Ifosfamide

Dosage Forms

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

Solution, Intravenous:

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

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)

Pharmacology

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/Pharmacodynamics

Distribution

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

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

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)

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

Protein Binding

Negligible

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

Bladder cancer, advancedb

Data from a small phase II trial supports the use of single agent ifosfamide as second-line treatment of advanced or metastatic bladder cancer Witte 1997. Additional trials may be necessary to further define the role of ifosfamide in the treatment of this condition.

Cervical cancer (recurrent or metastatic)c

Data from two small phase II studies support the use of ifosfamide in the treatment of advanced, recurrent, or relapsed cervical carcinoma Coleman 1986, Sutton 1993. Additional trials may be necessary to further define the role of ifosfamide in the treatment of this condition.

Ewing sarcomaa

Data from multiple trials supports the use of ifosfamide (in combination with other chemotherapy agents, such as etoposide, carboplatin, vincristine, doxorubicin, and/or dactinomycin) for the treatment of Ewing sarcoma Grier 2003, Juergens 2006, Miser 1987, Paulussen 2001, Paulussen 2008, van Winkle 2005.

Hodgkin lymphoma, relapsed or refractoryb

Data from small clinical trials supports the use of ifosfamide (in combination with carboplatin and etoposide [ICE regimen] and gemcitabine, vinorelbine and prednisolone [IGEV regimen]) for the treatment of relapsed or refractory Hodgkin lymphoma Moskowitz 2001, Santoro 2007. Additional trials may be necessary to further define the role of ifosfamide in the treatment of this condition.

Non-Hodgkin lymphomasb

Data from a phase II study supports the use of ifosfamide as part of the CODOX-M/IVAC regimen (cyclophosphamide vincristine, doxorubicin, and methotrexate [CODOX-M] alternating with etoposide, ifosfamide, and cytarabine [IVAC]) for the treatment of aggressive Burkitt lymphoma Mead 2008.

Data from a small phase II study supports the use of ifosfamide (in combination with rituximab, carboplatin and etoposide) for the treatment of relapsed or refractory diffuse large B-cell lymphoma Kewalramani 2004.

Osteosarcomab

Data from multiple trials support the use of ifosfamide (in combination with other chemotherapy agents, such as cisplatin, doxorubicin, methotrexate, epirubicin, carboplatin, and/or etoposide) for the treatment of osteosarcoma Bacci 2003, Basaran 2007, Gentet 1997, Le Deley 2007, van Winkle 2005. Additional trials may be necessary to further define the role of ifosfamide in treatment of this condition.

Ovarian cancer, advanced (platinum-resistant)c

Data from a phase II trial in patients with ovarian cancer previously treated with a platinum agent supports the use of ifosfamide (as a single agent) in patients with advanced disease after failure of second-line therapy including a platinum agent Markman 1992. Additional trials may be necessary to further define the role of ifosfamide in this condition.

Soft tissue sarcomaa

Data from multiple phase II and phase III trials support the use of ifosfamide as a single agent or as part of a combination chemotherapy regimen (eg, MAID, AIM, EIA, or ifosfamide/epirubicin) for the management of soft tissue sarcoma Antman 1993, Antman 1998, Elias 1989, Frustaci 2001, Grobmyer 2004, Issels 2010, van Oosterom 2002, Worden 2005.

Thymomas and thymic cancers, advancedc

Data from a small phase II trial suggests that ifosfamide (in combination with cisplatin and etoposide) has activity in the treatment of advanced thymomas and thymic cancers Loehrer 2001. Ifosfamide (as a single agent) may also be considered as second line therapy in patients with thymomas Highley 1999. Additional trials may be necessary to further define the role of ifosfamide in this condition.

Contraindications

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

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

Dosage and Administration

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 (Hesketh 2017; Roila 2016).

Testicular cancer: IV:

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

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

Off-label dosing/combinations:

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

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

Ewing sarcoma (off-label use): IV:

VAC/IE regimen: Adults ≤30 years: IE: 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: 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: 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: 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: 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)

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

ICE regimen: 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)

IGEV regimen: 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 (off-label use): IV:

Burkitt lymphoma (CODOX-M/IVAC regimen):

Adults ≤65 years: Cycles 2 and 4 (IVAC): 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: Cycles 2 and 4 (IVAC): 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): 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 (off-label use): IV:

Ifosfamide/cisplatin/doxorubicin/HDMT regimen: Adults <40 years: 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)

Ifosfamide/cisplatin/epirubicin regimen: 2,000 mg/m²/day 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) (Basaran 2007)

ICE regimen (adults ≤22 years): 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): IV: 1,000 to 1,200 mg/m²/day for 5 days (with mesna) every 28 days for up to 6 cycles (Markman 1992). Additional trials may be necessary to further define the role of ifosfamide in this condition.

Soft tissue sarcoma (off-label use): IV:

Single-agent ifosfamide: 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: 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: 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: 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: 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)

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). Additional trials may be necessary to further define the role of ifosfamide in this condition.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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.

Note: 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 (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013).

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 (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: 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: 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: 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: 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: 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)

Dosing: Adjustment for Toxicity

WBC <2,000/mm³ and/or platelets <50,000/mm³: Avoid administering treatment (unless clinically necessary)

Encephalopathy: Discontinue treatment

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Reconstitute powder with SWFI or bacteriostatic SWFI (1 g in 20 mL or 3 g in 60 mL) to a concentration of 50 mg/mL. Further dilution in 50 to 1,000 mL D5W, NS, or lactated Ringer's (to a final concentration of 0.6 to 20 mg/mL) is recommended for IV infusion (may also dilute in D2.5W, ¹/₂NS, or D5NS).

Administration

IV: Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; 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.

Storage

Store intact vials of powder for injection at room temperature of 20°C to 25°C (68°F to 77°F); avoid temperatures >30°C (86°F). Store intact vials of solution at 2°C to 8°C (36°F to 46°F). Reconstituted solutions and solutions diluted in D5W, NS, or LR for administration are stable for 24 hours refrigerated.

Drug Interactions

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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

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

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

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

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

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

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP2B6 Inducers (Moderate): May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). 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. 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. Monitor therapy

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

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

Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). 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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

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

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

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

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. 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. 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. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

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

Adverse Reactions

>10%:

Central nervous system: Brain disease (≤15%), central nervous system toxicity (≤15%)

Dermatologic: Alopecia (83% to 90%; combination therapy: 100%)

Endocrine & metabolic: Metabolic acidosis (31%)

Gastrointestinal: Nausea (≤58%), vomiting (≤58%)

Hematologic & oncologic: Leukopenia (≤100%; grade 4: ≤50%; nadir: 8 to 14 days), anemia (38%), thrombocytopenia (20%; grades 3/4: ≤8%)

Renal: Hematuria (6% to 92%, reduced with mesna; grade 2 [gross hematuria]: 8% to 12%)

1% to 10%:

Cardiovascular: Localized phlebitis (2% to 3%)

Gastrointestinal: Anorexia (1%)

Hematologic & oncologic: Febrile neutropenia (1%)

Hepatic: Hepatic insufficiency (2% to 3%), increased serum bilirubin (2% to 3%), increased serum transaminases (2% to 3%)

Infection: Infection (8% to 10%)

Renal: Renal insufficiency (6%)

Miscellaneous: Fever (1%)

<1%, postmarketing, and/or case reports: Abdominal pain, abnormal gait, acute renal failure, agranulocytosis, altered hormone level (increased gonadotropin), amenorrhea, amnesia, anaphylaxis, angina pectoris, angioedema, anovulation, anuria, arthralgia, asterixis, atrial premature contractions, atrial fibrillation, atrial flutter, atrial premature contractions, azoospermia, blood coagulation disorder, blurred vision, bone marrow failure, bradycardia, bronchospasm, bundle branch block, capillary leak syndrome, cardiac arrhythmia, cardiac failure, cardiogenic shock, cardiomyopathy, cardiotoxicity, casts in urine, catatonia, chest pain, chills, cholestasis, chronic renal failure, cognitive dysfunction, colitis, conjunctivitis, constipation, cough, increased serum creatinine, decreased creatinine clearance, decreased plasma estrogen concentration, deep vein thrombosis, delirium, delusions, dermatitis, diarrhea, disseminated intravascular coagulation, dysarthria, dysesthesia, dyspnea, dysuria, ECG abnormality (QRS complex abnormal), edema, enterocolitis, erythema, extrapyramidal reaction, facial swelling, Fanconi’s syndrome, fatigue, fecal incontinence, flushing, fulminant hepatitis, gastrointestinal hemorrhage, glycosuria, granulocytopenia, growth suppression (children), hearing loss, hemolytic anemia, hemolytic-uremic syndrome, hemorrhage (including myocardial), hemorrhagic cystitis, hepatic failure, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease), hepatitis (cytolytic), hepatorenal syndrome, herpes zoster, hyperglycemia, hyperhidrosis, hypertension, hyperpigmentation, hypersensitivity pneumonitis, hypersensitivity reaction, hypocalcemia, hypoesthesia, hypokalemia, hyponatremia, hypophosphatemia, hypotension, hypoxia, intestinal obstruction, immunosuppression, increased blood urea nitrogen, increased creatinine clearance, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased serum alkaline phosphatase, infertility, infusion site reaction (erythema, inflammation, pain, pruritus, swelling, tenderness), inhibition of spermatogenesis, interstitial nephritis, interstitial pneumonitis, interstitial pulmonary disease, inversion T wave on ECG, irritable bladder, jaundice, left ventricular dysfunction (failure), leukoencephalopathy, limb pain, lymphocytopenia, malaise, mania, menopause (premature), mental status changes, metastases (including ALL, AML, APL, lymphoma, MDS, RCC, sarcomas, thyroid cancer), methemoglobinemia, mucosal inflammation, mucous membrane ulceration, multi-organ failure, muscle twitching, mutism, myalgia, myocardial infarction, myocarditis, nail disease, nephrogenic diabetes insipidus, neuralgia, neutropenia, oligospermia, oliguria, osteomalacia (adults), ovarian failure, pain, palmar-plantar erythrodysesthesia, pancreatitis, pancytopenia, panic attack, paranoia, parenchymal damage (renal), paresthesia, pericardial effusion, pericarditis, peripheral neuropathy, petechia, phosphaturia, physical health deterioration, pleural effusion, pneumonia (including Pneumocystis jirovecii), pneumonitis, pollakiuria, polydipsia, polyneuropathy, polyuria, portal vein thrombosis, progressive multifocal leukoencephalopathy, proteinuria, pruritus, pulmonary edema, pulmonary embolism, pulmonary fibrosis, pulmonary hypertension, reduced ejection fraction, renal tubular acidosis, renal tubular necrosis, respiratory distress syndrome (acute), respiratory failure, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, rickets, salivation, seizure, sepsis, septic shock, SIADH, skin abnormalities related to radiation recall, skin necrosis, skin rash (including macular and papular), status epilepticus, sterility, Stevens-Johnson syndrome, stomatitis, ST segment changes on ECG, supraventricular extrasystole, tachycardia, talkativeness (logorrhea), tinnitus, toxic epidermal necrolysis, tumor lysis syndrome, typhlitis, uremia, urinary incontinence, urine abnormality (aminoaciduria and enzymuria), urticaria, vasculitis, ventricular fibrillation, ventricular premature contractions, ventricular tachycardia, vertigo, viral hepatitis, visual impairment, wound healing impairment

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Bone marrow suppression may occur (may be severe and lead to fatal infections); monitor blood counts before and after each cycle. 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. Unless clinically necessary, avoid administering to patients with WBC <2,000/mm³ and platelets <50,000/mm³. Bleeding events due to thrombocytopenia may occur. Antimicrobial prophylaxis may be necessary in some neutropenic patients; administer antibiotics and/or antifungal agents for neutropenic fever.
• 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: [US Boxed Warning]: May cause CNS toxicity which may be severe, resulting in encephalopathy and death; monitor for CNS toxicity; discontinue for encephalopathy. 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. 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.
• Gastrointestinal toxicity: Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).
• Hemorrhagic cystitis: [US Boxed Warning]: Hemorrhagic cystitis may occur (may be severe); concomitant mesna reduces the risk of hemorrhagic cystitis. 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. Obtain urinalysis prior to each dose; if microscopic hematuria is detected, withhold until complete resolution. 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. Monitor for signs and symptoms of pulmonary toxicity.
• Renal toxicity: [US Boxed Warning]: 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. Evaluate renal function prior to and during treatment; monitor urine for erythrocytes and signs of urotoxicity.
• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

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

Monitoring Parameters

CBC with differential (prior to each cycle and as clinically appropriate), urine output, urinalysis (prior to each dose), liver function, and renal function tests; signs and symptoms of neurotoxicity, pulmonary toxicity, and/or hemorrhagic cystitis

Pregnancy

Pregnancy Considerations

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

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. Women should not become pregnant during therapy and male patients should not father a child during and for at least 6 months after completion of therapy.

Patient Education

What is this drug used for?

• It is used to treat testicular cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Hair loss
• Vomiting
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out.
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
• Infection
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Severe loss of strength and energy
• Confusion
• Dizziness
• Passing out
• Sensing things that seem real but are not
• Bladder incontinence
• Seizures
• Burning or numbness feeling
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• No menstrual periods
• Fatigue
• Vision changes
• Eye pain
• Severe eye irritation
• Behavioral changes
• Abnormal movements
• Twitching
• Change in balance
• Trouble swallowing
• Trouble speaking
• Wound healing impairment
• Hearing loss
• Noise or ringing in the ears
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.