WARNING IFEX should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Urotoxic side effects, especially hemorrhagic cystitis, as well as CNS toxicities such as confusion and coma have been associated with the use of IFEX. When they occur, they may require cessation of IFEX therapy. Severe myelosuppression has been reported. (See ADVERSE REACTIONS section.)
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WARNINGS 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 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.
ADVERSE REACTIONS In patients receiving IFEX as a single agent, the dose-limiting toxicities are myelosuppression and urotoxicity. Dose fractionation, vigorous hydration, and a protector such as mesna can significantly reduce the incidence of hematuria, especially gross hematuria, associated with hemorrhagic cystitis. At a dose of 1.2 g/m 2 daily for 5 consecutive days, leukopenia, when it occurs, is usually mild to moderate. Other significant side effects include alopecia, nausea, vomiting, and central nervous system toxicities. Adverse Reaction *Incidence (%) *Based upon 2,070 patients from the published literature in 30 single agent studies. Alopecia 83 Nausea-Vomiting 58 Hematuria 46 Gross Hematuria 12 CNS Toxicity 12 Infection 8 Renal Impairment 6 Liver Dysfunction 3 Phlebitis 2 Fever 1 Allergic Reaction <1 Anorexia <1 Cardiotoxicity <1 Coagulopathy <1 Constipation <1 Dermatitis <1 Diarrhea <1 Fatigue <1 Hypertension <1 Hypotension <1 Malaise <1 Polyneuropathy <1 Pulmonary Symptoms <1 Salivation <1 Stomatitis <1 Hematologic Toxicity Myelosuppression was dose related and dose limiting. It consisted mainly of leukopenia and, to a lesser extent, thrombocytopenia. A WBC count<3000/µL is expected in 50% of the patients treated with IFEX single agent at doses of 1.2 g/m 2 per day for 5 consecutive days. At this dose level, thrombocytopenia (platelets <100,000/µL) occurred in about 20% of the patients. At higher dosages, leukopenia was almost universal, and at total dosages of 10-12 g/m 2 /cycle, one half of the patients had a WBC count below 1000/µL and 8% of patients had platelet counts less than 50,000/µL. Myelosuppression was usually reversible and treatment can be given every 3 to 4 weeks. When IFEX is used in combination with other myelosuppressive agents, adjustments in dosing may be necessary. Patients who experience severe myelosuppression are potentially at increased risk for infection. Anemia has been reported as part of postmarketing surveillance. Digestive System Nausea and vomiting occurred in 58% of the patients who received IFEX. They were usually controlled by standard antiemetic therapy. Other gastrointestinal side effects include anorexia, diarrhea, and in some cases, constipation. Urinary System Urotoxicity consisted of hemorrhagic cystitis, dysuria, urinary frequency and other symptoms of bladder irritation. Hematuria occurred in 6% to 92% of patients treated with IFEX. The incidence and severity of hematuria can be significantly reduced by using vigorous hydration, a fractionated dose schedule and a protector such as mesna. At daily doses of 1.2 g/m 2 for 5 consecutive days without a protector, microscopic hematuria is expected in about one half of the patients and gross hematuria in about 8% of patients. Renal toxicity occurred in 6% of the patients treated with ifosfamide as a single agent. Clinical signs, such as elevation in BUN or serum creatinine or decrease in creatinine clearance, were usually transient. They were most likely to be related to tubular damage. One episode of renal tubular acidosis which progressed into chronic renal failure was reported. Proteinuria and acidosis also occurred in rare instances. Metabolic acidosis was reported in 31% of patients in one study when IFEX was administered at doses of 2.0 to 2.5 g/m 2 /day for 4 days. Renal tubular acidosis, Fanconi syndrome, renal rickets, and acute renal failure have been reported. Close clinical monitoring of serum and urine chemistries including phosphorus, potassium, alkaline phosphatase and other appropriate laboratory studies is recommended. Appropriate replacement therapy should be administered as indicated. Central Nervous System CNS side effects were observed in 12% of patients treated with IFEX. Those most commonly seen were somnolence, confusion, depressive psychosis, and hallucinations. Other less frequent symptoms include dizziness, disorientation, and cranial nerve dysfunction. Seizures and coma with death were occasionally reported. The incidence of CNS toxicity may be higher in patients with altered renal function. Other Alopecia occurred in approximately 83% of the patients treated with IFEX as a single agent. In combination, this incidence may be as high as 100%, depending on the other agents included in the chemotherapy regimen. Increases in liver enzymes and/or bilirubin were noted in 3% of the patients. Other less frequent side effects included phlebitis, pulmonary symptoms, fever of unknown origin, allergic reactions, stomatitis, cardiotoxicity, and polyneuropathy.