Ifosfamide

IFOSFAMIDE- ifosfamide injection, powder, lyophilized, for solution
Fresenius Kabi USA, LLC

Rx only

WARNING

Ifosfamide for Injection, USP 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 ifosfamide. When they occur, they may require cessation of ifosfamide therapy. Severe myelosuppression has been reported (see ” ADVERSE REACTIONS“).

DESCRIPTION

Ifosfamide for Injection, USP single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile, lyophilized ifosfamide. 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:

ifosfamise structure
(click image for full-size original)

Ifosfamide is a white crystalline powder that is soluble in water.

CLINICAL PHARMACOLOGY

Ifosfamide has been shown to require metabolic activation by microsomal liver enzymes to produce biologically active metabolites. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. Opening of the ring results in formation of the stable urinary metabolite, 4-carboxyifosfamide. These urinary metabolites have not been found to be cytotoxic. N, N- bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. Enzymatic oxidation of the chloroethyl side chains, and subsequent dealkylation produces the major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide. The alkylated metabolites of ifosfamide have been shown to interact with DNA.

In vitro incubation of DNA with activated ifosfamide has produced phosphotriesters. The treatment of intact cell nuclei may also result in the formation of DNA-DNA cross-links. DNA repair most likely occurs in G-1 and G-2 stage cells.

Pharmacokinetics

Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5 g/m 2 , the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6 to 2.4 g/m 2 /day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours. Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses.

After administration of doses of 5 g/m 2 of 14 C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6 to 2.4 g/m 2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.

Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present. Small quantities (nmole/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.

In a study at Indiana University, 50 fully evaluable patients with germ cell testicular cancer were treated with Ifosfamide for Injection in combination with cisplatin and either vinblastine or etoposide after failing (47 of 50 patients) at least two prior chemotherapy regimens consisting of cisplatin/vinblastine/bleomycin, (PVB), cisplatin/vinblastine/actinomycin D/bleomycin/ cyclophosphamide, (VAB6), or the combination of cisplatin and etoposide. Patients were selected for remaining cisplatin sensitivity because they had previously responded to a cisplatin containing regimen and had not progressed while on the cisplatin containing regimen or within 3 weeks of stopping it. Patients served as their own control based on the premise that long-term complete responses could not be achieved by retreatment with a regimen to which they had previously responded and subsequently relapsed.

Ten of 50 fully evaluable patients were still alive 2 to 5 years after treatment. Four of the 10 long-term survivors were rendered free of cancer by surgical resection after treatment with the ifosfamide regimen; median survival for the entire group of 50 fully evaluable patients was 53 weeks.

INDICATIONS AND USAGE

Ifosfamide for Injection, used in combination with certain other approved antineoplastic agents, is indicated for third line chemotherapy of germ cell testicular cancer. It should ordinarily be used in combination with a prophylactic agent for hemorrhagic cystitis, such as mesna.

CONTRAINDICATIONS

Continued use of Ifosfamide for Injection is contraindicated in patients with severely depressed bone marrow function (see WARNINGS and PRECAUTIONS sections). Ifosfamide for Injection is also contraindicated in patients who have demonstrated a previous hypersensitivity to it.

WARNINGS

Urinary System

Urotoxic side effects, especially hemorrhagic cystitis, have been frequently associated with the use of ifosfamide. It is recommended that a urinalysis should be obtained prior to each dose of ifosfamide. 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 ifosfamide should be given with vigorous oral or parenteral hydration.

Hematopoietic System

When ifosfamide 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, ifosfamide 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 ifosfamide therapy. The occurrence of these symptoms requires discontinuing ifosfamide 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 ifosfamide 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.

PRECAUTIONS

General

Ifosfamide 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.

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