Ifosfamide - Uses, Dosage, Side Effects, Interaction - Rxharun

Ifosfamide – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

The exact mechanism of ifosfamide has not been determined but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra-strand cross-links in the DNA results in cell death. Mechanism of action: metabolites cause the alkylation of DNA.

Ifosfamide, a structural analog of cyclophosphamide, belongs to the oxazaphosphorine class of antitumor alkylating agents which must be activated by the mixed-function oxidase system of the liver. The 4-hydroxy oxazaphosphorines are a reactive species capable of interacting with nucleic acids & cellular materials to cause cell damage & death. The 4-hydroxy metabolite spontaneously liberates acrolein in many sites throughout the body & it is this substance that is responsible for oxazaphosphorine urotoxicity. Both ifosfamide & cyclophosphamide produce cystitis characterized by tissue edema & ulceration followed by sloughing of mucosal epithelial cells, necrosis of smooth muscle fibers & arteries, & culminating in focal hemorrhage. The selective urotoxicity of oxazaphosphorine occurs because the bladder contains a very low content of thiol cmpds (glutathionecysteine) which, by virtue of their nucleophilic sulfhydryl groups, are able to react & neutralize many reactive chemicals. Because the metabolic activation of ifosfamide proceeds more slowly than that of cyclophosphamide, doses of ifosfamide are 3-4 times higher than those of cyclophosphamide. This explains the higher incidence of urotoxicity associated with ifosfamide.

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 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite then rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon the opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (phosphoramide) 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.


  • 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 is a parenterally administered alkylating agent similar to cyclophosphamide that is used in the treatment of several forms of cancer including lymphomas, sarcoma and advanced forms of solid organ cancer such as breast, testicular, ovarian, gastric and lung cancer.
  • Ifosfamide is an alkylating and immunosuppressive agent used in chemotherapy for the treatment of cancers, including testicular cancer, ovarian cancer, cervical cancer, osteosarcoma, bladder cancer, small cell lung cancer, and non-Hodgkin’s lymphoma.
  • 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.
  • Bladder Cancer, Cancer
  • Cervical Cancer
  • Ewing’s Sarcoma
  • Head and Neck Carcinoma
  • Lymphoma, Hodgkins
  • Malignant Neoplasm of Pancreas
  • Non-Hodgkin’s Lymphoma (NHL)
  • Osteosarcoma
  • Ovarian Cancer
  • Small Cell Lung Cancer (SCLC)
  • Soft Tissue Sarcoma
  • Testicular Germ Cell Cancer
  • Advanced thymic carcinoma

Use in Cancer.gov

Ifosfamide is approved to be used with other drugs to treat:

Ifosfamide is also being studied in the treatment of other types of cancer.

Therapeutic Uses

  • Ifosfamide currently is approved for use in combination with other drugs for germ-cell testicular cancer & is widely used to treat pediatric & adult sarcomas. Clinical trials also have shown ifosfamide to be active against carcinomas of the cervix & lung & against lymphomas. It is a common component of high-dose chemotherapy regimens with bone marrow or stem cell rescue; in these regimens, in total doses of 12-14 g/sq m, it may cause severe neurological toxicity, including coma & death. This toxicity is thought to result from a metabolite, chloracetaldehyde. In addition to hemorrhagic cystitis, ifosfamide causes nausea, vomiting, anorexia, leukopenia, nephrotoxicity, & CNS disturbances (especially somnolence & confusion).
  • Ifosfamide is indicated, in combination with other antineoplastic agents and a prophylactic agent against hemorrhagic cystitis (such as mesna), for the treatment of germ cell testicular tumors.
  • Ifosfamide is indicated as reasonable medical therapy for the treatment of head and neck carcinoma.
  • Ifosfamide is used for the treatment of soft-tissue sarcomas, Ewing’s sarcoma, and Hodgkin’s and non-Hodgkin’s lymphomas.
  • Ifosfamide is indicated for the treatment of breast carcinomas, cervical carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, ovarian epithelial carcinoma, acute lymphocytic leukemia, neuroblastoma, and osteosarcoma.
  • Ifosfamide, in combination therapy, is considered reasonable medical therapy at some point in the management of germ-cell ovarian tumors. (Evidence rating: IIID).
  • Ifosfamide, alone and in combination with other chemotherapeutic agents, is considered reasonable medical therapy at some point in the management of bladder carcinoma (Evidence rating: IIID) and endometrial carcinoma (Evidence rating IIIA).
  • Ifosfamide is indicated, alone or in combination with other chemotherapeutic agents, as second-line therapy for the treatment of Wilms’ tumor in patients who have not responded to or whose disease has progressed during previous treatment (Evidence rating: IIID).

FDA Approved Indications

Ifosfamide is an alkylating agent and an analog of cyclophosphamide, used as a single agent or in combination with other agents to treat a wide variety of malignancies. These malignancies include:

  • Germline tumor of the testis
  • Soft tissue sarcomas
  • Ewing sarcoma
  • Cervical cancer, either recurrent or metastatic
  • Advanced bladder carcinoma
  • Non-Hodgkin lymphoma
  • Hodgkin lymphoma
  • Small and nonsmall cell lung carcinoma
  • Osteosarcoma
  • Ovarian cancer
  • Thymic cancer

Among all these cancers, the Food and Drug Administration (FDA) has approved the drug only for germline tumors of the testis. The indications for the use of ifosfamide include: 

  • Germline Tumor of the Testis – The FDA-approved regimen is ifosfamide and mesna at a 1.2 g/m²/day dose for five days, repeated every three weeks or following count recovery. When using ifosfamide and other chemotherapeutic drugs, mainly cisplatin, paclitaxel, or etoposide, there has been complete remission in about 21 to 26% of the treated population. Aggressive hydration (at least 2 liters oral or IV) is necessary during administration.
  • Soft Tissue Sarcomas (off-label use) – Noncomparative studies have shown that combination therapy with ifosfamide/mesna has demonstrated objective response rates of around 40% when used as induction therapy.
  • Ewing Sarcoma (off-label use) – Doses of ifosfamide vary based on the age group. Used alongside vincristine, etoposide, doxorubicin along with mesna in different regimens. Overall, survival is better with combination therapies. 
  • Cervical Cancer, Recurrent, or Metastatic (off-label use) – Ifosfamide is dosed along with mesna at 1500 g/m2/day every three weeks. When used along with paclitaxel and cisplatin, the response rate was 18 to 45%.
  • Bladder Carcinoma: Mainly Advanced Carcinoma (off-label use) 
  • Non-Hodgkin Lymphoma (off-label use) – Used in Burkitt lymphoma and diffuse large B cell lymphoma (DLBCL) as salvage therapy.
  • Hodgkin Lymphoma (off-label use) Used in relapsed or refractory cases in the RICE regimen (rituximab, ifosfamide, carboplatin, and etoposide) along with mesna.
  • Small and Non-small-cell cancer: When used as maintenance or consolidation has been shown to have more benefits than standard regimens.
  • Osteosarcoma (off-label use)
  • Ovarian Cancer – Used in advanced stages that are platinum-resistant. Many additional trials are underway. Response rates have been more than 40% when used as a combination.
  • Thymic Cancer – Used in advanced stages of thymic cancer. 


  • There are very few known contraindications for the use of ifosfamide. The absolute contraindications are known hypersensitivity to the drug or its components and urinary tract outflow obstruction. Relative contraindications include myelosuppression and severe renal or hepatic impairment.
  • Known hypersensitivity to the drug and/or its components – can result in anaphylaxis with drug administration.
  • Urinary outflow obstruction – there is a high chance of developing cystitis when there is urinary tract obstruction due to an accumulation of toxic compounds.
  • Severe thrombocytopenia and leukopenia – due to the known toxic effect of hematologically, the drug is avoided in severe thrombocytopenia and leukopenia.
  • Severe renal or hepatic impairment – drug metabolism occurs in the liver, and the drug is excreted by the kidneys, prohibiting its use in severe renal and hepatic impairment.
  • cancer metastasis to bone
  • dehydration
  • low amount of potassium in the blood
  • Fanconi syndrome is a condition of the kidneys resulting in excessive urination, thirst, and vomiting
  • anemia
  • decreased blood platelets
  • low levels of white blood cells
  • confusion
  • generalized disorder of peripheral nerves
  • liver problems
  • renal tubular acidosis
  • decreased kidney function
  • inflammation and bleeding of the bladder due to chemotherapy
  • coma
  • the high amount of bilirubin in the blood
  • abnormal liver function tests
  • impaired wound healing
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • the operation to remove kidney tissue


Strengths: 1 g; 3 g; 50 mg/mL

Testicular Cancer

  • 1.2 g/m2 IV over at least 30 minutes daily for 5 consecutive days; repeat every 3 weeks or after recovery from hematologic toxicity
  • To prevent bladder toxicity, this drug should be given with extensive hydration (at least 2 liters of oral or IV fluid daily). Mesna should be used to reduce hemorrhagic cystitis.
  • For germ-cell testicular cancer, the dosing regimen is 1.2 g/m²/day IV for the initial five days of a 21-day cycle. IV infusion is typically for a period of 30 minutes along with IV hydration and mesna to prevent bladder toxicity. Ifosfamide is emetogenic; hence, antiemetics are routinely prescribed to prevent chemotherapy-induced nausea and vomiting. Precipitation of ifosfamide-induced encephalopathy (IIE) by aprepitant has been reported in the literature. 

Side Effects

The Most Common

  • nausea
  • vomiting
  • loss of appetite
  • diarrhea
  • sores in the mouth and throat
  • hair loss
  • the general feeling of pain and tiredness
  • swelling, redness, and pain in the place where the medication was injected
  • rash
  • fever, chills, flu symptoms;
  • mouth and throat ulcers;
  • skin sores, pale skin, cold hands, and feet;
  • easy bruising, unusual bleeding
  • rapid heart rate, shallow breathing; or
  • little or no urination, painful or difficult urination, blood in your urine;
  • loss of bladder control; feeling light-headed or short of breath.
  • confusion, unusual thoughts or behavior, hallucinations, seizure (convulsions);
  • itching
  • difficulty breathing or swallowing
  • shortness of breath
  • wheezing
  • irregular heartbeat
  • chest pain
  • hoarseness
  • yellowing of the skin or eyes

More common

  • Agitation
  • black, tarry stools
  • blood in the urine
  • chest pain
  • confusion
  • cough or hoarseness
  • fever or chills
  • Diarrhea
  • hair loss or thinning of the hair
  • swelling or inflammation of the mouth
  • Redness, swelling, or pain at place of injection
  • weight loss
  • frequent urination
  • hallucinations (seeing, hearing, or feeling things that are not there)
  • lower back or side pain
  • painful or difficult urination
  • pale skin
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness


  • Abdominal or stomach pain or tenderness
  • bleeding gums
  • bluish color
  • changes in skin color
  • clay colored stools
  • dark urine
  • decreased appetite
  • dizziness
  • headache
  • itching
  • loss of appetite
  • nausea and vomiting
  • pain
  • pinpoint red spots on the skin
  • skin rash
  • swelling of the feet or lower legs
  • yellow eyes or skin
  • Blurred vision
  • burning, numbness, tingling, or painful sensations
  • confusion
  • convulsions (seizures)
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fast or irregular heartbeat
  • sweating
  • troubled breathing
  • unsteadiness or awkwardness
  • weakness in the arms, hands, legs, or feet

Drug Interactions

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Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.


This drug can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported. Adequate methods of contraception should be encouraged. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women should not become pregnant during therapy. Men should not father a child during therapy and for up to 6 months after. Animal studies have revealed evidence of embryotoxicity, gene mutations, and chromosomal damage. There are no controlled data on human pregnancy.


  • Use is contraindicated.
  • Excreted into human milk: Yes
  • This drug is tumorigenic and can harm a nursing infant.

How should this medicine be used?

Ifosfamide comes as a powder to be mixed with liquid to be injected over at least 30 minutes intravenously (into a vein) by a doctor or nurse in a medical facility. It may be injected once a day for 5 days in a row. This treatment may be repeated every 3 weeks. The length of treatment depends on how well your body responds to treatment with ifosfamide.

Your doctor may need to delay your treatment if you experience certain side effects. It is important for you to tell your doctor how you are feeling during your treatment with ifosfamide.

Ifosfamide is also sometimes used to treat bladder cancer, lung cancer, cancer of the ovaries (cancer that begins in the female reproductive organs where eggs are formed), cancer of the cervix, and certain types of soft tissue or bone sarcomas (cancer that forms in muscles and bones). Talk to your doctor about the risks of using this medication for your condition.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before receiving ifosfamide,

  • tell your doctor and pharmacist if you are allergic to ifosfamide, cyclophosphamide (Cytoxan), any other medications, or any of the ingredients in the ifosfamide injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins and nutritional supplements you are receiving or plan to take. Be sure to mention the medication listed in the IMPORTANT WARNING section and any of the following: aprepitant (Emend); certain antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral); certain seizure medications such as carbamazepine (Tegretol), phenobarbital (Luminal), and phenytoin (Dilantin); medications for allergies or hay fever; medications for nausea; opioid (narcotic) medications for pain; rifampin (Rifadin, Rimactane); sedatives; sleeping pills; or sorafenib (Nexavar). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Other medications may also interact with ifosfamide, so be sure to tell your doctor about all the medications you are receiving, even those that do not appear on this list.
  • tell your doctor what herbal products you are receiving, especially St. John’s wort.
  • tell your doctor if you have previously received treatment with other chemotherapy medications or if you have previously received radiation therapy. Also tell your doctor if you have or have ever had heart, kidney, or liver disease.
  • you should know that ifosfamide may slow the healing of wounds.
  • you should know that ifosfamide may interfere with the normal menstrual cycle (period) in women and may stop sperm production in men. Ifosfamide may cause permanent infertility (difficulty becoming pregnant); however, you should not assume that you cannot get pregnant or that you cannot get someone else pregnant. Women who are pregnant or breastfeeding should tell their doctors before they begin receiving this drug. You should not become pregnant or breast-feed while you are receiving ifosfamide. Use a reliable method of birth control to prevent pregnancy while you are receiving ifosfamide and for 6 months after treatments. If you are male, you and your female partner should continue to use birth control for 6 months after you stop receiving ifosfamide injections. If you become pregnant while receiving ifosfamide, call your doctor immediately. Ifosfamide may harm the fetus.


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