Ifosfamide

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 Ifosfamide for Injection 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 Ifosfamide for Injection 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 Ifosfamide for Injection. 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 Ifosfamide for Injection, at appropriate intervals during treatment, and as clinically indicated. Myelosuppression may require dosage delays. Avoid administration of Ifosfamide for Injection 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 Ifosfamide for Injection 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 Ifosfamide for Injection. Continue supportive care until complete resolution of CNS signs and symptoms. Monitor for signs and symptoms of encephalopathy during and after Ifosfamide for Injection 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 Ifosfamide for Injection 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 Ifosfamide for Injection 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 Ifosfamide for Injection, during Ifosfamide for Injection 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 Ifosfamide for Injection to reduce the incidence and severity of urotoxicity [see Dosage and Administration (2.1) ]. Obtain a urinalysis prior to each dose of Ifosfamide for Injection. Avoid administration of Ifosfamide for Injection in patients with active urinary tract infections. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then withhold administration of Ifosfamide for Injection until complete resolution. Further administration of Ifosfamide for Injection 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 Ifosfamide for Injection 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 Ifosfamide for Injection 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 Ifosfamide for Injection-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, Ifosfamide for Injection 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 Ifosfamide for Injection. Advise females of reproductive potential to use effective contraception during treatment with Ifosfamide for Injection 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 Ifosfamide for Injection 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 Ifosfamide for Injection. 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.

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

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 impaired hepatic function for adverse reactions during treatment with Ifosfamide for Injection.