Ifosfamide

Pronunciation: eye-FOSS-fuh-MIDE
Class: Nitrogen mustard

Trade Names

Ifex
- Powder for injection 1,000 mg
- Powder for injection 3,000 mg

Pharmacology

Ifosfamide requires metabolic activation by microsomal liver enzymes to produce biologically active metabolites. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation produces the major urinary metabolites, dichloroethyl ifosfamide and dichloroethyl cyclophosphamide. The alkylated metabolites of ifosfamide interact with DNA.

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Pharmacokinetics

Metabolism

Requires metabolic activation by hydroxylation.

Elimination

Mean t ½ is approximately 15 h (at doses of 3.8 to 5 g/m 2 ). Mean t ½ is approximately 7 h (at doses of 1.6 to 2.4 g/m 2 ). 70% to 86% is excreted in the urine.

Indications and Usage

Germ cell testicular cancer.

Unlabeled Uses

Soft-tissue, Ewing and osteogenic sarcomas; non-Hodgkin lymphomas; small cell lung, pancreatic, bladder, cervical, and ovarian carcinoma.

Contraindications

Continued use in patients with severely depressed bone marrow function; hypersensitivity to ifosfamide.

Dosage and Administration

Germ Cell Testicular Cancer
Adults

IV 1,200 mg/m 2 /day for 5 days, repeating this course every 3 wk. Delay further courses until platelets are least 100,000/mm 3 and WBC at least 4,000/mm 3 .

Germ Cell Testicular Cancer, Other Regimens
Adults

IV Other regimens use ifosfamide 2,000 mg/m 2 /day on days 1 through 3 (MAID regimen, total dose is 6,000 mg/m 2 over 72 h), or doses as high as 5,000 mg/m 2 continuous infusion for 24 h in combination with other antineoplastics.

General Advice

  • Reconstitute powder with sterile water for injection or bacteriostatic water for injection.
  • Reconstitute 1,000 mg ifosfamide with 20 mL diluent for a final concentration of 50 mg/mL; 3,000 mg ifosfamide with 60 mL diluent for a final concentration of 50 mg/mL.
  • Reconstituted 50 mg/mL solution may be further diluted to concentrations of 0.6 to 20 mg/mL with 5% dextrose, 0.9% sodium chloride, Lactated Ringer's solution, or sterile water for injection. Because stability is unchanged, other concentrations or mixtures of these solutions may be used, including 2.5% dextrose, 0.45% sodium chloride, or 5% dextrose with 0.9% sodium chloride.
  • Ifosfamide, at a concentration of 100 mg/mL, is incompatible with bacteriostatic water for injection with benzyl alcohol. It is compatible at ifosfamide concentrations of up to 60 mg/mL.
  • Administer by IV infusion over 30 or more minutes, continuous IV infusion.

Storage/Stability

  • Store powder at room temperature; avoid temperatures higher than 104°F.
  • Solutions reconstituted with Bacteriostatic Water for Injection are stable for 1 wk at room temperature or 3 wk under refrigeration.
  • Refrigerate solutions reconstituted with Sterile Water for Injection and use within 6 h of reconstitution.
  • Diluted solutions are chemically stable for up to 1 wk at room temperature and for up to 6 wk under refrigeration in glass or plastic bags. Consider the possibility of microbial contamination of diluted solutions. Use preservative-free solutions within 24 h.

Drug Interactions

Ifosfamide may increase the hypoprothrombinemic effect of warfarin.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Somnolence; confusion; depression; hallucinations. CNS effects more common in patients with renal dysfunction, hypoalbuminemia, or receiving large single doses.

Dermatologic

Alopecia.

GI

Moderate potential for nausea and vomiting; elevated liver function tests.

Genitourinary

Hematuria, dysuria, urinary frequency; hemorrhagic cystitis, which can be prevented with the administration of mesna.

Hematologic

Bone marrow suppression, nadir at 7 to 14 days.

Hypersensitivity

Allergic reactions observed with ifosfamide also can be attributed to mesna.

Renal

Renal tubular acidosis; Fanconi-like syndrome.

Precautions

Warnings

Myelosuppression

When given in combination with other chemotherapeutic agents, severe myelosuppression is frequent. It consisted mainly of leukopenia and, to a lesser extent, thrombocytopenia. A WBC count less than 3,000/mm 3 is expected in 50% of patients given ifosfamide alone at 1.2 g/m 2 /day for 5 consecutive days. At this dose level, thrombocytopenia (platelets less than 100,000/mm 3 ) occurred in approximately 20% of patients. At total dosages of 10 to 12 g/m 2 /cycle, 50% of the patients had a WBC count less than 1,000/mm 3 and 8% had platelet counts less than 50,000/mm 3 . Myelosuppression is usually reversible, and treatment can be given every 3 to 4 wk. Close hematologic monitoring is recommended.

Neurologic manifestations

Somnolence, confusion, hallucinations, and, in some instances, coma occurred.

Urotoxic side effects

Hemorrhagic cystitis frequently associated with ifosfamide. Obtain a urinalysis prior to each dose. Use ifosfamide with a protector, such as mesna, to prevent hemorrhagic cystitis.


Pregnancy

Category D .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Renal Function

Use with caution. Clinical signs (eg, elevation in BUN or serum creatinine or decrease in Ccr) were usually transient and most likely related to tubular damage.

Hematuria

At doses of 1.2 g/m 2 /day for 5 consecutive days without a protector, microscopic hematuria is expected in approximately 50% of the patients and gross hematuria in approximately 8% of patients. Dose fractionation, vigorous hydration (at least 2 L/day) and a protector (eg, mesna) can significantly reduce hematuria incidence, especially gross hematuria, associated with hemorrhagic cystitis.

Extravasation

Can cause local irritation or phlebitis. Refer to your institution-specific protocol.

Compromised bone marrow reserve

Administer cautiously to patients with leukopenia, granulocytopenia, extensive bone marrow metastases, prior therapy with radiation or other cytotoxic agents.

Wound healing

Ifosfamide may interfere with normal wound healing.

Patient Information

  • Notify health care provider of the following: unusual bleeding/bruising; fever; chills; sore throat; cough; shortness of breath; seizures; lack of menstrual flow; unusual lumps or masses; flank, stomach, or joint pain; sores in mouth or on lips; yellow discoloration of skin or eyes.
  • Contraceptive measures are recommended during therapy for men and women.

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