DESCRIPTION

IFEX® (ifosfamide for injection) single-dosevials for constitution and administration by intravenous infusion each contain1 gram or 3 grams of sterile ifosfamide. Ifosfamide is a chemotherapeuticagent chemically related to the nitrogen mustards and a synthetic analog ofcyclophosphamide. Ifosfamide is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine2-oxide. The molecular formula is C7H15Cl2N2O2P and its molecular weight is 261.1. Its structural formulais:

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

CLINICAL PHARMACOLOGY

Ifosfamide has been shown to require metabolic activation by microsomalliver enzymes to produce biologically active metabolites. Activation occursby hydroxylation at the ring carbon atom 4 to form the unstable intermediate4-hydroxyifosfamide. This metabolite rapidly degrades to the stable urinarymetabolite 4-ketoifosfamide. Opening of the ring results in formation of thestable urinary metabolite, 4-carboxyifosfamide. These urinary metaboliteshave not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoricacid diamide (ifosphoramide) and acrolein are also found. Enzymatic oxidationof the chloroethyl side chains and subsequent dealkylation produces the majorurinary 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 ifosfamidehas produced phosphotriesters. The treatment of intact cell nuclei may alsoresult in the formation of DNA-DNA cross-links. DNA repair most likely occursin G-1 and G-2 stage cells.

Pharmacokinetics

Ifosfamide exhibits dose-dependent pharmacokinetics in humans.At single doses of 3.8-5.0g/m2,the plasma concentrations decay biphasically and the mean terminal eliminationhalf-life is about 15 hours. At doses of 1.6-2.4 g/m2/day,the plasma decay is monoexponential and the terminal elimination half-lifeis about 7 hours. Ifosfamide is extensively metabolized in humans and themetabolic pathways appear to be saturated at high doses.

After administration of doses of 5 g/m2 of 14C-labeledifosfamide, from 70% to 86% of the dosed radioactivity was recovered in theurine, with about 61% of the dose excreted as parent compound. At doses of1.6-2.4 g/m2 only 12% to 18% of the dose was excretedin 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 identifiedas the major urinary metabolites of ifosfamide in humans and only small amountsof 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 biologicallyactive species and while metabolism is extensive, it is also quite variableamong patients.

In a study at Indiana University, 50 fully eva luable patients withgerm cell testicular cancer were treated with IFEX in combination with cisplatinand either vinblastine or etoposide after failing (47 of 50 patients) at leasttwo 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 forremaining cisplatin sensitivity because they had previously responded to acisplatin containing regimen and had not progressed while on the cisplatincontaining regimen or within 3 weeks of stopping it. Patients served as theirown control based on the premise that long term complete responses could notbe achieved by retreatment with a regimen to which they had previously respondedand subsequently relapsed.

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

INDICATION AND USAGE

IFEX, used in combination with certain other approved antineoplasticagents, is indicated for third line chemotherapy of germ cell testicular cancer.It should ordinarily be used in combination with a prophylactic agent forhemorrhagic cystitis, such as mesna.

CONTRAINDICATIONS

Continued use of IFEX is contraindicated in patients with severelydepressed bone marrow function (see WARNINGS and PRECAUTIONS sections). IFEX is also contraindicatedin patients who have demonstrated a previous hypersensitivity to it.

WARNINGS

Urinary System

Urotoxic side effects, especially hemorrhagic cystitis, have beenfrequently associated with the use of IFEX. It is recommended that a urinalysisshould be obtained prior to each dose of IFEX. If microscopic hematuria (greaterthan 10 RBCs per high power field), is present, then subsequent administrationshould be withheld until complete resolution.

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

Hematopoietic System

When IFEX is given in combination with other chemotherapeutic agents,severe myelosuppression is frequently observed. Close hematologic monitoringis recommended. White blood cell (WBC) count, platelet count and hemoglobinshould be obtained prior to each administration and at appropriate intervals.Unless clinically essential, IFEX should not be given to patients with a WBCcount 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 IFEXtherapy. The occurrence of these symptoms requires discontinuing IFEX therapy.The symptoms have usually been reversible and supportive therapy should bemaintained until their complete resolution.

Pregnancy

Animal studies indicate that the drug is capable of causing genemutations and chromosomal damage in vivo. Embryotoxic andteratogenic effects have been observed in mice, rats and rabbits at doses0.05 to 0.075 times the human dose. Ifosfamide can cause fetal damage whenadministered to a pregnant woman. If IFEX is used during pregnancy, or ifthe patient becomes pregnant while taking this drug, the patient should beapprised of the potential hazard to the fetus.

PRECAUTIONS

General

IFEX should be given cautiously to patients with impaired renalfunction as well as to those with compromised bone marrow reserve, as indicatedby: leukopenia, granulocytopenia, extensive bone marrow metastases, priorradiation therapy, or prior therapy with other cytotoxic agents.

Laboratory Tests

During treatment, the patient’s hematologic profile (particularlyneutrophils and platelets) should be monitored regularly to determine thedegree of hematopoietic suppression. Urine should also be examined regularlyfor red cells which may precede hemorrhagic cystitis.

Drug Interactions

The physician should be alert for possible combined drug actions,desirable or undesirable, involving ifosfamide even though ifosfamide hasbeen used successfully concurrently with other drugs, including other cytotoxicdrugs.

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 potentialfor serious adverse events and the tumorigenicity shown for ifosfamide inanimal studies, a decision should be made whether to discontinue nursing orto discontinue the drug, taking into account the importance of the drug tothe mother.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ifosfamide has been shown to be carcinogenic in rats, with femalerats showing a significant incidence of leiomyosarcomas and mammary fibroadenomas.

The mutagenic potential of ifosfamide has been documented in bacterialsystems in vitro and mammalian cells in vivo. Invivo, ifosfamide has induced mutagenic effects in mice and Drosophilamelanogaster germ cells, and has induced a significant increase indominant lethal mutations in male mice as well as recessive sex-linked lethalmutations in Drosophila.

In pregnant mice, resorptions increased and anomalies were presentat day 19 after 30 mg/m2 dose of ifosfamide wasadministered on day 11 of gestation. Embryolethal effects were observed inrats following the administration of 54 mg/m2 dosesof ifosfamide from the 6th through the 15th day of gestation and embryotoxiceffects were apparent after dams received 18mg/m2 dosesover the same dosing period. Ifosfamide is embryotoxic to rabbits receiving88mg/m2/day doses from the 6ththrough the 18th day after mating. The number of anomalies was also significantlyincreased over the control group.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

In patients receiving IFEX as a single agent, the dose-limitingtoxicities are myelosuppression and urotoxicity. Dose fractionation, vigoroushydration, and a protector such as mesna can significantly reduce the incidenceof hematuria, especially gross hematuria, associated with hemorrhagic cystitis.At a dose of 1.2 g/m2 daily for 5 consecutive days,leukopenia, when it occurs, is usually mild to moderate. Other significantside effects include alopecia, nausea, vomiting, and central nervous systemtoxicities.

Hematologic Toxicity

Myelosuppression was dose related and dose limiting. It consistedmainly of leukopenia and, to a lesser extent, thrombocytopenia. A WBC count<3000/µL is expected in 50% of the patients treated with IFEX single agentat doses of 1.2 g/m2 per day for 5 consecutivedays. At this dose level, thrombocytopenia (platelets <100,000/µL) occurredin about 20% of the patients. At higher dosages, leukopenia was almost universal,and at total dosages of 10-12 g/m2/cycle, one halfof the patients had a WBC count below 1000/µL and 8% of patients had plateletcounts less than 50,000/µL. Myelosuppression was usually reversible and treatmentcan be given every 3 to 4 weeks. When IFEX is used in combination with othermyelosuppressive agents, adjustments in dosing may be necessary. Patientswho experience severe myelosuppression are potentially at increased risk forinfection. Anemia has been reported as part of postmarketing surveillance.

Digestive System

Nausea and vomiting occurred in 58% of the patients who receivedIFEX. They were usually controlled by standard antiemetic therapy. Other gastrointestinalside effects include anorexia, diarrhea, and in some cases, constipation.

Urinary System

Urotoxicity consisted of hemorrhagic cystitis, dysuria, urinaryfrequency and other symptoms of bladder irritation. Hematuria occurred in6% to 92% of patients treated with IFEX. The incidence and severity of hematuriacan be significantly reduced by using vigorous hydration, a fractionated doseschedule and a protector such as mesna. At daily doses of 1.2 g/m2 for5 consecutive days without a protector, microscopic hematuria is expectedin about one half of the patients and gross hematuria in about 8% of patients.

Renal toxicity occurred in 6% of the patients treated with ifosfamideas