Tespamin
The properties are similar to thiotepa, so see below at thiotepa record for the details.
THIOTEPA
DESCRIPTION:
THIOTEPA (thiotepa for injection) is an ethylenimine-type compound. It is
supplied as a non-pyrogenic, sterile lyophilized powder for intravenous,
intracavitary or intravesical administration, containing 15 mg of thiotepa.
THIOTEPA is a synthetic product with antitumor activity. The chemical name for
thiotepa is Aziridine, 1,1',1(Prime)-phosphinothioylidynetris-, or Tris (1-
aziridinyl) phosphine sulfide.
Thiotepa has the empirical formula C6H12N3PS and a molecular weight of 189.22.
When reconstituted with Sterile Water for Injection, the resulting solution has
a pH of approximately 5.5 - 7.5. Thiotepa is stable in alkaline medium and
unstable in acid medium.
ACTIONS/CLINICAL PHARMACOLOGY:
Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and
pharmacologically to nitrogen mustard. The radiomimetic action of thiotepa is
believed to occur through the release of ethylenimine radicals which, like
irradiation, disrupt the bonds of DNA. One of the principal bond disruptions is
initiated by alkylation of guanine at the N-7 position, which severs the linkage
between the purine base and the sugar and liberates alkylated guanines.
The pharmacokinetics of thiotepa and TEPA in thirteen female patients (45 - 84
years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by
intravenous infusion on subsequent courses given at 4-week intervals are
presented in the following table:
Mean +/- SEM
Pharmacokinetic
Parameters Thiotepa TEPA
----------------------------------------------------------------------------------------------------
(units) 60 mg 80 mg 60 mg 80 mg
----------------------------------------------------------------------------------------------------------------------------------
Peak Serum concentration 1331 +/- 1828 +/- 273 +/- 353 +/-
(ng/mL) 119 135 46 46
Elimination half-life (h) 2.4 +/- 2.3 +/ 17.6 +/- 15.7 +/-
0.3 0.3 3.6 2.7
Area under the curve 2832 +/- 4127 +/- 4789 +/- 7452 +/-
(ng/h/mL) 412 668 1022 1667
Total body clearance 446 +/- 419 +/-
(mL/min) 63 56
TEPA, which possesses cytotoxic activity, appears to be the major metabolite of
thiotepa found in human serum and urine. Urinary excretion of 1C- labeled
thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of
the cecum who received a dose of 0.3 mg/kg intravenously was 63%. Thiotepa and
TEPA in urine each accounts for less than 2% of the administered dose.
The pharmacokinetics of thiotepa in renal and hepatic dysfunction patients have
not been evaluated. Possible pharmacokinetic interactions of thiotepa with any
concomitantly administered medications have not been formally investigated.
INDICATIONS AND USAGE:
Thiotepa has been tried with varying results in the palliation of a wide variety
of neoplastic diseases. However, the most consistent results have been seen in
the following tumors:
1. Adenocarcinoma of the breast.
2. Adenocarcinoma of the ovary.
3. For controlling intracavitary effusions secondary to diffuse or localized
neoplastic diseases of various serosal cavities.
4. For the treatment of superficial papillary carcinoma of the urinary bladder.
While now largely superseded by other treatments, thiotepa has been effective
against other lymphomas, such as lymphosarcoma and Hodgkin's disease.
CONTRAINDICATIONS:
THIOTEPA is contraindicated in patients with a known hypersensitivity (allergy)
to this preparation.
Therapy is probably contraindicated in cases of existing hepatic, renal, or
bone-marrow damage. However, if the need outweighs the risk in such patients,
thiotepa may be used in low dosage, and accompanied by hepatic, renal and
hemopoietic function tests.
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 (>/=)1
mg/kg (3.2 mg/m(squared)), approximately 8-fold less than the maximum
recommended human therapeutic dose (0.8 mg/kg, 27mg/m(squared)), based on body-
surface area. Thiotepa given by the IP route was teratogenic in rats at doses
(>/=)3 mg/kg (21 mg/m(squared)), 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/m(squared)), 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/m(squared))
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/m(squared)) 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/m(squared)). The
mouse micronucleus test was positive with IP administration of >1 mg/kg (3.2
mg/m(squared)). 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 (>/=)0.7 mg/kg (2.24
mg/m(squared)), 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 (>/=)0.5 mg/kg (1.6
mg/m(squared)), 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/m(squared)),
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 (>/=)1 mg/kg (3.2
mg/m(squared)), 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 (>/=)3 mg/kg (21 mg/m(squared)), 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/m(squared)), 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.
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.
ADVERSE REACTIONS:
In addition to its effect on the blood-forming elements (see WARNINGS and
PRECAUTIONS sections), thiotepa may cause other adverse reactions.
GENERAL: Fatigue, weakness. Febrile reaction and discharge from a subcutaneous
lesion may occur as the result of breakdown of tumor tissue.
HYPERSENSITIVITY REACTIONS: Allergic reactions - rash, urticaria, laryngeal
edema, asthma, anaphylactic shock, wheezing.
LOCAL REACTIONS: Contact dermatitis, pain at the injection site.
GASTROINTESTINAL: Nausea, vomiting, abdominal pain, anorexia.
RENAL: Dysuria, urinary retention. There have been rare reports of chemical
cystitis or hemorrhagic cystitis following intravesical, but not parenteral
administration of thiotepa.
RESPIRATORY: Prolonged apnea has been reported when succinylcholine was
administered prior to surgery, following combined use of thiotepa and other
anticancer agents. It was theorized that this was caused by decrease of
pseudocholinesterase activity caused by the anticancer drugs.
NEUROLOGIC: Dizziness, headache, blurred vision.
SKIN: Dermatitis, alopecia. Skin depigmentation has been reported following
topical use.
SPECIAL SENSES: Conjunctivitis.
REPRODUCTIVE: Amenorrhea, interference with spermatogenesis.
OVERDOSAGE:
Hematopoietic toxicity can occur following overdose, manifested by a decrease in
the white cell count and/or platelets. Red blood cell count is a less accurate
indicator of thiotepa toxicity. Bleeding manifestations may develop. The patient
may become more vulnerable to infection, and less able to combat such infection.
Dosages within and minimally above the recommended therapeutic doses have been
associated with potentially life-threatening hematopoietic toxicity. Thiotepa
has a toxic effect on the hematopoietic system that is dose related.
Thiotepa is dialyzable.
There is no known antidote for overdosage with thiotepa. Transfusions of whole
blood or platelets have proven beneficial to the patient in combating
hematopoietic toxicity.
DOSAGE AND ADMINISTRATION:
Since absorption from the gastrointestinal tract is variable, thiotepa should
not be administered orally.
Dosage must be carefully individualized. A slow response to thiotepa does not
necessarily indicate a lack of effect. Therefore, increasing the frequency of
dosing may only increase toxicity. After maximum benefit is obtained by initial
therapy, it is necessary to continue the patient on maintenance therapy (1 to 4
week intervals). In order to continue optimal effect, maintenance doses should
not be administered more frequently than weekly in order to preserve correlation
between dose and blood counts.
PREPARATION AND ADMINISTRATION PRECAUTIONS: Thiotepa is a cytotoxic anticancer
drug and as with other potentially toxic compounds, caution should be exercised
in handling and preparation of thiotepa. Skin reactions associated with
accidental exposure to thiotepa may occur. The use of gloves is recommended. If
thiotepa solution contacts the skin, immediately wash the skin thoroughly with
soap and water. If thiotepa contacts mucous membranes, the membranes should be
flushed thoroughly with water.
PREPARATION OF SOLUTION: THIOTEPA (thiotepa for injection) should be
reconstituted with 1.5 MLof Sterile Water for Injection resulting in a drug
concentration of approximately 10 MG/ML. The actual withdrawable quantities and
concentration achieved are illustrated in the following table:
Label Claim Actual Amount of Approximate Approximate Approximate
Content Diluent Withdrawable Withdrawable Reconstituted
(mg/vial) (mg/vial) to be Added Volume Amount Concentration
(mL) (mL) (mg/vial) (mg/mL)
------------ -------- ----------- ------------ ------------ -----------------------------------------------------
15.0 15.6 1.5 1.4 14.7 10.4
The reconstituted solution is hypotonic and should be further diluted with
Sodium Chloride Injection (0.9% sodium chloride) before use.
When reconstituted with Sterile Water for Injection, solutions of THIOTEPA
should be stored in a refrigerator and used within 8 hours. Reconstituted
solutions further diluted with Sodium Chloride Injection should be used
immediately.
IN ORDER TO ELIMINATE HAZE, SOLUTIONS SHOULD BE FILTERED THROUGH A 0.22 MICRON
FILTER* PRIOR TO ADMINISTRATION. FILTERING DOES NOT ALTER SOLUTION POTENCY.
RECONSTITUTED SOLUTIONS SHOULD BE CLEAR. SOLUTIONS THAT REMAIN OPAQUE OR
PRECIPITATE AFTER FILTRATION SHOULD NOT BE USED.
* Polysulfone membrane (Gelman's Sterile Aerodisc(R), Single Use) or triton-free
mixed ester of cellulose/PVC (Millipore's MILLEX(R)-GS Filter Unit).
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
INITIAL AND MAINTENANCE DOSES: Initially the higher dose in the given range is
commonly administered. The maintenance dose should be adjusted weekly on the
basis of pretreatment control blood counts and subsequent blood counts.
INTRAVENOUS ADMINISTRATION: Thiotepa may be given by rapid intravenous
administration in doses of 0.3 to 0.4 mg/kg. Doses should be given at 1 to 4
week intervals.
INTRACAVITARY ADMINISTRATION: The dosage recommended is 0.6 - 0.8 mg/kg.
Administration is usually effected through the same tubing which is used to
remove the fluid from the cavity involved.
INTRAVESICAL ADMINISTRATION: Patients with papillary carcinoma of the bladder
are dehydrated for 8 to 12 hours prior to treatment. Then 60 mg of thiotepa in
30 - 60 mL of Sodium Chloride Injection is instilled into the bladder by
catheter. For maximum effect, the solution should be retained for 2 hours. If
the patient finds it impossible to retain 60 mL for 2 hours, the dose may be
given in a volume of 30 mL. If desired, the patient may be positioned every 15
minutes for maximum area contact. The usual course of treatment is once a week
for 4 weeks. The course may be repeated if necessary, but second and third
courses must be given with caution since bone-marrow depression may be
increased. Deaths have occurred after intravesical administration, caused by
bone-marrow depression from systemically absorbed drug.
HANDLING AND DISPOSAL: Follow safe cytotoxic agent handling procedures. Several
guidelines on this subject have been published.1 There is no general agreement
that all of the procedures recommended in the guidelines are necessary or
appropriate.
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