Urinary System:   Urotoxic side effects, especially hemorrhagic cystitis, have been frequently associated with the use of IFEX. It is recommended that a urinalysis should be obtained prior to each dose of IFEX. If microscopic hematuria (greater than 10 RBCs per high power field), is present, then subsequent administration should be withheld until complete resolution.

Further administration of IFEX should be given with vigorous oral or parenteral hydration.

Hematopoietic System:   When IFEX is given in combination with other chemotherapeutic agents, severe myelosuppression is frequently observed. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals. Unless clinically essential, IFEX should not be given to patients with a WBC count below 2000/µL and/or a platelet count below 50,000/µL.

Central Nervous System:   Neurologic manifestations consisting of somnolence, confusion, hallucinations and in some instances, coma, have been reported following IFEX therapy. The occurrence of these symptoms requires discontinuing IFEX therapy. The symptoms have usually been reversible and supportive therapy should be maintained until their complete resolution.

Pregnancy:   Animal studies indicate that the drug is capable of causing gene mutations and chromosomal damage in vivo . Embryotoxic and teratogenic effects have been observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose. Ifosfamide can cause fetal damage when administered to a pregnant woman. If IFEX (ifosfamide for injection) is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

General:   IFEX should be given cautiously to patients with impaired renal function as well as to those with compromised bone marrow reserve, as indicated by: leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

Laboratory Tests:   During treatment, the patient's hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Wound Healing:   Ifosfamide may interfere with normal wound healing.

Pregnancy: Pregnancy "Category D".   (See WARNINGS section.)

Nursing Mothers:   Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Ifosfamide has been shown to be carcinogenic in rats, with female rats showing a significant incidence of leiomyosarcomas and mammary fibroadenomas.

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 .

In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m² dose of ifosfamide was administered on day 11 of gestation. Embryolethal effects were observed in rats following the administration of 54 mg/m² doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m² doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m²/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.

Pediatric Use:   Safety and effectiveness in pediatric patients have not been established.

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