Ifosfamide and Mesna Injection

Ifosfamide injection is indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis.

Ifosfamide is contraindicated in patients with:

• Known hypersensitivity to administration of ifosfamide.
• Urinary outflow obstruction.

Ifosfamide injection, single-dose vials for administration by intravenous infusion each contain 1 gram or 3 grams of sterile ifosfamide, USP. The 1 gram vial also contains 69 mg monobasic sodium phosphate monohydrate, USP, 21.3 mg dibasic sodium phosphate anhydrous, USP and water for injection, USP, qs. The 3 gram vial also contains 207 mg monobasic sodium phosphate monohydrate, USP, 63.9 mg dibasic sodium phosphate anhydrous, USP and water for injection, USP, qs. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. Ifosfamide is 3-(2-chloroethyl)- 2-[(2-chloroethyl)amino] tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide. Its structural formula is:

C7H15Cl2N2O2P M.W. 261.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m2, or about 3% of the daily human dose on a mg/m2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls.

The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo. In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila.

Ifosfamide was administered to male and female beagle dogs at doses of 1 or 4.64 mg/kg/day (20 or 93 mg/m2) orally 6 days a week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In a second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m2) ifosfamide intraperitoneally once every 3 weeks for 6 months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on a mg/m2 basis).

Ifosfamide Injection is available as follows:

Ifosfamide Injection is available in conjunction with mesna injection as an administration kit as follows:

STORAGE

Ifosfamide Injection: Store at 2° to 8°C (36° to 46°F).

Mesna Injection: Store at 2° to 30°C (36° to 86°F).

Exercise caution when handling ifosfamide injection. The handling and preparation of ifosfamide injection should always be in accordance with current guidelines on safe handling of cytotoxic agents. Several guidelines on this subject have been published.1-4 Skin reactions associated with accidental exposure to ifosfamide injection may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing ifosfamide injection. If ifosfamide solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water.

Specifically inform patients of the following:

• Treatment with ifosfamide may cause myelosuppression which can be severe and lead to fatal outcome. Significant suppression of immune responses can also occur which can lead to severe infections. Latent infections can be reactivated. Patients should report fever or other symptoms of an infection.
• The risk of bleeding and anemia.
• The risk of CNS toxicity and other neurotoxic effects with fatal outcome.
• The risk of bladder and kidney toxicity. Patients should be aware of the need to increase fluid intake and frequent voiding to prevent accumulation in the bladder.
• The risk of cardiotoxicity and fatal outcome. Patients should report preexisting cardiac disease.
• The risk of pulmonary toxicity leading to respiratory failure with fatal outcome.
• The risk of secondary malignancies due to therapy.
• The risk of veno-occlusive liver disease.
• The potential hazard to a fetus if a patient becomes pregnant or fathers a child during therapy and for up to 6 months after therapy. Effective methods of contraception should be used during therapy and for up to 6 months after therapy.
• The potential for serious adverse reactions and tumorigenicity when children are breastfed during therapy.
• The risk of amenorrhea, premature menopause, and sterility.
• The risk of alopecia, wound healing, and other serious skin and subcutaneous tissue disorders.
• Therapy may cause gastrointestinal disorders and alcohol may increase nausea and vomiting.
• The risk of stomatitis and the importance of proper oral hygiene.
• The risk of eye disorders such as visual impairment, blurred vision, and eye irritation.
• The risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus.

Rev. B 7/2012

Teva Parenteral Medicines, Inc.

Irvine, CA 92618