IFEX

1 INDICATIONS AND USAGE IFEX is indicated for use in adults in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. IFEX 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.

2 DOSAGE AND ADMINISTRATION • Administer IFEX 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 IFEX to reduce the incidence or severity of hemorrhagic cystitis. ( 2.1 , 5.3 ) • Administer IFEX 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 IFEX 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 IFEX 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 IFEX 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 IFEX is 1.2 grams per m 2 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 IFEX based on patient risk factors and adverse reactions. 2.3 Preparation and Administration IFEX is a hazardous drug. Follow applicable special handling and disposal procedures. 1 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. Prepare IFEX 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 Table 1 below to reconstitute the product: Table 1: IFEX 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 IFEX 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.

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 )

5 WARNINGS AND PRECAUTIONS • Myelosuppression: Monitor blood counts prior to treatment, during treatment, and as clinically indicated. ( 5.1 ) • Encephalopathy: Monitor for signs and symptoms of CNS toxicity during and after IFEX treatment. Dose interruption or permanent discontinuation may be required based on individual safety and tolerability. ( 5.2 ) • Nephrotoxicity and Urotoxicity: Monitor signs and symptoms. Monitor serum and urine chemistries. ( 2.1 , 5.3 ) • Cardiotoxicity: Arrhythmias, other ECG changes, and cardiomyopathy can occur and result in death. Cardiotoxicity is dose dependent and the risk is increased in patients with preexisting cardiac, treatment with other cardiotoxic agents, radiation, and renal impairment. ( 5.4 ) • Pulmonary toxicity: Interstitial pneumonitis, pulmonary fibrosis, and pulmonary toxicity with fatal outcomes can occur. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated. ( 5.5 ) • Secondary malignancies can occur. ( 5.6 ) • Veno-occlusive Liver Disease can occur. ( 5.7 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.8 , 8.1 , 8.3 ) • Infertility: Can impair male and female reproductive function. ( 5.9 ) • Anaphylactic/anaphylactoid reactions have been reported. ( 5.10 ) 5.1 Myelosuppression IFEX can cause myelosuppression that results in severe or fatal infections including sepsis or septic shock. Ifosfamide‑induced myelosuppression includes leukopenia, neutropenia, thrombocytopenia (with bleeding events), and anemia. The nadir of the leukocyte count usually occurs during the second week after administration of IFEX. The risk of myelosuppression is dose‑dependent and increased in patients with reduced renal function, bone marrow metastases, prior radiation, and concomitant or prior therapy with other cytotoxic agents. Monitor complete blood counts, including leukocytes, neutrophils, platelets, and hemoglobin prior to each administration of IFEX, at appropriate intervals during treatment, and as clinically indicated. Myelosuppression may require dosage delays. Avoid administration of IFEX to patients with a WBC count below 2000/µL, a platelet count below 50,000/µL, or when signs or symptoms of active infection or severe immunosuppression are present. 5.2 Encephalopathy IFEX can cause encephalopathy which may be fatal. Signs and symptoms may include confusion, somnolence, coma, hallucination, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, and seizures. Risk factors include high ifosfamide dosage, hypoalbuminemia, impaired renal function, poor performance status, bulky abdominal-pelvic disease, nephrotoxic treatments including cisplatin, CNS active drugs, or alcohol use. Signs and symptoms may occur or recur within hours to days after administration of IFEX. Continue supportive care until complete resolution of CNS signs and symptoms. Monitor for signs and symptoms of encephalopathy during and after IFEX treatment. Dose interruption or permanent discontinuation may be required based on individual safety and tolerability. Consider methylene blue for treatment of encephalopathy. 5.3 Nephrotoxicity and Urotoxicity IFEX can cause severe or fatal nephrotoxicity and urotoxicity including glomerular or tubular dysfunction, tubular necrosis, renal parenchymal necrosis, acute renal failure, chronic renal failure, and hemorrhagic cystitis (requiring blood transfusion). Tubular damage may occur up to years after cessation of IFEX treatment. The risk of nephrotoxicity is increased in patients with renal impairment or reduced nephron reserve. Hemorrhagic cystitis is dose‑dependent and the risk is increased with past or concomitant radiation of the bladder or busulfan treatment. Evaluate glomerular and tubular kidney function before treatment with IFEX, during IFEX treatment, and as clinically indicated. Monitor serum and urine chemistries (including phosphorus and potassium) and urinary sediment for the presence of erythrocytes or other signs of nephrotoxicity. Signs and symptoms may include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, glycosuria, osteomalacia, tubular acidosis, Fanconi syndrome, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4) ] . During or immediately after administration, provide oral or intravenous fluid to force dieresis to reduce the risk of urinary tract toxicity. Administer mesna with IFEX to reduce the incidence and severity of urotoxicity [see Dosage and Administration (2.1) ] . Obtain a urinalysis prior to each dose of IFEX. Avoid administration of IFEX in patients with active urinary tract infections. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then withhold administration of IFEX until complete resolution. Further administration of IFEX should be given with vigorous oral or parenteral hydration. Dosage interruption or permanent discontinuation may be required based on individual safety and tolerability. 5.4 Cardiotoxicity IFEX can cause severe or fatal cardiotoxicity including any of the following: • Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia • Decreased QRS voltage and ST-segment or T-wave changes • Toxic cardiomyopathy leading to heart failure with congestion and hypotension • Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis Cardiotoxic effects are dose‑dependent and the risk is increased in patients with cardiac disease, prior or concomitant treatment with other cardiotoxic agents, radiation of the cardiac region, and renal impairment. 5.5 Pulmonary Toxicity IFEX can cause severe or fatal pulmonary toxicities including interstitial pneumonitis, pulmonary fibrosis, and respiratory failure. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated. 5.6 Secondary Malignancies The incidence of secondary malignancies is increased in patients treated with IFEX-containing regimens. Cases of myelodysplastic syndrome, acute leukemias, lymphomas, thyroid cancers, and sarcomas have occurred and may develop several years after chemotherapy has been discontinued. 5.7 Veno-occlusive Liver Disease Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide. 5.8 Embryo-Fetal Toxicity Based on mechanism of action and human and animal data, IFEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1) ] . Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide‑containing chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ cells. Embryotoxic and teratogenic effects have been observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1) ] . Verify the pregnancy status of females of reproductive potential prior to initiation of IFEX. Advise females of reproductive potential to use effective contraception during treatment with IFEX and for up to 12 months after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IFEX and for 6 months after completion of therapy [see Use in Specific Populations (8.1 , 8.3) ] . 5.9 Infertility Male and female reproductive function and fertility may be impaired in patients treated with IFEX. Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia; and sterility in both sexes have been reported. Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment. Sterility may be irreversible in some patients. Advise patients on the potential risks for infertility [see Use in Specific Populations 8. 3 and 8.4) ] . 5.10 Anaphylactic/Anaphylactoid Reactions and Cross-sensitivity Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide. Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported. 5.11 Impairment of Wound Healing Ifosfamide may interfere with normal wound healing.

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.

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 IFEX Adverse Reaction Single Agent IFEX % (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) 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 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. 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 Congenital Disorders : fetal growth retardation Ear Disorders : deafness, hypoacusis, tinnitus, vertigo Endocrine Disorder : SIADH Eye Disorders : conjunctivitis, eye irritation, vision blurred, visual impairment Gastrointestinal Disorders : abdominal pain, cecitis, colitis, constipation, enterocolitis, ileus, gastrointestinal hemorrhage, mucosal ulceration, pancreatitis, salivary hypersecretion General Disorders and Administrative Site Conditions : multi‑organ failure*, chest pain, chills, injection/infusion site reactions (including erythema, inflammation, pain, pruritus, swelling, tenderness), edema, general physical deterioration, mucosal inflammation, pain, pyrexia Hepatobiliary Disorders : hepatic failure*, hepatitis fulminant* cholestasis, cytolytic hepatitis, portal vein thrombosis, veno‑occlusive liver disease Immune System Disorders : anaphylactic reaction, angioedema, hypersensitivity reaction, immunosuppression, urticaria Infections : 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 Metabolic and Nutrition Disorders : hypocalcemia, hypokalemia, hypophosphatemia, hyperglycemia, metabolic acidosis, polydipsia, tumor lysis syndrome Musculoskeletal and Connective Tissue Disorders : arthralgia, growth retardation, myalgia, muscle twitching, osteomalacia, pain in extremity, rhabdomyolysis, rickets Neoplasms : secondary malignancies*, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, myelodysplastic syndrome, Non‑Hodgkin’s lymphoma, renal cell carcinoma, sarcomas, thyroid cancer Nervous System Disorders : seizure*, asterixis, dysarthria, dysesthesia, extrapyramidal disorder, fecal incontinence, gait disturbance hypothesia, leukoencephalopathy, movement disorder, neuralgia, paresthesia, polyneuropathy, reversible posterior leukoencephalopathy syndrome. Ifosfamide has been reintroduced after neurotoxicity. While some patients did not experience neurotoxicity, others had recurrent, including fatal, events. Psychiatric Disorders : amnesia, bradyphrenia, catatonia, delirium, delusion, echolalia, logorrhea, mania mental status change, mutism, paranoia, panic attack, perseveration Renal and Urinary Disorders : aminoaciduria, diabetes insipidus, enuresis, Fanconi syndrome, feeling of residual urine, nephrogenic phosphaturia, polyuria, tubulointerstitial nephritis Reproductive System and Breast Disorders : amenorrhea, azoospermia, decreased blood estrogen, impairment of spermatogenesis, increased blood gonadotrophin, infertility, oligospermia, ovarian disorder, ovarian failure, ovulation disorder, premature menopause Respiratory, Thoracic, and Mediastinal Disorders: acute respiratory distress syndrome*, pulmonary fibrosis*, pneumonitis*/interstitial lung disease*, pulmonary edema*, pulmonary hypertension*, respiratory failure*, alveolitis allergic, bronchospasm, cough, dyspnea, hypoxia, pleural effusion Skin and Subcutaneous Disorders : erythema, facial swelling, hyperhidrosis, macular rash, nail disorder, palmar‑plantar erythrodysesthesia syndrome, petechiae, pruritus, radiation recall dermatitis, rash, skin hyperpigmentation, skin necrosis, Stevens‑Johnson syndrome, toxic epidermal necrolysis Vascular Disorders: capillary leak syndrome, deep vein thrombosis, flushing, hypertension, pulmonary embolism, vasculitis * Includes fatal outcomes

8.1 Pregnancy Risk Summary Based on mechanism of action [see Clinical Pharmacology (12.1) ] , and human and animal data (see Data) , 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data 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.