnote: All dose comparisons presented in the
Carcinogenesis, Mutagenesis, Impairment of Fertility, and Pregnancy
subsections are based on the human AUC following administration of a single 5
mg/kg intravenous infusion of CYTOVENE-IV as used during the maintenance phase
of treatment. Compared with the single 5 mg/kg intravenous infusion, human
exposure is doubled during the intravenous induction phase (5 mg/kg bid) and
approximately halved during maintenance treatment with CYTOVENE capsules (1000
mg tid). The cross-species dose comparisons should be divided by 2 for
intravenous induction treatment with CYTOVENE-IV and multiplied by 2 for
CYTOVENE capsules.
Nursing Mothers: It is not known whether ganciclovir is excreted in human
milk. However, many drugs are excreted in human milk and, because carcinogenic
and teratogenic effects occurred in animals treated with ganciclovir, the
possibility of serious adverse reactions from ganciclovir in nursing infants is
considered likely (see Pregnancy: Category
C). Mothers should be instructed to discontinue nursing if they are receiving
CYTOVENE-IV or CYTOVENE. The minimum interval before nursing can safely be
resumed after the last dose of CYTOVENE-IV or CYTOVENE is unknown.
Pediatric Use: SAFETY AND EFFICACY OF CYTOVENE-IV AND CYTOVENE IN PEDIATRIC
PATIENTS HAVE NOT BEEN ESTABLISHED. THE USE OF CYTOVENE-IV OR CYTOVENE IN THE
PEDIATRIC POPULATION WARRANTS EXTREME CAUTION DUE TO THE PROBABILITY OF
LONG-TERM CARCINOGENICITY AND REPRODUCTIVE TOXICITY. ADMINISTRATION TO
PEDIATRIC PATIENTS SHOULD BE UNDERTAKEN ONLY AFTER CAREFUL EVALUATION AND ONLY
IF THE POTENTIAL BENEFITS OF TREATMENT OUTWEIGH THE RISKS.
The
spectrum of adverse events reported in 120 immunocompromised pediatric clinical
trial participants with serious CMV infections receiving CYTOVENE-IV solution
were similar to those reported in adults. Granulocytopenia (17%) and
thrombocytopenia (10%) were the most common adverse events reported.
Sixteen
pediatric patients (8 months to 15 years of age) with life- or
sight-threatening CMV infections were evaluated in an open-label, CYTOVENE-IV
solution, pharmacokinetics study. Adverse events reported for more than one
pediatric patient were as follows: hypokalemia (4/16, 25%), abnormal kidney
function (3/16, 19%), sepsis (3/16, 19%), thrombocytopenia (3/16, 19%),
leukopenia (2/16, 13%), coagulation disorder (2/16, 13%), hypertension (2/16,
13%), pneumonia (2/16, 13%) and immune system disorder (2/16, 13%).
There
has been very limited clinical experience using CYTOVENE-IV for the treatment
of CMV retinitis in patients under the age of 12 years. Two pediatric patients
(ages 9 and 5 years) showed improvement or stabilization of retinitis for 23
and 9 months, respectively. These pediatric patients received induction
treatment with 2.5 mg/kg tid followed by maintenance therapy with 6 to 6.5
mg/kg once per day, 5 to 7 days per week. When retinitis progressed during
once-daily maintenance therapy, both pediatric patients were treated with the 5
mg/kg bid regimen. Two other pediatric patients (ages 2.5 and 4 years) who
received similar induction regimens showed only partial or no response to
treatment. Another pediatric patient, a 6-year-old with T-cell dysfunction,
showed stabilization of retinitis for 3 months while receiving continuous
infusions of CYTOVENE-IV at doses of 2 to 5 mg/kg/24 hours. Continuous infusion
treatment was discontinued due to granulocytopenia.
Eleven
of the 72 patients in the placebo-controlled trial in bone marrow transplant
recipients were pediatric patients, ranging in age from 3 to 10 years (5
treated with CYTOVENE-IV and 6 with placebo). Five of the pediatric patients
treated with CYTOVENE-IV received 5 mg/kg intravenously bid for up to 7 days; 4
patients went on to receive 5 mg/kg qd up to day 100 posttransplant. Results
were similar to those observed in adult transplant recipients treated with
CYTOVENE-IV. Two of the 6 placebo-treated pediatric patients developed CMV
pneumonia vs none of the 5 patients treated with CYTOVENE-IV. The spectrum of
adverse events in the pediatric group was similar to that observed in the adult
patients.