IFEX

6 ADVERSE REACTIONS In clinical trials of ifosfamide monotherapy, the most common (≥ 10%) adverse reactions were alopecia, nausea/vomiting, leukopenia, anemia, CNS toxicity, hematuria, and 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 Adverse Reactions from Clinical Trials 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 and frequencies below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m 2 per course. System Organ Class (SOC) Adverse Reaction Percentage (Ratio) INFECTIONS AND INFESTATIONS Infection 9.9% (112/1128) BLOOD AND LYMPHATIC SYSTEM DISORDERS Leukopenia The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see below. (any) -- Leukopenia <1 x 10 3 /µL 43.5% (267/614) Thrombocytopenia Thrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported. (any) -- Thrombocytopenia, 50 x 10 3 /µL 4.8% (35/729) Anemia Includes cases reported as anemia and decrease in hemoglobin/hematocrit. 37.9% (202/533) METABOLISM AND NUTRITION DISORDERS Anorexia 1.1% (15/1317) NERVOUS SYSTEM DISORDERS Central nervous system toxicity Encephalopathy with coma and death has been reported. , Central nervous system toxicity was reported to be manifested by the following signs and symptoms: 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. 15.4% (154/1001) Peripheral neuropathy 0.4% (5/1317) CARDIAC DISORDERS Cardiotoxicity Cardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported. 0.5% (7/1317) VASCULAR DISORDERS Hypotention Hypotension leading to shock and fatal outcome has been reported. 0.3% (4/1317) GASTROINTESTINAL DISORDERS Nausea/Vomiting 46.8% (443/964) Diarrhea 0.7% (9/1317) Stomatitis 0.3% (4/1317) HEPATOBILIARY DISORDERS Hepatotoxicity Hepatotoxicity was reported as increases in liver enzymes, i.e., serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase, increased bilirubin, jaundice, hepatorenal syndrome. 1.8% (22/1190) SKIN AND SUBCUTANEOUS TISSUES DISORDERS Alopecia 89.6% (540/603) Dermatitis 0.08% (1/1317) Papular rash 0.08% (1/1317) RENAL AND URINARY DISORDERS Hemorrhagic cystitis Reported symptoms of hemorrhagic cystitis included dysuria and pollakiuria. See also Post-marketing Adverse Reactions (6.2). -- Hematuria - without mesna 44.1% (282/640) - with mesna 21.3% (33/155) Macrohematuria - without mesna 11.1% (66/594) - with mesna 5.2% (5/97) Renal dysfunction Renal dysfunction was reported to be manifested as: Renal failure (including acute renal failure, irreversible renal failure; fatal outcomes have been reported), Serum creatinine increased, BUN increased, Creatinine clearance decreased, Metabolic acidosis, Anuria, Oliguria, Glycosuria, Hyponatremia, Uremia, Creatinine clearance increased. Renal structural damage was reported to be manifested as: Acute tubular necrosis, renal parenchymal damage, Enzymuria, Cylindruria, Proteinuria. -- Renal structural damage -- GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Phlebitis Includes cases reported as phlebitis and irritation of the venous walls. 2.8% (37/1317) Neutropenic fever Includes cases reported as granulocytopenic fever. 1.0% (13/1317) Fatigue 0.3% (4/1317) Malaise Unable to calculate 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of IFEX. 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. INFECTIONS AND INFESTATIONS: The following manifestations have been associated with myelosuppression and immunosuppression caused by ifosfamide: increased risk for and severity of infections†, pneumonias†, sepsis and septic shock (including fatal outcomes), as well as reactivation of latent infections, including viral hepatitis†, Pneumocystis jiroveci †, herpes zoster, Strongyloides , progressive multifocal leukoencephalopathy†, and other viral and fungal infections. † Severe immunosuppression has led to serious, sometimes fatal, infections. NEOPLASMS, BENIGN AND MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS): As treatment-related secondary malignancy*, Acute leukemia* (Acute myeloid leukemia)*, Acute promyelocytic leukemia*, Acute lymphocytic leukemia*, Myelodysplastic syndrome, Lymphoma (Non-Hodgkin’s lymphoma), Sarcomas*, Renal cell carcinoma, Thyroid cancer BLOOD AND LYMPHATIC SYSTEM DISORDERS: Hematotoxicity*, Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic syndrome, Hemolytic anemia, Neonatal anemia, Methemoglobinemia IMMUNE SYSTEM DISORDERS: Angioedema*, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reaction ENDOCRINE DISORDERS: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) METABOLISM AND NUTRITION DISORDERS: Tumor lysis syndrome, Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia, Polydipsia PSYCHIATRIC DISORDERS: Panic attack, Catatonia, Mania, Paranoia, Delusion, Delirium, Bradyphrenia, Mutism, Mental status change, Echolalia, Logorrhea, Perseveration, Amnesia NERVOUS SYSTEM DISORDERS: Convulsion*, Status epilepticus (convulsive and nonconvulsive), reversible posterior leukoencephalopathy syndrome, Leukoencephalopathy, Extrapyramidal disorder, Asterixis, Movement disorder, Polyneuropathy, Dysesthesia, Hypothesia, Paresthesia, Neuralgia, Gait disturbance, Fecal incontinence, Dysarthria Ifosfamide has been reintroduced after neurotoxicity. While some patients did not experience neurotoxicity, others had recurrent, including fatal, events. EYE DISORDERS: Visual impairment, Vision blurred, Conjunctivitis, Eye irritation EAR AND LABYRINTH DISORDERS: Deafness, Hypoacusis, Vertigo, Tinnitus CARDIAC DISORDERS: Cardiotoxicity*, Cardiac arrest*, Ventricular fibrillation*, Ventricular tachycardia*, Cardiogenic shock*, Myocardial infarction*, Cardiac failure*, Bundle branch block left, Bundle branch block right, Pericardial effusion, Myocardial hemorrhage, Angina pectoris, Left ventricular failure, Cardiomyopathy*, Congestive cardiomyopathy, Myocarditis*, Arrhythmia*, Pericarditis, Atrial fibrillation, Atrial flutter, Bradycardia, Supraventricular extrasystoles, Premature atrial contractions, Ventricular extrasystoles, Myocardial depression, Palpitations, Ejection fraction decreased*, Electrocardiogram ST-segment abnormal, Electrocardiogram T-wave inversion, Electrocardiogram QRS complex abnormal VASCULAR DISORDERS: Pulmonary embolism, Deep vein thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing, Blood pressure decreased RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Respiratory failure*, Acute respiratory distress syndrome*, Pulmonary hypertension*, Interstitial lung disease* as manifested by Pulmonary fibrosis*, Alveolitis allergic, Interstitial pneumonitis, Pneumonitis*, Pulmonary edema*, Pleural effusion, Bronchospasm, Dyspnea, Hypoxia, Cough GASTROINTESTINAL DISORDERS: Cecitis, Colitis, Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretion HEPATOBILIARY DISORDERS: Hepatic failure*, Hepatitis fulminant*, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic hepatitis, Cholestasis SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation recall dermatitis, Skin necrosis, Facial swelling, Petechiae, Macular rash, Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, nail disorder MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER: Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle twitching RENAL AND URINARY DISORDERS: Fanconi syndrome, Tubulointerstitial nephritis, Nephrogenic diabetes insipidus, Phosphaturia, Aminoaciduria, Polyuria, Enuresis, Feeling of residual urine Fatal outcomes from acute and chronic renal failure have been documented. REPRODUCTIVE SYSTEM AND BREAST DISORDERS: Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia, Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood gonadotrophin increased CONGENITAL, FAMILIAL AND GENETIC DISORDERS: Fetal growth retardation GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS: Multi-organ failure*, General physical deterioration, Injection/Infusion site reactions including swelling, inflammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal inflammation, Pain, Pyrexia, Chills * Including fatal outcomes

4 CONTRAINDICATIONS IFEX is contraindicated in patients with: • Known hypersensitivity to administration of ifosfamide. • Urinary outflow obstruction. • Known hypersensitivity to administration of ifosfamide. ( 4 ) • Urinary outflow obstruction. ( 4 )

11 DESCRIPTION IFEX (ifosfamide for injection, USP) 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 C 7 H 15 Cl 2 N 2 O 2 P and its molecular weight is 261.1. Ifosfamide is a white crystalline powder soluble in water. There are no excipients in the formulation. Each vial contains 1 gram or 3 grams of sterile ifosfamide alone. Its structural formula is: IFEX Structural Formula

2 DOSAGE AND ADMINISTRATION IFEX should be administered intravenously at a dose of 1.2 grams per m 2 per day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. 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. Mesna should be used to reduce the incidence of hemorrhagic cystitis. IFEX should be administered as a slow intravenous infusion lasting a minimum of 30 minutes. Studies of IFEX in patients with hepatic or renal impairment have not been conducted [see Use in Specific Populations ( 8.6 , 8.7 )] . Injections are prepared for parenteral 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 parenteral administration, the substance must be completely dissolved. Use the quantity of diluents shown below to constitute the product: 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. Constituted or constituted and further diluted solutions of IFEX should be refrigerated and used 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. Dosage and duration of treatment and/or treatment intervals depend on the scheme of combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring. ( 2 ) • IFEX (ifosfamide) should be administered as a slow intravenous infusion lasting a minimum of 30 minutes at a dose of 1.2 grams per m 2 per day for 5 consecutive days. ( 2 ) • Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. ( 2 ) • To prevent bladder toxicity, IFEX should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. ( 2 , 5.3 ) • Mesna should be used to reduce the incidence of hemorrhagic cystitis. ( 2 )

1 INDICATIONS AND USAGE IFEX is indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis. IFEX (ifosfamide) is an alkylating drug indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis. (1)

10 OVERDOSAGE No specific antidote for IFEX is known. Patients who receive an overdose should be closely monitored for the development of toxicities. Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis [see Warnings and Precautions (5) ]. Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur, including appropriate state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity. Ifosfamide as well as ifosfamide metabolites are dialyzable. Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.

7 DRUG INTERACTIONS Ifosfamide is a substrate for both CYP3A4 and CYP2B6. • 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 (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John Wort) 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 (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.

12 CLINICAL PHARMACOLOGY 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 as well as multiple other nontoxic products. 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. 12.3 Pharmacokinetics Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 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 exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m 2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hour on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1. Distribution Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m 2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. Ifosfamide shows little plasma protein binding. Ifosfamide and its active metabolites are extensively bound by red blood cells. Ifosfamide is not a substrate for P-glycoprotein. Metabolism Ifosfamide is extensively metabolized in humans through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/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. Excretion 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 urine as metabolites, 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. Pediatrics Population PK analysis was performed on plasma data from 32 pediatric patients various malignant diseases aged between 1 and 18 years. Patients received a total of 45 courses of ifosfamide at doses of 1.2, 2.0 and 3.0 g/m 2 given intravenously over 1 or 3 hours on 1, 2, or 3 days. The mean±standard error population estimates for the initial clearance and volume of distribution of ifosfamide were 2.4±0.33 L/h/m 2 and 21±1.6 L/m 2 with an interindividual variability of 43% and 32%, respectively. Effect of Age A study of 20 patients between 40 to 71 years of age receiving 1.5 g/m 2 of ifosfamide daily for 3 or 5 days indicated that elimination half-life appears to increase with age. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age. No significant changes in total plasma clearance or renal clearance with age were reported.

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 as well as multiple other nontoxic products. 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.

12.3 Pharmacokinetics Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 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 exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m 2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hour on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1. Distribution Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m 2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. Ifosfamide shows little plasma protein binding. Ifosfamide and its active metabolites are extensively bound by red blood cells. Ifosfamide is not a substrate for P-glycoprotein. Metabolism Ifosfamide is extensively metabolized in humans through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/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. Excretion 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 urine as metabolites, 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. Pediatrics Population PK analysis was performed on plasma data from 32 pediatric patients various malignant diseases aged between 1 and 18 years. Patients received a total of 45 courses of ifosfamide at doses of 1.2, 2.0 and 3.0 g/m 2 given intravenously over 1 or 3 hours on 1, 2, or 3 days. The mean±standard error population estimates for the initial clearance and volume of distribution of ifosfamide were 2.4±0.33 L/h/m 2 and 21±1.6 L/m 2 with an interindividual variability of 43% and 32%, respectively. Effect of Age A study of 20 patients between 40 to 71 years of age receiving 1.5 g/m 2 of ifosfamide daily for 3 or 5 days indicated that elimination half-life appears to increase with age. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age. No significant changes in total plasma clearance or renal clearance with age were reported.

20180726

14

3 DOSAGE FORMS AND STRENGTHS 1 gram single-dose vial 3 gram single-dose vial Single dose vials: 1 gram, 3 grams ( 3 )

IFEX ifosfamide IFOSFAMIDE IFOSFAMIDE IFEX ifosfamide IFOSFAMIDE IFOSFAMIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m 2 , or about 3% of the daily human dose on a mg/m 2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls. 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. Ifosfamide was administered to male and female beagle dogs at doses of 1.00 or 4.64 mg/kg/day (20 or 93 mg/m 2 ) orally 6 days a week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m 2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In a second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m 2 ) ifosfamide intraperitoneally once every 3 weeks for 6 months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on a mg/m 2 basis).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m 2 , or about 3% of the daily human dose on a mg/m 2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls. 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. Ifosfamide was administered to male and female beagle dogs at doses of 1.00 or 4.64 mg/kg/day (20 or 93 mg/m 2 ) orally 6 days a week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m 2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In a second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m 2 ) ifosfamide intraperitoneally once every 3 weeks for 6 months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on a mg/m 2 basis).

NDA019763

IFEX

ifosfamide

0338-3991

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL - PRINCIPLE DISPLAY PANEL Vial Label NDC 0338-3991-01 IFEX IFOSFAMIDE FOR INJECTION, USP 1 g/vial Rx only SINGLE-DOSE VIAL This vial contains 1g ifosfamide. Add 20 mL Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP, (benzyl alcohol or parabens preserved), shaking to dissolve, for a reconstituted concentration of 50 mg per mL. Store at controlled room temperature 20° C to 25° C (68° F to 77° F) Protect from temperatures above 30° C (86° F). FOR IV USE READ ACCOMPANYING PACKAGE INSERT for detailed indications, dosage, and precautions. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA USA HA-65-01-561 C130 Bar Code N(01)1 03 0338 3991 01 7 Lot:/Exp.: JMXXX JJJJ - MM Carton Label 1 vial NDC 0338-3991-01 IFEX (ifosfamide for injection, USP) Single-Dose Vial FOR IV USE Rx only 1 g Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA See bottom panel for lot number and expiration date. Bar Code N3 0338399101 0 This vial contains 1 g ifosfamide. Add 20 mL Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP, (benzyl alcohol or parabens preserved), shaking to dissolve, for a reconstituted concentration of 50 mg per mL. READ ACCOMPANYING PACKAGE INSERT for detailed indications, dosage, and precautions. Store at controlled room temperature 20° C to 25° C (68° F to 77° F). Protect from temperatures above 30° C (86° F). Constituted solutions should be refrigerated and used within 24 hours. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Germany Vial Label NDC 0338-3993-01 IFEX IFOSFAMIDE FOR INJECTION, USP 3 g/vial Rx only SINGLE-DOSE VIAL This vial contains 3g ifosfamide. Add 60 mL Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP, (benzyl alcohol or parabens preserved), shaking to dissolve, for a reconstituted concentration of 50 mg per mL. Store at controlled room temperature 20° C to 25° C (68° F to 77° F) Protect from temperatures above 30° C (86° F). FOR IV USE READ ACCOMPANYING PACKAGE INSERT for detailed indications, dosage, and precautions. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA USA HA-65-01-564 C 132 Bar Code N(01)1 03 0338 3993 01 1 Lot:/Exp.: JMXXX JJJJ - MM Carton Label 1 vial NDC 0338-3993-01 IFEX (ifosfamide for injection, USP) Single-Dose Vial FOR IV USE Rx only 3 g /vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA HA-80-02-154 USA See bottom panel for lot number and expiration date. Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA C 837 (01) 0030338993014 (21) XXXXXXXXXXXX (17) JJMMTT (10)JMXXXA 1 vial NDC 0338-3993-01 IFEX (Ifosfamide for injection, USP) Single Dose Vial Rx only FOR IV USE 3 g /vial Baxter Logo Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA Lot/Exp.: JMXXXA JJJJ - MM 2617B5079 Barcode FOLDING BOX CAN BE RECYCLED symbol This vial contains 3 g ifosfamide. Add 60 mL Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP, (benzyl alcohol or parabens preserved), shaking to dissolve, for a reconstituted concentration of 50 mg per mL. READ ACCOMPANYING PACKAGE INSERT for detailed indications, dosage, and precautions. Store at controlled room temperature 20° C to 25° C (68° F to 77° F). Protect from temperatures above 30° C (86° F). Constituted solutions should be refrigerated and used within 24 hours. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in Germany IFEX vial 0338-3991-01 IFEX 0338-3991-01 carton 1 of 4 IFEX 0338-3991-01 carton 2 of 4 IFEX 0338-3991-01 carton 3 of 4 IFEX 0338-3991-01 carton 4 of 4 IFEX vial 0338-3993-01 Ifex Carton 0338-3993-01 1 of 4 Ifex Carton 0338-3993-01 2 of 4 Ifex Carton 0338-3993-01 3 of 4 Ifex Carton 0338-3993-01 4 of 4

Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1-800 ANA DRUG (1-800-262-3784) Made in Germany Baxter, Ifex and Viaflex are trademarks of Baxter International Inc. PAB is a trademark of B Braun HA-30-01-800

17 PATIENT COUNSELING INFORMATION Myelosuppression, Immunosuppression, and Infections • Advise patients that treatment with IFEX may cause myelosuppression which can be severe and lead to infections and fatal outcomes. • Inform patients of the risks associated with the use of IFEX and plan for regular blood monitoring during therapy [see Boxed Warning, Warnings and Precautions (5.1 )]. • Inform patients to report fever or other symptoms of an infection [see Boxed Warning, Warnings and Precautions (5.1) , Adverse Reactions (6.2) ]. • Advise patients on the risks of bleeding and anemia [see Warnings and Precautions (5.1 , 5.8 ), Adverse Reactions (6.2) ], Use in Specific Populations (8.1 )]. Central Nervous System Toxicity, Neurotoxicity • Advise patients on the risk of CNS toxicity and other neurotoxic effects with fatal outcome [see Boxed Warning, Warnings and Precautions (5.2) ]. Renal and Urothelial Toxicity and Effects • Advise patients on the risk of bladder and kidney toxicity. • Advise patients of the need to increase fluid intake and frequent voiding to prevent accumulation in the bladder [see Warnings and Precautions (5.3) ]. Cardiotoxicity • Advise patients on the risk of cardiotoxicity and fatal outcome. Advise patients to report preexisting cardiac disease and manifestations of cardiotoxicity [see Warnings and Precautions (5.4) , Adverse Reactions (6.2) ] . Pulmonary Toxicity • Advise patients on the risk of pulmonary toxicity leading to respiratory failure with fatal outcome. • Inform patients to report signs and symptoms of pulmonary toxicity [see Warnings and Precautions (5.5) ]. Secondary Malignancies • Advise patients on the risk of secondary malignancies due to therapy [see Warnings and Precautions (5.6) ] . Veno-occlusive Liver Disease • Advise patients on the risk of veno-occlusive liver disease [see Warnings and Precautions (5.7) ]. Pregnancy • Advise patients on the potential hazard to a fetus if a patient becomes pregnant or fathers a child during therapy and for up to 6 months after therapy. • Advise patients to use effective contraception during therapy and for up to 6 months after therapy [see Warnings and Precautions (5.8) , Adverse Reactions (6.2) ] . Lactation • Advise patients on the potential for serious adverse reactions and tumorigenicity when children are breastfed during therapy [see Use in Specific Populations (8.3) ] . Reproductive System Disorders • Advise patients on the risk of amenorrhea, premature menopause, and sterility [see Warnings and Precautions (5.9) , Adverse Reactions (6.2 )]. Skin and Subcutaneous Tissue Disorders • Advise patients on the risk of alopecia, wound healing, and other serious skin and subcutaneous tissue disorders [see Warnings and Precautions (5.11) , Adverse Reactions (6.2) ]. Gastrointestinal Disorders • Advise patients that the therapy may cause gastrointestinal disorders and alcohol may increase nausea and vomiting [see Adverse Reactions (6.2) ]. • Advise patients on the risk of stomatitis and the importance of proper oral hygiene [see Adverse Reactions (6.2) ]. Eye Disorders • Advise patients on the risk of eye disorders such as visual impairment, blurred vision, and eye irritation [see Adverse Reactions (6.2) ]. Ear and Labyrinth Disorders • Advise patients on the risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus [see Adverse Reactions (6.2) ].

14 CLINICAL STUDIES Patients with refractory testicular cancer (n=59) received a combination of ifosfamide, cisplatin, and either etoposide (VePesid) or vinblastine (VIP) as third-line therapy or later. The selection of etoposide or vinblastine (“V” in the VIP regimen) was guided by the therapeutic effect achieved with prior regimens. The contribution of ifosfamide to the VIP combination was determined in patients treated with cisplatin-etoposide prior to ifosfamide- cisplatin-etoposide or those who received cisplatin-vinblastine prior to ifosfamide-cisplatin-vinblastine. A total of 59 patients received a third-line salvage regimen which consisted of ifosfamide 1.2 g/m 2 /day intravenously on days 1 to 5, cisplatin 20 mg/m 2 /day intravenously on days 1 to 5, and either etoposide 75 mg/m 2 /day intravenously on days 1 to 5 or vinblastine 0.22 mg/kg intravenously on day 1. Efficacy results with the VIP regimen were compared to data pooled from six single agent phase II trials conducted between August 1980 and October 1985 including a total of 90 patients of whom 65 were eligible as controls of this study. Twenty-three patients in the VIP regimen became free of disease with VIP alone or VIP plus surgery, whereas a single patient in the historical control group achieved complete response. The median survival time exceeded two years in the VIP group versus less than one year in the control group. Performance status ≥ 80, embryonal carcinoma and minimal disease were favorable prognostic factors for survival. In all prognostic categories, the difference between VIP and historical controls remained highly significant. Table 1. Efficacy Results Number. (%) of Patients VIP Control p-value Total Patients 59 (100) 65 (100) Disease-free 23 (39) 1 (2) < 0.001 Chemotherapy alone 15 (25) 1 (2) < 0.001 Chemotherapy plus surgery 8 (14) 0 Overall Response 32 (54) 2 (3) < 0.001 Time to progression (weeks) Median 19 4 < 0.001 Gehan-Breslow and Mantel-Cox tests Range 1 – 205+ 1 – 29 Disease-free interval (weeks) Median 114 29 Range 13 – 205+ -- Survival (weeks) Median 53 10 < 0.001 Range 1 – 205+ 1 – 123+ In a study, 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.

15 REFERENCES 1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

8.5 Geriatric Use In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age [see Pharmacokinetics (12.3) ]. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported. Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.3 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. Women must not breastfeed during treatment with ifosfamide.

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients.

8.1 Pregnancy IFEX can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide‑containing chemotherapy regimens during pregnancy. Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo . In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m 2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m 2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m 2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m 2 /day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group. Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: fetal growth retardation and neonatal anemia. ( 8.1 ) • Geriatric use: dose selection should be cautious. ( 8.5 ) • Patients with renal impairment: monitor for toxicity and consider dose reduction as needed ( 8.6 ) 8.1 Pregnancy IFEX can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide‑containing chemotherapy regimens during pregnancy. Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo . In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m 2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m 2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m 2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m 2 /day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group. Women should not become pregnant and men should not father a child during therapy with ifosfamide. Further, men should not father a child for up to 6 months after the end of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus. 8.3 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. Women must not breastfeed during treatment with ifosfamide. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age [see Pharmacokinetics (12.3) ]. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported. Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Use in Patients with Renal Impairment No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable . 8.7 Use in Patients with Hepatic Impairment No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. IFEX should be given cautiously to patients with impaired hepatic function.

16 HOW SUPPLIED/STORAGE AND HANDLING IFEX (ifosfamide for injection, USP) is available in single-dose vials as follows: IFEX (ifosfamide for injection) NDC 0338-3991-01 1-gram Single-Dose Vial NDC 0338-3993-01 3-gram Single-Dose Vial Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Protect from temperatures above 30°C (86°F). Exercise caution when handling IFEX. The handling and preparation of ifosfamide should always be in accordance with current guidelines on safe handling of cytotoxic agents. Several guidelines on this subject have been published. 1-4 Skin reactions associated with accidental exposure to IFEX may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing IFEX. 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.

WARNING: MYELOSUPPRESSION, NEUROTOXICITY, and UROTOXICITY Myelosuppression can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after each treatment cycle. CNS toxicities can be severe and result in encephalopathy and death. Monitor for CNS toxicity and discontinue treatment for encephalopathy. Nephrotoxicity can be severe and result in renal failure. Hemorrhagic cystitis can be severe and can be reduced by the prophylactic use of mesna. [see Warnings and Precautions (5.1-5.3)] WARNING: MYELOSUPPRESSION, NEUROTOXICITY, and UROTOXICITY See full prescribing information for complete boxed warning . - Myelosuppression can be severe and lead to fatal infections ( 5.1 ) - CNS toxicities can be severe and result in encephalopathy and death ( 5.2 ) - Nephrotoxicity can be severe and result in renal failure. Hemorrhagic cystitis can be severe. ( 5.3 )