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
Temodar Warnings, Precautions, Pregnancy, Nursing, Abuse - Temozolomide
Temodar Warnings, Precautions, Pregnancy, Nursing, Abuse - Temozolomide
WARNINGS
Patients treated with TEMODAR may experience
myelosuppression. Prior to dosing patients must have an absolute
neutrophil count
(ANC) ³1.5 x 109/L and
a platelet count
³100 x 109/L. A complete
blood count
should be obtained on Day 22 (21 days after the first dose) or within
48 hours of that day, and weekly until the ANC
is above 1.5 x 109/L and platelet
count exceeds 100 x 109/L.
In the clinical
trials, if the ANC fell
to <1.0 x 109/L or the platelet
count was <50 x 109/L
during any cycle, the next cycle
was reduced by 50 mg/m2 , but not below 100 mg/m2
. Patients who do not tolerate 100 mg/m2 should not receive
TEMODAR. Geriatric patients and women have been shown in clinical
trials to have a higher risk
of developing myelosuppression. Myelosuppression generally occurred
late in the treatment
cycle. The median nadirs occurred at 26 days for platelets [range
21- 40 days] and 28 days for neutrophils [range 1-44 days]. Only
14% (22/158) of patients had a neutrophil nadir and 20% (32/158)
of patients had a platelet
nadir which may have delayed the start of the next cycle. Neutrophil
and platelet counts
returned to normal, on
average, within 14 days
of nadir counts (see PRECAUTIONS
).
Pregnancy
Temozolomide may cause
fetal harm when administered
to a pregnant woman.
Five consecutive days of oral
administration
of 75 mg/m2/day in rats and 150 mg/m2/day
in rabbits during the period
of organogenesis (3/8 and 3/4 the maximum
recommended human dose,
respectively) caused numerous malformations of the external
organs, soft tissues and
skeleton in both species.
Doses of 150 mg/m2/day in rats and rabbits also caused
embryolethality as indicated by increased resorptions. There are
no adequate and well-controlled
studies in pregnant
women. If this drug is
used during pregnancy, or if the patient
becomes pregnant while
taking this drug, the patient
should be apprised of the potential
hazard to the fetus. Women of childbearing
potential should be
advised to avoid becoming pregnant during therapy
with TEMODAR.
PRECAUTIONS
Information for Patients
In clinical trials,
the most frequently occurring adverse effects were nausea and vomiting.
These were usually either self-limiting or readily controlled with
standard anti-emetic
therapy. Capsules should not be opened. If capsules are accidentally
opened or damaged, rigorous precautions should be taken with the
capsule contents to
avoid inhalation
or contact with the
skin or mucous
membranes. The medication
should be kept away from children and pets.
Drug Interaction
Administration of valproic acid
decreases oral clearance
of temozolomide by about 5%. The clinical
implication of this effect
is not known.
Patients with Severe Hepatic or Renal Impairment
Caution should be exercised when TEMODAR is administered to patients
with severe hepatic
or renal impairment. (See
CLINICAL PHARMACOLOGY: Special
Populations).
Geriatrics
Clinical studies of temozolomide did not include sufficient numbers
of subjects aged 65 and
over to determine whether they responded differently from younger
subjects. Other reported clinical
experience has not
identified differences in responses between the elderly and younger
patients. Caution should be exercised when treating elderly patients.
In the anaplastic astrocytoma
study population, patients 70 years of age
or older had a higher incidence of Grade 4 neutropenia
and Grade 4 thrombocytopenia
(2/8; 25%, p=.31 and 2/10; 20%, p=.09, respectively) in the first
cycle of therapy
than patients under 70 years of age. (See ADVERSE
REACTIONS).
Laboratory Tests
A complete blood count
should be obtained on day 22 (21 days after the first dose). Blood
counts should be performed weekly until recovery
if the ANC falls below 1.5
x 109/L and the platelet
count falls below 100
x 109/L.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Standard carcinogenicity studies were not conducted with temozolomide.
In rats treated with 200 mg/m2 temozolomide (equivalent
to the maximum recommended daily human
dose) on 5 consecutive days every 28 days for 3 cycles, mammary
carcinomas were found in both males and females. With 6 cycles of
treatment at 25, 50
and 125 mg/m2 (about 1/ 8-1/2 the maximum
recommended daily human
dose), mammary carcinomas
were observed at all doses and fibrosarcomas of the heart,
eye, seminal
vesicles, salivary glands, abdominal
cavity, uterus and prostate;
carcinoma of the seminal
vesicles, schwannoma
of the heart, optic
nerve and harderian gland;
and adenomas of the skin,
lung, pituitary
and thyroid were observed
at at the high dose.
Temozolomide was mutagenic in vitro in bacteria
(Ames assay) and clastogenic
in mammalian cells (human peripheral
blood lymphocyte
assays).
Reproductive function
studies have not been conducted with temozolomide. However, multicycle
toxicology studies
in rats and dogs have demonstrated testicular toxicity
(syncytial cells/immature sperm,
testicular atrophy)
at doses of 50 mg/m2 in rats and 125 mg/m2
in dogs (1/4 and 5/8 respectively of the maximum
recommended human dose
on a body surface area
basis).
Pregnancy Category D. See WARNINGS
Section.
Nursing Mothers
It is not known whether this drug
is excreted in human milk.
Because many drugs are excreted in human
milk and because of the
potential for serious
adverse reactions in nursing
infants from TEMODAR, patients receiving TEMODAR should discontinue
nursing.
Pediatric Use
Safety and effectiveness
in pediatric patients
have not been established.
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