A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Valcyte Warnings, Precautions, Pregnancy, Nursing, Abuse - valganciclovir
Valcyte Warnings, Precautions, Pregnancy, Nursing, Abuse - valganciclovir
WARNINGS
THE CLINICAL TOXICITY OF VALCYTE, WHICH IS METABOLIZED TO GANCICLOVIR,
INCLUDES GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL STUDIES
GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED ASPERMATOGENESIS.
Hematologic
Valcyte tablets should not be administered if the absolute neutrophil
count is less than 500 cells/µL, the platelet count is less than 25,000/µL,
or the hemoglobin is less than 8 g/dL.
Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia,
bone marrow depression and aplastic anemia have been observed in patients
treated with Valcyte tablets (and ganciclovir) (see PRECAUTIONS
: Laboratory Testing and ADVERSE
EVENTS ).
Valcyte tablets should, therefore, be used with caution in patients with
pre-existing cytopenias, or who have received or who are receiving myelosuppressive
drugs or irradiation. Cytopenia may occur at any time during treatment
and may increase with continued dosing. Cell counts usually begin to recover
within 3 to 7 days of discontinuing drug.
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 ). It
is considered probable that in humans, valganciclovir at the recommended
doses may cause temporary or permanent inhibition of spermatogenesis.
Animal data also indicate that suppression of fertility in females may
occur.
Teratogenesis, Carcinogenesis and Mutagenesis
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
Valcyte tablets (see PRECAUTIONS
: Carcinogenesis,
Mutagenesis and Pregnancy: Category C ).
In animal studies, ganciclovir was found to be mutagenic and carcinogenic.
Valganciclovir should, therefore, be considered a potential teratogen
and carcinogen in humans with the potential to cause birth defects and
cancers (see DOSAGE AND ADMINISTRATION
: Handling and Disposal ).
PRECAUTIONS
General
Strict adherence to dosage recommendations is essential to avoid overdose.
The bioavailability of ganciclovir from Valcyte tablets is significantly
higher than from ganciclovir capsules. Patients switching from ganciclovir
capsules should be advised of the risk of overdosage if they take more
than the prescribed number of Valcyte tablets. Valcyte tablets cannot
be substituted for Cytovene capsules on a one-to-one basis (see OVERDOSAGE
and 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 VALCYTE TABLETS. Such adjustments should be based
on measured or estimated creatinine clearance values (see DOSAGE
AND ADMINISTRATION : Renal Impairment ).
For patients on hemodialysis (CrCl <10 mL/min) it is recommended that
ganciclovir be used (in accordance with the dose-reduction algorithm cited
in the Cytovene®-IV and Cytovene® Package Insert section on DOSAGE AND
ADMINISTRATION : Renal Impairment ) rather than Valcyte tablets (see DOSAGE
AND ADMINISTRATION : Hemodialysis and CLINICAL
PHARMACOLOGY : Special Populations : Hemodialysis ).
Information for Patients (see Patient Package Insert)
Valcyte tablets cannot be substituted for ganciclovir capsules on
a one-to-one basis. Patients switching from ganciclovir capsules should
be advised of the risk of overdosage if they take more than the prescribed
number of Valcyte tablets (see OVERDOSAGE
and DOSAGE AND ADMINISTRATION
).
Valcyte is changed to ganciclovir once it is absorbed into the body.
All patients should be informed that the major toxicities of ganciclovir
include 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 Valcyte tablets with food to maximize
bioavailability.
Patients should be advised that ganciclovir has caused decreased sperm
production in animals and may cause decreased fertility in humans. Women
of childbearing potential should be advised that ganciclovir causes birth
defects in animals and should not be used during pregnancy. Because of
the potential for serious adverse events in nursing infants, mothers should
be instructed not to breastfeed if they are receiving Valcyte tablets.
Women of childbearing potential should be advised to use effective contraception
during treatment with Valcyte tablets. Similarly, men should be advised
to practice barrier contraception during and for at least 90 days following
treatment with Valcyte tablets.
Although there is no information from human studies, patients should
be advised that ganciclovir should be considered a potential carcinogen.
Convulsions, sedation, dizziness, ataxia and/or confusion have been reported
with the use of Valcyte tablets and/or ganciclovir. If they occur, such
effects may affect tasks requiring alertness including the patient's ability
to drive and operate machinery.
Patients should be told that ganciclovir is not a cure for CMV retinitis,
and that they 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 Valcyte tablets. Some patients will require more frequent
follow-up.
Laboratory Testing
Due to the frequency of neutropenia, anemia and thrombocytopenia in patients
receiving Valcyte tablets (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 monitoring for cytopenias may be warranted if
therapy with oral ganciclovir is changed to oral valganciclovir, because
of increased plasma concentrations of ganciclovir after valganciclovir
administration (see CLINICAL PHARMACOLOGY
).
Increased serum creatinine levels have been observed in trials evaluating
Valcyte tablets. Patients should have serum creatinine or creatinine clearance
values monitored carefully to allow for dosage adjustments in renally
impaired patients (see DOSAGE AND
ADMINISTRATION : Renal Impairment ). The mechanism of impairment
of renal function is not known.
Drug Interactions
Drug Interaction Studies Conducted With Valganciclovir:
No in vivo drug-drug interaction studies were conducted with valganciclovir.
However, because valganciclovir is rapidly and extensively converted to
ganciclovir, interactions associated with ganciclovir will be expected
for Valcyte tablets.
Drug Interaction Studies Conducted With Ganciclovir:
Binding of ganciclovir to plasma proteins is only about 1% to 2%, and
drug interactions involving binding site displacement are not anticipated.
Drug-drug interaction studies were conducted in patients with normal
renal function. Patients with impaired renal function may have increased
concentrations of ganciclovir and the coadministered drug following concomitant
administration of Valcyte tablets and drugs excreted by the same pathway
as ganciclovir. Therefore, these patients should be closely monitored
for toxicity of ganciclovir and the coadministered drug.
Table 4. Results of Drug Interaction Studies with
Ganciclovir: Effects of Co-administered
Drug on Ganciclovir Plasma AUC and C max Values
|
Co-administered
Drug
|
Ganciclovir
Dosage
|
n
|
Ganciclovir
Pharmacokinetic (PK)
Parameter
|
Clinical Comment
|
|
Zidovudine 100 mg every 4 hours
|
1000 mg
every 8 hours
|
12
|
AUC down 17 ± 25%
(range: -52% to 23%)
|
Zidovudine and Valcyte each have the potential to
cause neutropenia and anemia. Some patients may not tolerate concomitant
therapy at full dosage.
|
|
Didanosine 200 mg every 12 hours administered 2 hours
before ganciclovir
|
1000 mg
every 8 hours
|
12
|
AUC down 21 ± 17%
(range: -44% to 5%)
|
Effect not likely to be clinically significant.
|
|
Didanosine 200 mg every 12 hours stimultaneously administered
with ganciclovir
|
1000 mg
every 8 hours
|
12
|
No effect on ganciclovir
PK parameters observed
|
No effect expected.
|
|
IV ganciclovir
5 mg/kg twice daily
|
11
|
No effect on ganciclovir
PK parameters observed
|
No effect expected.
|
|
IV ganciclovir
5 mg/kg once daily
|
11
|
No effect on ganciclovir
PK parameters observed
|
No effect expected.
|
|
Probenecid 500 mg every 6 hours
|
1000 mg
every 8 hours
|
10
|
AUC up 53 ± 91%
(range: -14% to 299%)
Ganciclovir renal
clearance down 22 ± 20%
(Range: -54% to -4%)
|
Patients taking probenecid and Valcyte should be monitored
for evidence of ganciclovir toxicity.
|
|
Zalcitabine 0.75 mg every 8 hours administered 2 hours
before ganciclovir
|
1000 mg
every 8 hours
|
10
|
AUC up 13%
|
Effect not likely to be clinically significant.
|
|
Trimethoprim
200 mg once daily
|
1000 mg
every 8 hours
|
12
|
Ganciclovir renal
clearance down16.3%
Half-life up15%
|
Effect not likely to be clinically significant.
|
|
Mycophenolate Mofetil
1.5 g single dose
|
IV ganciclovir
5 mg/kg single dose
|
12
|
No effect on ganciclovir
PK parameters observed (patients with normal renal function)
|
Patients with renal impairment should be monitored
carefully as levels of metabolites of both drugs may increase.
|
Table 5. Results of Drug Interaction Studies with
ganciclovir: Effects of ganciclovir on
Plasma AUC and C max Values of Co-administered Drug
|
Co-administered
Drug
|
Ganciclovir
Dosage
|
n
|
Co-administered Drug
Pharmacokinetic (PK)
Parameter
|
Clinical Comment
|
|
Zidovudine 100 mg every 4 hours
|
1000 mg
every 8 hours
|
12
|
AUC 0-4 up 19 ± 27%
(range: -11% to 74%)
|
Zidovudine and Valcyte each have the potential to
cause neutropenia and anemia. Some patients may not tolerate concomitant
therapy at full dosage.
|
|
Didanosine 200 mg every 12 hours when administered
2 hours prior to or concurrent with ganciclovir
|
1000 mg
every 8 hours
|
12
|
AUC 0-12 up111 ± 114%
(range: 10% to 493%)
|
Patients should be closely monitored for didanosine
toxicity.
|
|
Didanosine 200 mg every 12 hours
|
IV ganciclovir
5 mg/kg twice daily
|
11
|
AUC 0-12 up70 ± 40%
(range: 3% to 121%)
C max up49 ± 48%
(range: -28% to 125%)
|
Patients should be closely monitored for didanosine
toxicity.
|
|
Didanosine 200 mg every 12 hours
|
IV ganciclovir
5 mg/kg once daily
|
11
|
AUC 0-12 up50 ± 26%
(range: 22% to 110%)
C max up36 ± 36%
(range: -27% to 94%)
|
Patients should be closely monitored for didanosine
toxicity.
|
|
Zalcitabine 0.75 mg every 8 hours administered 2 hours
before ganciclovir
|
1000 mg
every 8 hours
|
10
|
No clinically relevant PK parameter changes
|
No effect expected.
|
|
Trimethoprim
200 mg once daily
|
1000 mg
every 8 hours
|
12
|
Increase in C min
|
Effect not likely to be clinically significant.
|
|
Mycophenolate Mofetil
1.5 g single dose
|
IV ganciclovir
5 mg/kg single dose
|
12
|
No PK interaction observed (patients with normal renal
function)
|
Patients with renal impairment should be monitored
carefully as levels of metabolites of both drugs may increase.
|
Carcinogenesis, Mutagenesis and Impairment of Fertility **
No long-term carcinogenicity studies have been conducted with valganciclovir.
However, upon oral administration, valganciclovir is rapidly and extensively
converted to ganciclovir. Therefore, like ganciclovir, valganciclovir
is a potential carcinogen.
Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000
mg/kg/day (approximately 0.1 × and 1.4 × , 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 0.01 × the
human dose based on AUC comparison). Ganciclovir should be considered
a potential carcinogen in humans.
Valganciclovir increases mutations in mouse lymphoma cells. In the mouse
micronucleus assay, valganciclovir was clastogenic at a dose of 1500 mg/kg
(60 × human mean exposure for ganciclovir based upon AUC). Valganciclovir
was not mutagenic in the Ames Salmonella assay. Ganciclovir increased
mutations in mouse lymphoma cells and DNA damage in human lymphocytes
in vitro. 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.
Valganciclovir is converted to ganciclovir and therefore is expected
to have similar reproductive toxicity effects as ganciclovir (see WARNINGS
: 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
1.7 × 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 0.1 × the AUC of the recommended human intravenous
dose. Valganciclovir caused similar effects on spermatogenesis in mice,
rats, and dogs. It is considered likely that ganciclovir (and valganciclovir)
could cause inhibition of human spermatogenesis.
Pregnancy
Category C **
Valganciclovir is converted to ganciclovir and therefore is expected
to have reproductive toxicity effects similar to ganciclovir. 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 (2 × 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 Teratogenesis,
Carcinogenesis and Mutagenesis ). The drug exposure in mice as estimated
by the AUC was approximately 1.7 × the human AUC.
Data obtained using an ex vivo human placental model show that ganciclovir
crosses the placenta and that simple diffusion is the most likely mechanism
of transfer. The transfer was not saturable over a concentration range
of 1 to 10 mg/mL and occurred by passive diffusion.
Valganciclovir may be teratogenic or embryotoxic at dose levels recommended
for human use. There are no adequate and well-controlled studies in pregnant
women. Valcyte tablets should be used during pregnancy only if the potential
benefit justifies 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 infusion
of intravenous ganciclovir.
Nursing Mothers
It is not known whether ganciclovir or valganciclovir is excreted in
human milk. Because valganciclovir caused granulocytopenia, anemia and
thrombocytopenia in clinical trials and ganciclovir was mutagenic and
carcinogenic in animal studies, the possibility of serious adverse events
from ganciclovir in nursing infants is possible (see WARNINGS
). Because of potential for serious adverse events in nursing infants,
mothers should be instructed not to breastfeed if they are receiving
Valcyte tablets. In addition, the Centers for Disease Control and
Prevention recommend that HIV-infected mothers not breastfeed their infants
to avoid risking postnatal transmission of HIV.
Pediatric Use
Safety and effectiveness of Valcyte tablets in pediatric patients have
not been established.
Geriatric Use
The pharmacokinetic characteristics of Valcyte in elderly patients have
not been established. Since elderly individuals frequently have a reduced
glomerular filtration rate, particular attention should be paid to assessing
renal function before and during administration of Valcyte (see DOSAGE
AND ADMINISTRATION ).
Clinical studies of Valcyte 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.
Valcyte 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 elderly patients are more likely to have decreased
renal function, care should be taken in dose selection. In addition, renal
function should be monitored and dosage adjustments should be made accordingly
(see PRECAUTIONS
: General , CLINICAL
PHARMACOLOGY : Special Populations : Renal Impairment ,
and DOSAGE AND ADMINISTRATION : Renal Impairment ).
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