HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Ifosfamide Injection is available as follows: NDC NumberContentsPackage0703-3427-11 g/20 mL Individually packaged0703-3429-11 g/60 mL Individually packagedREFRIGERATE: Store at to 8C (36 to 46F).Discard Unused Portion.Exercise caution when handling Ifosfamide Injection. The handling and preparation of Ifosfamide Injection should always be in accordance with current guidelines on safe handling of cytotoxic agents. Several guidelines on this subject have been published.1-4 Skin reactions associated with accidental exposure to Ifosfamide Injection may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing Ifosfamide Injection. If ifosfamide solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. In clinical trials of ifosfamide monotherapy, the most common (>=10%) adverse reactions were alopecia, nausea/vomiting, leukopenia, anemia, CNS toxicity, hematuria, and infection. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Adverse Reactions from Clinical Trials. Because clinical trials are conducted from widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions and frequencies below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with total dose of to 12 g/m2 per course.System Organ Class (SOC)Adverse ReactionPercentage (Ratio)INFECTIONS AND INFESTATIONSInfection9.9% (112/1128)BLOOD AND LYMPHATIC SYSTEM DISORDERSLeukopenia1 (any) Leukopenia<1 103/microliter43.5% (267/614)Thrombocytopenia2 (any) Thrombocytopenia50 103/ microliter4.8% (35/729)Anemia3 37.9% (202/533)METABOLISM AND NUTRITION DISORDERSAnorexia1.1% (15/1317)NERVOUS SYSTEM DISORDERSCentral nervous system toxicity4,5 15.4% (154/1001)Peripheral neuropathy0.4% (5/1317)CARDIAC DISORDERSCardiotoxicity6 0.5% (7/1317)VASCULAR DISORDERSHypotension7 0.3% (4/1317)GASTROINTESTINAL DISORDERSNausea/Vomiting46.8% (443/964)Diarrhea0.7% (9/1317)Stomatitis0.3% (4/1317)HEPATOBILIARY DISORDERSHepatotoxicity8 1.8% (22/1190)SKIN AND SUBCUTANEOUS TISSUES DISORDERSAlopecia89.6% (540/603)Dermatitis0.08% (1/1317)Papular rash0.08% (1/1317)RENAL AND URINARY DISORDERSHemorrhagic cystitis9 Hematuria- without mesna44.1% (282/640)- with mesna21.3% (33/155)Macrohematuria- without mesna11.1% (66/594)- with mesna5.2% (5/97)Renal dysfunction10 --Renal structural damage--GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONSPhlebitis11 2.8% (37/1317)Neutropenic fever12 1.0% (13/1317)Fatigue0.3% (4/1317)MalaiseUnable to calculate1 The following adverse reaction terms have been reported for leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. For neutropenic fever, see below.2 Thrombocytopenia may also be complicated by bleeding. Bleeding with fatal outcome has been reported.3 Includes cases reported as anemia and decrease in hemoglobin/hematocrit.4 Encephalopathy with coma and death has been reported.5 Central nervous system toxicity was reported to be manifested by the following signs and symptoms: Abnormal behavior, Affect lability Aggression, Agitation, Anxiety, Aphasia, Asthenia, Ataxia, Cerebellar syndrome, Cerebral function deficiency, Cognitive disorder, Coma, Confusional state, Convulsions, Cranial nerve dysfunction, Depressed state of consciousness, Depression, Disorientation, Dizziness, Electroencephalogram abnormal, Encephalopathy, Flat affect, Hallucinations, Headache, Ideation, Lethargy, Memory impairment, Mood change, Motor dysfunction, Muscle spasms, Myoclonus, Progressive loss of brainstem reflexes, Psychotic reaction, Restlessness, Somnolence, Tremor, Urinary incontinence.6 Cardiotoxicity was reported as congestive heart failure, tachycardia, pulmonary edema. Fatal outcome has been reported.7 Hypotension leading to shock and fatal outcome has been reported.8 Hepatotoxicity was reported as increases in liver enzymes, i.e., serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, gamma- glutamyltransferase and lactate dehydrogenase, increased bilirubin, jaundice, hepatorenal syndrome.9 Reported symptoms of hemorrhagic cystitis included dysuria and pollakiuria. See also Post-marketing Adverse Reactions (6.2).10 Renal dysfunction was reported to be manifested as: Renal failure (including acute renal failure, irreversible renal failure; fatal outcomes have been reported), Serum creatinine increased, BUN increased, Creatinine clearance decreased, Metabolic acidosis, Anuria, Oliguria, Glycosuria, Hyponatremia, Uremia, Creatinine clearance increased. Renal structural damage was reported to be manifested as: Acute tubular necrosis, renal parenchymal damage, Enzymuria, Cylindruria, Proteinuria.11 Includes cases reported as phlebitis and irritation of the venous walls.12 Includes cases reported as granulocytopenic fever.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Ifosfamide. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. INFECTIONS AND INFESTATIONS:The following manifestations have been associated with myelosuppression and immunosuppression caused by ifosfamide: increased risk for and severity of infections+, pneumonias+, sepsis and septic shock (including fatal outcomes), as well as reactivation of latent infections, including viral hepatitis+, Pneumocystis jiroveci +, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy+, and other viral and fungal infections.+Severe immunosuppression has led to serious, sometimes fatal, infections.NEOPLASMS, BENIGN AND MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS):As treatment-related secondary malignancy, Acute leukemia (Acute myeloid leukemia), Acute promyelocytic leukemia, Acute lymphocytic leukemia, Myelodysplastic syndrome, Lymphoma (Non-Hodgkins lymphoma), Sarcomas, Renal cell carcinoma, Thyroid cancerBLOOD AND LYMPHATIC SYSTEM DISORDERS:Hematotoxicity, Myelosuppression manifested as Bone marrow failure, Agranulocytosis; Febrile bone marrow aplasia; Disseminated intravascular coagulation, Hemolytic uremic syndrome, Hemolytic anemia, Neonatal anemia, MethemoglobinemiaIMMUNE SYSTEM DISORDERS:Angioedema, Anaphylactic reaction, Immunosuppression, Urticaria, Hypersensitivity reactionENDOCRINE DISORDERS:Syndrome of inappropriate antidiuretic hormone secretion (SIADH)METABOLISM AND NUTRITION DISORDERS:Tumor lysis syndrome, Metabolic acidosis, Hypokalemia, Hypocalcemia, Hypophosphatemia, Hyperglycemia, PolydipsiaPSYCHIATRIC DISORDERS:Panic attack, Catatonia, Mania, Paranoia, Delusion, Delirium, Bradyphrenia, Mutism, Mental status change, Echolalia, Logorrhea, Perseveration, AmnesiaNERVOUS SYSTEM DISORDERS:Convulsion, Status epilepticus (convulsive and nonconvulsive), reversible posterior leukoencephalopathy syndrome, Leukoencephalopathy, Extrapyramidal disorder, Asterixis, Movement disorder, Polyneuropathy, Dysesthesia, Hypothesia, Paresthesia, Neuralgia, Gait disturbance, Fecal incontinence, DysarthriaIfosfamide has been reintroduced after neurotoxicity. While some patients did not experience neurotoxicity, others had recurrent, including fatal, events.EYE DISORDERS: Visual impairment, Vision blurred, Conjunctivitis, Eye irritationEAR AND LABYRINTH DISORDERS:Deafness, Hypoacusis, Vertigo, TinnitusCARDIAC DISORDERS: Cardiotoxicity, Cardiac arrest, Ventricular fibrillation, Ventricular tachycardia, Cardiogenic shock, Myocardial infarction, Cardiac failure, Bundle branch block left, Bundle branch block right, Pericardial effusion, Myocardial hemorrhage, Angina pectoris, Left ventricular failure, Cardiomyopathy, Congestive cardiomyopathy, Myocarditis, Arrhythmia, Pericarditis, Atrial fibrillation, Atrial flutter, Bradycardia, Supraventricular extrasystoles, Premature atrial contractions, Ventricular extrasystoles, Myocardial depression, Palpitations, Ejection fraction decreased, Electrocardiogram ST-segment abnormal, Electrocardiogram T-wave inversion, Electrocardiogram QRS complex abnormalVASCULAR DISORDERS:Pulmonary embolism, Deep vein thrombosis, Capillary leak syndrome, Vasculitis, Hypertension, Flushing, Blood pressure decreasedRESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS:Respiratory failure, Acute respiratory distress syndrome, Pulmonary hypertension, Interstitial lung disease as manifested by Pulmonary fibrosis, Alveolitis allergic, Interstitial pneumonitis, Pneumonitis, Pulmonary edema, Pleural effusion, Bronchospasm, Dyspnea, Hypoxia, CoughGASTROINTESTINAL DISORDERS:Cecitis, Colitis, Enterocolitis, Pancreatitis, Ileus, Gastrointestinal hemorrhage, Mucosal ulceration, Constipation, Abdominal pain, Salivary hypersecretionHEPATOBILIARY DISORDERS:Hepatic failure, Hepatitis fulminant, Veno-occlusive liver disease, Portal vein thrombosis, Cytolytic hepatitis, CholestasisSKIN AND SUBCUTANEOUS TISSUE DISORDERS:Toxic epidermal necrolysis, Stevens-Johnson syndrome, Palmar-plantar erythrodysesthesia syndrome, Radiation recall dermatitis, Skin necrosis, Facial swelling, Petechiae, Macular rash, Rash, Pruritus, Erythema, Skin hyperpigmentation, Hyperhidrosis, nail disorderMUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER:Rhabdomyolysis, Osteomalacia, Rickets, Growth retardation, Myalgia, Arthralgia, Pain in extremity, Muscle twitchingRENAL AND URINARY DISORDERS:Fanconi syndrome, Tubulointerstitial nephritis, Nephrogenic diabetes insipidus, Phosphaturia, Aminoaciduria, Polyuria, Enuresis, Feeling of residual urineFatal outcomes from acute and chronic renal failure have been documented.REPRODUCTIVE SYSTEM AND BREAST DISORDERS:Infertility, Ovarian failure, Premature menopause, Amenorrhea, Ovarian disorder, Ovulation disorder, Azoospermia, Oligospermia, Impairment of spermatogenesis, Blood estrogen decreased, Blood gonadotrophin increasedCONGENITAL, FAMILIAL AND GENETIC DISORDERS:Fetal growth retardationGENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS:Multi-organ failure, General physical deterioration, Injection/Infusion site reactions including swelling, inflammation, pain, erythema, tenderness, pruritus; Chest pain, Edema, Mucosal inflammation, Pain, Pyrexia, Chills Including fatal outcomes.

BOXED WARNING SECTION.

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

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at mg/kg (37 mg/m2, or about 3% of the daily human dose on mg/m2 basis) times week for 52 weeks. Female rats had 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 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/m2) orally days week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on mg/m2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m2) ifosfamide intraperitoneally once every weeks for months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on mg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ifosfamide is prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard as well as multiple other nontoxic products. The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in the DNA results in cell death.. 12.3 Pharmacokinetics. Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 g/m2, 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/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about hours.Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hours once daily for days to 15 patients with neoplastic disease, decrease in the median elimination half-life from 7.2 hours on Day to 4.6 hours on Day occurred with concomitant increase in the median clearance from 66 mL/min on Day to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day compared with Day 1. DistributionIfosfamide 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/m2 over 0.5 hours once daily for days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 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 substrate for P-glycoprotein.MetabolismIfosfamide 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.ExcretionAfter administration of doses of g/m2 of 14C-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/m2 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.PediatricsPopulation PK analysis was performed on plasma data from 32 pediatric patients various malignant diseases aged between and 18 years. Patients received total of 45 courses of ifosfamide at doses of 1.2, 2.0 and 3.0 g/m2 given intravenously over or hours on 1, 2, or days. The mean+-standard error population estimates for the initial clearance and volume of distribution of ifosfamide were 2.4+-0.33 L/h/m2 and 21+-1.6 L/m2 with an interindividual variability of 43% and 32%, respectively.Effect of AgeA study of 20 patients between 40 to 71 years of age receiving 1.5 g/m2 of ifosfamide daily for or 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.

INDICATIONS & USAGE SECTION.

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

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Patients with refractory testicular cancer (n=59) received 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 third-line salvage regimen which consisted of ifosfamide 1.2 g/m2/day intravenously on days to 5, cisplatin 20 mg/m2/day intravenously on days to 5, and either etoposide 75 mg/m2/day intravenously on days to 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 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 single patient in the historical control group achieved complete response. The median survival time exceeded two years in the VIP group versus less than one year in the control group. Performance status >=80, embryonal carcinoma and minimal disease were favorable prognostic factors for survival. In all prognostic categories, the difference between VIP and historical controls remained highly significant.Table 1. Efficacy Results Number. (%) of PatientsVIPControlp-valueTotal Patients59 (100)65 (100)Disease-free23 (39)1 (2)<0.001 Chemotherapy alone15 (25)1 (2)<0.001 Chemotherapy plus surgery8 (14)0Overall Response32 (54)2 (3)<0.001Time to progression (weeks) Median194<0.001a Range1 to 205+1 to 29Disease-free interval (weeks) Median11429 Range13 to 205+--Survival (weeks) Median5310<0.001a Range1 to 205+1 to 123+ a: Gehan-Breslow and Mantel-Cox testsIn study, 50 fully evaluable patients with germ cell testicular cancer were treated with ifosfamide 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 cisplatin containing regimen and had not progressed while on the cisplatin containing regimen or within 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 regimen to which they had previously responded and subsequently relapsed.Ten of 50 fully evaluable patients were still alive to 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.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Ifosfamide Injection, single dose vials for administration by intravenous infusion each contain gram or grams of sterile ifosfamide, USP. The gram vial also contains 69.0 mg monobasic sodium phosphate monohydrate, 21.3 mg dibasic sodium phosphate anhydrous, and water for injection, qs. The gram vial also contains 207 mg monobasic sodium phosphate monohydrate, 63.9 mg dibasic sodium phosphate anhydrous, and water for injection, qs. Ifosfamide, USP is chemotherapeutic agent chemically related to the nitrogen mustards and synthetic analog of cyclophosphamide. Ifosfamide, USP is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine2-oxide. Its structural formula is: C7H15Cl2N2O2P M.W. 261.1 Chemical Structure for Ifosfamide.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Ifosfamide injection should be administered intravenously at dose of 1.2 grams per m2 per day for consecutive days. Treatment is repeated every weeks or after recovery from hematologic toxicity.In order to prevent bladder toxicity, ifosfamide injection should be given with extensive hydration consisting of at least liters of oral or intravenous fluid per day. Mesna should be used to reduce the incidence of hemorrhagic cystitis. Ifosfamide injection should be administered as slow intravenous infusion lasting minimum of 30 minutes. Studies of ifosfamide injection in patients with hepatic or renal impairment have not been conducted [see Use in Specific Populations 8.6, 8.7)]. Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:5% Dextrose Injection, USP0.9% Sodium Chloride Injection, USPLactated Ringers Injections, USPSterile Water for Injection, USPBecause 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 Ringers Injection), the use of large volume parenteral glass bottles, VIAFLEX bags or PAB bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable.Constituted or constituted and further diluted solutions of ifosfamide injection should be refrigerated and used within 24 hours. Benzyl-alcohol-containing solutions can reduce the stability of ifosfamide.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.. Dosage and duration of treatment and/or treatment intervals depend on the scheme of combination therapy, the patients general state of health and organ function, and the results of laboratory monitoring. (2)Ifosfamide injection should be administered as slow intravenous infusion lasting minimum of 30 minutes at dose of 1.2 grams per m2 per day for consecutive days. (2)Treatment is repeated every weeks or after recovery from hematologic toxicity. (2)To prevent bladder toxicity, ifosfamide injection should be given with extensive hydration consisting of at least liters of oral or intravenous fluid per day. (2, 5.3)Mesna should be used to reduce the incidence of hemorrhagic cystitis. (2). Ifosfamide injection should be administered as slow intravenous infusion lasting minimum of 30 minutes at dose of 1.2 grams per m2 per day for consecutive days. (2). Treatment is repeated every weeks or after recovery from hematologic toxicity. (2). To prevent bladder toxicity, ifosfamide injection should be given with extensive hydration consisting of at least liters of oral or intravenous fluid per day. (2, 5.3). Mesna should be used to reduce the incidence of hemorrhagic cystitis. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. gram single dose vial3 gram single dose vial. Single dose vials: gram, grams (3). Single dose vials: gram, grams (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Ifosfamide is substrate for both CYP3A4 and CYP2B6.. CYP3A4 Inducers: monitor for increased toxicity when used in combination with CYP3A4 inducers. (7.1)CYP3A4 Inhibitors: use in combination with CYP3A4 inhibitors could decrease the effectiveness of ifosfamide. (7.2). CYP3A4 Inducers: monitor for increased toxicity when used in combination with CYP3A4 inducers. (7.1). CYP3A4 Inhibitors: use in combination with CYP3A4 inhibitors could decrease the effectiveness of ifosfamide. (7.2). 7.1 Inducers of CYP3A4. CYP3A4 inducers (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. Johns Wort) may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.. 7.2 Inhibitors of CYP3A4. CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grapefruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.

GERIATRIC USE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Myelosuppression, Immunosuppression, and InfectionsAdvise patients that treatment with ifosfamide 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 and plan for regular blood monitoring during therapy [see Boxed Warning, Warnings and Precautions (5.1)] Inform patients to report fever or other symptoms of an infection [see Boxed Warning, Warnings and Precautions (5.1), Adverse Reactions (6.2)]. Advise patients on the risks of bleeding and anemia [see Warnings and Precautions (5.1, 5.8), Adverse Reactions (6.2)], Use in Specific Populations (8.1)]. Central Nervous System Toxicity, NeurotoxicityAdvise patients on the risk of CNS toxicity and other neurotoxic effects with fatal outcome [see Boxed Warning, Warnings and Precautions (5.2)]. Renal and Urothelial Toxicity and EffectsAdvise 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)]. CardiotoxicityAdvise 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 ToxicityAdvise 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 MalignanciesAdvise patients on the risk of secondary malignancies due to therapy [see Warnings and Precautions (5.6)].Veno-occlusive Liver DiseaseAdvise patients on the risk of veno-occlusive liver disease [see Warnings and Precautions (5.7)]. PregnancyAdvise patients on the potential hazard to fetus if patient becomes pregnant or fathers child during therapy and for up to months after therapy.Advise patients to use effective contraception during therapy and for up to months after therapy [see Warnings and Precautions (5.8), Adverse Reactions (6.2)].LactationAdvise patients on the potential for serious adverse reactions and tumorigenicity when children are breastfed during therapy [see Use in Specific Populations (8.3)].Reproductive System DisordersAdvise patients on the risk of amenorrhea, premature menopause, and sterility [see Warnings and Precautions (5.9), Adverse Reactions (6.2)]. Skin and Subcutaneous Tissue DisordersAdvise 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 DisordersAdvise 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 DisordersAdvise patients on the risk of eye disorders such as visual impairment, blurred vision, and eye irritation [see Adverse Reactions (6.2)]. Ear and Labyrinth DisordersAdvise patients on the risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus [see Adverse Reactions (6.2)]. Distributed by:Teva Pharmaceuticals USA, Inc.Parsippany, NJ 07054 19454Rev. 2/2020. Advise patients that treatment with ifosfamide 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 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)]. Advise patients on the risk of CNS toxicity and other neurotoxic effects with fatal outcome [see Boxed Warning, Warnings and Precautions (5.2)]. 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)]. 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)].. 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)]. Advise patients on the risk of secondary malignancies due to therapy [see Warnings and Precautions (5.6)].. Advise patients on the risk of veno-occlusive liver disease [see Warnings and Precautions (5.7)]. Advise patients on the potential hazard to fetus if patient becomes pregnant or fathers child during therapy and for up to months after therapy.. Advise patients to use effective contraception during therapy and for up to months after therapy [see Warnings and Precautions (5.8), Adverse Reactions (6.2)].. Advise patients on the potential for serious adverse reactions and tumorigenicity when children are breastfed during therapy [see Use in Specific Populations (8.3)].. Advise patients on the risk of amenorrhea, premature menopause, and sterility [see Warnings and Precautions (5.9), Adverse Reactions (6.2)]. 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)]. 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)]. Advise patients on the risk of eye disorders such as visual impairment, blurred vision, and eye irritation [see Adverse Reactions (6.2)]. Advise patients on the risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus [see Adverse Reactions (6.2)].

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

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 mg/kg (37 mg/m2, or about 3% of the daily human dose on mg/m2 basis) times week for 52 weeks. Female rats had 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 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/m2) orally days week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on mg/m2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m2) ifosfamide intraperitoneally once every weeks for months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on mg/m2 basis).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Women must not breastfeed during treatment with ifosfamide.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No specific antidote for ifosfamide 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. carton g/20 mL. Ifosfamide Injection 50 mg/mL, 20 mL Single Dose Vial Carton Text. NDC 0703-3427-11Rx onlyIfosfamideInjection1 g/20 mL(50 mg/mL)Single Dose VialFor Intravenous UseSterileTEVA.

PEDIATRIC USE SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 g/m2, 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/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about hours.Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hours once daily for days to 15 patients with neoplastic disease, decrease in the median elimination half-life from 7.2 hours on Day to 4.6 hours on Day occurred with concomitant increase in the median clearance from 66 mL/min on Day to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day compared with Day 1. DistributionIfosfamide 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/m2 over 0.5 hours once daily for days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 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 substrate for P-glycoprotein.MetabolismIfosfamide 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.ExcretionAfter administration of doses of g/m2 of 14C-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/m2 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.PediatricsPopulation PK analysis was performed on plasma data from 32 pediatric patients various malignant diseases aged between and 18 years. Patients received total of 45 courses of ifosfamide at doses of 1.2, 2.0 and 3.0 g/m2 given intravenously over or hours on 1, 2, or days. The mean+-standard error population estimates for the initial clearance and volume of distribution of ifosfamide were 2.4+-0.33 L/h/m2 and 21+-1.6 L/m2 with an interindividual variability of 43% and 32%, respectively.Effect of AgeA study of 20 patients between 40 to 71 years of age receiving 1.5 g/m2 of ifosfamide daily for or 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.

PREGNANCY SECTION.

8.1 Pregnancy. Ifosfamide can cause fetal harm when administered to pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.Women should not become pregnant and men should not father child during therapy with ifosfamide. Further, men should not father child for up to months after the end of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to fetus.

REFERENCES SECTION.

15 REFERENCES. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otmvi/otmvi2.html. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am Health-Syst Pharm. 2006;63:1172-1193.Polovich M, White JM, Kelleher LO, (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. (2nd ed.) Pittsburgh, PA: Oncology Nursing Society.. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otmvi/otmvi2.html. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am Health-Syst Pharm. 2006;63:1172-1193.. Polovich M, White JM, Kelleher LO, (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. (2nd ed.) Pittsburgh, PA: Oncology Nursing Society.

SPL UNCLASSIFIED SECTION.

5.1 Myelosuppression, Immunosuppression, and Infections. Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When ifosfamide is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dose-dependent and is increased with administration of single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function.Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, ifosfamide should not be given to patients with WBC count below 2000/microliter and/or platelet count below 50,000/microliter.Ifosfamide should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: fetal growth retardation and neonatal anemia. (8.1)Geriatric use: dose selection should be cautious. (8.5)Patients with renal impairment: monitor for toxicity and consider dose reduction as needed (8.6). Pregnancy: fetal growth retardation and neonatal anemia. (8.1). Geriatric use: dose selection should be cautious. (8.5). Patients with renal impairment: monitor for toxicity and consider dose reduction as needed (8.6). 8.1 Pregnancy. Ifosfamide can cause fetal harm when administered to pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group.Women should not become pregnant and men should not father child during therapy with ifosfamide. Further, men should not father child for up to months after the end of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to fetus.. 8.3 Nursing Mothers. Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events and the tumorigenicity shown for ifosfamide in animal studies, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Women must not breastfeed during treatment with ifosfamide.. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age [see Pharmacokinetics (12.3)]. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported.Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.. 8.6 Use in Patients with Renal Impairment. No formal studies were conducted in patients with renal impairment. Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Patients with renal impairment should be closely monitored for toxicity and dose reduction may be considered. Ifosfamide and its metabolites are dialyzable. 8.7 Use in Patients with Hepatic Impairment. No formal studies were conducted in patients with hepatic impairment. Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Ifosfamide should be given cautiously to patients with impaired hepatic function.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myelosuppression: Can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after treatment. (5.1)Neurotoxicity: Severe and fatal neurotoxicity can occur. Carefully monitor the patient for CNS toxicity and other neurotoxic effects. Discontinue therapy should encephalopathy develop. (5.2) Urotoxicity: Severe nephrotoxicity with renal failure and death can occur. Monitor for nephrotoxicity with serum and urine chemistries. Mesna should be used to reduce hemorrhagic cystitis. (5.3) Cardiotoxicity: Arrhythmias, other ECG changes, and cardiomyopathy can occur and result in death. Use with caution in patients with cardiac risk factors and in patients with preexisting cardiac disease. The risk of cardiotoxicity is dose dependent. (5.4) Pulmonary toxicity: Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity with fatal outcomes can occur. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated (5.5) Secondary malignancies as late sequelae have occurred. (5.6) Pregnancy: Can cause fetal harm. Women should not become pregnant and men should not father child during therapy. (5.8) Anaphylactic/anaphylactoid reactions have been reported. (5.10). Myelosuppression: Can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after treatment. (5.1). Neurotoxicity: Severe and fatal neurotoxicity can occur. Carefully monitor the patient for CNS toxicity and other neurotoxic effects. Discontinue therapy should encephalopathy develop. (5.2) Urotoxicity: Severe nephrotoxicity with renal failure and death can occur. Monitor for nephrotoxicity with serum and urine chemistries. Mesna should be used to reduce hemorrhagic cystitis. (5.3) Cardiotoxicity: Arrhythmias, other ECG changes, and cardiomyopathy can occur and result in death. Use with caution in patients with cardiac risk factors and in patients with preexisting cardiac disease. The risk of cardiotoxicity is dose dependent. (5.4) Pulmonary toxicity: Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity with fatal outcomes can occur. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated (5.5) Secondary malignancies as late sequelae have occurred. (5.6) Pregnancy: Can cause fetal harm. Women should not become pregnant and men should not father child during therapy. (5.8) Anaphylactic/anaphylactoid reactions have been reported. (5.10). 5.1 Myelosuppression, Immunosuppression, and Infections. Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of ifosfamide-associated myelosuppression have been reported. Ifosfamide-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When ifosfamide is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dose-dependent and is increased with administration of single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function.Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with ifosfamide include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with ifosfamide, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, ifosfamide should not be given to patients with WBC count below 2000/microliter and/or platelet count below 50,000/microliter.Ifosfamide should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.. 5.2 Central Nervous System Toxicity, Neurotoxicity. Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. The risk of CNS toxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, have been reported following ifosfamide therapy. There have also been reports of peripheral neuropathy associated with ifosfamide use.Ifosfamide neurotoxicity may manifest within few hours to few days after first administration and in most cases resolves within 48 to 72 hours of ifosfamide discontinuation. Symptoms may persist for longer periods of time. Supportive therapy should be maintained until their complete resolution. Occasionally, recovery has been incomplete. Fatal outcomes of CNS toxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses has been reported. If encephalopathy develops, administration of ifosfamide should be discontinued. Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide-induced encephalopathy. Manifestations of CNS toxicity may impair patients ability to operate an automobile or other heavy machinery.. 5.3 Renal and Urothelial Toxicity and Effects. Ifosfamide is both nephrotoxic and urotoxic. Glomerular and tubular kidney function must be evaluated before commencement of therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity.Monitor serum and urine chemistries, including phosphorus and potassium regularly. Administer appropriate replacement therapy as indicated. Renal parenchymal and tubular necrosis have been reported in patients treated with ifosfamide. Acute tubular necrosis, acute renal failure, and chronic renal failure secondary to ifosfamide therapy have been reported, and fatal outcome from nephrotoxicity has been documented.Disorders of renal function, (glomerular and tubular) following ifosfamide administration are very common. Manifestations include decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Fanconi syndrome, renal rickets, and growth retardation in children as well as osteomalacia in adults also have been reported. Development of syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported with ifosfamide. Tubular damage may become apparent during therapy, months or even years after cessation of treatment. Glomerular or tubular dysfunction may resolve with time, remain stable, or progress over period of months or years, even after completion of ifosfamide treatment. The risk and expected benefits of ifosfamide therapy should be carefully weighed when considering the use of ifosfamide in patients with preexisting renal impairment or reduced nephron reserve.Urotoxic side effects, especially hemorrhagic cystitis, have been very commonly associated with the use of ifosfamide. These urotoxic effects can be reduced by prophylactic use of mesna.Hemorrhagic cystitis requiring blood transfusion has been reported with ifosfamide. The risk of hemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration. Hemorrhagic cystitis after single dose of ifosfamide has been reported. Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis. Before starting treatment, it is necessary to exclude or correct any urinary tract obstructions [see Contraindications (4)]. During or immediately after administration, adequate amounts of fluid should be ingested or infused to force dieresis in order to reduce the risk of urinary tract toxicity. Obtain urinalysis prior to each dose of ifosfamide. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution. Further administration of ifosfamide should be given with vigorous oral or parenteral hydration.Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections.. 5.4 Cardiotoxicity. Manifestations of cardiotoxicity reported with ifosfamide treatment include:Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardiaDecreased QRS voltage and ST-segment or T-wave changesToxic cardiomyopathy leading to heart failure with congestion and hypotensionPericardial effusion, fibrinous pericarditis, and epicardial fibrosisFatal outcome of ifosfamide-associated cardiotoxicity has been reported. The risk of developing cardiotoxic effects is dose-dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.Particular caution should be exercised when ifosfamide is used in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.. 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. 5.5 Pulmonary Toxicity. Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment. Pulmonary toxicity leading to respiratory failure as well as fatal outcome has also been reported. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.. 5.6 Secondary Malignancies. Treatment with ifosfamide involves the risk of secondary tumors and their precursors as late sequelae. The risk of myelodysplastic alterations, some progressing to acute leukemias, is increased. Other malignancies reported after use of ifosfamide or regimens with ifosfamide include lymphoma, thyroid cancer, and sarcomas.The secondary malignancy 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 Pregnancy. Ifosfamide can cause fetal harm when administered to pregnant woman. 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.Women should not become pregnant and men should not father child during therapy with ifosfamide. Further, men should not father child for up to months after the end of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to fetus [see Use in Specific Populations (8.1)].. 5.9 Effects on Fertility. 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.Female PatientsAmenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapy-induced amenorrhea increases with age. Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause.Male PatientsMen treated with ifosfamide may develop oligospermia or azoospermia. Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have 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.. 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.. 5.12 Nursing. Ifosfamide is excreted in breast milk. Women must not breastfeed during treatment with ifosfamide [see Use in Specific Populations (8.3)].