IFOSFAMIDE

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.

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) 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 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 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

4 CONTRAINDICATIONS Ifosfamide for Injection 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 Ifosfamide for Injection (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 alkylating drug 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: Ifosfamide NovaPlus Structural Formula

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 m2 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 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 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 Table 1 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.

10 OVERDOSAGE No specific antidote for Ifosfamide for Injection 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 • 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.

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. 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. Specific Populations Pediatric Patients 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. 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. Specific Populations Pediatric Patients 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.

20241202

9

3 DOSAGE FORMS AND STRENGTHS For injection: white, crystalline powder available in: • 1 gram single-dose vial for reconstitution • 3 gram single-dose vial for reconstitution • For injection: Single dose vials: 1 gram, 3 grams (3)

IFOSFAMIDE ifosfamide IFOSFAMIDE IFOSFAMIDE IFOSFAMIDE 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

IFOSFAMIDE

ifosfamide

10019-927

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Container Label LOT/EXP: Single Dose Vial NDC 10019-927-20 Ifosfamide for Injection 1g /vial Rx only FOR IV USE Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA NOVAPLUS Logo N+ and NOVAPLUS are registered trademarks of Vizient, Inc. 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. Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Protect from temperatures above 30°C (86°F). READ ACCOMPANYING PACKAGE INSERT for detailed indications, dosage, and precautions. Bar code (01)00310019927206 USA HA-65-01-560 C 780 Carton Label Black P 286 C P 1777C Ifosfamide for Injection 1g /vial NDC 10019-927-01 Ifosfamide for Injection Single Dose Vial FOR IV USE Rx only Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA NOVAPLUS Logo N+ and NOVAPLUS are registered trademarks of Vizient, Inc. HA-80-02-150 USA 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. C 772 NDC 10019-927-01 Ifosfamide for Injection 1g /vial Single Dose Vial FOR IV USE Rx only Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA LOT/EXP: 2617B5115 Bar code FOLDING BOX CAN BE RECYCLED Logo NDC 10019-927-01 Ifosfamide for Injection 1g /vial Single Dose Vial FOR IV USE Rx only Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA Container Label LOT/EXP: Single Dose Vial NDC 10019-929-60 Ifosfamide for Injection 3g /vial Rx only FOR IV USE Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA NOVAPLUS Logo N+ and NOVAPLUS are registered trademarks of Vizient, Inc. 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. Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Protect from temperatures above 30°C (86°F). READ ACCOMPANYING PACKAGE INSERT for detailed indications, dosage, and precautions. Bar code (01)00310019929606 USA HA-65-01-563 C 781 Carton Label Black P 286 C P 2705 C Ifosfamide for Injection 3g /vial NDC 10019-929-03 Ifosfamide for Injection 3g /vial Single Dose Vial FOR IV USE Rx only Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA HA-80-02-153 USA 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. C 775 NDC 10019-929-03 Ifosfamide for Injection 3g /vial Single Dose Vial FOR IV USE Rx only Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA NOVAPLUS Logo N+ and NOVAPLUS are registered trademarks of Vizient, Inc. LOT/EXP: 2617B5116 Bar code FOLDING BOX CAN BE RECYCLED Logo NDC 10019-929-03 Ifosfamide for Injection 3g /vial Single Dose Vial FOR IV USE Rx only Manufactured by Baxter Healthcare Corporation Deerfield, IL 60015 USA NOVAPLUS Logo N+ and NOVAPLUS are registered trademarks of Vizient, Inc. Representative Ifosfamide NovaPlus Container Label 10019-927-20 Representative Ifosfamide NovaPlus Carton Label 10019-927-01 Representative Ifosfamide NovaPlus Container Label 10019-929-60 Representative Ifosfamide NovaPlus Carton Label 10019-929-03

Boxed Warning 12/2024 Dosage and Administration ( 2.1 , 2.2 , 2.3 ) 12/2024 Warnings and Precautions ( 5 ) 12/2024

17 PATIENT COUNSELING INFORMATION Myelosuppression • Advise patients that treatment with Ifosfamide for Injection may cause myelosuppression which can be severe and lead to infections and fatal outcomes. • Inform patients of the risks associated with the use of Ifosfamide for Injection 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) ]. Encephalopathy • Advise patients on the risk of encephalopathy and other neurotoxic effects with fatal outcome [see Boxed Warning, Warnings and Precautions (5.2) ] . • Inform patients that Ifosfamide for Injection may impair the ability to operate an automobile or other heavy machinery [see Boxed Warning, Warnings and Precautions (5.2) ] . Nephrotoxicity and Urotoxicity • 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) ] . Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1) ] . • Advise females of reproductive potential to use effective contraception during treatment with Ifosfamide for Injection and for 12 months after the last dose [see Use in Specific Populations (8.3) ] . • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Ifosfamide for Injection and for 6 months after the last dose [see Use in Specific Populations (8.3) ] . Lactation • Advise women not to breastfeed during treatment with Ifosfamide for Injection and for 1 week after the last dose [see Use in Specific Populations (8.2) ]. Infertility • Advise females and males of reproductive potential that Ifosfamide for Injection may cause temporary or permanent infertility [see Use in Specific Populations (8.3) ]. 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) ]. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1-800 ANA DRUG (1-800-262-3784) Made in Germany Novaplus Logo NOVAPLUS is a registered trademark of Vizient, Inc. Baxter and Viaflex are trademarks of Baxter International Inc. PAB is a trademark of B Braun HA-30-02-447

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 3: 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 Ifosfamide for Injection 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. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

8.5 Geriatric Use Clinical studies of Ifosfamide for Injection did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. 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, closely monitor for adverse reactions and monitor renal function as clinically indicated.

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. Renal rickets and growth retardation in pediatric patients treated with ifosfamide have been reported. Ifosfamide for Injection may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential and may have an increased risk of developing premature menopause. Ifosfamide for Injection may cause abnormal secondary sexual characteristic development in prepubertal males. Sterility, azoospermia, and testicular atrophy have been reported in male patients. Azoospermia may be reversible in some patients, but may not occur for several years after cessation of Ifosfamide for Injection therapy.

8.1 Pregnancy Risk Summary Based on mechanism of action [see Clinical Pharmacology 12.1) ] , and human and animal data (see Data) , Ifosfamide for Injection 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.

8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed. ( 8.2 ) • Renal impairment: Closely monitor for adverse reactions and consider dosage modifications. (8.6) 8.1 Pregnancy Risk Summary Based on mechanism of action [see Clinical Pharmacology 12.1) ] , and human and animal data (see Data) , Ifosfamide for Injection 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. 8.2 Lactation Risk Summary Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events, and the tumorigenicity shown for ifosfamide in animal studies, advise women not to breastfeed during treatment with Ifosfamide for Injection and for one week after the last dose. 8.3 Females and Males of Reproductive Potential Ifosfamide for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating Ifosfamide for Injection [see Use in Specific Populations (8.1) ] . Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with Ifosfamide for Injection and for 12 months after the last dose. Males Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Ifosfamide for Injection and for 6 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Females Amenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapy induced amenorrhea increases with age. Males Men treated with ifosfamide may develop oligospermia or azoospermia. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children. Females and Males Based on animal studies, Ifosfamide for Injection may impair fertility in females and males of reproductive potential. The reversibility of these effects is unknown [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. Renal rickets and growth retardation in pediatric patients treated with ifosfamide have been reported. Ifosfamide for Injection may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential and may have an increased risk of developing premature menopause. Ifosfamide for Injection may cause abnormal secondary sexual characteristic development in prepubertal males. Sterility, azoospermia, and testicular atrophy have been reported in male patients. Azoospermia may be reversible in some patients, but may not occur for several years after cessation of Ifosfamide for Injection therapy. 8.5 Geriatric Use Clinical studies of Ifosfamide for Injection did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. 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, closely monitor for adverse reactions and monitor renal function as clinically indicated. 8.6 Use 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. Closely monitor patients with renal impairment for adverse reactions and consider dosage modifications. Ifosfamide and its metabolites are dialyzable . 8.7 Use in Patients with Hepatic Impairment Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Closely monitor patients with with impaired hepatic function for adverse reactions during treatment with Ifosfamide for Injection.

16 HOW SUPPLIED/STORAGE AND HANDLING Ifosfamide for injection is available in single‑dose vials as follows: NDC 10019-927-01 1‑gram Single‑Dose Vial NDC 10019-929-03 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).

WARNING: MYELOSUPPRESSION, ENCEPHALOPATHY, NEPHROTOXICITY and UROTOXICITY • Myelosuppression can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after each treatment cycle [see Warnings and Precautions (5.1) ] . • Encephalopathy can be severe and may result in death. Monitor for CNS toxicity and discontinue treatment for encephalopathy [see Warnings and Precautions (5.2) ] . • 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 (5.3) ]. WARNING: MYELOSUPPRESSION, ENCEPHALOPATHY, NEPHROTOXICITY and UROTOXICITY See full prescribing information for complete boxed warning. • Myelosuppression can be severe and lead to fatal infections (5.1) • Encephalopathy can be severe and may result in death (5.2) • Nephrotoxicity can be severe and result in renal failure. Hemorrhagic cystitis can be severe. (5.3)