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Ifosfamide

Pronunciation

(eye FOSS fa mide)

Index Terms

  • Isophosphamide
  • Z4942

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)

Brand Names: U.S.

  • Ifex

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)

Pharmacology

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

Distribution

Vd: 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

US labeling: 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)

Canadian labeling (not approved indications in the US): Treatment of soft tissue sarcoma (first or second-line single-agent therapy), pancreatic cancer (relapsed or refractory; second-line single-agent therapy), cervical cancer (advanced or recurrent; as monotherapy or in combination with cisplatin and bleomycin)

Use: Unlabeled

Treatment of bladder cancer (metastatic), cervical cancer (recurrent or metastatic), head and neck cancers (recurrent or metastatic), ovarian cancer, small cell lung cancer (relapsed), Hodgkin lymphoma (relapsed or refractory), non-Hodgkin lymphomas, thymomas and thymic cancers (advanced), sarcomas (Ewing’s sarcoma, osteosarcoma, and soft tissue sarcoma)

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

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 (Basch 2011; Roila 2010).

Testicular cancer: IV:

US 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)

Canadian labeling: Soft tissue sarcoma, cervical cancer (advanced or recurrent), pancreatic cancer (relapsed or refractory): IV: 2,000 to 2,400 mg/m2/day for 5 consecutive days (with mesna), may repeat after 3 to 4 weeks (or longer depending on patient status) or if lower daily dosage or total dosage over a longer time period is indicated, administer every other day (eg, days 1, 3, 5, 7, 9) or over 10 consecutive days at reduced doses.

High single-dose infusions of up to 5,000 to 8,000 mg/m2/24 hour with continuous mesna may also be feasible; may repeat after 3 to 4 weeks (or longer depending on patient’s condition).

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)

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:

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)

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)

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)

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)

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)

ICE regimen: 1,500 mg/m2/day for 4 days every 4 weeks for 4 to 6 cycles (in combination with carboplatin, etoposide, and regional hyperthermia) (Nickenig 2009)

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)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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 (Dupuis 2011).

Ewing sarcoma (off-label use): IV:

VAC/IE regimen: 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)

ICE-CAV regimen: ICE: 1,800 mg/m2/day for 5 days every 3 to 4 weeks for 2 courses (in combination with carboplatin and etoposide [and mesna]), followed by CAV (cyclophosphamide, doxorubicin, and vincristine) (Milano 2006)

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 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: 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: 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)

Osteosarcoma (off-label use): IV:

Ifosfamide/cisplatin/doxorubicin/HDMT regimen: 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: Children ≥15 years: 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)

IE regimen: 3,000 mg/m2/day over 3 hours for 4 days every 3 to 4 weeks (in combination with etoposide and mesna) (Gentet 1997)

ICE regimen: Children ≥1 year: 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)

Ifosfamide/HDMT/etoposide regimen: 3,000 mg/m2/day over 3 hours for 4 days during weeks 4 and 9 (3 additional postop courses were administered in good responders) (in combination with methotrexate [high-dose], etoposide, and mesna) (Le Deley 2007)

Dosing: Renal Impairment

US labeling: Consider dosage reduction in patients with renal impairment; however, there are no dosage adjustments provided in the manufacturer’s labeling; ifosfamide (and metabolites) are excreted renally and may accumulate in patients with renal dysfunction. Ifosfamide and metabolites are dialyzable.

Canadian labeling:

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: Use is contraindicated.

The following adjustments have also been recommended:

Aronoff 2007:

CrCl ≥10 mL/minute: Children and Adults: No dosage adjustment necessary.

CrCl <10 mL/minute: Children and Adults: Administer 75% of dose.

Hemodialysis (supplement for dialysis):

Children: 1 g/m2 followed by hemodialysis 6 to 8 hours later

Adults: No supplemental dose needed

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

Dosing: Hepatic Impairment

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.

Canadian labeling:

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer labeling; use with caution.

Severe impairment: Use is contraindicated.

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

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). 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

Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2010).

Administer IV over at least 30 minutes (infusion times may vary by protocol; refer to specific protocol for infusion duration)

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5LR, D5NS, D5W, LR, 1/2NS, NS.

Y-site administration: Incompatible with cefepime, methotrexate.

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

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

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. 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. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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. Consider therapy modification

Lumacaftor: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

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

Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

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

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

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

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

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

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. 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. Avoid combination

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

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. 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: CNS toxicity or encephalopathy (12% to 15%)

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

Endocrine & metabolic: Metabolic acidosis (31%)

Gastrointestinal: Nausea/vomiting (47% to 58%)

Hematologic: Leukopenia (50% to ≤100%; grade 4: ≤50%; nadir: 8-14 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%:

Central nervous system: Fever (1%)

Gastrointestinal: Anorexia (1%)

Hematologic: Neutropenic fever (1%)

Hepatic: Bilirubin increased (2% to 3%), liver dysfunction (2% to 3%), transaminases increased (2% to 3%)

Local: Phlebitis (2% to 3%)

Renal: Renal impairment (6%)

Miscellaneous: Infection (8% to 10%)

<1% (Limited to important or life-threatening): Acute respiratory distress syndrome, acute tubular necrosis, agranulocytosis, alkaline phosphatase increased, allergic reaction, alveolitis (allergic), amenorrhea, aminoaciduria, amnesia, anaphylactic reaction, angina, angioedema, anuria, arrhythmia, arthralgia, asterixis, atrial ectopy, atrial fibrillation/flutter, azoospermia, bladder irritation, bleeding, blurred vision, bone marrow failure, bradycardia, bradyphrenia, bronchospasm, bundle branch block, BUN increased, capillary leak syndrome, cardiac arrest, cardiogenic shock, cardiomyopathy, cardiotoxicity, catatonia, cecitis, chest pain, cholestasis, coagulopathy, colitis, conjunctivitis, creatinine clearance decreased/increased, creatinine increased, cylindruria, cytolytic hepatitis, delirium, delusion, dermatitis, diarrhea, DIC, DVT, dysesthesia, dyspnea, dysuria, echolalia, edema, ejection fraction decreased, enterocolitis, enuresis, enzymuria, erythema, extrapyramidal disorder, facial swelling, Fanconi syndrome, fatigue, gait disturbance, GGT increased, GI hemorrhage, glycosuria, gonadotropin increased, granulocytopenia, growth retardation (children), hemolytic anemia, hemolytic uremic syndrome, hemorrhagic cystitis, hepatic failure, hepatic sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease [VOD]), hepatitis fulminant, hepatitis (viral), hepatorenal syndrome, herpes zoster, hyperglycemia, hyper-/hypotension, hypersensitivity reactions, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia, hypoxia, ileus, immunosuppression, infertility, infusion site reactions (erythema, inflammation, pain, pruritus, swelling, tenderness), interstitial lung disease, jaundice, LDH increased, leukoencephalopathy, lymphopenia, malaise, mania, mental status change, methemoglobinemia, MI, mucosal inflammation/ulceration, multiorgan failure, mutism, myocardial hemorrhage, myocarditis, nephrogenic diabetes insipidus, neuralgia, neutropenia, oligospermia, oliguria, osteomalacia (adults), ovarian failure, ovulation disorder, palmar-plantar erythrodysesthesia syndrome, pancreatitis, pancytopenia, panic attack, paranoia, paresthesia, pericardial effusion, pericarditis, peripheral neuropathy, petechiae, phosphaturia, pleural effusion, Pneumocystis jiroveci pneumonia, pneumonia, pneumonitis, pollakiuria, polydipsia, polyneuropathy, polyuria, portal vein thrombosis, premature atrial contractions, premature menopause, progressive multifocal leukoencephalopathy, proteinuria, pruritus, pulmonary edema, pulmonary embolism, pulmonary fibrosis, pulmonary hypertension, QRS complex abnormal, radiation recall dermatitis, rash (including macular and papular), renal failure, renal parenchymal damage, renal tubular acidosis, respiratory failure, reversible posterior leukoencephalopathy syndrome (RPLS), rhabdomyolysis, rickets, salivation, secondary malignancy, seizure, sepsis, septic shock, SIADH, skin necrosis, spermatogenesis impaired, status epilepticus, sterility, Stevens-Johnson syndrome, stomatitis, ST segment abnormal, supraventricular extrasystoles, tachycardia, tinnitus, toxic epidermal necrolysis, tubulointerstitial nephritis, tumor lysis syndrome, T-wave inversion, uremia, urticaria, vasculitis, ventricular extrasystoles/fibrillation/tachycardia, ventricular failure, vertigo, visual impairment, wound healing impairment

ALERT: U.S. Boxed Warning

Nephrotoxicity:

Nephrotoxicity can be severe and result in renal failure.

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.

Urotoxicity:

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

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.

• 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 (Basch 2011; Dupuis 2011; Roila 2010).

• 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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 Risk Factor

D

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies. Fetal growth retardation and neonatal anemia have been reported with exposure to ifosfamide-containing regimens during human pregnancy. Male and female fertility may be affected (dose and duration dependent). Ifosfamide interferes with oogenesis and spermatogenesis; amenorrhea, azoospermia, and sterility have been reported and may be irreversible. Avoid pregnancy during treatment; male patients should not father a child for at least 6 months after completion of therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience alopecia, vomiting, or nausea. Have patient report immediately to prescriber signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), illogical thinking, bruising, bleeding, loss of strength and energy, severe dizziness, passing out, hallucination, seizures, shortness of breath, excessive weight gain, swelling of arms or legs, amenorrhea, fatigue, vision changes, eye pain, severe eye irritation, behavioral changes, abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, arrhythmia, wound healing impairment, hearing loss, or tinnitus (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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