IFOSFAMIDE

Ifosfamide for Injection, USP single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile, lyophilized ifosfamide. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. Ifosfamide is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino] tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide. Its structural formula is: Ifosfamide is a white crystalline powder that is soluble in water. ifosfamise structure

Ifosfamide for Injection, used in combination with certain other approved antineoplastic agents, is indicated for third line chemotherapy of germ cell testicular cancer. It should ordinarily be used in combination with a prophylactic agent for hemorrhagic cystitis, such as mesna.

Ifosfamide for Injection should be administered intravenously at a dose of 1.2 g/m 2 per day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity (Platelets ≥100,000/μL, WBC ≥4,000/μL). In order to prevent bladder toxicity, Ifosfamide for Injection should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. A protector, such as mesna, should also be used to prevent hemorrhagic cystitis. Ifosfamide for Injection should be administered as a slow intravenous infusion lasting a minimum of 30 minutes. Although Ifosfamide for Injection has been administered to a small number of patients with compromised hepatic and/or renal function, studies to establish optimal dose schedules of Ifosfamide for Injection in such patients have not been conducted. Preparation for Intravenous Administration/Stability Injections are prepared for parenteral use by adding Sterile Water for Injection, USP , or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved), to the vial and shaking to dissolve. Use the quantity of diluent shown below to constitute the product: Dosage Strength Quantity of Diluent Final Concentration 1 gram 20 mL 50 mg/mL 3 grams 60 mL 50 mg/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 Injection, USP Sterile Water for Injection, USP Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use of large volume parenteral glass bottles, Viaflex bags or PAB™ bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable. Constituted or constituted and further diluted solutions of Ifosfamide for Injection should be refrigerated and used within 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparation for Intravenous Administration/Stability Injections are prepared for parenteral use by adding Sterile Water for Injection, USP , or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved), to the vial and shaking to dissolve. Use the quantity of diluent shown below to constitute the product: Dosage Strength Quantity of Diluent Final Concentration 1 gram 20 mL 50 mg/mL 3 grams 60 mL 50 mg/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 Injection, USP Sterile Water for Injection, USP Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use of large volume parenteral glass bottles, Viaflex bags or PAB™ bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable. Constituted or constituted and further diluted solutions of Ifosfamide for Injection should be refrigerated and used within 24 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Continued use of Ifosfamide for Injection is contraindicated in patients with severely depressed bone marrow function (see WARNINGS and PRECAUTIONS sections). Ifosfamide for Injection is also contraindicated in patients who have demonstrated a previous hypersensitivity to it.

In patients receiving ifosfamide as a single agent, the dose-limiting toxicities are myelosuppression and urotoxicity. Dose fractionation, vigorous hydration, and a protector such as mesna can significantly reduce the incidence of hematuria, especially gross hematuria, associated with hemorrhagic cystitis. At a dose of 1.2 g/m 2 daily for 5 consecutive days, leukopenia, when it occurs, is usually mild to moderate. Other significant side effects include alopecia, nausea, vomiting, and central nervous system toxicities. Adverse Reaction *Incidence (%) Alopecia 83 Nausea-Vomiting 58 Hematuria 46 Gross Hematuria 12 CNS Toxicity 12 Infection 8 Renal Impairment 6 Liver Dysfunction 3 Phlebitis 2 Fever 1 Allergic Reaction <1 Anorexia <1 Cardiotoxicity <1 Coagulopathy <1 Constipation <1 Dermatitis <1 Diarrhea <1 Fatigue <1 Hypertension <1 Hypotension <1 Malaise <1 Polyneuropathy <1 Pulmonary Symptoms <1 Salivation <1 Stomatitis <1 * Based upon 2,070 patients from the published literature in 30 single agent studies. Hematologic Toxicity Myelosuppression was dose related and dose limiting. It consisted mainly of leukopenia and, to a lesser extent, thrombocytopenia. A WBC count <3000/μL is expected in 50% of the patients treated with ifosfamide single agent at doses of 1.2 g/m 2 per day for 5 consecutive days. At this dose level, thrombocytopenia (platelets <100,000/μL) occurred in about 20% of the patients. At higher dosages, leukopenia was almost universal, and at total dosages of 10 to 12 g/m 2 /cycle, one half of the patients had a WBC count below 1000/μL and 8% of patients had platelet counts less than 50,000/μL. Myelosuppression was usually reversible and treatment can be given every 3 to 4 weeks. When ifosfamide is used in combination with other myelosuppressive agents, adjustments in dosing may be necessary. Patients who experience severe myelosuppression are potentially at increased risk for infection. Anemia has been reported as part of postmarketing surveillance. Digestive System Nausea and vomiting occurred in 58% of the patients who received ifosfamide. They were usually controlled by standard antiemetic therapy. Other gastrointestinal side effects include anorexia, diarrhea, and in some cases, constipation. Urinary System Urotoxicity consisted of hemorrhagic cystitis, dysuria, urinary frequency and other symptoms of bladder irritation. Hematuria occurred in 6% to 92% of patients treated with ifosfamide. The incidence and severity of hematuria can be significantly reduced by using vigorous hydration, a fractionated dose schedule and a protector such as mesna. At daily doses of 1.2 g/m 2 for 5 consecutive days without a protector, microscopic hematuria is expected in about one half of the patients and gross hematuria in about 8% of patients. Renal toxicity occurred in 6% of the patients treated with ifosfamide as a single agent. Clinical signs, such as elevation in BUN or serum creatinine or decrease in creatinine clearance, were usually transient. They were most likely to be related to tubular damage. One episode of renal tubular acidosis which progressed into chronic renal failure was reported. Proteinuria and acidosis also occurred in rare instances. Metabolic acidosis was reported in 31% of patients in one study when ifosfamide was administered at doses of 2 to 2.5 g/m 2 /day for 4 days. Renal tubular acidosis, Fanconi syndrome, renal rickets, and acute renal failure have been reported. Close clinical monitoring of serum and urine chemistries including phosphorus, potassium, alkaline phosphatase and other appropriate laboratory studies is recommended. Appropriate replacement therapy should be administered as indicated. Central Nervous System CNS side effects were observed in 12% of patients treated with ifosfamide. Those most commonly seen were somnolence, confusion, depressive psychosis, and hallucinations. Other less frequent symptoms include dizziness, disorientation, and cranial nerve dysfunction. Seizures and coma with death were occasionally reported. The incidence of CNS toxicity may be higher in patients with altered renal function. Other Alopecia occurred in approximately 83% of the patients treated with ifosfamide as a single agent. In combination, this incidence may be as high as 100%, depending on the other agents included in the chemotherapy regimen. Increases in liver enzymes and/or bilirubin were noted in 3% of the patients. Other less frequent side effects included phlebitis, pulmonary symptoms, fever of unknown origin, allergic reactions, stomatitis, cardiotoxicity, and polyneuropathy. Hematologic Toxicity Myelosuppression was dose related and dose limiting. It consisted mainly of leukopenia and, to a lesser extent, thrombocytopenia. A WBC count <3000/μL is expected in 50% of the patients treated with ifosfamide single agent at doses of 1.2 g/m 2 per day for 5 consecutive days. At this dose level, thrombocytopenia (platelets <100,000/μL) occurred in about 20% of the patients. At higher dosages, leukopenia was almost universal, and at total dosages of 10 to 12 g/m 2 /cycle, one half of the patients had a WBC count below 1000/μL and 8% of patients had platelet counts less than 50,000/μL. Myelosuppression was usually reversible and treatment can be given every 3 to 4 weeks. When ifosfamide is used in combination with other myelosuppressive agents, adjustments in dosing may be necessary. Patients who experience severe myelosuppression are potentially at increased risk for infection. Anemia has been reported as part of postmarketing surveillance. Digestive System Nausea and vomiting occurred in 58% of the patients who received ifosfamide. They were usually controlled by standard antiemetic therapy. Other gastrointestinal side effects include anorexia, diarrhea, and in some cases, constipation. Urinary System Urotoxicity consisted of hemorrhagic cystitis, dysuria, urinary frequency and other symptoms of bladder irritation. Hematuria occurred in 6% to 92% of patients treated with ifosfamide. The incidence and severity of hematuria can be significantly reduced by using vigorous hydration, a fractionated dose schedule and a protector such as mesna. At daily doses of 1.2 g/m 2 for 5 consecutive days without a protector, microscopic hematuria is expected in about one half of the patients and gross hematuria in about 8% of patients. Renal toxicity occurred in 6% of the patients treated with ifosfamide as a single agent. Clinical signs, such as elevation in BUN or serum creatinine or decrease in creatinine clearance, were usually transient. They were most likely to be related to tubular damage. One episode of renal tubular acidosis which progressed into chronic renal failure was reported. Proteinuria and acidosis also occurred in rare instances. Metabolic acidosis was reported in 31% of patients in one study when ifosfamide was administered at doses of 2 to 2.5 g/m 2 /day for 4 days. Renal tubular acidosis, Fanconi syndrome, renal rickets, and acute renal failure have been reported. Close clinical monitoring of serum and urine chemistries including phosphorus, potassium, alkaline phosphatase and other appropriate laboratory studies is recommended. Appropriate replacement therapy should be administered as indicated. Central Nervous System CNS side effects were observed in 12% of patients treated with ifosfamide. Those most commonly seen were somnolence, confusion, depressive psychosis, and hallucinations. Other less frequent symptoms include dizziness, disorientation, and cranial nerve dysfunction. Seizures and coma with death were occasionally reported. The incidence of CNS toxicity may be higher in patients with altered renal function. Other Alopecia occurred in approximately 83% of the patients treated with ifosfamide as a single agent. In combination, this incidence may be as high as 100%, depending on the other agents included in the chemotherapy regimen. Increases in liver enzymes and/or bilirubin were noted in 3% of the patients. Other less frequent side effects included phlebitis, pulmonary symptoms, fever of unknown origin, allergic reactions, stomatitis, cardiotoxicity, and polyneuropathy.