Ifosfamide/mesna Disease Interactions

Because of their cytotoxic effects on rapidly proliferating tissues, antineoplastic agents frequently can, to varying extent, induce myelosuppression. The use of these drugs may be contraindicated in patients with known infectious diseases. All patients should be instructed to immediately report any signs or symptoms suggesting infection such as fever, sore throat, or local infection during antineoplastic therapy. Close clinical monitoring of hematopoietic function is recommended.

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe or fatal infections. Patients should be instructed to immediately report any signs or symptoms suggesting bone marrow suppression such as fever, sore throat, local infection, or bleeding. Complete blood counts should be obtained prior to administration of each dose and unless clinically essential, ifosfamide should be withheld if white blood cell counts falls below 1,500 to 2,000/mm3 and/or platelet counts falls below 50,000/mm3. Ifosfamide should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

Parenteral medications formulated in multidose vials often contain benzyl alcohol as a preservative. Their use is considered by drug manufacturers to be contraindicated in neonates, particularly premature infants and infants of low birth weight. When used in bacteriostatic saline intravascular flush and endotracheal tube lavage solutions, benzyl alcohol has been associated with fatalities and severe respiratory and metabolic complications in low-birth-weight premature infants. Thus, single-dose formulations should always be used in infants whenever possible. However, many experts feel that, in the absence of benzyl alcohol-free equivalents, the amount of the preservative present in these formulations should not necessarily preclude their use if they are clearly indicated. The American Academy of Pediatrics considers benzyl alcohol in low doses (such as when used as a preservative in some medications) to be safe for newborns. However, the administration of high dosages of these medications must take into account the total amount of benzyl alcohol administered. The level at which toxicity may occur is unknown.

Mesna is a thiol (SH) compound. Hypersensitivity reactions including anaphylaxis have occurred in patients with autoimmune disorders, the majority of whom received high dosages of mesna orally. Therapy with mesna should be administered cautiously in patients with autoimmune disorders.

Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, and extrapyramidal symptoms, have been reported following ifosfamide therapy. There have also been reports of peripheral neuropathy associated with ifosfamide Episodes of depressive psychoses and hallucinations have been reported during ifosfamide therapy. These neurological symptoms are usually reversible, but ifosfamide should be discontinued and supportive care maintained until symptoms completely resolve. Therapy with ifosfamide should be administered cautiously in patients with a history of or predisposition to psychotic episodes.

Ifosfamide is metabolized by the liver to a biologically active form. Metabolic activation and therapeutic activity may be altered in patients with hepatic impairment. Therapy with ifosfamide should be administered cautiously in patients with compromised hepatic function. Clinical monitoring of hepatic function is recommended.

Ifosfamide is primarily eliminated by the kidney. Approximately 12% to 18% of ifosfamide is excreted unchanged in the urine. Additionally, iIfosfamide is both nephrotoxic and urotoxic. Hemorrhagic cystitis due to metabolites excreted in the urine can develop during therapy with ifosfamide. Adequate hydration and use of a prophylactic agent such as mesna prior to each course of ifosfamide therapy can reduce bladder irritation and hematuria. Clinical signs of renal toxicity such as elevation in BUN or serum creatinine or decrease in creatinine clearance have been reported. Therapy with ifosfamide should be administered cautiously in patients with a history of or predisposition to cystitis or impaired renal function. Close clinical monitoring of serum and urinary chemistries is recommended.