IFOXAN

Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide.

It is active as an alkylating agent and an immunosuppressive agent.

Used as a component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer.

Also used as a component of various chemotherapeutic regimens for the treatment of cervical cancer, as well as in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas.

Other indications include treatment of osteosarcoma, bladder cancer, ovarian cancer. small cell lung cancer, and non-Hodgkin's lymphoma.

Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects.

Activation occurs by hydroxylation at the ring carbon atom to form the unstable intermediate 4-hydroxyifosfamide.

This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide.

The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring.

These urinary metabolites have not been found to be cytotoxic.

N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found.

The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation.

It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA.

Ifosfamide is cycle-phase nonspecific.

Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding.

Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day and 0.72 L/kg on Day 5.

When given to pediatric patients, the volume of distribution was 21±1.6 L/m^2.

Primarily hepatic.

Ifosfamide is metabolized 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.

Hover over products below to view reaction partners Ifosfamide 3-Dechloroethylifosfamide Dechloroethylifosfamide Chloroacetaldehyde 2-chloroethanol 4-Hydroxyifosfamide 4-Thioifosfamide aldoifosfamide Isophosphamide mustard Ifosforamide Aziridinium Acrolein Acrylic Acid Carboxylifosfamide Alcoifosfamide 4-Ketoifosfamide.

Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses.

After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound.

At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.

The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.

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(mouse) = 390-1005 mg/kg, LD 50 (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression.

Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).

• Known hypersensitivity to administration of ifosfamide.

• Urinary outflow obstruction.

• Administer Ifosfamide for Injection with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day to reduce the incidence or severity of bladder toxicity.

• Administer mesna with Ifosfamide for Injection to reduce the incidence or severity of hemorrhagic cystitis.

• Administer Ifosfamide for Injection as a slow intravenous infusion (at least 30 minutes) at a dose of 1.2 grams per m 2 per day for 5 consecutive days.

Repeat every 3 weeks or after recovery from hematologic toxicity.

• Individualize the dose and dosing schedule of Ifosfamide for Injection based on patient risk factors and adverse reactions.

• See Full Prescribing Information for instructions on preparation and administration. 2.1 Important Administration Instructions Administer Ifosfamide for Injection with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day to reduce the incidence or severity of bladder toxicity.

Administer Ifosfamide for

Injection with mesna to reduce the incidence or severity of hemorrhagic cystitis. 2.2 Recommended Dosage The recommended dosage of Ifosfamide for Injection is 1.2 grams per m2 per day administered as a slow intravenous infusion (lasting at least 30 minutes) for 5 consecutive days.

Treatment is repeated every 3 weeks or after recovery from hematologic toxicity.

Individualize the dose and dosing schedule of Ifosfamide for Injection based on patient risk factors and adverse reactions. 2.3 Preparation and Administration Ifosfamide for Injection is a hazardous drug.

Follow applicable special handling and disposal procedures.1 Skin reactions associated with accidental exposure to Ifosfamide for Injection may occur.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing Ifosfamide for Injection.

If Ifosfamide for

Injection solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water.

Prepare Ifosfamide for Injection for intravenous use by adding Sterile Water for Injection, USP or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved) to the vial and shaking to dissolve.

Before administration, the substance must be completely dissolved.

Use the quantity of diluents shown in below to reconstitute the product: Table 1: Ifosfamide for Injection Quantities for Dilution and Final Concentrations Dosage Strength Quantity of Diluent Final Concentration 1 gram 20 mL 50 mg per mL 3 grams 60 mL 50 mg per mL Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:

• Sterile Water for Injection, USP Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use of large volume parenteral glass bottles, VIAFLEX bags or PAB bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable.

Refrigerate constituted or constituted and further diluted solutions of Ifosfamide for Injection and use within 24 hours.

Benzyl-alcohol-containing solutions can reduce the stability of ifosfamide.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Ifosfamide for injection is available in single-dose vials as follows: NDC 10019-925-01 1-gram Single-Dose Vial NDC 10019-926-02 3-gram Single-Dose Vial Store at controlled room temperature 20°C to 25°C (68°F to 77°F).

Protect from temperatures above 30°C (86°F).

Based on mechanism of action, and human and animal 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 to 4% and to 20%, respectively.

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 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.

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.

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.

Clinical studies of Ifosfamide for

Injection did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger subjects.

A study of patients to 71 years of age indicated that elimination half-life appears to increase with advancing age.

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.