IFEX® (ifosfamide for injection) single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile 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. The molecular formula is C₇H₁₅Cl₂N₂O₂P and its molecular weight is 261.1. Its structural formula is:

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

Last updated on RxList: 10/3/2008

IFEX, 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.

IFEX should be administered intravenously at a dose of 1.2 g/m² per day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity (Platelets ≥ 100,000/µL, WBC ≥ 4,000/µL). In order to prevent bladder toxicity, IFEX should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. A protector, such as mesna, should also be used to prevent hemorrhagic cystitis. IFEX should be administered as a slow intravenous infusion lasting a minimum of 30 minutes. Although IFEX has been administered to a small number of patients with compromised hepatic and/or renal function, studies to establish optimal dose schedules of IFEX in such patients have not been conducted.

Preparation for Intravenous Administration/Stability

Injections are prepared for parenteral use by adding Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved), to the vial and shaking to dissolve. Use the quantity of diluent shown below to constitute the product:

Dosage Strength	Quantity of Diluent	Final Concentration
1 gram	20 mL	50 mg/mL
3 grams	60 mL	50 mg/mL

Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:

5% Dextrose Injection, USP
0.9% Sodium Chloride Injection, USP
Lactated Ringer's Injection, USP
Sterile Water for Injection, USP

Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer's Injection), the use of large volume parenteral glass bottles, Viaflex bags or PAB™ bags that contain intermediate concentrations or mixtures of excipients (eg, 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable.

Constituted or constituted and further diluted solutions of IFEX should be refrigerated and used within 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

IFEX® (ifosfamide for injection) is available in combination packages with the uroprotective agent Mesnex® (mesna) injection or as single-dose vials as follows:

IFEX (ifosfamide for injection)/Mesnex (mesna) injection.

NDC 0015-3556-26...........5 x 1-gram Single-Dose Vial of Ifex/3 x 1-gram Multidose Vial of Mesnex
NDC 0015-3554-27...........10 x 1-gram Single-Dose Vial of Ifex/10 x 1-gram Multidose Vial of Mesnex
NDC 0015-3564-15...........2 x 3-gram Single-Dose Vial of Ifex/6 x 1-gram Multidose Vial of Mesnex

IFEX (ifosfamide for injection).

NDC 0015-0556-05...........1-gram Single-Dose Vial
NDC 0015-0557-41...........3-gram Single-Dose Vials

Store at controlled room temperature 20° C to 25° C (68° F to 77° F).

Protect from temperatures above 30° C (86° F).

Procedures for proper handling and disposal of anticancer drugs should be considered. Skin reactions associated with accidental exposure to IFEX may occur. The use of gloves is recommended. If IFEX solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Several guidelines on this subject have been published.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.

2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253 (11):1590-1592.

3. National Study Commission on Cytotoxic Exposure-Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983;1:426-428.

5. Jones, RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center, CA-A Cancer Journal for Clinicians 1983; (Sept./Oct.) 258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990;47:1033-1049.

7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996; 53:1669-1685.

Manufactured by: Baxter Healthcare Corporation, Deerfield, IL 60015 USA. Distributed by: Bristol Myers Squibb Company, Princeton, New Jersey 08543, USA. Made in Germany. Rev Jul 2007. FDA Rev date: 11/21/2001

Last updated on RxList: 10/3/2008

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/m² 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 (%)
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
*Based upon 2,070 patients from the published literature in 30 single agent studies.

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/m² 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/m²/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/m² 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/m²/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.

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

Wound Healing

Ifosfamide may interfere with normal wound healing.

Last updated on RxList: 10/3/2008

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.

General

IFEX 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.

Laboratory Tests

During treatment, the patient's hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Pregnancy

Pregnancy "Category D." (See WARNINGS section.)

Nursing Mothers

Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo. In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila.

In pregnant mice, resorptions increased and anomalies were present at day 19 after 30 mg/m² dose of ifosfamide was administered on day 11 of gestation. Embryolethal effects were observed in rats following the administration of 54 mg/m² doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m² doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m²/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Last updated on RxList: 10/3/2008

No specific antidote for IFEX is known. Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur.

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

Last updated on RxList: 10/3/2008

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 3.8-5.0 g/m², the plasma concentrations decay biphasically and the mean terminal elimination half-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-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/m² of ¹⁴C-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 1.6-2.4 g/m² 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 IFEX 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.

Last updated on RxList: 10/3/2008

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 10/3/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

IFOSFAMIDE - INJECTION

(eye-FOSS-fuh-mide)

COMMON BRAND NAME(S): Ifex

WARNING: Ifosfamide may cause serious side effects (e.g., urinary problems such as hemorrhagic cystitis, mental/mood changes, and blood/bone marrow disorders), which may require your treatment with this medication to be stopped. Tell your doctor immediately if you develop symptoms such as pink/bloody urine, frequent/painful urination, severe drowsiness, confusion, or hallucinations. Blood/bone marrow disorders can affect your body's ability to stop bleeding or fight infection. Tell your doctor immediately if you develop easy bruising/bleeding or signs of infection (e.g., fever, chills, persistent sore throat).

USES: Ifosfamide is used to treat various cancers (e.g., testicular cancer, sarcomas, lung cancer). It works by slowing or stopping the growth of cancer cells.

HOW TO USE: This medication is given by injection into a vein as directed by your doctor. Dosage is based on your medical condition, body size, and response to treatment.

Read and learn all preparation and usage instructions supplied by the manufacturer. Follow all instructions for proper handling and mixing with the correct IV fluids. Before using, check the product visually for particles or discoloration. If either is present, do not use the liquid.

If this medication touches your skin, immediately wash the area well with soap and water. If this medication gets in your eye, open the eyelid and flush with water for 15 minutes, then seek immediate medical attention.

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist for details.

To help prevent urinary problems, drink plenty of fluids and urinate frequently while using this medication unless otherwise directed by your doctor. Your doctor may also prescribe other medication (e.g., mesna, IV fluids) to decrease the risk.

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, diarrhea, stomach/abdominal pain, loss of appetite, or redness/pain/swelling at the injection site may occur. Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Severe nausea, vomiting, and diarrhea may infrequently result in a loss of too much body water (dehydration). Contact your doctor promptly if you notice any symptoms of dehydration such as unusual decreased urination, unusual dry mouth/increased thirst, lack of tears, dizziness/lightheadedness, or pale/wrinkled skin.

Temporary hair loss frequently occurs in patients using this drug. Normal hair growth should return after treatment has ended.

Many people using this medication have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual weakness, seizure.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before receiving ifosfamide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood/bleeding disorders (e.g., anemia, low blood cell counts), current infection, kidney disease, liver disease, radiation treatment.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. Wash your hands well to prevent the spread of infections.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Before having surgery, tell your doctor or dentist that you are using this medication.

This drug may make you drowsy. Use caution while driving, using machinery, or taking part in any other activity that requires alertness. Limit alcoholic beverages.

This medication may affect the production of sperm, increasing the risk of fathering a child with birth defects. Therefore, men receiving treatment with this drug should use reliable forms of birth control (e.g., condoms). Consult your doctor for details and to discuss effective forms of birth control.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. If you become pregnant or think you may be pregnant, tell your doctor immediately. To avoid pregnancy, both males and females using this drug should use reliable form(s) of birth control (e.g., birth control pills, condoms) during treatment. Consult your doctor for details and to discuss effective forms of birth control.

This medication passes into breast milk and may have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: nalidixic acid.

If you are currently using the medication listed above, tell your doctor or pharmacist before starting ifosfamide.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other anti-cancer drugs, aprepitant/fosaprepitant.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (e.g., complete blood counts, blood salt/mineral levels, kidney function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store the unmixed powder form at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Protect from high heat. After mixing, store at room temperature or in the refrigerator. Consult the package instructions or your pharmacist for other storage details. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.