Ifosfamide

12.1 Mechanism of Action Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4‑hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard isophosphoramide mustard. The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in the DNA results in cell death.

1 INDICATIONS AND USAGE Ifosfamide for Injection is indicated for use in adults in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. Ifosfamide for Injection is an alkylating drug indicated for use in adults in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. ( 1 )

2 DOSAGE AND ADMINISTRATION • Administer Ifosfamide for Injection with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day to reduce the incidence or severity of bladder toxicity. ( 2.1 , 5.3 ) • Administer mesna with Ifosfamide for Injection to reduce the incidence or severity of hemorrhagic cystitis. ( 2.1 , 5.3 ) • Administer Ifosfamide for Injection as a slow intravenous infusion (at least 30 minutes) at a dose of 1.2 grams per m 2 per day for 5 consecutive days. Repeat every 3 weeks or after recovery from hematologic toxicity. ( 2.2 ) • Individualize the dose and dosing schedule of Ifosfamide for Injection based on patient risk factors and adverse reactions. ( 2.2 ) • See Full Prescribing Information for instructions on preparation and administration. ( 2.3 ) 2.1 Important Administration Instructions Administer Ifosfamide for Injection with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day to reduce the incidence or severity of bladder toxicity. Administer Ifosfamide for Injection with mesna to reduce the incidence or severity of hemorrhagic cystitis [see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage The recommended dosage of Ifosfamide for Injection is 1.2 grams per m2 per day administered as a slow intravenous infusion (lasting at least 30 minutes) for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. Individualize the dose and dosing schedule of Ifosfamide for Injection based on patient risk factors and adverse reactions. 2.3 Preparation and Administration Ifosfamide for Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1 Skin reactions associated with accidental exposure to Ifosfamide for Injection may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing Ifosfamide for Injection. If Ifosfamide for Injection solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Prepare Ifosfamide for Injection for intravenous use by adding Sterile Water for Injection, USP or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved) to the vial and shaking to dissolve. Before administration, the substance must be completely dissolved. Use the quantity of diluents shown in below to reconstitute the product: Table 1: Ifosfamide for Injection Quantities for Dilution and Final Concentrations Dosage Strength Quantity of Diluent Final Concentration 1 gram 20 mL 50 mg per mL 3 grams 60 mL 50 mg per 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 Injections, 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 (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable. Refrigerate constituted or constituted and further diluted solutions of Ifosfamide for Injection and use within 24 hours. Benzyl-alcohol-containing solutions can reduce the stability of ifosfamide. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

6 ADVERSE REACTIONS The most common (≥ 10%) adverse reactions were alopecia, nausea/vomiting, hematuria, leukopenia, anemia, CNS toxicity, infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at phone: 1 866 888 2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted from widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions in Table 2 below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as a single agent with a total dose of 4 to 12 g/m 2 per course. Table 2: Adverse Reactions in Patients Treated with Single Agent Ifosfamide for Injection Adverse Reaction Single Agent Ifosfamide for Injection % (number of patients) Skin and Subcutaneous Tissue Disorders Alopecia 90% (540/603) Dermatitis 0.08% (1/1317) Papular rash 0.08% (1/1317) Gastrointestinal Disorders Nausea/Vomiting 47% (443/964) Diarrhea 0.7% (9/1317) Stomatitis 0.3% (4/1317) Renal and Urinary Disorders Hemorrhagic cystitis Includes dysuria and pollakiuria Hematuria - without mesna 44% (282/640) - with mesna 21% (33/155) Macrohematuria - without mesna 11% (66/594) - with mesna 5% (5/97) Renal dysfunction Includes acute renal failure, irreversible renal failure (fatal outcomes) serum creatinine increased, BUN increased, creatinine clearance decreased, metabolic acidosis, anuria, oliguria, glycosuria, hyponatremia, uremia, creatinine clearance increased -- Renal structural damage Includes acute tubular necrosis, renal parenchymal damage, enzymuria, cylindruria, proteinuria -- Blood and Lymphatic System Disorders Leukopenia Includes neutropenia, granulocytopenia, lymphopenia, and pancytopenia (any) -- Leukopenia <1 x 10 3 /µL 44% (267/614) Anemia Includes anemia and decrease in hemoglobin/hematocrit 38% (202/533) - with mesna 21.3% (33/155) Thrombocytopenia Includes severe or fatal bleeding (any) -- Thrombocytopenia, 50 x 10 3 /µL 4.8% (35/729) Nervous System Disorders Central nervous system toxicity Includes coma and death Includes abnormal behavior, affect lability aggression, agitation, anxiety, aphasia, asthenia, ataxia, cerebellar syndrome, cerebral function deficiency, cognitive disorder, coma, confusional state, convulsions, cranial nerve dysfunction, depressed state of consciousness, depression, disorientation, dizziness, electroencephalogram abnormal, encephalopathy, flat affect, hallucinations, headache, ideation, lethargy, memory impairment, mood change, motor dysfunction, muscle spasms, myoclonus, progressive loss of brainstem reflexes, psychotic reaction, restlessness, somnolence, tremor, urinary incontinence 15% (154/1001) Peripheral neuropathy 0.4% (5/1317) Infections and Infestations Infection 10% (112/1128) General Disorders and Administration Site Conditions Phlebitis Includes phlebitis and irritation of the venous walls 2.8% (37/1317) Neutropenic fever Includes granulocytopenic fever 1% (13/1317) Fatigue 0.3% (4/1317) Malaise Unable to calculate Hepatobiliary Disorders Hepatotoxicity Includes increased serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyltransferase (GGT) and lactate dehydrogenase (LDH) 1.8% (22/1190) Metabolism and Nutrition Disorders Anorexia 1.1% (15/1317) Cardiac Disorders Cardiotoxicity Includes severe or fatal congestive heart failure, tachycardia, pulmonary edema 0.5% (7/1317) Vascular Disorders Hypotension Includes shock and death 0.3% (4/1317) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Ifosfamide for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic Disorders : agranulocytosis, febrile bone marrow aplasia, bone marrow failure, disseminated intravascular coagulation, hemolytic anemia, hemolytic febrile uremic syndrome, methemoglobinemia, neonatal anemia Cardiac Disorders : cardiac arrest*, cardiac failure*, arrhythmia*, cardiomyopathy*, cardiotoxicity, cardiac shock, ejection fraction decreased*, myocardial infarction*, myocarditis*, ventricular fibrillation*, ventricular tachycardia*, angina pectoris, atrial fibrillation, atrial flutter, bradycardia, bundle branch block left, bundle branch block right, congestive cardiomyopathy, electrocardiogram ST – segment abnormal, electrocardiogram QRD complex abnormal, electrocardiogram T-wave inversion, myocardial depression, myocardial hemorrhage, left ventricular failure, premature atrial contractions, palpitations pericardial effusion, pericarditis, supraventricular extrasystoles, ventricular extrasystoles Cong

7 DRUG INTERACTIONS • CYP3A4 Inducers: Monitor for increased toxicity when used in combination with CYP3A4 inducers. ( 7.1 ) • CYP3A4 Inhibitors: Use in combination with CYP3A4 inhibitors could decrease the effectiveness of ifosfamide. ( 7.2 ) 7.1 Inducers of CYP3A4 CYP3A4 inducers may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment. 7.2 Inhibitors of CYP3A4 CYP3A4 inhibitors may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.