INFORMATION FOR HEALTH PROFESSIONALS
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THIOTEPA for injection, for single use only, is available in vials containing 15 mg of non-pyrogenic, sterile cryodesiccated powder.
THIOTEPA is a polyfunctional alkylating agent for use in the chemotherapy of certain neoplastic diseases.
THIOTEPA is an ethylenimine-type compound, 1,1',1"-Phosphino-thioylidynetrisaziridine. THIOTEPA has also been known as TESPA and TSPA and is not the same as TEPA.
The chemical structure of THIOTEPA is:
THIOTEPA is stable in alkaline medium and unstable in acid medium. It has a solubility of 19 g/100 mL in water and is soluble in ethanol, ether, benzene and chloroform. The pKa is low (unspecified). When reconstituted with Sterile Water for Injection, the resulting solution has a pH of approximately 5.5-7.5.
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 that, 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. Only traces of unchanged THIOTEPA and triethylene phosphoramide are excreted in the urine, together with a large proportion of metabolites.
The following pharmacokinetic parameters were reported in a study with 21 patients:
Protein binding under physiological conditions is reported to be less than 40% (determined by ultrafiltration).
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 tumours:
While now largely superseded by other treatments, THIOTEPA has been effective against other lymphomas, such as lymphosarcoma and Hodgkin's disease.
Complete response rates of 27% and 48% were obtained with a dose of 30 mg THIOTEPA in the treatment of bladder cancer.
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 haematopoietic function tests.
THIOTEPA is contraindicated in patients with a known hypersensitivity (allergy) to this preparation.
THIOTEPA is highly toxic to the haematopoietic 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 three weeks after therapy has been discontinued.
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 leucopenia, thrombocytopenia and anaemia. Death from septicaemia and haemorrhage has occurred as a direct result of haematopoietic depression by THIOTEPA.
Patients should notify the physician of any sign of bleeding (epistaxis, easy bruising, change in colour of urine, black stool) or infection (fever, chills). Female patients should tell the physician if they are planning pregnancy or if they believe they may be pregnant. A male patient who plans to father a child should discuss this with the physician.
WBC and platelet counts are recommended 12-24 hours before each dose of THIOTEPA regardless of route of administration. Dosage should be reduced as indicated above in the presence of compromised bone marrow as manifested by a reduced WBC or platelet count.
The most reliable guide to THIOTEPA toxicity is the white blood cell count. If this falls to 3,000 or less, therapy 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.
Pregnancy Category D.
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.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the tumourigenic potential of 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.
Safety has not been established.
Like all 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. Rarely myelodysplastic syndromes and acute non-lymphocytic leukaemia have been reported to develop in patients following parenteral THIOTEPA for breast and ovarian cancer and intravesical THIOTEPA for superficial bladder cancer.
THIOTEPA has been reported to be carcinogenic in studies with mice and rats when the drug was administered intermittently for one year by the intraperitoneal route at doses between 0.7 and 2.8 mg/kg. In mice, THIOTEPA induced lymphoma or lymphocytic leukaemia and squamous cell carcinoma of the skin and associated glands. In rats, the drug induced combined neoplasms of the haematopoietic systems (lymphoma, lymphocytic or granulocytic leukaemia), adenocarcinoma of the uterus and squamous cell carcinoma of the skin or ear canal.
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.
THIOTEPA has been reported to possess mutagenic potential based upon positive results of in vitro bacterial and mammalian assays and in vivo assays in animals. In vitro, THIOTEPA produced chromosomal aberrations and sister chromatid exchanges in plant root cells. The drug was also positive in the host-mediated, dominant lethal and drosophila sex-linked recessive assays. In vivo, THIOTEPA was positive in the mouse micronucleus assay and induced chromosomal aberrations in bone marrow cells and heterozygous translocations in a fairly high percentage of offspring of mice, evidence of somatic and germ cell mutagenic potential. Such effects are not unexpected in view of its activity as an alkylating agent.
Studies in animals have shown that THIOTEPA impairs male fertility. In rodent species, THIOTEPA has been reported to interfere with both spermatogenesis and ovarian function at doses at or slightly above the therapeutic dose.
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 that are known to produce bone marrow depression should be avoided.
In addition to its effect on the blood-forming elements (See PRECAUTIONS), THIOTEPA may cause other adverse reactions. Deaths have occurred after intravesical administration, caused by bone marrow depression from systemically absorbed drug.
General: Febrile reaction and discharge from a subcutaneous lesion may occur as the result of breakdown of tumour tissue. Fatigue has been reported.
Hypersensitivity Reactions: Allergic reactions are rare, but urticaria and laryngeal oedema have been reported. Wheezing has been reported.
Local Reactions: Conjunctival inflammation following topical use and pain at the injection site have been reported.
Gastrointestinal: Nausea, vomiting, abdominal pain and anorexia have been reported.
Renal: Dysuria and urinary retention have been reported. There have been rare reports of chemical cystitis or haemorrhagic cystitis following intravesical, or intravenous, administration of THIOTEPA. A single case of extensive bladder reaction to THIOTEPA leading to partial ureteral obstruction and compromised renal function has been reported.
Pulmonary: Prolonged apnoea 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 a decrease of pseudocholinesterase activity caused by the anticancer drugs.
Central Nervous System: Dizziness, headache and blurred vision have been reported.
Reproductive: Amenorrhoea and interference with spermatogenesis have been reported.
Dermatological: Dermatitis and alopecia have been reported. Skin depigmentation has been reported following topical use.
Haematopoietic: Myelosuppression (bone marrow) has been reported at a variety of doses. Some patients have tolerated doses up to 0.8 mg/kg once a week for several weeks, while others showed depression after 1-2 doses of 0.1 mg/kg. Myelosuppression is also the most common side effect of intravesical therapy.
THIOTEPA is intended for IV, intracavitary or intravesical use. Parenteral routes of administration are most reliable since absorption of THIOTEPA from the gastrointestinal tract is variable.
Since THIOTEPA is nonvesicant, intravenous doses may be given directly and rapidly without need for slow drip or large volumes of diluent. Some physicians prefer to give THIOTEPA directly into the tumour mass. This may be effected transrectally, transvaginally, or intra-cerebrally. The technique is discussed in the appropriate section which follows. For the control of malignant effusions, THIOTEPA is instilled directly into the cavity involved.
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.
The injection should be used no more than 24 hours after reconstitution with water. Further dilutions or other admixtures should be used immediately with any unused portion discarded after use.
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 0.3-0.4 mg/kg. Doses should be given at 1-4 week intervals.
For conversion of mg/kg of bodyweight to mg/m² of body surface or the reverse, a ratio of 1:30 is given as a guideline. The conversion factor varies between 1:20 and 1:40 depending on age and body build.
Intracavitary Administration: The dosage recommended is 0.6-0.8 mg/kg. Administration is usually effected through the same tubing that 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 distilled water 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 repositioned 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. Side effects due to systemic absorption of intravesical THIOTEPA may occur. Deaths have occurred after intravesical administration caused by bone-marrow depression from systemically absorbed substance.(See ADVERSE REACTIONS)
Intratumour Administration: THIOTEPA in initial doses of 0.6-0.8mg/kg may be injected directly into a tumour by means of a 22-gauge needle. A small amount of local anaesthetic is injected first, then the syringe is removed and the THIOTEPA solution is injected through the same needle. The substance is diluted in sterile water, 10mg per 1mL. Maintenance doses at one to four week intervals range from 0.07mg/kg to 0.8mg/kg depending on the condition of the patient.
Larger volumes are usually employed for intracavitary use, intravenous drip or perfusion therapy. The 1.5mL reconstituted preparation may be added to larger volumes of other diluents: Sodium Chloride Injection USP, Dextrose Injection USP, Dextrose and Sodium Chloride Injection USP, Ringer's Injection USP or Lactated Ringer's
Injection USP. Reconstituted solutions should be clear to slightly opaque but solutions that are grossly opaque or precipitated should not be used.
For local use into single or multiple sites, THIOTEPA may be mixed with procaine HCL 2%, adrenaline HCl 1:1000 or both.
Preparation of Solution: THIOTEPA for injection should be reconstituted with 1.5 mL of Sterile Water for Injection resulting in a drug concentration of 10 mg/mL. Reconstituted solutions can be further diluted with Sterile Water for Injection, Sodium Chloride Injection (0.9%) or Glucose Injection (5%) to give a concentration of 0.5-5 mg/mL. Larger volumes are usually employed for intracavitary use, intravenous drip or perfusion therapy.
* THIOTEPA reconstituted with 1.5 mL of water for injection (10 mg/mL) should be stored under refrigerated conditions for not more than 24 hours.
* Further dilutions with Water for Injection or other admixtures (0.9% Sodium Chloride, 5% Glucose) should be used immediately with any unused portion discarded after use.
Reconstituted solutions should be clear to slightly cloudy but solutions that are grossly cloudy or precipitated should not be used.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-6 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Haematopoietic 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 haematopoietic toxicity. THIOTEPA has a toxic effect on the haematopoietic system that is dose related.
THIOTEPA is dialyzable.
There is no known antidote for overdosage with THIOTEPA.
Transfusions of whole blood or platelets or leucocytes have proven beneficial to the patient in combating haematopoietic toxicity. Gastric lavage, forced fluids and general supportive measures are recommended.
| Powder for Injection. | Vial 15 mg: 1's (solvent required) PC 4651.91. |
|---|---|
| Shelf life (vials): | 2 years if stored at 2-8°C (refrigerate; do not freeze) and protected from light. |
| Reconstituted solutions (with water for injection to 10 mg/mL) can be stored for 24 hours between 2-8°C
(refrigerate; do not freeze). |
|
| Further dilutions of the reconstituted solution should be used immediately and any remainder discarded. |
Prescription Only Medicine
Zuellig Pharma Limited
54 Carbine Road
Mt Wellington
Auckland
Telephone: (09) 570 1080
19 May 2002
