Physicians' Cancer Chemotherapy Drug Manual 2004
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

 

I

 

Ifosfamide


Generic Drug Name
Ifosfamide

 

 



 

Trade Names
Ifex, Isophosphamide
 


 

Classification
Alkylating agent


 

Category
Chemotherapy drug


 

Drug Manufacturer
Bristol-Myers Squibb


 

Mechanism of Action
 

  • Inactive in its parent form.
  • Activated by the liver cytochrome P450 microsomal system to various cytotoxic metabolites, including ifosfamide mustard and acrolein.
  • Cytotoxic metabolites form cross-links with DNA resulting in inhibition of DNA synthesis and function.
  • Cell cycle–nonspecific agent, active in all phases of the cell cycle.

 


 

Mechanism of Resistance
 

  • Decreased cellular uptake of drug.
  • Decreased expression of activating enzymes of the liver P450 system.
  • Increased expression of sulfhydryl proteins, including glutathione and glutathione-associated enzymes.
  • Increased expression of aldehyde dehydrogenase resulting in enhanced inactivation of drug.
  • Enhanced activity of DNA repair enzymes.

 


 

Absorption
Well-absorbed by the GI tract with a bioavailability of nearly 100%. However, only IV form is available commercially because oral form is highly neurotoxic.


 

Distribution
Widely distributed into body tissues. About 20% of drug is bound to plasma protein.


 

Metabolism
Extensively metabolized in the liver by the cytochrome P450 system. Activated at a four-fold slower rate than cyclophosphamide because of lower affinity to the liver P450 system. For this reason, about fourfold more drug is required to produce equitoxic antitumor effects with cyclophosphamide. The half-life of the drug is 3–10 hours for standard therapy and up to 14 hours for high-dose therapy. Approximately 50%–70% of the drug and its metabolites are excreted in urine.


 

Indications
 

  1. Recurrent germ cell tumors.
  2. Soft tissue sarcoma, osteogenic sarcoma.
  3. Non-Hodgkin's lymphoma.
  4. Hodgkin's disease.
  5. Non–small cell and small cell lung cancer.
  6. Bladder cancer.
  7. Head and neck cancer.
  8. Cervical cancer.
  9. Ewing's sarcoma.

 


 

Dosage Range
 

  1. Testicular cancer: 1,200 mg/m2 IV on days 1–5 every 21 days, as part of the VeIP salvage regimen.
  2. Soft tissue sarcoma: 2,000 mg/m2 IV continuous infusion on days 1–3 every 21 days, as part of the MAID regimen.
  3. Non-Hodgkin's lymphoma: 1,000 mg/m2 on days 1 and 2 every 28 days, as part of the ICE regimen.
  4. Head and neck cancer: 1,000 mg/m2 on days 1–3 every 21–28 days, as part of the TIC regimen.

 


 

Drug Preparation
 

  • Available in 1 and 3 gm single-dose vials for IV use, prepackaged with mesna.
  • Reconstitute with sterile water.
  • May dilute further to concentrations of 0.6–20 mg/mL in either 5% dextrose or 0.9% sodium chloride.
  • Solution should be inspected for particulate matter and discoloration.
  • Reconstituted solution should be refrigerated and used within 24 hours.

 


 

Drug Interaction 1
Phenobarbital, phenytoin, and other drugs that stimulate the liver P450 system―Increase the rate of metabolic activation of ifosfamide to its toxic metabolites resulting in enhanced host toxicity.


 

Drug Interaction 2
Cimetidine and allopurinol―Increase the formation of ifosfamide metabolites resulting in increased host toxicity.


 

Drug Interaction 3
Cisplatin―Increases ifosfamide-associated renal toxicity.


 

Drug Interaction 4
Warfarin―Ifosfamide may enhance the anticoagulant effects of warfarin.



 

Special Considerations
 

  1. Administer prophylactic antiemetics to avoid nausea and vomiting.
  2. Contraindicated in patients with a history of thrombophlebitis or thromboembolic disorders.
  3. Use with caution in patients with abnormal renal function. Dose reduction is necessary in this setting. Baseline creatinine clearance must be obtained, and renal function should be monitored during therapy.
  4. Uroprotection with mesna and hydration must be used to prevent bladder toxicity. Pre- and post-hydration (1,500–2,000 mL/day) or continuous bladder irrigations are recommended to prevent hemorrhagic cystitis. Important to monitor urine for presence of gross and/or microscopic hematuria before each cycle of therapy.
  5. Monitor coagulation parameters, including PT and INR, when ifosfamide is used concurrently with warfarin, as ifosfamide may enhance its anticoagulant effects.
  6. Contraindicated in patients with peptic ulcer disease, severe liver disease, and/or cardiac disease.
  7. Pregnancy category D.

 


 

Toxicity 1
Myelosuppression is dose-limiting. Mainly leukopenia and to a lesser extent thrombocytopenia. Nadir occurs at 10–14 days with recovery in 21 days.
 


 

Toxicity 2
Bladder toxicity can be dose-limiting and manifested by hemorrhagic cystitis, dysuria, and increased urinary frequency. Chronic fibrosis of bladder leads to an increased risk of secondary bladder cancer. Uroprotection with mesna and hydration must be used to prevent bladder toxicity.
 


 

Toxicity 3
Nausea and vomiting. Usually occurs within 3–6 hours of therapy and may last up to 3 days. Anorexia is fairly common.
 


 

Toxicity 4
Neurotoxicity in the form of lethargy, confusion, seizure, cerebellar ataxia, weakness, hallucinations, cranial nerve dysfunction, and rarely stupor and coma. Incidence may be higher in patients receiving high-dose therapy and in those with impaired renal function.
 


 

Toxicity 5
Alopecia is common (> 80%). Skin rash, hyperpigmentation, and nail changes are occasionally seen.
 


 

Toxicity 6
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
 


 

Toxicity 7
Amenorrhea, oligospermia, and infertility.
 


 

Toxicity 8
Mutagenic, teratogenic, and carcinogenic.