Thiotepa - Thiotepa injection, Powder, Lyophilized, For Solution prescribing information
INDICATIONS AND USAGE
Thiotepa for Injection, USP 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While now largely superseded by other treatments, thiotepa has been effective against other lymphomas, such as lymphosarcoma and Hodgkin's disease.
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 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/vial) | Actual Content (mg/vial) | Amount of Diluent to be Added (mL) | Approximate Withdrawable Volume (mL) | Approximate Withdrawable Amount (mg/vial) | Approximate Reconstituted Concentration (mg/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.
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 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 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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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.
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.
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.
DESCRIPTION
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 Tris(1-aziridinyl) phosphine sulfide. Thiotepa has the following structural formula:
Thiotepa has the molecular 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.
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 to 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 (ng/mL) | 1331 ± 119 | 1828 ± 135 | 273 ± 46 | 353 ± 46 |
| Elimination half-life (h) | 2.4 ± 0.3 | 2.3 ± 0.3 | 17.6 ± 3.6 | 15.7 ± 2.7 |
| Area under the curve (ng/h/mL) | 2832 ± 412 | 4127 ± 668 | 4789 ± 1022 | 7452 ± 1667 |
| Total body clearance (mL/min) | 446 ± 63 | 419 ± 56 | ||
TEPA, which possesses cytotoxic activity, appears to be the major metabolite of thiotepa found in human serum and urine. Urinary excretion of 14 C-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.
HOW SUPPLIED
Thiotepa for Injection, USP is supplied as follows:
| NDC | Thiotepa for Injection, USP | Package Factor |
| 83634-204-02 | 15 mg Single-Dose Vial | 1 vial per carton |
For single-use only. Discard unused portion.
Store in a refrigerator between 2° to 8°C (36° to 46°F).
PROTECT FROM LIGHT AT ALL TIMES.
Lyophilized. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.
To report SUSPECTED ADVERSE REACTIONS, contact Avenacy at 1-855-283-6229 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
For Product Inquiry call 1-855-283-6229.
