CYTOVENE®-IV
(ganciclovir sodium for injection)
FOR INTRAVENOUS INFUSION ONLY
CYTOVENE®
(ganciclovir capsules)
FOR ORAL ADMINISTRATION
| 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.
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).
|
Patients
with Positive CMV Cultures |
|
Heart
Allograft* (n=147) |
Bone
Marrow Allograft (n=72) |
|
|
| Time |
CYTOVENE-IV# |
Placebo |
CYTOVENE-IV## |
Placebo |
|
Pretreatment
Week 2
Week 4 |
1/67
(2%)
2/75 (3%)
3/66 (5%) |
5/64
(8%)
11/67 (16%)
28/66 (43%) |
37/37
(100%)
2/31 (6%)
0/24 (0%) |
35/35 (100%)
19/28 (68%)
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 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.
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