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
Thioplex Warnings, Precautions, Pregnancy, Nursing, Abuse - Thiotepa (injection)
Thioplex Warnings, Precautions, Pregnancy, Nursing, Abuse - Thiotepa (injection)
WARNINGS
Death has occurred after intravesical
administration, caused by bone-marrow depression from systematically
absorbed drug.
Death from septicemia
and hemorrhage has
occurred as a direct result of hematopoietic
depression by thiotepa.
Thiotepa is highly toxic
to the hematopoietic
system. A rapidly falling white blood
cell or platelet
count indicates the necessity
for discontinuing or reducing the dosage
of thiotepa. Weekly blood
and platelet counts
are recommended during therapy
and for at least 3 weeks after therapy
has been discontinued.
Thiotepa can cause fetal
harm when administered to a pregnant
woman. Thiotepa given by the intraperitoneal
(IP) route was teratogenic
in mice at doses ³1 mg/kg (3.2 mg/m2),
approximately 8-fold less than the maximum
recommended human therapeutic
dose (0.8 mg/kg, 27 mg/m2), based
on body-surface area. Thiotepa given by the IP route was teratogenic
in rats at doses ³3 mg/kg (21 mg/m2),
approximately equal to the maximum
recommended human therapeutic
dose, based on body-surface area. Thiotepa was lethal
to rabbit fetuses at a dose
of 3 mg/kg (41 mg/m2), approximately
two times the maximum
recommended human therapeutic
dose based on body-surface area.
Effective contraception
should be used during thiotepa
therapy if either the
patient or partner is
of childbearing
potential. There are no adequate
and well-controlled studies in pregnant
women. If thiotepa
is used during pregnancy, or if pregnancy
occurs during thiotepa
therapy, the patient
and partner should be apprised of the potential
hazard to the fetus.
Thiotepa is a polyfunctional alkylating agent,
capable of cross-linking the DNA
within a cell and changing
its nature. The replication
of the cell is, therefore, altered, and thiotepa
may be described as mutagenic. An in vitro study has shown
that it causes chromosomal aberrations of the chromatid
type and that the frequency
of induced aberrations
increases with the age of
the subject.
Like many alkylating agents, thiotepa
has been reported to be carcinogenic when administered to laboratory
animals. Carcinogenicity is shown most clearly in studies using
mice, but there is some evidence
of carcinogenicity in man. In
patients treated with thiotepa, cases of myelodysplastic syndromes
and acute non-lymphocytic
leukemia have been
reported.
PRECAUTIONS
General
The serious complication
of excessive thiotepa
therapy, or sensitivity
to the effects of thiotepa, is bone-marrow depression. If proper
precautions are not observed thiotepa
may cause leukopenia,
thrombocytopenia,
and anemia.
Information for Patients
The patient should
notify the physician
in the case of any sign
of bleeding (epistaxis, easy bruising, change in color
of urine, black
stool) or infection (fever, chills) or for possible pregnancy
to patient or partner.
Effective contraception
should be used during thiotepa
therapy if either the
patient or the partner
is of childbearing
potential.
Laboratory Tests
The most reliable guide
to thiotepa toxicity
is the white blood
cell count. If this falls to 3000 or less, the dose
should be discontinued. Another good index
of thiotepa toxicity
is the platelet count;
if this falls to 150,000, therapy
should be discontinued. Red blood
cell count is a less accurate
indicator of thiotepa
toxicity. If the drug is
used in patients with hepatic
or renal damage (see CONTRAINDICATIONS
section), regular assessment
of hepatic and renal
function tests are
indicated.
Drug Interactions
It is not advisable to combine, simultaneously or sequentially,
cancer chemotherapeutic agents or a cancer
chemotherapeutic agent
and a therapeutic modality having the same mechanism
of action. Therefore, thiotepa
combined with other alkylating agents such
as nitrogen mustard
or cyclophosphamide or thiotepa
combined with irradiation
would serve to intensify toxicity rather than to enhance therapeutic
response. If these agents must follow each other, it is important
that recovery from
the first agent, as indicated
by white blood
cell count, be complete
before therapy with
the second agent is instituted.
Other drugs which are known to produce bone-marrow depression
should be avoided.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Also see WARNINGS
section.
Carcinogenesis
In mice, repeated IP administration
of thiotepa (1.15 or
2.3 mg/kg three times per
week for 52 or 43 weeks, respectively) produced a significant increase
in the combined incidence
of squamous-cell carcinomas of the skin, preputial gland,
and ear canal, and combined
incidence of lymphoma
and lymphocytic leukemia. In
other studies in mice, repeated IP administration of thiotepa
(4 or 8 mg/kg three times per
week for 4 weeks followed by a 20-week observation period
or 1.8 mg/kg three times per
week for 4 weeks followed by a 35-week observation period) resulted
in an increased incidence of lung
tumors. In rats, repeated
IP administration
of thiotepa (0.7 or
1.4 mg/kg three times per
week for 52 or 34 weeks, respectively) produced significant increases
in the incidence of
squamous-cell carcinomas of the skin or ear
canal, combined hematopoietic
neoplasms, and uterine
adenocarcinomas. Thiotepa given intravenously (IV) to rats (1 mg/kg
once per week for 52 weeks)
produced an increased incidence
of malignant tumors
(abdominal cavity sarcoma, lymphosarcoma, myelosis, seminoma, fibrosarcoma,
salivary gland hemangioendothelioma,
mammary sarcoma, pheochromocytoma)
and benign tumors.
The lowest reported carcinogenic
dose in mice (1.15 mg/kg,
3.68 mg/m2) is approximately 7-fold
less than the maximum
recommended human therapeutic
dose based on body-surface area. The lowest reported carcinogenic
dose in rats (0.7 mg/kg, 4.9 mg/m2)
is approximately 6-fold less than the maximum
recommended human therapeutic
dose based on body-surface
area.
Mutagenesis
Thiotepa was mutagenic in in vitro assays in Salmonella
typhimurium, E. coli, Chinese hamster
lung and human
lymphocytes. Chromosomal aberrations and sister
chromatid exchanges
were observed in vitro with thiotepa
in bean root tips, human
lymphocytes, Chinese hamster
lung, and monkey lymphocytes. Mutations were observed with oral
thiotepa in mouse at
doses >2.5 mg/kg (8 mg/m2). The
mouse micronucleus test
was positive with IP
administration
of >1 mg/kg (3.2 mg/m2). Other
positive in vivo
chromosomal aberration or mutation
assays included Drosophila melanogaster, Chinese hamster
marrow, murine marrow,
monkey lymphocyte,
and murine germ cell.
Impairment of Fertility
Thiotepa impaired fertility
in male mice at PO or IP
doses ³0.7 mg/kg (2.24 mg/m2),
approximately 12-fold less than the maximum
recommended human therapeutic
dose based on body-surface
area. Thiotepa (0.5 mg) inhibited implantation
in female rats when instilled
into the uterine cavity.
Thiotepa interfered with spermatogenesis
in mice at IP doses ³0.5 mg/kg (1.6
mg/m2), approximately 17-fold less
than the maximum recommended
human therapeutic dose
based on body-surface area. Thiotepa interfered with spermatogenesis
in hamsters at an IP dose
of 1 mg/kg (4.1 mg/m2), approximately
7-fold less than the maximum
recommended human therapeutic
dose based on body-surface area.
Pregnancy
Category D: See WARNINGS
section.
Thiotepa can cause fetal
harm when administered to a pregnant
woman. Thiotepa given by the IP route was teratogenic
in mice at doses ³1 mg/kg (3.2 mg/m2),
approximately 8-fold less than the maximum
recommended human therapeutic
dose based on body-surface
area. Thiotepa given by the IP route was teratogenic
in rats at doses ³3 mg/kg (21 mg/m2),
approximately equal to the maximum
recommended human therapeutic
dose based on body-surface
area. Thiotepa was lethal
to rabbit fetuses at a dose
of 3 mg/kg (41 mg/m2), approximately
2 times the maximum
recommended human therapeutic
dose based on body-surface
area. Patients of childbearing
potential should be
advised to avoid pregnancy. There are no
adequate and well-controlled studies in pregnant women. If thiotepa
is used during pregnancy,
or if pregnancy occurs
during thiotepa therapy,
the patient and partner
should be apprised of the potential
hazard to the fetus.
Nursing Mothers
It is not known whether thiotepa
is excreted in human milk.
Because many drugs are excreted in human
milk and because of the
potential for tumorigenicity
shown for thiotepa
in animal studies, a
decision should be made whether to discontinue nursing
or to discontinue the drug,
taking into account the importance of the drug
to the mother.
Pediatric Use
Safety and effectiveness
in pediatric patients
have not been established.
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