Ifosfamide (Monograph)

Brand name: Ifex/Mesnex Kit
Drug class: Antineoplastic Agents
- Alkylating Agents
VA class: AN100
CAS number: 3778-73-2

Medically reviewed by Drugs.com on Jun 30, 2023. Written by ASHP.

Introduction

Antineoplastic agent; alkylating agent structurally related to cyclophosphamide.

Uses for Ifosfamide

Testicular Cancer

Component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer (designated an orphan drug by FDA for this use).

Soft Tissue Sarcomas

Component of various chemotherapeutic regimens in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas^{† [off-label]} (designated an orphan drug by FDA for this use).

Osteosarcoma

Used alone or in conjunction with other drugs (e.g., etoposide) for treatment of localized, metastatic, and recurrent osteosarcoma^{† [off-label]} (designated an orphan drug by FDA for this use).

Bladder Cancer

Used alone or in combination with other antineoplastic agents for treatment of advanced or metastatic bladder cancer^{† [off-label]}.

Small Cell Lung Cancer

Treatment of small cell lung cancer^{† [off-label]} as part of a combination regimen.

Cervical Cancer

Component of various combination regimens (e.g., cisplatin and ifosfamide with or without bleomycin) for the treatment of metastatic or recurrent cervical cancer^{† [off-label]}.

Ovarian Cancer

Used alone or in conjunction with other antineoplastic agents for second-line (salvage) therapy in patients with advanced or recurrent ovarian carcinoma^†.

Non-Hodgkin’s Lymphoma

Treatment of advanced small noncleaved cell lymphoma (Burkitt’s and non-Burkitt’s) in children as part of a combination regimen.

Related/similar drugs

Keytruda, Avastin, carboplatin, pembrolizumab, fluorouracil, doxorubicin, cyclophosphamide

Ifosfamide Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Adequately hydrate patient prior to and during ifosfamide therapy (e.g., 2 L of oral or IV fluid daily) to minimize urotoxicity.

• Concomitant therapy with a uroprotective agent (e.g., mesna) recommended during ifosfamide therapy to decrease the incidence of bladder toxicity. (See Bladder Toxicity under Cautions.)

Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow IV infusion.

Handle cautiously (e.g., use protective gloves); avoid exposure during handling and preparation of IV solution. If skin or mucosal contact occurs, immediately wash skin with soap and water and flush mucosa with water.

IV Administration

Reconstitution

Reconstitute vial containing 1 or 3 g of ifosfamide powder with 20 or 60 mL, respectively, of sterile or bacteriostatic water for injection, to provide a solution containing 50 mg/mL.

Shake well to ensure complete dissolution. May be infused directly or further diluted prior to IV infusion.

Dilution

May be diluted with 5% dextrose injection, 0.9% sodium chloride injection, lactated Ringer’s injection, or sterile water for injection to a concentration of 0.6–20 mg/mL.

Rate of Administration

Administer as a slow IV infusion over a period of ≥30 minutes.

Dosage

Consult published protocols for the dosage of ifosfamide and other chemotherapeutic agents and the method and sequence of administration.

Adults

Testicular Cancer

IV

1.2 g/m² daily for 5 consecutive days. Repeat course of therapy every 3 weeks (or following recovery of patient’s hematologic functions to within acceptable limits), usually for a total of 4 courses.

Cautions for Ifosfamide

Contraindications

• Severe bone marrow depression.

• Known hypersensitivity to ifosfamide or any ingredient in the formulation.

Warnings/Precautions

Warnings

Bladder Toxicity

Hemorrhagic cystitis, hematuria, dysuria, and urinary frequency reported frequently. Hemorrhagic cystitis can be severe and may be fatal.

Attributed to chemical irritation by metabolites (e.g., acrolein) that accumulate in concentrated urine.

Reduce bladder toxicity with conventional uroprophylaxis (e.g., high fluid intake, frequent urination) and use of fractionated ifosfamide dosage schedule, and concurrent administration of mesna.

Examine urine prior to administration of each ifosfamide dose for presence of erythrocytes, which may precede hemorrhagic cystitis.

If microscopic hematuria is present (>10 erythrocytes per high power field [HPF]), discontinue ifosfamide until complete resolution; use vigorous oral or parenteral hydration as well as mesna for subsequent courses of ifosfamide.

Discontinue ifosfamide or reduce dosage in patients who develop hematuria (>50 erythrocytes/HPF) while receiving usual dosages of ifosfamide in conjunction with mesna.

Hematologic Effects

Dose-dependent myelosuppression, principally leukopenia and, to a lesser extent, thrombocytopenia, occurs commonly.

Carefully monitor hematologic status during therapy; evaluate leukocyte and platelet counts and hemoglobin concentrations prior to and at appropriate intervals during therapy. Do not administer ifosfamide if leukocyte count <2000/mm³ and/or platelet count <50,000/mm³. In general, withhold subsequent courses until leukocyte count >4000/mm³ and platelet count >100,000/mm³.

Use with caution in patients with compromised bone marrow reserve (i.e., leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents).

Nervous System Effects

Risk of neurotoxicity, characterized by somnolence, confusion, encephalopathy, coma, confusion, mutism, auditory and/or visual hallucinations, and stupor.

If one or more signs of serious neurotoxicity (i.e., somnolence, confusion, hallucinations, and/or coma) occur during therapy, discontinue therapy and institute appropriate supportive therapy. Effects generally are reversible and resolve within 2–4 days. Methylene blue has been used in management of ifosfamide-induced encephalopathy.

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.

If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Major Toxicities

Renal Effects

Potentially serious nephrotoxicity (e.g., acute or chronic renal failure, Fanconi’s syndrome, renal tubular acidosis, nephrogenic diabetes insipidus); may be evidenced by aminoaciduria, glycosuria, proteinuria, cells or casts in the urine, increase in S_cr or BUN, or decreased Cl_cr.

Nephrotoxicity may develop during therapy or following discontinuance of the drug and can be reversible.

Increased risk of nephrotoxicity associated with previous or concurrent cisplatin therapy and in patients with preexisting renal impairment, infiltrating renal tumor, or prior nephrectomy.

Electrolyte Disturbances

Potentially fatal electrolyte abnormalities and/or acidosis reported. Closely monitor serum and urine chemistries (i.e, phosphorus, potassium, alkaline phosphatase) and other appropriate laboratory studies. If electrolyte abnormalities develop, institute appropriate therapy to correct any imbalance(s).

General Precautions

Wound Healing

May interfere with normal wound healing.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Has been used in children 15 days to 17 years of age for the treatment of certain malignancies (e.g., Ewing’s sarcoma, rhabdomyosarcoma, Wilms’ tumor); adverse effects reported in these children appear to be similar to those reported in adults.

Children ≤5 years of age may be more susceptible to ifosfamide-induced renal toxicity than older children or adults.

Geriatric Use

Select dosage based on the clinical, renal, and hematologic response and tolerance of the patient; consider age-related decrease in hepatic, renal and/or hematopoietic function.

Renal Impairment

Use with caution. Possible increased risk of nephrotoxicity and neurotoxicity. (See Nervous System Effects under Cautions.)

Common Adverse Effects

Alopecia, nausea/vomiting, hematuria, CNS toxicity, infection, renal impairment.

Drug Interactions

Converted to active metabolites by mixed-function oxidases (cytochrome P-450 system).

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased or decreased metabolism of ifosfamide); may result in increased or decreased conversion to active metabolites.

Specific Drugs

Ifosfamide Pharmacokinetics

Absorption

Bioavailability

Following IV administration, peak plasma concentrations of the principal alkylating metabolite are reached within 20–30 minutes.

Distribution

Extent

Widely distributed throughout the body, including the brain and CSF. Distributed into milk.

Elimination

Metabolism

Extensively metabolized, principally in the liver, to active and inactive metabolites.

Metabolized to 4-hydroxyifosfamide (in equilibrium with acyclic tautomer aldoifosfamide), then to 4-ketoifosfamide. Also metabolized to chloroacetaldehyde, 2-dechloroethylifosfamide, and 3-dechloroethylifosfamide.

Aldoifosfamide spontaneously splits into ifosfamide mustard (primary alkylating metabolite) and to acrolein and may be enzymatically metabolized to carboxyifosfamide.

Elimination Route

Excreted principally in urine.

Half-life

Terminal half-life averages 4–8 hours in adults.

Stability

Storage

Parenteral

Powder for Injection

20–25°C; protect from temperature >30°C.

Compatibility

Parenteral

Solution CompatibilityHID

Drug Compatibility

Actions

• Interferes with DNA replication and transcription of RNA, resulting in disruption of nucleic acid function.

• Also has immunosuppressive activity.

Advice to Patients

• Risk of bladder toxicity, myelosuppression, and neurotoxicity.

• Importance of informing clinicians if excessive sleepiness, confusion, or hallucinations occur.

• Advise that alopecia is likely.

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed. Advise pregnant women of risk to the fetus.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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