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Ifosfamide [Ifex]
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General Considerations

Ifosfamide is quite toxic to the bone marrow and urinary system, and occasionally, to the brain. It MUST be given with mesna to protect the urinary system. As a single agent, its effectiveness in terms of response and duration of response is probably approximately equivalent to doxorubicin's.

During the pre-Gleevec years, GIST was included in the NON-uterine LMS statistics, which may account for Ifosfamide's low response rate against this category. GastroIntestinal Stromal Tumors are very difficult to treat. It is hard to know what Ifosfamide's record with extremity or other LMS is, because of the confounding inclusion of GIST in the earlier studies.

Ifosfamide might actually be the agent of choice, given equal effectiveness with Adriamycin, if there is to be radiation to the left chest or mediastinum. It would decrease the additive cardiotoxicity.

In Uterine LMS, doxorubicin and ifosfamide are about equivalent in their single agent abilities. Both as single agents with response rates approximately in the late teens, and somewhat short-lived, but LMS is a resistant cancer. If they are used together, or even sequentially, however, the response rate can go up as high as around 30%. This is the idea behind the AIM [adriamycin, ifosfamide, mesna] regimen. There is no survival advantage in their being used together, and there is a much increased toxicity if they are used together.
URLs for Patient Information
Ifosfamide - Ifex
Online Information


CancerBacup Drug Information

CancerSource Drug Information

MedlinePlus Drug Information

Additional MedlinePlus Information

Medscape Drug Information. Registration is free.


Mesna

Medline Plus

ifosfamide clinical trials and LMS

Descriptive Information

Ifosfamide, Ifex, or iphosphamide, is a alkylating agent used in chemotherapy. It is always given with Mesna, which protects the urinary tract.

It is activated by the liver [cytochrome P450] to ifosfamide mustard, and acrolein, the active ingredients. These cytotoxic products form cross-links with DNA, resulting in prevention of DNA synthesis [for reproduction] and function. It is active in all phases of the cell cycle.

Resistance to Ifosfamide can occur from:
* decreased cellular uptake of drug
* decreased expression of drug-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.

Ifosfamide is a powder which when dissolved in sterile water forms a clear/colorless solution. The solution should be inspected for particulate matter and discoloration, and should be refrigerated and used within 24 hours. Ifosfamide is well absorbed from the GI tract, but is only given intravenously because the oral form is highly neurotoxic.

Ifosfamide is widely distributed throughout the body's tissues, with about 20% of drug bound to plasma protein. It is extensively metabolized in the liver by the cytochrome P450 system and approximately 50-70% of the drug and its metabolites are excreted in urine. The half-life of the drug is 3-10 hours for standard therapy and up to 14 hours for high-dose therapy.
The dosage range for soft tissue sarcomas runs to 2000 mg/m2 IV continuous infusion on days 1-3 every 21 days, as part of the MAID regimen [Mesna, Adriamycin, Ifosfoamide, Dacarbazine] . Ifosfamide also used as part of the AIM regimen [Adriamycin, Ifosfamide, Mesna], and the CYVADIC regimen.

Considerations:
* Administer prophylactic antiemetics to avoid nausea and vomiting.
* Contraindicated in patients with peptic ulcer disease, severe liver disease, pregnancy and/or cardiac disease. * Contraindicated in patients with a history of thrombophlebitis or thromboembolic disorders. Monitor coagulation parameters including PT and INR when ifosfamide is used concurrently with warfarin, as ifosfamide may enhance its anticoagulant effects.
* 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.
* Uroprotection with mesna and hydration must be used to prevent bladder toxicity. Pre- and post-hydration (1500-2000 mL/day) or continuous bladder irrigations are recommended to prevent hemorrhagic cystitis. Important to monitor urine analysis for presence of gross and/or microscopic hematuria prior to each cycle of therapy.

Interactions with other drugs:
Phenobarbital, dilantin, 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.
Cimetidine or allopurinol increases the synthesis of ifosfamide metabolites resulting in increased host toxicity.
Cisplatin increases ifosfamide-associated renal toxicity.
Ifosfamide may enhance the anticoagulant effects of warfarin.

Toxicity
In one series, toxicity included two deaths from renal insufficiency and a third death related to neurologic impairment.


Side Effects

Bone Marrow
suppression is dose-limiting. Mainly white blood cell suppression and to a lesser extent lowered platelets. Lowest numbers occurs at 10-14 days with recovery in 21 days. The extent to which your blood count is reduced depends on the dose of chemotherapy you receive and which other chemotherapy drugs, if any, are given in combination. Neupogen or Procrit may be necessary [Colony Stimulating Factors like Neupogen can cause severe bone pain. Acetaminophen is recommended for that pain.] Blood counts will be done before each dose is given. Low white cell counts can increase your risk of getting a serious and overwhelming infection. Milder opportunistic infections are common: oral or vaginal thrush, fungal infections of nails. Report IMMEDIATELY if you have a fever of 100.5 F or higher, or signs of infection such as pain on passing your urine, cough, and bringing up sputum.
Lowered platelet counts can increase your risk of bleeding. DO NOT take any aspirin or aspirin-containing medicines. Report unusual bruising, or bleeding such as nose bleeds, bleeding of gums when you brush your teeth, or black, tarry stools.

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. Urinary tract protection with mesna and hydration must be used to prevent bladder toxicity. It is important to try to drink plenty of fluids to prevent any irritation. While you are having the chemotherapy you will be encouraged to pass urine every 3-4 hours during the day, and last thing at night. All your urine will be measured and tested for the presence of blood. If blood is present in the urine further doses of mesna will be given.

Nausea and vomiting. Usually occurs within 3-6 hours of therapy and may last up to 3 days. There are now very effective anti-sickness drugs to prevent or substantially reduce this. Loss of appetite is fairly common.

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. Doctors must be notified immediately if any of these symptoms occur.

Hair loss is common (about 80%) usually starting 3-4 weeks after the first dose of ifosfamide, although it may occur earlier. Hair may be lost completely or may just thin. Hair loss is temporary, and your hair will grow back after treatment. You may also experience thinning and loss of eyelashes, eyebrows and other body hair. Getting a wig before starting treatment may make it easier to deal with hair loss. Talk to your nurse or doctor about this. If your insurance does not cover it, there may be other resources to help you.

Skin rash, darkened [tanned] skin, ridged nail changes, can happen, and eventually resolve.

Water Retention. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This results in water retention.
Genital.

Amenorrhea [no periods], oligospermia [few sperm produced in semen], and infertility.
Ifosfamide is mutagenic [causes mutations], teratogenic [harms the developing fetus], and carcinogenic [causes cancer].

Fatigue.

Liver Ifosfamide may cause changes in liver function, which will return to normal when the treatment is finished. Liver function is also followed by doing blood tests.


Before taking this drug, notify your doctor of any of the following:
Some other medicines can be harmful when you are having chemotherapy.
Always let your doctor know about any other medicine you are taking, including over-the-counter drugs, vitamins, and herbals.
If you are pregnant, breast feeding or planning children in the future, inform your doctor of this before treatment. This drug may cause birth defects if either the male or female is taking it at the time of conception or during pregnancy. Men and women who are taking this drug need to use some kind of birth control. However, do not use oral contraceptives ("the pill") without checking with your doctor. Many chemotherapy drugs can cause sterility.

Notify your doctor if you have any of the following medical problems:
chickenpox or exposure to chickenpox,
gout,
heart disease,
congestive heart failure,
shingles,
kidney stones,
liver disease.

Precautions: While you are being treated with ifosfamide, and after you stop treatment, do not have any immunizations (vaccinations) without your doctor's okay. Try to avoid contact with people who have recently taken the oral polio vaccine.
Clinical Trial Results

The Clinical Trials results are the experiments done in the past to see if the drug works, and how well, and for how long.


PubMed Searches
Directions for use:


When you click on the search link, it will connect you to Pubmed and display the first 20 citations [which they will call Summaries]. What you WANT is the complete listing of all the summaries of the article [which they will call Abstracts. ]

Go to the second toolbar, and use the drop down menu to change summaries to Abstracts, and 20 to 200, and sort by DATE, and then click on DISPLAY on that same toolbar. You may have to wait while the page loads.

NOW you can save this search to a folder on your hard drive as "IfosfamideClinicalTrials" as an HTML file - or as a text file. The entire file, or just those parts which you wish to discuss, can be printed out and taken to talk over with your doctor.

Search Pubmed for ifosfamide clinical trials and sarcoma

Search Pubmed for ASCO abstracts search page


ASCO Searches

You will have to go to the site and search year by year with the keywords of the chemotherapy agent AND sarcoma.


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compiled by doctordee
updated October 2003


The information on this site is not a substitute for professional medical advice. You should not use this information to diagnose or treat a health problem or disease without consulting with your doctor. Please consult your doctor with any questions or concerns you may have regarding your condition. Copyright 2001-2010 LMSWEBSITE