Article Author:
Mounika Gangireddy

Article Editor:
Vinod Nookala

Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch

Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi

5/10/2019 12:01:14 PM


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[1]:

  • Germline tumor of the testis
  • Soft tissue sarcomas
  • Ewings sarcoma
  • Cervical cancers 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 tumor of the testis. The indications for the use of ifosfamide include: 

1. Germline tumor of the testis[2][3][2]:

The FDA approved regimen is ifosfamide along with mesna at a dose of 1200g/m^2/day for five days and is repeated every three weeks or following count recovery. When ifosfamide is used along with other chemotherapeutic drugs mainly cisplatin, paclitaxel or etoposide, there has been complete remission in about 21 to 26% of the population. Aggressive hydration (at least 2 liters oral or IV) is necessary during administration.

2. Soft tissue sarcomas (off label use)[4]

Non-comparative studies have shown that the combination therapies with ifosfamide/mesna, when used as induction therapy, have shown objective response rates around 40%.

3. Ewings Sarcoma (off label use)[5]:

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. 

4. Cervical cancer, recurrent or metastatic (off label use)[6][2][6]:

Ifosfamide is dosed along with mesna at 1500g/m2/day every three weeks. When used along with paclitaxel and cisplatin, the response rate was 18 to 45%.

5. Bladder Carcinoma: mainly advanced carcinoma (off label use)[7]:

6. Non-Hodgkins Lymphoma (off label Use)[8]:

Used in Burkitt lymphoma and diffuse large B cell lymphoma (DLBCL) as salvage therapy. 

7. Hodgkins Lymphoma (off-label use)[8]:

Used in relapsed or refractory cases in ICE regimen (ifosfamide, carboplatin, and etoposide) along with mesna.

8. Small and Non-small cell cancer[9]:

When used as maintenance or consolidation have shown to have more benefit than the standard regimens.

9. Osteosarcoma (off label use)[10]

10. Ovarian Cancer[11][2][11]

Used in advanced stages which are platinum resistant. Many additional trials are underway. Response rates have been more than 40% when used as a combination.

11.Thymic cancer[12]:

Ifosfamide has off label use in the advanced stage of thymic cancer.

Mechanism of Action

Ifosfamide belongs to the class of the oxazaphosphorine alkylating agents. It is an inactive compound in its parent form (pro-drug). It gets metabolized in the liver by CYP450 enzymes to active metabolites. These active metabolites (phosphoramide mustard derivatives and acrolein) bind to the DNA and inhibit DNA synthesis.[13] The two mechanisms by which this metabolite acts are as follows. First, it causes cell damage by forming interstrand or intrastrand crosslinks, and second, it leads to apoptosis of the damaged cell.[14] These active metabolites upregulate the reactive oxygen species (ROS) which results in irreparable DNA damage and cease the protein formation. When compared to other alkylating compounds, cyclophosphamide, and ifosfamide have more anti-tumor activity as their derivatives mainly, phosphoramide mustard derivatives and acrolein are cytotoxic rather than cytostatic.[14] Filtration primarily occurs through the kidney, and the doses require adjustment according to renal function. 


The primary mode of administration of the drug is through the intravenous (IV) route.[2] The oral form had a bioavailability close to 100 percent but resulted in severe neurotoxicity, and since then the administration has switched to the intravenous form.[15] Researchers discovered ifosfamide over two decades ago, but it was subject to dose limitations due to the development of hemorrhagic cystitis. Only after the availability of the thiol neuroprotective compound mesna was the drug was used more commonly to treat a wide range of malignancies. For this reason, the administration is almost always along with mesna[2]. Mesna converts to dimesna in the plasma gets filtered at the level of kidneys where it switches back to mesna. At the urothelium, mesna combines with the active metabolites like acrolein (urotoxic) and forms a non-toxic compound which then gets eliminated in the urine.[2] Mesna administration can be either orally or IV. The half-life of mesna is around 0.4 hours. It is completely excreted in four hours if given IV and in eight hours if given orally.

Adverse Effects

Adverse effects are mainly dose-related. They can be described based on the systems.[16] These include gastrointestinal, dermatological, central nervous system, hematological, renal, endocrine, and cardiac[17][18]:

  1. Gastrointestinal: nausea and vomiting (over 50%); abdominal cramps; anorexia - usually patients are advised to stay hydrated and are encouraged to drinks lots of water while on this therapy.[17]Antiemetics are generally given along with the drug. 
  2. Dermatological: alopecia - it is a universal side effect noted with ifosfamide. (90%)
  3. Central nervous system: encephalopathy. (15%)
  4. Hematological: leukopenia, anemia, thrombocytopenia. (30 to 50%)
  5. Renal: hematuria (90%) - when used alone.
  6. Endocrine and metabolic: metabolic acidosis. (30%)
  7. Cardiac: Arrhythmias. (under 10%)


There are very few known contraindications for the drug. The absolute contraindications are known hypersensitivity to the drug or its components and urinary tract outflow obstruction. Relative contraindications include myelosuppression and severe renal/hepatic involvement.

  1. Known hypersensitivity to the drug and/or its components - can result in anaphylaxis with drug administration.[15]
  2. Urinary outflow obstruction - there is a high chance of developing cystitis when there is urinary tract obstruction due to an accumulation of toxic compounds.[19]
  3. Severe thrombocytopenia and leukopenia - due to the known toxic effect hematologically, the drug is avoided in case of severe thrombocytopenia and leukopenia. 
  4. Severe renal/hepatic impairment - drug metabolism occurs in the liver, and it gets excreted through the kidneys; prohibits its usage in severe renal and hepatic impairment.[20]


To understand the therapeutic index of the drug, one needs to know the pharmacokinetics and pharmacodynamics of the drug. Regarding the pharmacokinetics, the volume of distribution(Vd) of the drug is almost equal to the total body water when administered in the IV form. Vd varies with weight as well with age(elderly and pediatric).[15] Vd increases with age and in obese individuals.[2] The half-life of the drug after a single administration is four to seven hours. Total clearance of the drug is 3.6L/h. Usually fractionation of the drug results in faster rates of elimination.

The most common dose administered is 1.2 gm/m/day, given very slowly over 30 minutes for five consecutive days.[2] Complete blood count with differential, renal function, liver function, urine output, and urinalysis are necessary before each dose. Dosing repeats every three weeks or after hematological recovery. Drug levels can be measured in the urine by gas chromatography-mass spectrometry.[21] The therapeutic drug monitoring takes place after assessing the pharmacokinetics of the first course of the drug followed by subsequent alterations in the dose as there is wide variability in the pharmacokinetics of ifosfamide.

Dosing needs to be adjusted in renal impairment as the drug undergoes renal elimination.[22] Dose reduction is to 80% of the dose if creatinine clearance (CrCl) is 46 to 60 mL/minute. However, if CrCl is 31 to 45 mL/minute, administer 75% of the dose and with CrCl under 30 mL/minute reduce to 70% of the regular dose. There is no requirement for dose adjustment with hepatic impairment, but caution is advised. The drug requires adjustment according to weight.[23]

The dose also needs to be adjusted according to the toxicity profile. Instances of severe leukopenia or thrombocytopenia require dosage reduction. In case more severe toxicity such as encephalopathy probably requires termination of therapy.


Most of the toxicities of ifosfamide are from its active metabolites. Acrolein plays a significant role in causing major renal and bladder related toxicities. As the kidneys filter these metabolites, they generate reactive oxygen species and nitrogen compounds which results in damage to the renal as well as urothelial cells. The etiology behind neurotoxicity is similar to that of renal toxicity but is not fully understood. As with other anti-neoplastic drugs, ifosfamide is toxic to the bone marrow. Specific case reports have shown an association between ifosfamide and Fanconi syndrome. It results in cardiac toxicity and can cause pneumonitis. These toxicities include:  

1. Hemorrhagic cystitis

The main adverse effects for years has been hemorrhagic cystitis. The theory behind it was during its hepatic metabolism, a product named acrolein was produced which was excreted by the kidneys and accumulates in the bladder.[19] Through its apoptotic properties and production of multiple ROS as well as nitric oxide, it results in the release of numerous cytokines which cause ulceration of the bladder epithelium. As a result, it causes hemorrhagic cystitis. Mesna is a drug developed in 1983 to help with this adverse effect of ifosfamide. As described earlier, mesna combines with the urotoxic metabolites at the level of urothelium and results in a non-toxic product for excretion in the urine. It is always important to prevent the development of cystitis rather than treating it. The current treatment options available are continuous bladder irrigation, intravesicular infusion of ammonium potassium sulfate and formalin, and in some instances cystectomy.[19] Mesna should be administered before, during and after ifosfamide along with aggressive hydration (at least 2 liters oral of IV form) per day to prevent urotoxicity.

2. Neurotoxicity

 Central nervous system toxicity appears as encephalopathy with varying severity (confusion, hallucinations, drowsiness, coma). It presents in about 30% of the cases.[24] The mechanism is unknown, and the symptoms occur with administration of high doses of the drug either orally or intravenously but more with oral administration.[24] Usually, the symptoms present within 2 to 96 hours after drug administration and are reversible within 48 to 72 hours after discontinuation of the drug.[15] The mechanism of neurotoxicity is still unknown. Risk factors associated for development of neurotoxicity include oral administration, previous chemotherapy with cisplatin, impaired renal and hepatic function, low albumin and brain metastasis. Recent studies showed the utilization of methylene blue for both treatment and prophylaxis of ifosfamide-induced encephalopathy.[25] Methylene blue helps in the reversal of symptoms within 24 hours of its administration. As prophylaxis, the severity of symptoms has reduced when compared to previous cycles and can restore the therapy with ifosfamide. The dosage of methylene blue is 50 mg orally in 5% glucose solution every four hours till recovery.[15] 

3. Hematological toxicity 

A dose-limiting toxicity is myelosuppression. The blood counts reach a nadir in about 8 to 13 days of the treatment cycle. Recovery generally occurs around day 17 of the treatment cycle; this allows starting the next cycle in around three weeks after the first treatment. This effect is dose-related. Incidence of myelosuppression is low when fractionated doses are used rather than higher doses.[26] At a dose of 1.2gm/m^2/day for five days, the white cell count is below 3 x 109/L, and platelet count below 20000 occurs in 30% of cases.[26]

4. Nephrotoxicity

Most commonly noted in children and is seen when co-administered with cisplatin. It can lead to Fanconi syndrome, in which there is impairment of proximal tubule function resulting in irreversible damage. Clinically manifested as metabolic acidosis, polyuria, and renal phosphate wasting. Seen in about 5% of cases.[27] Supplementation with vitamin D and phosphate is essential in the pediatric population affected. Etiology remains unclear.

4. Miscellaneous toxicities: There are reports of arrhythmias, heart failure and pulmonary toxicity in the form of pneumonitis.[28]

5. Malignancy of ureter and bladder: There have been case reports which demonstrated a case of multifocal urothelial carcinoma in a patient treated with ifosfamide many years ago.[13]            

Enhancing Healthcare Team Outcomes

For chemotherapy drug administration and monitoring, the role of nursing and pharmacy is very crucial. All healthcare providers need to collaborate as an interprofessional team to ensure optimal care and minimal adverse effects with any drug therapy, but even more so with a chemotherapeutic agent like ifosfamide. Nursing is helpful in closely watching the patient during and after drug administration, identifying the adverse reactions and reporting them immediately. Oncology nurses are specially trained to administer chemotherapy. The role of pharmacists is crucial as they help formulate the dosing as well as monitor them for potential toxicity. For better outcomes, plan needs to be discussed in detail among all the members involved in patient care like nurses, pharmacists, physicians as well as family to lower the mortality and morbidity. [Level V]

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Ifosfamide - Questions

Take a quiz of the questions on this article.

Take Quiz
A 16 year old was recently diagnosed with germ cell tumor of the testis. He was started on a chemotherapy combinations containing ifosfamide. The patient developed gross hematuria a week after completion of chemotherapy and was subsequently diagnosed with hemorrhagic cystitis. Which of the following steps would have prevented the above mentioned complication?

Click Your Answer Below

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

Sign Up

Ifosfamide - References


Ifosfamide-Induced Malignancy of Ureter and Bladder., Sannu A,Radha R,Mathews A,Padmakumari Mony R,Prahladan A,James FV,, Cureus, 2017 Aug 22     [PubMed]
Zalupski M,Baker LH, Ifosfamide. Journal of the National Cancer Institute. 1988 Jun 15;     [PubMed]
Voelcker G, Influence of the alkylating function of aldo-Ifosfamide on the anti-tumor activity. Anti-cancer drugs. 2018 Jan;     [PubMed]
Dechant KL,Brogden RN,Pilkington T,Faulds D, Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs. 1991 Sep;     [PubMed]
Matz EL,Hsieh MH, Review of Advances in Uroprotective Agents for Cyclophosphamide- and Ifosfamide-induced Hemorrhagic Cystitis. Urology. 2017 Feb;     [PubMed]
Klastersky J, Side effects of ifosfamide. Oncology. 2003;     [PubMed]
Dupuis LL,Boodhan S,Holdsworth M,Robinson PD,Hain R,Portwine C,O'Shaughnessy E,Sung L, Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatric blood     [PubMed]
Floyd JD,Nguyen DT,Lobins RL,Bashir Q,Doll DC,Perry MC, Cardiotoxicity of cancer therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 Oct 20;     [PubMed]
Kerbusch T,de Kraker J,Keizer HJ,van Putten JW,Groen HJ,Jansen RL,Schellens JH,Beijnen JH, Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites. Clinical pharmacokinetics. 2001 Jan;     [PubMed]
Floyd J,Mirza I,Sachs B,Perry MC, Hepatotoxicity of chemotherapy. Seminars in oncology. 2006 Feb;     [PubMed]
Kerbusch T,Jeuken MJ,Derraz J,van Putten JW,Huitema AD,Beijnen JH, Determination of ifosfamide, 2- and 3-dechloroethyifosfamide using gas chromatography with nitrogen-phosphorus or mass spectrometry detection. Therapeutic drug monitoring. 2000 Oct;     [PubMed]
Kintzel PE,Dorr RT, Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer treatment reviews. 1995 Jan;     [PubMed]
Griggs JJ,Mangu PB,Anderson H,Balaban EP,Dignam JJ,Hryniuk WM,Morrison VA,Pini TM,Runowicz CD,Rosner GL,Shayne M,Sparreboom A,Sucheston LE,Lyman GH, Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 May 1;     [PubMed]
Nicolao P,Giometto B, Neurological toxicity of ifosfamide. Oncology. 2003;     [PubMed]
Turner AR,Duong CD,Good DJ, Methylene blue for the treatment and prophylaxis of ifosfamide-induced encephalopathy. Clinical oncology (Royal College of Radiologists (Great Britain)). 2003 Oct;     [PubMed]
Morgan LR,Harrison EF,Hawke JE,Hunter HL,Costanzi JJ,Plotkin D,Tucker WG,Worrall PM, Toxicity of single- vs. fractionated-dose ifosfamide in non-small cell lung cancer: a multi-center study. Seminars in oncology. 1982 Dec;     [PubMed]
Loebstein R,Koren G, Ifosfamide-induced nephrotoxicity in children: critical review of predictive risk factors. Pediatrics. 1998 Jun;     [PubMed]
Kandylis K,Vassilomanolakis M,Tsoussis S,Efremidis AP, Ifosfamide cardiotoxicity in humans. Cancer chemotherapy and pharmacology. 1989;     [PubMed]
Noujaim J,Constantinidou A,Messiou C,Thway K,Miah A,Benson C,Judson I,Jones RL, Successful Ifosfamide Rechallenge in Soft-Tissue Sarcoma. American journal of clinical oncology. 2018 Feb;     [PubMed]
Wagner MJ,Gopalakrishnan V,Ravi V,Livingston JA,Conley AP,Araujo D,Somaiah N,Zarzour MA,Ratan R,Wang WL,Patel SR,Lazar A,Ludwig JA,Benjamin RS, Vincristine, Ifosfamide, and Doxorubicin for Initial Treatment of Ewing Sarcoma in Adults. The oncologist. 2017 Oct;     [PubMed]
Scandurra G,Scibilia G,Banna GL,D'Agate G,Lipari H,Gieri S,Scollo P, Efficacy and tolerability of paclitaxel, ifosfamide, and cisplatin as a neoadjuvant chemotherapy in locally advanced cervical carcinoma. Journal of gynecologic oncology. 2015 Apr;     [PubMed]
Shin W,Lee HJ,Yang SJ,Paik ES,Choi HJ,Kim TJ,Choi CH,Lee JW,Bae DS,Kim BG, Retrospective study of combination chemotherapy with etoposide and ifosfamide in patients with heavily pretreated recurrent or persistent epithelial ovarian cancer. Obstetrics     [PubMed]
Siefker-Radtke AO,Dinney CP,Shen Y,Williams DL,Kamat AM,Grossman HB,Millikan RE, A phase 2 clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer: final results. Cancer. 2013 Feb 1;     [PubMed]
Fukunaga A,Hyuga M,Iwasaki M,Nakae Y,Kishimoto W,Maesako Y,Arima N, Dose-Modified Ifosfamide, Epirubicin, and Etoposide is a Safe and Effective Salvage Therapy with High Peripheral Blood Stem Cell Mobilization Capacity for Poorly Mobilized Hodgkin's Lymphoma and Non-Hodgkin's Lymphoma Patients. Journal of clinical and experimental hematopathology : JCEH. 2016;     [PubMed]
Zhou Y,Xu Y,Zhao J,Zhong W,Wang M, [Combined Chemotherapy with Vinorelbine and Ifosfamide as Third-line Treatment and Beyond of Advanced Non-small Cell Lung Cancer]. Zhongguo fei ai za zhi = Chinese journal of lung cancer. 2015 Jun;     [PubMed]
Basaran M,Bavbek ES,Saglam S,Eralp L,Sakar B,Atalar AC,Bilgic B,Ozger H,Onat H, A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007;     [PubMed]
Grassin F,Paleiron N,André M,Caliandro R,Bretel JJ,Terrier P,Margery J,Le Chevalier T,Ruffié P, Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma. A French experience. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2010 Jun;     [PubMed]
Kondagunta GV,Bacik J,Donadio A,Bajorin D,Marion S,Sheinfeld J,Bosl GJ,Motzer RJ, Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 Sep 20;     [PubMed]


The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pharmacy-Technician (PTCB). The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pharmacy-Technician (PTCB), it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pharmacy-Technician (PTCB), you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pharmacy-Technician (PTCB). When it is time for the Pharmacy-Technician (PTCB) board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pharmacy-Technician (PTCB).