THIOTEPA

Thiotepa for Injection, USP 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''-phosphinothioylidynetris-, or Tris (1-aziridinyl) phosphine sulfide. Thiotepa has the following structural formula: Thiotepa has the empirical formula C 6 H 12 N 3 PS, and a molecular weight of 189.22. When reconstituted with sterile water for injection, the resulting solution has a pH of approximately 5.5 to 7.5. Thiotepa is stable in alkaline medium and unstable in acid medium. Structural Formula

Thiotepa for Injection 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. For the treatment of superficial papillary carcinoma of the urinary bladder. While now largely superseded by other treatments, Thiotepa for Injection has been effective against other lymphomas, such as lymphosarcoma and Hodgkin's disease.

Since absorption from the gastrointestinal tract is variable, thiotepa for injection should not be administered orally. Dosage must be carefully individualized. A slow response to thiotepa for injection 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 for injection is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised in handling and preparation of thiotepa for injection. Skin reactions associated with accidental exposure to thiotepa for injection 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 for injection contacts mucous membranes, the membranes should be flushed thoroughly with water. Preparation of Solution Thiotepa for injection should be reconstituted with 1.5 mL of sterile water for injection resulting in a drug concentration of approximately 10 mg per mL . The actual withdrawable quantities and concentration achieved are illustrated in the following table: Label Claim (mg per vial) Actual Content (mg per vial) Amount of Diluent to be Added (mL) Approximate Withdrawable Volume (mL) Approximate Withdrawable Amount (mg per vial) Approximate Reconstituted Concentration (mg per mL) 15 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. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. In order to eliminate haze, filter solutions 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 ® , Single Use) or triton-free mixed ester of cellulose/PVC (Millipore's MILLEX ® -GS Filter Unit). 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 for injection 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 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 for injection in 30 to 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. 1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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.

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.

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.

Storage Conditions Store refrigerated between 2° to 8°C (36° to 46°F). Protect from light. Discard unused portion. Lyophilized Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. For Product Inquiry call 1-866-625-1618.