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).
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