Tepadina Injection

Recommended Dosage

The recommended dose of TEPADINA in pediatric patients is two administrations of 5 mg/kg given intravenously approximately 12 hours apart on Day -6 before allogeneic HSCT in conjunction with high-dose busulfan and cyclophosphamide as outlined in Table 1. See Prescribing Information for cyclophosphamide and busulfan for information on these drugs.

Infuse TEPADINA via a central venous catheter over 3 hours using an infusion set equipped with a 0.2 micron in-line filter. Prior to and following each infusion, flush the catheter with approximately 5 ml sodium chloride 0.9% solution for injection.

TEPADINA is excreted through the skin of patients receiving high-dose therapy. Take precautions to prevent skin toxicity [ see Warnings and Precautions ( 5.3)].

Adenocarcinoma of the Breast or Ovary

The recommended dose of TEPADINA for treatment of adenocarcinoma of the breast or ovary is 0.3 to 0.4 mg/kg intravenously. Doses should be given at 1 to 4 week intervals. 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. Maintenance doses should not be administered more frequently than weekly.

Malignant Effusions

The recommended dose of TEPADINA for treatment of malignant effusions is 0.6 to 0.8 mg/kg intracavitary. Administration is usually effected through the same tubing which is used to remove the fluid from the cavity involved. Doses should be given at 1 to 4 week intervals. 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. Maintenance doses should not be administered more frequently than weekly.

Superficial Papillary Carcinoma of the Urinary Bladder

The recommended dose of TEPADINA for treatment of superficial papillary carcinoma of the urinary bladder is 60 mg in 30 to 60 mL of Sodium Chloride Injection into the bladder by catheter. 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. 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.

Preparation Instructions

TEPADINA is a cytotoxic drug. Follow applicable special handling and disposal procedures1.

Reconstitution
Reconstitute TEPADINA 15 mg with 1.5 ml of sterile water for injection. Using a syringe fitted with a needle, aseptically
withdraw 1.5 ml of sterile water for injection. Inject the content of the syringe into the vial through the rubber stopper.
Remove the syringe and needle, and mix manually by repeated inversions.

Reconstitute TEPADINA 100 mg with 10 ml of sterile water for injection. Using a syringe fitted with a needle, aseptically
withdraw 10 ml of sterile water for injection. Inject the content of the syringe into the vial through the rubber stopper.
Remove the syringe and needle, and mix manually by repeated inversions.

The reconstituted solution is hypotonic and must be diluted in saline prior to administration. Reconstituted solutions, free of
visible particulate matter, may occasionally show opalescence; such solutions can still be used for further dilution.
If not used immediately after reconstitution, the product is stable for 8 hours when stored at 2°C to 8°C (36° to 46°F).

Dilution in the infusion bag
Prior to administration, dilute the reconstituted solution further with an appropriate volume of sodium chloride 0.9% solution
for injection to obtain a final TEPADINA concentration between 0.5 and 1 mg/mL. Dilute TEPADINA as recommended in
Table 2.

Table 2: Dilution of TEPADINA in the infusion bag

After dilution the product is stable for 24 hours when stored at 2°C to 8°C (36° to 46°F) and for 4 hours when stored at 25°C
(77°F). From a microbiological point of view, the product should be used immediately.

Inspect the diluted solution visually for particulate matter and discoloration prior to administration. Use TEPADINA diluted
solutions only if free of visible particulate matter. Filter using a 0.2 micron filter prior to administration. Filtering does not
alter solution potency

• For injection, 15 mg, lyophilized white powder in single-dose vial for reconstitution
• For injection, 100 mg, lyophilized white powder in single-dose vial for reconstitution

TEPADINA is contraindicated in:

• Patients with severe hypersensitivity to thiotepa [see Warnings and Precautions (5.2)]
• Concomitant use with live or attenuated vaccines [see Warnings and Precautions (5.4)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

In mice, repeated intraperitoneal (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 2) 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 2) is approximately 6-fold less than the maximum recommended human therapeutic dose based on body-surface area.

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 2). The mouse micronucleus test was positive with intraperitoneal administration of > 1 mg/kg (3.2 mg/m 2). Other positive in vivo chromosomal aberration or mutation assays included Drosophila melanogaster, Chinese hamster marrow, murine marrow, monkey lymphocyte, and murine germ cell.

Thiotepa impaired fertility in male mice at oral or intraperitoneal doses ≥ 0.7 mg/kg (2.24 mg/m 2), 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 2), 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 2), approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area.

1. OSHA Hazardous Drugs. OSHA. [Accessed from http://www.osha.gov/SLTC/hazardousdrugs/index.html].