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Ifosfamide: Drug information

Ifosfamide: Drug information
(For additional information see "Ifosfamide: Patient drug information" and see "Ifosfamide: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Bone marrow suppression:

Myelosuppression can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after each treatment cycle.

CNS toxicity:

CNS toxicities can be severe and result in encephalopathy and death. Monitor for CNS toxicity and discontinue treatment for encephalopathy.

Hemorrhagic cystitis:

Hemorrhagic cystitis can be severe and can be reduced by the prophylactic use of mesna.

Nephrotoxicity:

Nephrotoxicity can be severe and result in renal failure.

Brand Names: US
  • Ifex
Brand Names: Canada
  • Ifex
Pharmacologic Category
  • Antineoplastic Agent, Alkylating Agent;
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)
Dosing: Adult

Note: To prevent bladder toxicity, ifosfamide should be given with mesna and hydration (at least 2 L of oral or IV fluid per day). Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]; MASCC/ESMO [Roila 2016]).

Bladder cancer, advanced

Bladder cancer, advanced (off-label use): IV: 1,500 mg/m2/day for 5 days every 3 weeks (with mesna) until disease progression (Witte 1997).

Cervical cancer, recurrent or metastatic

Cervical cancer, recurrent or metastatic (off-label use): IV: 1,500 mg/m2/day for 5 days every 3 weeks (with mesna) (Coleman 1986; Sutton 1993).

Ewing sarcoma

Ewing sarcoma (off-label use):

VAC/IE regimen: Adults ≤30 years: IE: IV: 1,800 mg/m2/day for 5 days (in combination with mesna and etoposide) alternate with VAC (vincristine, doxorubicin, and cyclophosphamide) every 3 weeks for a total of 17 courses (Grier 2003).

VAIA regimen: IV: 3,000 mg/m2 day on days 1, 2, 22, 23, 43, and 44 for 4 courses (in combination with vincristine, doxorubicin, dactinomycin, and mesna) (Paulussen 2001) or Adults ≤35 years: 2,000 mg/m2/day for 3 days every 3 weeks for 14 courses (in combination with vincristine, doxorubicin, dactinomycin, and mesna) (Paulussen 2008).

VIDE regimen: Adults ≤50 years: IV: 3,000 mg/m2/day over 1 to 3 hours for 3 days every 3 weeks for 6 courses (in combination with vincristine, doxorubicin, etoposide, and mesna) (Juergens 2006).

IE regimen: IV: 1,800 mg/m2/day over 1 hour for 5 days every 3 weeks for 12 cycles (in combination with etoposide and mesna) (Miser 1987).

ICE regimen: Adults ≤22 years: IV: 1,800 mg/m2/day for 5 days every 3 weeks for up to 12 cycles (in combination with carboplatin and etoposide [and mesna]) (van Winkle 2005).

Extranodal NK/T-cell lymphoma, nasal type

Extranodal NK/T-cell lymphoma, nasal type (off-label use):

DeVIC regimen: IV: 1,000 mg/m2/day on days 1, 2, and 3 every 3 weeks (in combination with dexamethasone, etoposide, carboplatin, filgrastim, and radiation therapy) for 3 cycles (Yamaguchi 2009). Refer to protocol for dosage adjustment details.

m-SMILE regimen: IV: 1,500 mg/m2/day on days 2, 3, and 4 every 3 weeks (in combination with dexamethasone, methotrexate, leucovorin, etoposide, pegaspargase, mesna, and radiation therapy) for 2 to 6 cycles (Qi 2016). Refer to protocol for further information.

SMILE regimen: IV: 1,500 mg/m2/day on days 2, 3, and 4 every 4 weeks (in combination with dexamethasone, methotrexate, leucovorin, etoposide, L-asparaginase, mesna, and filgrastim) for 2 cycles; therapy could continue beyond 2 cycles based on clinical condition and prescriber discretion; the median number of cycles administered was 3 (range: 1 to 6) (Yamaguchi 2011). Refer to protocol for further information.

VIDL regimen: IV: 1,200 mg/m2/day on days 1, 2, and 3 every 4 weeks (in combination with etoposide, dexamethasone, and L-asparaginase) for 2 cycles (Kim 2014). Note: Chemoradiotherapy was administered prior to VIDL; refer to protocol for further information.

VIPD regimen: IV: 1,200 mg/m2/day on days 1, 2, and 3 every 3 weeks (in combination with etoposide, cisplatin, dexamethasone, and mesna) for 3 cycles (Kim 2009) or 1,200 mg/m2/day on days 1, 2, 3, and 4 every 4 weeks (in combination with etoposide, cisplatin, dexamethasone, and mesna) for 2 cycles (Tsai 2015). Note: Chemoradiotherapy was administered prior to VIPD; refer to protocols for further information.

Gestational trophoblastic neoplasia, high-risk, refractory

Gestational trophoblastic neoplasia, high-risk, refractory (off-label use): ICE regimen: IV: 1,200 mg/m2/day on days 1, 2, and 3 every 3 weeks (in combination with mesna, carboplatin, etoposide, and filgrastim) for at least 2 treatment cycles after a normal hCG level (Lurain 2005; Lurain 2012).

Hodgkin lymphoma, relapsed or refractory

Hodgkin lymphoma, relapsed or refractory (off-label use):

ICE regimen: IV: 5,000 mg/m2 (over 24 hours) beginning on day 2 every 2 weeks for 2 cycles (in combination with mesna, carboplatin, and etoposide) (Moskowitz 2001).

Fractionated ICE regimen: IV: 1,667 mg/m2/day (infused over 2 to 3 hours each day) for 3 consecutive days every 21 days (in combination with mesna, carboplatin, etoposide, and filgrastim) for at least 2 cycles (Hertzberg 2006).

IGEV regimen: IV: 2,000 mg/m2/day for 4 days every 3 weeks for 4 cycles (in combination with mesna, gemcitabine, vinorelbine, and prednisolone) (Santoro 2007).

Non-Hodgkin lymphomas

Non-Hodgkin lymphomas (off-label use):

Burkitt lymphoma (CODOX-M/IVAC regimen):

Adults ≤65 years of age: Cycles 2 and 4 (IVAC): IV: 1,500 mg/m2/day for 5 days (IVAC is combination with cytarabine, mesna, and etoposide; IVAC alternates with CODOX-M) (Mead 2008).

Adults >65 years of age: Cycles 2 and 4 (IVAC): IV: 1,000 mg/m2/day for 5 days (IVAC is combination with cytarabine, mesna, and etoposide; IVAC alternates with CODOX-M) (Mead 2008).

Diffuse large B-cell lymphoma (RICE regimen): IV: 5,000 mg/m2 (over 24 hours) beginning on day 4 every 2 weeks for 3 cycles (in combination with mesna, carboplatin, etoposide, and rituximab) (Kewalramani 2004).

Osteosarcoma

Osteosarcoma (off-label use):

Ifosfamide/cisplatin/doxorubicin/HDMT regimen: Adults <40 years of age: IV: 3,000 mg/m2/day continuous infusion for 5 days during weeks 4 and 10 (preop) and during weeks 16, 25, and 34 (postop) (in combination with cisplatin, doxorubicin, methotrexate [high-dose], and mesna) (Bacci 2003).

ICE regimen (adults ≤22 years of age): IV: 1,800 mg/m2/day for 5 days every 3 weeks for up to 12 cycles (in combination with carboplatin and etoposide [and mesna]) (van Winkle 2005).

Ovarian cancer, advanced, platinum-resistant

Ovarian cancer, advanced, platinum-resistant: IV: 1,000 to 1,200 mg/m2/day for 5 days (with mesna) every 28 days for up to 6 cycles (Markman 1992).

Penile cancer, metastatic, squamous cell; neoadjuvant therapy

Penile cancer, metastatic, squamous cell; neoadjuvant therapy (off-label use): TIP regimen: IV: 1,200 mg/m2/day on days 1, 2, and 3 every 3 to 4 weeks (in combination with paclitaxel, cisplatin, and mesna ± filgrastim) for 4 cycles (Pagliaro 2010).

Soft tissue sarcoma

Soft tissue sarcoma (off-label use):

Single-agent ifosfamide: IV: 3,000 mg/m2/day over 4 hours for 3 days every 3 weeks for at least 2 cycles or until disease progression (van Oosterom 2002).

EIA regimen: IV: 1,500 mg/m2/day for 4 days every 3 weeks until disease progression or unacceptable toxicity (in combination with etoposide, doxorubicin, and regional hyperthermia) (Issels 2010).

MAID regimen: IV: 2,000 mg/m2/day continuous infusion for 3 days every 3 weeks (in combination with mesna, doxorubicin, and dacarbazine) (Antman 1993; Antman 1998) or 2,500 mg/m2/day continuous infusion for 3 days every 3 weeks (in combination with mesna, doxorubicin, and dacarbazine); reduce ifosfamide to 1,500 mg/m2/day if prior pelvic irradiation (Elias 1989).

Ifosfamide/epirubicin: IV: 1,800 mg/m2/day over 1 hour for 5 days every 3 weeks for 5 cycles (in combination with mesna and epirubicin) (Frustaci 2001).

AIM regimens: IV: 1,500 mg/m2/day over 2 hours for 4 days every 3 weeks for 4 to 6 cycles (in combination with mesna and doxorubicin) (Worden 2005) or 2,000 to 3,000 mg/m2/day over 3 hours for 3 days (in combination with mesna and doxorubicin) (Grobmyer 2004).

Testicular cancer

Testicular cancer:

VIP regimen: IV: 1,200 mg/m2/day for 5 days every 3 weeks for 4 cycles (in combination with etoposide, mesna, and cisplatin) (Nichols 1998).

VeIP regimen: IV: 1,200 mg/m2/day for 5 days every 3 weeks for 4 cycles (in combination with vinblastine, mesna, and cisplatin) (Loehrer 1998).

Manufacturer's labeling; as part of combination chemotherapy and with mesna: IV: 1,200 mg/m2/day for 5 days every 3 weeks or after hematologic recovery.

Off-label dosing/combinations:

TIP regimen (off-label dosing): IV: 1,500 mg/m2/day for 4 days (days 2 to 5) every 3 weeks for 4 cycles (in combination with paclitaxel, mesna, and cisplatin) (Kondagunta 2005).

TICE regimen (off-label dosing): IV: 2,000 mg/m2/day over 4 hours for 3 days (days 2 to 4) every 2 weeks for 2 cycles (in combination with paclitaxel and mesna; followed by carboplatin and etoposide) (Kondagunta 2007).

Thymomas and thymic cancers, advanced

Thymomas and thymic cancers, advanced (off-label use): IV: 1,200 mg/m2/day for 4 days every 3 weeks for 4 cycles (in combination with mesna, cisplatin, and etoposide); colony-stimulating growth factor support was administered on days 5 to 15 (or until WBC ≥10,000/mm3) (Loehrer 2001) or 1,500 mg/m2/day for 5 days (with mesna) every 3 weeks for up to 9 cycles (Highley 1999).

Uterine carcinosarcoma

Uterine carcinosarcoma (off- label use):

Adjuvant therapy for stage 1 to 4 disease: IV: 1,500 mg/m2/day for 4 days (in combination with cisplatin and mesna) every 3 weeks for 3 cycles (Wolfson 2007).

Persistent or refractory advanced disease: IV: 1,600 mg/m2/day for 3 days (in combination with mesna, paclitaxel, and filgrastim) every 3 weeks for up to 8 cycles; reduce ifosfamide dose to 1,200 mg/m2/day for 3 days every 3 weeks in patients who received prior radiation (Homesley 2007).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Consider dosage reduction in patients with renal impairment; however, there are no dosage adjustments provided in the manufacturer's labeling and specific recommendations for kidney dose adjustment have not been established; ifosfamide (and metabolites) are excreted renally and may accumulate in patients with renal dysfunction. Ifosfamide and metabolites are dialyzable.

General dosage adjustment recommendations for altered kidney function:

Kintzel 1995:

CrCl 46 to 60 mL/minute: Administer 80% of dose

CrCl 31 to 45 mL/minute: Administer 75% of dose

CrCl <30 mL/minute: Administer 70% of dose

Krens 2019:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: Use is not recommended.

Hemodialysis: Use is not recommended.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, ifosfamide is extensively hepatically metabolized to both active and inactive metabolites; use with caution. The following adjustments have been recommended:

Floyd 2006: Bilirubin >3 mg/dL: Administer 25% of dose.

Krens 2019:

Mild or moderate impairment: No dosage adjustment necessary.

Severe impairment: Use is not recommended.

Dosing: Pediatric

(For additional information see "Ifosfamide: Pediatric drug information")

Note: To prevent bladder toxicity, combination therapy with mesna (bladder protectant or chemoprotectant) and hydration in adults and pediatric patients is necessary; in adults, at least 2 L/day of oral or IV fluid. In pediatric patients, specific protocols should be consulted for hydration recommendation; for example, some centers have used 2 times maintenance or 3 L/m2/day. Dosing may be based on either BSA (mg/m2) or weight (mg/kg); use extra precautions to verify dosing parameters during calculations. Protocol-specific details concerning dosing, frequency, and combination regimens should be consulted. Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (POGO [Dupuis 2011]).

Ewing sarcoma

Ewing sarcoma: Limited data available; dosing regimens and combinations variable: Children and Adolescents:

IE regimen: IV: 1,800 mg/m2 over 1 hour once daily for 5 days in combination with mesna and etoposide every 3 weeks for 12 cycles; or may alternate with VAC (vincristine, doxorubicin, and cyclophosphamide) every 3 weeks for a total of 17 courses (Grier 2003; Miser 1987)

HD-IE regimen: 2,800 mg/m2 over 1 hour once daily for 5 days in combination with mesna and etoposide every 3 weeks alternating with VAC (vincristine, doxorubicin, cyclophosphamide) (Miser 2007)

ICE regimen: IV: 1,800 mg/m2 once daily for 5 days every 3 to 4 weeks for up to 12 cycles in combination with carboplatin, etoposide, and mesna; or may follow with 2 courses of CAV (cyclophosphamide, doxorubicin, and vincristine) (Milano 2006; van Winkle 2005)

VAIA regimen: Reported dosing variable: IV: 3,000 mg/m2 on days 1, 2, 22, 23, 43, and 44 for 4 courses in combination with vincristine, doxorubicin, dactinomycin, and mesna (Paulussen 2001) or 2,000 mg/m2 once daily for 3 days every 3 weeks for 14 courses in combination with vincristine, doxorubicin, and dactinomycin (Paulussen 2008)

VIDE regimen: IV: 3,000 mg/m2 over 1 to 3 hours once daily for 3 days every 3 weeks for 6 courses in combination with vincristine, doxorubicin, etoposide, and mesna (Juergens 2006)

Lymphoma, Hodgkin and Non-Hodgkin, recurrent/refractory

Lymphoma, Hodgkin (HL) and Non-Hodgkin (NHL), recurrent/refractory: Limited data available; dosing regimens and combinations variable:

ICE regimen:

Cairo 2005: Children and Adolescents: IV: 1,800 mg/m2 once daily for 5 days every 3 weeks for 6 courses in combination with etoposide, carboplatin, and mesna; in the trial, although the minimum age for inclusion was 1 year of age, the reported patient age range was 8 months to 26 years (median: 10.5 years)

Moskowitz 2001: Children ≥12 years and Adolescents: IV: 5,000 mg/m2/day continuous infusion over 24 hours beginning on day 2 every 2 weeks for 2 cycles (in combination with mesna, carboplatin, and etoposide)

IE regimen: Children and Adolescents: IV: 1,800 mg/m2 once daily for 5 days alternating in combination with etoposide and mesna; alternate at 3-week intervals with DECAL (dexamethasone, etoposide, cisplatin, cytarabine [high-dose ara-C]), and L-asparaginase for 4 cycles; in the trial, all patients were <21 years of age, the median age for NHL: 11 years; median age for HL: 15 years (Kobrinsky 2001)

MIED regimen: Children and Adolescents:

Sandlund 2011: IV: 2,000 mg/m2 over 2 hours on days 2 to 4 in combination with high-dose methotrexate, etoposide, and dexamethasone (and mesna); patients with NHL also received intrathecal methotrexate, hydrocortisone, and cytarabine

Griffin 2009: IV: 3,000 mg/m2 over 2 hours on days 3 to 5 in combination with rituximab and ICE (carboplatin, etoposide, and mensa) every 23 days for up to 3 courses has been used in NHL patients

Osteosarcoma

Osteosarcoma: Limited data available; dosing regimens and combinations variable:

IE regimen: Children and Adolescents: IV: 1,800 to 3,000 mg/m2 for 4 to 5 days; frequency and duration protocol specific with etoposide and mesna (Gentet 1997; Marina 2016; O’Kane 2015)

ICE regimen: Children and Adolescents: IV: 1,800 mg/m2 once daily for 5 days every 3 weeks for up to 12 cycles in combination with carboplatin, etoposide, and mesna (van Winkle 2005)

Newly diagnosed high-grade osteosarcoma of the extremity with metastases:

Bacci 2003: Children and Adolescents: IV: 3,000 mg/m2/day continuous infusion for 5 days (total dose: 15 g/m2) during weeks 4 and 10 (preop) and during weeks 16, 25, and 34 (postop) in combination with cisplatin, doxorubicin, methotrexate (high-dose), and mesna

Basaran 2007: Adolescents: IV: 2,000 mg/m2 over 4 hours for 3 days (days 2, 3, and 4) every 3 weeks for 3 cycles (preop) and every 4 weeks for 3 cycles (postop) in combination with cisplatin, epirubicin, and mesna

Le Deley 2007: Children and Adolescents: IV: 3,000 mg/m2 over 3 hours for 4 days during weeks 4 and 9 (three additional postop courses were administered in good responders) in combination with methotrexate (high-dose), etoposide, and mesna

Neuroblastoma, refractory or relapsed

Neuroblastoma, refractory or relapsed: Limited data available: HD-ICE regimen: Children and Adolescents IV: 2,000 mg/m2 over 2 hours once daily for 5 days in combination with mesna, carboplatin, and etoposide with or without peripheral blood stem cell support (depending on hematologic reserve (Kushner 2013)

Rhabdomyosarcoma

Rhabdomyosarcoma: Limited data available:

Interval-compressed I/E regimen (Weigel 2016):

Infants: IV: 900 mg/m2 once daily for 5 days in combination with mesna and etoposide on weeks 9, 13, 17, 26, and 30 (2 weeks after vincristine, doxorubicin, and cyclophosphamide therapy). Note: Infant dose is 50% of full dose in children; if infant tolerates dose (ie, no delayed count recovery or delayed resolution of other toxicities which delays administration), may consider increasing to 75% and then to 100% calculated full dose.

Children and Adolescents: IV: 1,800 mg/m2 once daily for 5 days in combination with mesna and etoposide on weeks 9, 13, 17, and 30 (2 weeks after vincristine, doxorubicin, and cyclophosphamide therapy)

VAI (IRS-IV) (Baker 2000):

Infants: IV: 900 mg/m2 once daily for 5 days in combination with mesna, vincristine, and dactinomycin for a 21-day cycle for 8 cycles (omitting dactinomycin during radiation). Note: Infant dose is 50% of full-dose in children; if infant tolerates dose (ie, no delayed count recovery or delayed resolution of other toxicities which delays administration), may consider increasing to 75% and then to 100% calculated full dose.

Children and Adolescents: IV: 1,800 mg/m2 once daily for 5 days in combination with mesna, vincristine, and dactinomycin for a 21-day cycle for 8 cycles (omitting dactinomycin during radiation)

VIE (IRS-IV; Baker 2000):

Infants: IV: 900 mg/m2 once daily for 5 days in combination with mesna, vincristine, and etoposide for a 21-day cycle for 8 cycles (omitting etoposide during radiation). Note: Infant dose is 50% of full-dose in children; if infant tolerates dose (ie, no delayed count recovery or delayed resolution of other toxicities which delays administration), may consider increasing to 75% and then to 100% calculated full dose.

Children and Adolescents: IV: 1,800 mg/m2 once daily for 5 days in combination with mesna, vincristine, and etoposide for a 21-day cycle for 8 cycles (omitting etoposide during radiation)

Sarcomas; soft tissue, non-Rhabdomyosarcoma

Sarcomas; soft tissue, non-Rhabdomyosarcoma: Limited data available: Children and Adolescents: 3,000 mg/m2 once daily for 3 days every 21 days for 4 cycles in combination with mesna and doxorubicin (Ferrari 2015)

Wilms tumor, relapsed

Wilms tumor, relapsed: Limited data available: ICE regimen: Children and Adolescents: IV: 1,800 mg/m2 once daily for 5 days every 21 days for at least 2 cycles (median of 4 cycles reported) in combination with mesna, carboplatin, and etoposide (Abu-Ghosh 2002)

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Infants, Children, and Adolescents: The following adjustments have been recommended (Aronoff 2007):

GFR ≥10 mL/minute/1.73 m2: No dosage adjustment necessary

GFR <10 mL/minute/1.73 m2: Administer 75% of dose

Hemodialysis: 1,000 mg/m2 followed by hemodialysis 6 to 8 hours later

Continuous renal replacement therapy (CRRT): No dosage adjustment necessary

Dosing: Hepatic Impairment: Pediatric

There are no pediatric specific recommendations; refer to protocol. Ifosfamide is extensively metabolized in the liver to both active and inactive metabolites; use with caution.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Obesity: Adult

American Society of Clinical Oncology guidelines for appropriate chemotherapy dosing in adults with cancer with a BMI ≥30 kg/m2: Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (ASCO [Griggs 2021]).

Dosing: Adjustment for Toxicity: Adult

WBC <2,000/mm3 and/or platelets <50,000/mm3: Avoid administering ifosfamide (unless clinically necessary). Antimicrobial prophylaxis may be necessary in some neutropenic patients; administer antibiotics and/or antifungal agents for neutropenic fever.

Encephalopathy: Discontinue ifosfamide.

Microscopic hematuria (detected via urinalysis): Withhold ifosfamide until complete resolution.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Generic: 1 g/20 mL (20 mL); 3 g/60 mL (60 mL)

Solution Reconstituted, Intravenous:

Ifex: 1 g (1 ea); 3 g (1 ea)

Generic: 1 g (1 ea); 3 g (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 1 g (1 ea); 3 g (1 ea)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intravenous:

Ifex: 1 g (20 mL); 3 g (60 mL)

Generic: 1 g ([DSC]); 3 g (1 ea)

Administration: Adult

IV: Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (ASCO [Hesketh 2020]; MASCC/ESMO [Roila 2016]).

Administer IV over at least 30 minutes (infusion times may vary by protocol; refer to specific protocol for infusion duration). To prevent bladder toxicity, ifosfamide should be given with mesna and hydration.

Administration: Pediatric

Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (POGO [Dupuis 2011]).

IV: Administer as a slow IV intermittent infusion or continuous infusion; infusion times may vary by protocol; in adults, usually over at least 30 minutes; in pediatric trials, infusion time varied; doses usually infused over 1 to 6 hours or administered as a 24-hour infusion; refer to specific protocols.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Use: Labeled Indications

Testicular cancer: Treatment (third-line) of germ cell testicular cancer (in combination with other chemotherapy drugs and with concurrent mesna for prophylaxis of hemorrhagic cystitis)

Use: Off-Label: Adult

Bladder cancer, advanced; Cervical cancer (recurrent or metastatic); Ewing sarcoma; Extranodal NK/T-cell lymphoma, nasal type; Gestational trophoblastic neoplasia, high-risk, refractory; Hodgkin lymphoma, relapsed or refractory; Non-Hodgkin lymphomas; Osteosarcoma; Ovarian cancer, advanced (platinum-resistant); Penile cancer, metastatic, squamous cell; Soft tissue sarcoma; Thymomas and thymic cancers, advanced; Uterine carcinosarcoma

Medication Safety Issues
Sound-alike/look-alike issues:

Ifosfamide may be confused with cycloPHOSphamide, fostamatinib

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions include ifosfamide monotherapy or combination therapy with other chemotherapeutic agents.

>10%:

Dermatologic: Alopecia (90%)

Gastrointestinal: Nausea and vomiting (47%)

Genitourinary: Gross hematuria (11%; with mesna: 5%), hematuria (44%; with mesna: 21%)

Hematologic & oncologic: Bone marrow depression (including anemia [38%], granulocytopenia, leukopenia [grade 4: 44%], lymphocytopenia, neutropenia, pancytopenia, and thrombocytopenia [5%])

Nervous system: Central nervous system toxicity (≤15%; including neurotoxicity: abnormal electroencephalogram, aphasia, ataxia, cerebellar syndrome, coma, cranial nerve disorder, encephalopathy, extrapyramidal reaction, hallucination, impaired consciousness, motor dysfunction, muscle spasm, myoclonus, peripheral neuropathy [<1%], psychotic reaction, seizure, tremor)

1% to 10%:

Gastrointestinal: Anorexia (1%)

Hematologic & oncologic: Febrile neutropenia (1%)

Hepatic: Hepatotoxicity (2% including hepatorenal syndrome, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin, jaundice)

Infection: Infection (10%; including bacterial infection, fungal infection, infection due to an organism in genus Pneumocystis, parasitic infection [Strongyloides infection], pneumonia, reactivation of disease [latent infections], sepsis, septic shock, and viral infection [herpes zoster infection])

Local: Localized phlebitis (3%)

<1%:

Cardiovascular: Cardiotoxicity (including abnormal T waves on ECG, atrial fibrillation, atrial tachycardia, cardiomyopathy, epicardial fibrosis, decreased QRS voltage, heart failure, hypotension, pericardial effusion, pericarditis [fibrinous], pulmonary edema, ST segment changes on ECG, supraventricular cardiac arrhythmia, supraventricular tachycardia, tachycardia, ventricular arrhythmia, and ventricular tachycardia)

Dermatologic: Dermatitis, papular rash

Gastrointestinal: Diarrhea

Nervous system: Fatigue

Postmarketing:

Cardiovascular: Acute myocardial infarction, angina pectoris, atrial flutter, atrial premature contractions, bradycardia, capillary leak syndrome, cardiac insufficiency, cardiogenic shock, chest pain, congestive cardiomyopathy, deep vein thrombosis, ECG abnormality (QRS complex abnormal), edema (Banh 2022), flushing, hypertension, inversion T wave on ECG, left bundle branch block, left ventricular failure, myocarditis, palpitations, portal vein thrombosis, pulmonary embolism, reduced ejection fraction, right bundle branch block, supraventricular extrasystole, vasculitis, ventricular fibrillation, ventricular premature contractions

Dermatologic: Erythema of skin, hyperhidrosis, hyperpigmentation, macular eruption, nail disease, palmar-plantar erythrodysesthesia, pruritus, skin abnormalities related to radiation recall, skin necrosis, skin rash (Banh 2022), Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Amenorrhea, decreased plasma estrogen concentration, growth retardation (Stohr 2007), hyperglycemia, hypocalcemia, hypokalemia (Skinner 1989), hyponatremia (Cantwell 1990), hypophosphatemia (Skinner 1989 2503116), increased gonadal hormones, malignant neoplasm of thyroid, menopause (premature), metabolic acidosis, nephrogenic diabetes insipidus (Skinner 1989), polydipsia, rickets (Stohr 2007), SIADH (Cantwell 1990)

Gastrointestinal: Abdominal pain (Banh 2022), cholestasis, colitis, constipation, enterocolitis, fecal incontinence, gastrointestinal hemorrhage, intestinal obstruction, mucous membrane ulceration, neutropenic typhlitis, pancreatitis (Hung 2007), sialorrhea, stomatitis (Banh 2022)

Genitourinary: Azoospermia (Williams 2008), increased post-void residual urine volume (sensation of), infertility, inhibition of spermatogenesis, oligospermia, ovarian disease, ovarian failure, ovulatory cycle (disorder), sterility, urinary incontinence (Alici-Evcimen 2007), urotoxicity (including hemorrhagic cystitis) (Mashhasi 2011)

Hematologic & oncologic: Agranulocytosis, bone marrow aplasia (febrile), disseminated intravascular coagulation, hemolytic anemia, hemolytic-uremic syndrome, hemorrhage (including myocardial) (Banh 2022), leukemia (including acute myelocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia), malignant lymphoma, methemoglobinemia, myelodysplastic syndrome, Non-Hodgkin lymphoma, petechia, sarcoma, tumor lysis syndrome (Luminais 2022)

Hepatic: Fulminant hepatitis, hepatic cytolysis, hepatic failure, hepatic sinusoidal obstruction syndrome, viral hepatitis

Hypersensitivity: Anaphylaxis, angioedema, facial swelling, hypersensitivity reaction, nonimmune anaphylaxis

Immunologic: Immunosuppression

Infection: Reactivation of HBV (Chhibar 2016)

Local: Erythema at injection site, inflammation at injection site, injection-site pruritus, pain at injection site, swelling at injection site, tenderness at injection site

Nervous system: Abnormal gait, amnesia, asterixis (Ataseven 2021), bradyphrenia, catatonia, chills, delirium (Szabatura 2015), delusion (Alici-Evcimen 2007), dysarthria, dysesthesia, Guillain-Barre syndrome (Muzaffar 2018), hypoesthesia, leukoencephalopathy, malaise, mania (Ataseven 2021), mental status changes (Yeager 2020), movement disorder (Ames 2010), mutism (Ataseven 2021), neuralgia, pain (Banh 2022), panic attack, paranoid ideation, paresthesia, polyneuropathy, progressive multifocal leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, speech disturbance (echolalia), status epilepticus (convulsive and nonconvulsive) (Ataseven 2021), talkativeness, vertigo

Neuromuscular & skeletal: Arthralgia, limb pain, muscle twitching, myalgia, osteomalacia, rhabdomyolysis

Ophthalmic: Conjunctivitis, eye irritation, visual impairment

Otic: Deafness, hypoacusis, tinnitus

Renal: Interstitial nephritis, nephrotoxicity (including acute kidney injury, chronic renal failure, Fanconi syndrome, renal parenchymal necrosis, renal tubular acidosis, renal tubular disease, renal tubular necrosis) (Boskabadi 2022, Leem 2014, Mashhasi 2011, Morrison 1997, Skinner 1989, Stohr 2007, Yeager 2020), polyuria, renal cell carcinoma

Respiratory: Acute respiratory distress syndrome, bronchospasm, cough, dyspnea, hypoxia, interstitial lung disease, interstitial pneumonitis, pleural effusion, pneumonitis, pulmonary alveolitis (allergic), pulmonary fibrosis, pulmonary hypertension, respiratory failure

Miscellaneous: Fever, multi-organ failure

Contraindications

Known hypersensitivity to ifosfamide or any component of the formulation; urinary outflow obstruction

Canadian labeling: Additional contraindications (not in the US labeling): Severe leukopenia/thrombocytopenia; severe renal and/or hepatic impairment; cystitis; active infection; advanced cerebral arteriosclerosis

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Bone marrow suppression may occur (may be severe and lead to fatal infections). Leukopenia, neutropenia, thrombocytopenia, and anemia are associated with ifosfamide. Myelosuppression is dose dependent, increased with single high doses (compared to fractionated doses) and increased with decreased renal function. Severe myelosuppression may occur when administered in combination with other chemotherapy agents or radiation therapy. Use with caution in patients with compromised bone marrow reserve. Bleeding events due to thrombocytopenia may occur.

• Cardiotoxicity: Ifosfamide-induced cardiotoxicity has been reported; may be fatal. Arrhythmias (eg, atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia), ST-segment or T-wave changes, cardiomyopathy, pericardial effusion, pericarditis, and epicardial fibrosis have been observed. The risk for cardiotoxicity is dose-dependent; concomitant cardiotoxic agents (eg, anthracyclines), irradiation of the cardiac region, and renal impairment may also increase the risk. Use with caution in patients with cardiac risk factors or pre-existing cardiac disease. In a scientific statement from the American Heart Association, ifosfamide has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]).

• CNS toxicity: Ifosfamide may cause CNS toxicity, which may be severe, resulting in encephalopathy and death. Symptoms of CNS toxicity (somnolence, confusion, dizziness, disorientation, hallucinations, cranial nerve dysfunction, psychotic behavior, extrapyramidal symptoms, seizures, coma, peripheral neuropathy, blurred vision, and/or urinary incontinence) have been observed within a few hours to a few days after initial dose, and generally resolve within 2 to 3 days of treatment discontinuation (although symptoms may persist longer); maintain supportive care until complete resolution. Recurrence of CNS toxicity (after several cycles with no CNS incidents) has been reported. Ifosfamide-induced encephalopathy may be due to the accumulation of the metabolite chloroacetaldehyde (Shin 2011). Risk factors for CNS toxicity may include hypoalbuminemia, renal dysfunction, and high-dose antiemetic therapy. Concomitant centrally acting medications may result in additive CNS effects. Peripheral neuropathy has been reported.

• Hemorrhagic cystitis: Hemorrhagic cystitis may occur (may be severe); concomitant mesna reduces the risk of hemorrhagic cystitis. Acrolein (an ifosfamide metabolite) causes urotoxicity. Hydration (at least 2 L/day in adults), dose fractionation, and/or mesna administration will reduce the incidence of hematuria and protect against hemorrhagic cystitis. Exclude or correct urinary tract obstructions prior to treatment. Use with caution (if at all) in patients with active urinary tract infection. Hemorrhagic cystitis is dose dependent and is increased with high single doses (compared with fractionated doses); past or concomitant bladder radiation or busulfan treatment may increase the risk for hemorrhagic cystitis.

• Hepatic effects: Hepatic sinusoidal obstruction syndrome (SOS), formerly called veno-occlusive disease (VOD), has been reported with ifosfamide-containing regimens.

• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions have been associated with ifosfamide. Cross sensitivity with similar agents may occur.

• Infection: May cause significant suppression of the immune responses; may lead to serious infection, sepsis or septic shock. Reported infections have included bacterial, viral, fungal, and parasitic; latent viral infections may be reactivated. Use with caution with other immunosuppressants or in patients with infection.

• Pulmonary toxicity: Interstitial pneumonitis, pulmonary fibrosis, and pulmonary toxicity leading to respiratory failure (may be fatal) have been reported.

• Renal toxicity: May cause severe nephrotoxicity, resulting in renal failure. Nephrotoxicity may be fatal. Acute and chronic renal failure, as well as renal parenchymal and tubular necrosis (including acute), have been reported; tubular damage may be delayed (months to years) and may persist. Renal manifestations include decreased glomerular rate, increased creatinine, proteinuria, enzymuria, cylindruria, tubular acidosis, aminoaciduria, phosphaturia, and glycosuria. Syndrome of inappropriate antidiuretic hormone (SIADH), renal rickets, and Fanconi syndrome have been reported.

• Secondary malignancy: Secondary malignancies may occur (onset may be delayed); the risk for myelodysplastic syndrome (which may progress to acute leukemia) is increased with treatment.

• Wound healing: May interfere with wound healing.

Other warnings/precautions:

• Radiation therapy: Use with caution in patients with prior radiation therapy.

Metabolism/Transport Effects

Substrate of CYP2B6 (minor), CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Aprepitant: May increase the serum concentration of Ifosfamide. Specifically, concentrations of the toxic metabolites of ifosfamide may increase. Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Brivudine [INT]: May enhance the adverse/toxic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

BUPivacaine: Ifosfamide may enhance the adverse/toxic effect of BUPivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy

Busulfan: May enhance the adverse/toxic effect of Ifosfamide. Specifically, the risk of hemorrhagic cystitis may be increased. Risk C: Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination

Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Fosaprepitant: May increase the serum concentration of Ifosfamide. Specifically, concentrations of the toxic metabolites of ifosfamide may increase. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification

Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination

Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification

Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy

Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy

Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination

Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Ifosfamide may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

Male and female fertility may be affected. Sterility in males and females is dose and duration dependent. Ifosfamide interferes with oogenesis and spermatogenesis; amenorrhea, azoospermia, and sterility have been reported and may be irreversible. Patients should not become pregnant during therapy and patients with partners who could become pregnant should not father a child for at least 6 months after completion of therapy.

Pregnancy Considerations

Fetal growth retardation and neonatal anemia have been reported with exposure to ifosfamide-containing regimens during pregnancy.

Breastfeeding Considerations

Ifosfamide is present in breast milk. Breastfeeding is not recommended during ifosfamide treatment; due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue ifosfamide or to discontinue breastfeeding, taking into account the benefits of treatment to the mother.

Monitoring Parameters

CBC with differential (prior to and at appropriated intervals after each cycle, and as clinically appropriate), urine output, urinalysis (for erythrocytes prior to each dose), liver function, and renal function tests (prior to and during treatment). Monitor for signs/symptoms of neurotoxicity, pulmonary toxicity, urotoxicity/hemorrhagic cystitis, and secondary malignancies.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Ifosfamide causes cross-linking of strands of DNA by binding with nucleic acids and other intracellular structures, resulting in cell death; inhibits protein synthesis and DNA synthesis

Pharmacokinetics (Adult Data Unless Noted)

Pharmacokinetics are dose dependent

Distribution: Vd: Approximates total body water; penetrates CNS, but not in therapeutic levels

Protein binding: Negligible

Metabolism: Hepatic to active metabolites isofosforamide mustard, 4-hydroxy-ifosfamide, acrolein, and inactive dichloroethylated and carboxy metabolites; acrolein is the agent implicated in development of hemorrhagic cystitis

Half-life elimination (increased in the elderly):

High dose (3,800 to 5,000 mg/m2): ~15 hours

Lower dose (1,600 to 2,400 mg/m2): ~7 hours

Excretion:

High dose (5,000 mg/m2): Urine (70% to 86%; 61% as unchanged drug)

Lower dose (1,600 to 2,400 mg/m2): Urine (12% to 18% as unchanged drug)

Pricing: US

Solution (Ifosfamide Intravenous)

1 g/20 mL (per mL): $2.20

3 g/60 mL (per mL): $2.15

Solution (reconstituted) (Ifex Intravenous)

1 g (per each): $44.09

3 g (per each): $125.56

Solution (reconstituted) (Ifosfamide Intravenous)

1 g (per each): $42.28 - $69.66

3 g (per each): $129.05

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Alquimid (CR, DO, GT, HN, NI, PA, SV);
  • Cuantil (AR, PY);
  • Farmamide (DE);
  • Fosfa (PH);
  • Fosfidex (CR, DO, GT, HN, NI, PA, SV);
  • Holoxan (AE, AT, AU, BD, BE, BG, BH, CH, CL, CN, CY, CZ, DE, DK, EC, EE, EG, FI, FR, HK, HN, HR, HU, ID, IE, IL, IQ, IR, IS, IT, JO, KR, LB, LT, LU, LV, LY, MT, MY, NL, NO, NZ, OM, PH, PK, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, SY, TH, TR, TW, UY, VN, YE);
  • Holoxane (BR);
  • Ifadex (CR, DO, GT, HN, MX, NI, PA, SV);
  • Ifamide (BD);
  • Ifo-Cell (IL);
  • Ifolem (MX, TH);
  • Ifomida (MX);
  • Ifomide (JP);
  • Ifos (EG, LB, PE, PY);
  • Ipamide (IN);
  • Iphox (PH);
  • Isoxan (EG);
  • Mitoxana (IE);
  • Tolcamin (CO);
  • Tronoxal (ES);
  • Xifox (BD)


For country code abbreviations (show table)
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  12. Basaran M, Bavbek ES, Saglam S, et al, “A Phase II Study of Cisplatin, Ifosfamide and Epirubicin Combination Chemotherapy in Adults With Nonmetastatic and Extremity Osteosarcomas,” Oncology, 2007, 72(3-4):255-60. [PubMed 18185020]
  13. Boskabadi J, Yousefi-Mazhin E, Salehifar E. Ifosfamide-induced acute kidney injury in a patient with leiomyosarcoma: a case report. Cancer Rep (Hoboken). 2022;5(10):e1666. doi:10.1002/cnr2.1666 [PubMed 35830327]
  14. Cairo MS, Davenport V, Bessmertny O, et al, "Phase I/II Dose Escalation Study of Recombinant Human Interleukin-11 Following Ifosfamide, Carboplatin and Etoposide in Children, Adolescents and Young Adults With Solid Tumours or Lymphoma: A Clinical, Haematological and Biological Study," Br J Haematol, 2005, 128(1):49-58. [PubMed 15606549]
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