Thiotepa (Cytotoxic Agent)

THIOTEPA

Wyeth-Ayerst

Cytotoxic Agent

Action and Clinical Uses:

Thiotepa is a cytotoxic agent of the polyfunctional alkylating type (more than one reactive ethylenimine group) related chemically and pharmacologically to nitrogen mustard. Its radiomimetic action 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.:

On the basis of tissue concentration studies, it is reported that thiotepa has no differential affinity for neoplasms. Thiotepa and triethylenephosphoramide (TEPA) in urine each accounts for less than 2% of the administered dose.

Indications And Clinical Uses:

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: adenocarcinoma of the breast; adenocarcinoma of the ovary; for controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities; and 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 While now largely superseded by other treatments, thiotepa has been effective against other lymphomas, such as lymphosarcoma and Hodgkin’s disease.

Contra-Indications:

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.

Thiotepa is contraindicated in patients with a known hypersensitivity (allergy) to this preparation.

Warnings in Clinical States:

Pregnancy: The administration of thiotepa to pregnant women is not recommended except in cases where the benefit to be gained outweighs the risk of teratogenicity involved.

Death has occurred after intravesical administration, caused by bone-marrow depression from systemically absorbed drug.

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 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 strong circumstantial evidence of carcinogenicity in man. In patients treated with thiotepa, cases of myelodysplastic syndromes and acute nonlymphocytic leukemia have been reported.

Precautions:

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. Death from septicemia and hemorrhage has occurred as a direct result of hematopoietic depression by thiotepa.:

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. Thiotepa impaired fertility, inhibited implantation and interfered with spermatogenesis in animal studies. 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.

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.

The most reliable guide to thiotepa toxicity is the white blood cell count. If this falls to 3 000/mm

Other drugs which are known to produce bone marrow depression should be avoided.

There is no known antidote for overdosage with thiotepa. Transfusions of whole blood or platelets or leukocytes have proved beneficial to the patient in combatting hematopoietic toxicity.

Lactation: 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.

Children: Safety and effectiveness in children have not been established.

Adverse Reactions:

In addition to its effect on the blood-forming elements (see Warnings and Precautions), thiotepa may cause other adverse reactions.

General: fatigue, weakness. Febrile reaction and discharge from a s.c. 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

Symptoms And Treatment Of Overdose:

OverdoseHematopoietic 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 combatting hematopoietic toxicity.

Dosage And Administration:

Parenteral routes of administration are most reliable since absorption of thiotepa from the gastrointestinal tract is variable.

Since thiotepa is nonvesicant, i.v. doses may be given directly and rapidly without need for slow drip or large volumes of diluent.

Dosage must be carefully individualized. A slow response to thiotepa may be deceptive and may occasion unwarranted frequency of administration with subsequent signs of 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 be no more frequent than weekly in order to preserve correlation between dose and blood counts.

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.

I.V. Administration: Thiotepa may be given by rapid i.v. administration in doses of 0.3 to 0.4 mg/kg. Doses should be given at 1 to 4 week intervals.

For conversion of mg/kg of body weight to mg/m

Intracavitary Administration: The dosage recommended is 0.6 to 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 to 60 mL of 0.9% 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.

Stability and Storage: When in its original powder form, thiotepa must be stored in the refrigerator at 2 to 8°C. Protect from light.

Reconstituted Solutions: The powder should be reconstituted preferably in Sterile Water for Injection. The amount of diluent most often used is 1.5 mL resulting in a drug concentration of 5 mg in each 0.5 mL of solution. The reconstituted solution is hypotonic and should be further diluted with 0.9% sodium chloride injection 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 0.9% sodium chloride injection should be used immediately.

In order to eliminate haze, solutions should be filtered through a 0.22 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, Single Use) or triton-free mixed ester of cellulose/PVC (Millipore’s Millex-GS Filter Unit).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Larger volumes are usually employed for intracavitary use, i.v. drip or perfusion therapy. The 1.5 mL reconstituted preparation may be added to larger volumes of 0.9% sodium chloride injection. Reconstituted solutions should be clear to slightly opaque but solutions that are grossly opaque or precipitated should not be used.

Special Instructions: 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.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Trained personnel should reconstitute thiotepa in a designated area. Adequate protective gloves and goggles should be worn and the work surface should be covered with disposable plastic-backed absorbent paper. Thiotepa is not vesicant and should not cause harm if it comes in contact with the skin. It should, of course, be washed off with water immediately. Any transient stinging may be treated with a bland cream.

The cytotoxic preparation should not be handled by pregnant staff.

Availability And Storage:

Vials of 15 mg (sterile cryodesiccated powder), boxes of 10.

THIOTEPA Wyeth-Ayerst Cytotoxic Agent

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