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    Nitrogen Mustard Analogs

    BOXED WARNING

    Dehydration, hematuria, hemorrhagic cystitis, hepatic disease, nephrotoxicity

    Ifosfamide should be administered under the supervision of a qualified clinician experienced in the use of cancer chemotherapeutic agents. Ifosfamide undergoes hepatic metabolism and should be used with caution in patients with hepatic disease. Effective treatment is dependent on ifosfamide metabolism to cytotoxic metabolites. The active metabolite is further broken down to a bladder toxic metabolite, acrolein, which is eliminated renally. The duration of exposure of acrolein to the bladder wall should be minimized. Patients should receive vigorous hydration during therapy to prevent nephrotoxicity and hemorrhagic cystitis. In addition, all patients should receive concurrent treatment with mesna. Mesna binds to acrolein and decreases the incidence of hemorrhagic cystitis. Dehydration should be corrected prior to therapy. All patients should have a urinalysis prior to each dose. If microscopic hematuria (> 10 RBCs per high-power field) is present, then subsequent administration should be held until hematuria has resolved.

    Coma, neurotoxicity

    Ifosfamide should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Neurotoxicity and neurologic manifestations consisting of somnolence, confusion, hallucinations, and in some instances, coma have been reported following ifosfamide therapy. The occurrence of these symptoms requires discontinuation of ifosfamide therapy. The symptoms have usually been reversible and supportive therapy should be maintained until their complete resolution.

    DEA CLASS

    Rx

    DESCRIPTION

    Alkylating agent; synthetic analog of cyclophosphamide; spectrum of activity differs from cyclophosphamide; active in sarcomas, NHL, breast, lung, bladder/urothelial tract, cervical, and testicular cancers; must be given in combination with mesna.

    COMMON BRAND NAMES

    Ifex

    HOW SUPPLIED

    Ifex/Ifosfamide Intravenous Inj Pwd F/Sol: 1g, 3g
    Ifosfamide Intravenous Inj Sol: 1mL, 50mg

    DOSAGE & INDICATIONS

    For use as a third line chemotherapeutic agent in the treatment of germ cell testicular cancer.
    NOTE: Ifosfamide has been designated an orphan drug by the FDA for the treatment of testicular cancer.
    Intravenous Dosage
    Adult

    1.2—2 g/m2/day IV for 5 consecutive days, in combination with mesna. Treatment may be repeated every three weeks after recovery from hematologic toxicity. As a single agent, overall response rates of 20—66% are achieved. Ifosfamide has been included in various salvage regimens after relapse following BEP therapy. Ifosfamide 1.2 g/m2/day IV on days 1—5 in combination with mesna for uroprotection, cisplatin (20 mg/m2/day IV for 5 days), and vinblastine ( 0.11 mg/kg IV on days 1 and 2) were administered as salvage therapy resulting in an 83% complete remission rate. Additional salvage regimens include use of ifosfamide 1.2 g/m2/day IV x 5 days and paclitaxel (250 mg/m2 as a 24-hour continuous IV infusion on day 1) and cisplatin (20 mg/m2 IV x 5 days). Poor-risk, disseminated germ cell tumors have been treated effectively with the VIP regimen (ifosfamide 1.2 g/m2/day IV, etoposide 75 mg/m2 IV , and cisplatin 20 mg/m2/day IV each drug given daily on 5 consecutive days) with progression-free survival of 64% and overall survival of 69% at a median follow-up of 10 years.

    For the treatment of non-Hodgkin's lymphoma (NHL)†.
    For the treatment of relapsed or refractory NHL in combination with carboplatin and etoposide†.
    Intravenous dosage
    Adults

    5 g/m2 IV mixed with equal dose of mesna via continuous intravenous infusion over 24 hours beginning on day 2, etoposide (100 mg/m2/day on days 1—3), carboplatin AUC 5 IV on day 2 (maximum of 800 mg), every 2 weeks (ICE regimen) for 3 cycles, was developed to treated relapsed NHL and allow for adequate stem cell collection prior to transplant. Alternative dosage regimens have been used, including some in the outpatient setting.

    For the treatment of relapsed or refractory CD20-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with rituximab, carboplatin, and etoposide†.
    Intravenous dosage
    Adults

    The R-ICE regimen consists of rituximab 375 mg/m2 IV on day -2 of the first cycle only, then rituximab 375 mg/m2 IV on day 1, etoposide 100 mg/m2 IV daily on days 1—3, carboplatin AUC 5 (maximum dose = 800 mg) IV on day 2, and ifosfamide 5 gm/m2 IV (with mesna) as a continuous 24 hour IV infusion starting on day 2, plus filgrastim daily on days 6—13, repeated every 21 days for 3 cycles.

    For the treatment soft-tissue sarcoma†.
    NOTE: Ifosfamide has been designated an orphan drug by the FDA for the treatment of soft-tissue sarcoma.
    As first-line treatment for advanced soft-tissue sarcoma in combination with epirubicin†.
    Intravenous dosage
    Adults and Adolescents aged 17 years

    2.5 grams/m2 per day continuous IV infusion over 24 hours on days 1, 2, 3, 4, and 5 (with hydration and mesna 1.5 grams/m2 per day CIV) plus epirubicin 45 mg/m2 per day CIV on days 2 and 3 administered every 3 weeks (median of 5 cycles; range, 2 to 6 cycles) with growth-factor support with filgrastim (5 mcg/kg per day subcutaneously on days 6 to 15 or until leukocyte recovery) OR ifosfamide 1.8 grams/m2 per day IV over 1 hour on days 1, 2, 3, 4, and 5 (with mesna at 20% of ifosfamide dose given every 4 hours for 3 daily doses on days 1, 2, 3, 4, and 5) plus epirubicin 75 mg/m2 IV on day 1 repeated every 3 to 4 weeks for at least 3 cycles have been evaluated in patients with previously untreated, advanced soft-tissue sarcoma in phase II studies.

    As adjuvant therapy for advanced soft-tissue sarcoma in combination with epirubicin†.
    Intravenous dosage
    Adults younger than 65 years

    1.8 grams/m2 per day IV over 1 hour on days 1, 2, 3, 4, and 5 with mesna (20% of ifosfamide dose given prior to and 4 and 8 hours after ifosfamide on days 1, 2, 3, 4, and 5) plus epirubicin 60 mg/m2 per day IV on day 1 and 2 administered every 3 weeks for 5 cycles following local treatment with surgery with or without radiation therapy was evaluated in 104 patients with high-risk soft-tissue sarcoma in a randomized study. All patients received hydration, antiemetics, and filgrastim 300 mcg subcutaneously daily on days 8 to 15.

    For the first-line treatment of unresectable or metastatic soft-tissue sarcoma† in combination with dacarbazine, doxorubicin, and mesna.
    Intravenous dosage
    Adults

    2,000 mg/m2 per day as a continuous IV infusion over 24 hours (CIV) for 3 days in combination with doxorubicin 15 mg/m2 per day CIV for 4 days, dacarbazine 250 mg/m2 per day CIV for 4 days, and mesna 2,500 mg/m2 per day CIV for 4 days repeated every 21 days (median of 3 cycles) (MAID regimen) was evaluated in patients with soft-tissue and bone sarcomas in a randomized, phase III trial. Due to unacceptable myelosuppression in the first 154 patients treated, the ifosfamide dose was reduced from 2,500 mg/m2 per day to 2,000 mg/m2 per day. Five cycles of an intensified MAID regimen was compared with 6 cycles of a more standard MAID regimen (dacarbazine 300 mg/m2 per day IV over 1 hour on days 1, 2, and 3 plus doxorubicin 20 mg/m2 per day as an IV bolus or CIV on days 1, 2, and 3; ifosfamide 2.5 grams/m2 per day IV over 3 hours on days 1, 2 and 3; and mesna 2.5 grams/m2 per day CIV on days 1, 2, and 3) in patients with inoperable locally advanced or metastatic soft-tissue sarcoma in another randomized, phase III study.

    For the treatment of unresectable or metastatic osteogenic sarcoma†, in combination with mesna, dacarbazine, and doxorubicin.
    Ifosfamide has been designated an orphan drug by the FDA for the treatment of osteogenic sarcomas
    Intravenous Dosage
    Adults

    Dacarbazine 250 mg/m2/day as a continuous IV infusion (CIV) for 4 days plus doxorubicin 15 mg/m2/day CIV for 4 days, ifosfamide 2000 mg/m2/day CIV for 3 days, and mesna 2000 mg/m2/day CIV for 4 days repeated every 21 days (MAID regimen) until disease progression (or a cumulative doxorubicin dose of 450 mg/m2) was evaluated in 69 patients with unresectable or metastatic Ewing sarcoma, osteosarcoma, or rhabdomyosarcoma in a nonrandomized, phase II trial. Due to life-threatening myelosuppression in the first 15 patients treated, the ifosfamide and mesna doses were reduced from 2500 mg/m2/day to 2000 mg/m2/day. Of the 31 patients with osteosarcoma, the ORR was 26% (complete response, 3%), the median time to progression was 6 months, and the median overall survival time was 10 months. Additionally, 1 patient with osteosarcoma who received multimodal therapy with surgery and/or radiotherapy had long-term disease free survival.

    For the treatment of Ewing's sarcoma†.
    For the treatment of recurrent or refractory Ewing's sarcoma as a high-dose single-agent†.
    Intravenous dosage
    Adults <= 50 years, Adolescents, and Children >= 6 years

    Ifosfamide 3000 mg/m2/day CIVI over 120 hours on days 1—5, in combination with mesna 3000 mg/m2/day CIVI over 120 hours on days 1—5, mesna 400 mg/m2 IV prior to the first ifosfamide dose, and mesna 1500 mg/m2 CIVI over 12 hours, starting at hour 121; cycles were given every 3 weeks or upon hematologic recovery (ANC > 1,000/microL and platelets > 100,000/microL) for total of 2 cycles (preceding hematopoietic stem-cell transplant (HSCT), in patients who are HSCT-naive) or 4 cycles (in patients with a prior HSCT).

    For the treatment of newly diagnosed Ewing's sarcoma in combination with vincristine, doxorubicin, and etoposide (VIDE) followed by ifosfamide, vincristine, and dactinomycin (VAI)†.
    Intravenous dosage
    Adults <= 36 years, Adolescents, and Children

    For patients with localized disease, ifosfamide 3000 mg/m2/day IV was given on days 1—3 plus mesna 3000 mg/m2/day CIVI on days 1—3 in combination with vincristine 1.4 mg/m2 (max. 2 mg/dose) IV on day 1, doxorubicin 20 mg/m2/day IV on days 1—3, and etoposide 150 mg/m2/day IV on days 1—3, every 21 days for 6 cycles (VIDE regimen). Following induction, patients were taken for surgery (if surgically resectable) and then administered chemotherapy with the VAI regimen or concurrent chemoradiation (if unresectable) with VAI. The VAI regimen consists of vincristine 1.4 mg/m2 (max. 2 mg/dose) IV on day 1 in combination with dactinomycin 0.75 mg/m2/day IV on days 1—2 and ifosfamide 3000 mg/m2/day IV on days 1—2 with mesna 3000 mg/m2/day IV on days 1—2, every 21 days for 8 cycles. Patients with metastatic disease, treatment was administered as above, however, after 1 or more cycles of VAI, patients were considered for hematopoietic stem-cell transplant.

    For the treatment of newly diagnosed Ewing's sarcoma family tumors, in combination with etoposide, alternating with vincristine, doxorubicin, and cyclophoshpamide†.
    Intravenous dosage
    Adults <= 30 years, Adolescents, and Children

    1800 mg/m2/day IV on days 1—5 (with equal dose mesna) in combination with etoposide 100 mg/m2/day IV on days 1—5, every 3 weeks; alternating with vincristine 2 mg/m2 (max 2 mg/dose) on day 1 with doxorubicin 75 mg/m2 IV bolus day 1, and cyclophosphamide 1200 mg/m2 day 1, every 3 weeks. Dactinomycin 1.25 mg/m2 IV on day 1 was substituted for doxorubicin once a cumulative doxorubicin dose of 375 mg/m2 IV was reached.

    For the treatment of newly diagnosed unresectable or metastatic Ewing's sarcoma in combination with doxorubicin and dacarbazine†.
    Intravenous dosage
    Adults


    2000 mg/m2/day CIVI over 72 hours on days 1—3 in combination with mesna 2000 mg/m2/day CIVI over 96 hours on days 1—4, doxorubicin 15 mg/m2/day CIVI over 96 hours on days 1—4, and dacarbazine 250 mg/m2/day CIVI over 96 hours on days 1—4, every 21 days.


    For the treatment of recurrent or refractory Ewing's sarcoma in combination with carboplatin and etoposide†.
    Intravenous dosage
    Adults <= 22 years, Adolescents, and Children

    1800 mg/m2/day on days 1—5 in combination with carboplatin 400 mg/m2/day on days 1—2 and etoposide 100 mg/m2/day on days 1—5, every 21 days after hematopoietic recovery.

    For the treatment of newly diagnosed Ewing's sarcoma in combination with carboplatin and etoposide, followed by cyclophosphamide, doxorubicin, and vincristine†.
    Intravenous dosage
    Adolescents and Children

    Ifosfamide 1800 mg/m2/day IV on days 1—5 in combination with carboplatin 400 mg/m2/day IV on days 1—2 and etoposide 100 mg/m2/day on days 1—5, every 21—28 days for 2 cycles (ICE). ICE was followed by cyclophosphamide 1500 mg/m2/day IV on days 1—2 in combination with doxorubicin 75 mg/m2/day CIVI over 72 hours and vincristine 1.5 mg/m2/cycle CIVI over 72 hours, every 21—28 days for 2 cycles (CAV) (4 total cycles as neoadjuvant treatment).

    For the treatment of rhabdomyosarcoma†.
    For the treatment of rhabdomyosarcoma as part of the MAID regimen.
    Intravenous dosage
    Adults

    2 g/m2/day as a continuous IV infusion (CIV) on days 1—3 with mesna (2 g/m2/day CIV on days 1—4) in combination with doxorubicin (15 mg/m2/day CIV on days 1—4; 60 mg/m2 total dose per cycle) and dacarbazine (250 mg/m2/day CIV on days 1—4; 1000 mg/m2 total dose per cycle), repeated every 21 days until disease progression or doxorubicin 450 mg/m2 IV total dose reached (MAID regimen). The MAID regimen was evaluated in 69 patients with unresectable or metastatic Ewing sarcoma, osteosarcoma, or rhabdomyosarcoma (RMS) in a nonrandomized, phase II trial. Due to life-threatening myelosuppression in the first 15 patients treated, the ifosfamide and mesna doses were reduced from 2500 mg/m2/day to 2000 mg/m2/day. Of the 25 patients with RMS, the ORR was 64% (complete response, 28%), the median time to progression was 10 months, and the median overall survival time was 15 months. Additionally, 3 patients with RMS who received multimodal therapy with surgery and/or radiotherapy had long-term disease free survival.

    For the first-line treatment of rhabdomyosarcoma in children and adolescents in combination with vincristine, dactinomycin, and doxorubicin†.
    Intravenous dosage
    Adolescents and Children

    Ifosfamide 6000 mg/m2 CIVI over 48 hours on days 1, 29, and 50 in combination with mesna 6000 mg/m2/day CIVI over 48 hours on days 1, 29, and 50, doxorubicin 40 mg/m2/day IV on days 29 and 30, dactinomycin 0.5 mg/m2/day IV on days 1—3 and 50—52, and vincristine 1.5 mg/m2 IV on days 1, 8, 15, and 22. The duration of therapy was dependent on stage at diagnosis (stage I: 16 weeks; II: 26 weeks; III: 40 weeks; IV: 48 weeks).

    For the treatment of refractory desmoid tumor† and fibromatosis†.
    Intravenous Dosage
    Adults

    A small series of patients with recurrent desmoid tumors were treated with combination chemotherapy including ifosfamide 2500 mg/m2/day IV with mesna in combination with etoposide (100 mg/m2/day IV) for 3 days repeated every 3—4 weeks. Clinical benefit was reported in 6 of 7 patients and objective responses were noted in 3 patients.

    For the treatment of bladder cancer†.
    For the treatment of previously treated bladder cancer†.
    Intravenous dosage
    Adults

    Ifosfamide 1500 mg/m2/day IV on days 1—5 plus mesna 750 mg/m2 IV every 4 hours for three doses (starting just before ifosfamide) on days 1—5, every 3 weeks has been studied.

    For the treatment of recurrent metastatic bladder cancer in combination with gemcitabine†.
    Intravenous dosage
    Adults

    Dosage not established. Various regimens have been studied. Gemcitabine 800 mg/m2 IV over 30 minutes on days 1 and 8 plus ifosfamide 2000 mg/m2 IV over 2 hours on days 1 and 8 plus mesna at 33% of the ifosfamide dose given IV push over 10 minutes prior to each dose of ifosfamide, second and third doses of mesna at 66% of the ifosfamide dose were given PO four and eight hours, respectively, after each dose of ifosfamide; the regimen was repeated every 3 weeks for at least 6 cycles.

    For the treatment of advanced or metastatic bladder cancer in combination with cisplatin and a taxane†.
    Intravenous dosage
    Adults

    Ifosfamide 1500 mg/m2 IV daily on days 1—3 in combination with paclitaxel 200 mg/m2 IV over 3 hours on day 1, cisplatin 70 mg/m2 IV on day 1, plus filgrastim 5 mcg/kg/day SC daily on days 6—17, repeated every 28 days for a maximum of 6 cycles. Mesna 300 mg/m2 IV was given 30 minutes before, and 4 and 8 hours after, each dose of ifosfamide. Mesna 600 mg/m2 PO was allowed for the 4- and 8-hour doses.

    For the treatment of unresectable, advanced thymoma†, in combination with cisplatin and etoposide.
    Intravenous dosage
    Adults

    1200 mg/m2/day IV (with mesna 240 mg/m2 IV push prior to and at 4 and 8 hours after each ifosfamide dose) on days 1—4 plus cisplatin 20 mg/m2/day IV (with hydration) on days 1—4 and etoposide 75 mg/m2/day IV on days 1—4 repeated every 3 weeks for 4 cycles (median of 4 cycles; range, 1—6 cycles) or until disease progression or unacceptable toxicity resulted in favorable overall response rates in a nonrandomized study of 28 patients (20 with thymoma). All patients received granulocyte colony-stimulating factor 5 mcg/kg/day subcutaneously on days 5—15 or until a postnadir white blood cell count of 10,000/mm3.

    For the first-line treatment of unresectable, advanced thymic carcinoma†, in combination with cisplatin and etoposide.
    Intravenous dosage
    Adults

    1200 mg/m2/day IV (with mesna 240 mg/m2 IV push prior to and at 4 and 8 hours after each ifosfamide dose) on days 1—4 plus cisplatin 20 mg/m2/day IV (with hydration) on days 1—4 and etoposide 75 mg/m2/day IV on days 1—4 repeated every 3 weeks for 4 cycles or until disease progression or unacceptable toxicity (median of 4 cycles; range, 1—6 cycles) resulted in an overall response rate (ORR) of 32% (all partial responses; median duration of response, 11.9 months) in 28 patients with advanced thymoma or thymic carcinoma in a nonrandomized study. All patients received granulocyte colony-stimulating factor 5 mcg/kg/day subcutaneously on days 5—15 or until a postnadir white blood cell count of 10,000/mm3. At a median follow-up of 43 months, the median overall survival (OS) time was 31.6 months and the 1- and 2-year OS rates were 89% and 70%, respectively. In the 8 patients with advanced thymic carcinoma, the ORR was 25% and the 1- and 2-year OS rates were 75% and 50%, respectively. Serious toxicity reported in this study included grade 3 or 4 thrombocytopenia (18%), leukopenia (16%), and anemia (15%).

    For the treatment of poor-risk relapsed Wilms' tumor† in combination with carboplatin and etoposide.
    Intravenous dosage
    Adults <= 21 years, Adolescents, and Children

    Ifosfamide 1800 mg/m2/day IV for 5 days (on days 0—4), carboplatin 400 mg/m2/day IV for 2 days (on day 0—1) and etoposide 100 mg/m2/day IV for 5 days (on days 0—4), repeated every 21 days.

    For stem cell transplant preparation†.
    For stem cell mobilization in combination with carboplatin and etoposide, in transplant eligible patients with non-Hodgkin's lymphoma†.
    Intravenous dosage
    Adults

    Etoposide 100 mg/m2/day IV on days 1 to 3 in combination with carboplatin AUC 5 (max dose: 800 mg) IV on day 2 and ifosfamide 5 g/m2 mixed with an equal dose of mesna administered via continuous IV infusion for 24 hours beginning day 2. Filgrastim was administered at 10 mcg/kg/day starting on day 5 until completion of leukapheresis.

    For the treatment of relapsed or refractory acute lymphocytic leukemia (ALL)† in combination with carboplatin, etoposide, and rituximab.
    Intravenous dosage
    Adults <= 21 years, Adolescents, and Children

    Carboplatin 635 mg/m2 IV on day 3 in combination with ifosfamide 3000 mg/m2/day IV on days 3—5 (each dose mixed with mesna 600 mg/m2 IV, followed by mesna 600 mg/m2 IV over 15 minutes at 3, 6, 9, and 12 hours after the start of ifosfamide) and etoposide 100 mg/m2/day IV on days 3—5, repeated each cycle. Rituximab 375 mg/m2 IV was given on days 1 and 3 of cycles 1 and 2, and on day 3 only of cycle 3. Treatment was given up to a maximum of 3 cycles. Colony-stimulating factors were initiated on day 6 of each cycle and IT chemotherapy was also given as appropriate. The overall response rate was 60% and overall survival was 37.5%.

    For the neoadjuvant treatment of locally advanced or metastatic penile cancer† in combination with paclitaxel and cisplatin.
    Intravenous dosage
    Adults

    1200 mg/m2/day IV over 2 hours on days 1—3 in combination with cisplatin 25 mg/m2/day IV over 2 hours on days 1—3 and paclitaxel 175 mg/m2 IV over 3 hours on day 1, repeated every 3—4 weeks.

    †Indicates off-label use

    MAXIMUM DOSAGE

    The suggested maximum tolerated dose (MTD) for ifosfamide is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    There have been no studies of ifosfamide in patients with severe hepatic dysfunction and no guidelines are available.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment. The following dosage adjustments have been suggested:
    CrCl > 60 mL/min: No change.
    CrCl 31—60 mL/min: Reduce dose by 25%.
    CrCl 10—30 mL/min: Reduce dose by 50%.
    CrCl < 10 mL/min: Omit dose.

    ADMINISTRATION

    For storage information, see the specific product information within the How supplied section.
     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Ifosfamide is administered as an intravenous infusion as intermittent infusions or as a continuous infusion.
    Patients should be well hydrated while receiving ifosfamide. At least 2 L/day of oral or IV fluids should be given to prevent bladder toxicity.
    Ifosfamide must be given in combination with mesna to prevent hemorrhagic cystitis.
    Close hematologic monitoring is recommended. WBC count, platelet count, and hemoglobin should be obtained prior to each ifosfamide administration and at appropriate intervals thereafter.
    A urinalysis should be performed prior to each dose of ifosfamide to monitor for hematuria.
     
    Reconstitution and further dilution:
    Reconstitute 1 or 3 grams with 20 or 60 mL, respectively, of sterile water for injection or bacteriostatic water for injection containing parabens or benzyl alcohol to give IV solutions containing 50 mg/mL.
    Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6—20 mg/mL in the following solutions: 5% dextrose for injection, 0.9% sodium chloride for injection, lactated ringer's injection, or sterile water for injection.
    Infuse slowly over at least 30 minutes.
    Diluted and reconstituted solutions of ifosfamide should be refrigerated and used within 24 hours.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Refrigerate (between 36 and 46 degrees F)
    Ifex:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Bone marrow suppression, herpes infection, infection, radiation therapy, varicella

    Ifosfamide has a low therapeutic index, and therapeutic doses are likely to cause toxicity. Ifosfamide should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy. Severe bone marrow suppression, including neutropenia and/or thrombocytopenia, is a contraindication to ifosfamide use. Unless clinically indicated, ifosfamide should not be given to patients with a WBC count < 2000/mm3 or a platelet count < 50,000/mm3. Therefore, this drug should be used only by clinicians experienced in the use of cancer chemotherapy. The hematological status (leukocyte and platelet counts) of a patient should be monitored closely during ifosfamide therapy. Patients with an active infection should be treated prior to receiving ifosfamide. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Dental disease, dental work

    Myelosuppressive effects of ifosfamide can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Intramuscular injections

    Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving ifosfamide. IM injections may cause bleeding, bruising, or hematomas due to ifosfamide-induced thrombocytopenia.

    Dehydration, hematuria, hemorrhagic cystitis, hepatic disease, nephrotoxicity

    Ifosfamide should be administered under the supervision of a qualified clinician experienced in the use of cancer chemotherapeutic agents. Ifosfamide undergoes hepatic metabolism and should be used with caution in patients with hepatic disease. Effective treatment is dependent on ifosfamide metabolism to cytotoxic metabolites. The active metabolite is further broken down to a bladder toxic metabolite, acrolein, which is eliminated renally. The duration of exposure of acrolein to the bladder wall should be minimized. Patients should receive vigorous hydration during therapy to prevent nephrotoxicity and hemorrhagic cystitis. In addition, all patients should receive concurrent treatment with mesna. Mesna binds to acrolein and decreases the incidence of hemorrhagic cystitis. Dehydration should be corrected prior to therapy. All patients should have a urinalysis prior to each dose. If microscopic hematuria (> 10 RBCs per high-power field) is present, then subsequent administration should be held until hematuria has resolved.

    Children, renal failure, renal impairment

    Ifosfamide is associated with nephrotoxicity. Patients with renal impairment or renal failure may experience worsening of renal function during or following treatment with ifosfamide. Some experts recommend dosage adjustments of ifosfamide in patients with a creatinine clearance < 60 mL/minute. Children may be at increased risk for ifosfamide-induced nephrotoxicity. Risk factors for ifosfamide-induced nephrotoxicity in children have included age < 5 years, total cumulative dose of ifosfamide received > 60 g/m2, prior or concurrent cisplatin or carboplatin treatment, pre-existing renal impairment, nephrectomy, or renal infiltration of tumor, and interpatient variability in metabolism.

    Pregnancy

    Ifosfamide should not be used during pregnancy and is classified as FDA pregnancy risk category D. Females of childbearing age should avoid becoming pregnant while receiving ifosfamide. Although human studies are not available, animal studies indicate it is capable of causing gene mutations and chromosomal damage in vivo. Embryotoxic and teratogenic effects have been observed in animal models at doses of 0.05—0.075 times the human dose. Ifosfamide can cause fetal damage when administered to a pregnant woman. If it is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

    Breast-feeding

    Ifosfamide should be avoided while breast-feeding. Since ifosfamide passes into breast milk a decision should be made whether to discontinue breast-feeding or to discontinue ifosfamide, taking into account the importance of the drug to the mother.

    Coma, neurotoxicity

    Ifosfamide should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Neurotoxicity and neurologic manifestations consisting of somnolence, confusion, hallucinations, and in some instances, coma have been reported following ifosfamide therapy. The occurrence of these symptoms requires discontinuation of ifosfamide therapy. The symptoms have usually been reversible and supportive therapy should be maintained until their complete resolution.

    Accidental exposure, ocular exposure

    Use care to avoid accidental exposure to ifosfamide during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed.

    Vaccination

    Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of most live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    ADVERSE REACTIONS

    Severe

    hemorrhagic cystitis / Delayed / 0-44.1
    pancytopenia / Delayed / 0-43.5
    coma / Early / 0-15.4
    seizures / Delayed / 0-15.4
    acute cerebellar syndrome / Early / 0-15.4
    thrombocytopenia / Delayed / 0-4.8
    heart failure / Delayed / 0-0.5
    Stevens-Johnson syndrome / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    Fanconi syndrome / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    anuria / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    azotemia / Delayed / Incidence not known
    renal tubular acidosis (RTA) / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    intraventricular hemorrhage / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    atrial flutter / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    hepatic failure / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    SIADH / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    hearing loss / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    capillary leak syndrome / Early / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known

    Moderate

    hematuria / Delayed / 5.2-44.1
    dysuria / Early / 0-44.1
    neutropenia / Delayed / 0-43.5
    leukopenia / Delayed / 42.5-43.5
    lymphopenia / Delayed / 0-43.5
    anemia / Delayed / 37.9-37.9
    metabolic acidosis / Delayed / 0-31.0
    impaired cognition / Early / 0-15.4
    myoclonia / Delayed / 0-15.4
    aphasia / Delayed / 0-15.4
    confusion / Early / 0-15.4
    depression / Delayed / 0-15.4
    ataxia / Delayed / 0-15.4
    memory impairment / Delayed / 0-15.4
    urinary incontinence / Early / 0-15.4
    encephalopathy / Delayed / 0-15.4
    hallucinations / Early / 0-15.4
    psychosis / Early / 0-15.4
    phlebitis / Rapid / 2.8-2.8
    hyperbilirubinemia / Delayed / 0-1.8
    elevated hepatic enzymes / Delayed / 0-1.8
    jaundice / Delayed / 0-1.8
    peripheral neuropathy / Delayed / 0.4-0.4
    stomatitis / Delayed / 0.3-0.3
    hypotension / Rapid / 0.3-0.3
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    impaired wound healing / Delayed / Incidence not known
    radiation recall reaction / Delayed / Incidence not known
    erythema / Early / Incidence not known
    constipation / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    proteinuria / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    phosphaturia / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    fecal incontinence / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    bundle-branch block / Early / Incidence not known
    angina / Early / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    palpitations / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypertension / Early / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    delirium / Early / Incidence not known
    mania / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hypoxia / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known
    osteomalacia / Delayed / Incidence not known
    testicular atrophy / Delayed / Incidence not known
    anovulation / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    immunosuppression / Delayed / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    alopecia / Delayed / 89.6-89.6
    nausea / Early / 48.6-48.6
    vomiting / Early / 48.6-48.6
    drowsiness / Early / 0-15.4
    restlessness / Early / 0-15.4
    asthenia / Delayed / 0-15.4
    anxiety / Delayed / 0-15.4
    tremor / Early / 0-15.4
    agitation / Early / 0-15.4
    lethargy / Early / 0-15.4
    headache / Early / 0-15.4
    dizziness / Early / 0-15.4
    infection / Delayed / 9.9-9.9
    anorexia / Delayed / 1.1-1.1
    diarrhea / Early / 0.7-0.7
    fatigue / Early / 0.3-0.3
    maculopapular rash / Early / 0-0.1
    skin hyperpigmentation / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    petechiae / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    polyuria / Early / Incidence not known
    cylindruria / Delayed / Incidence not known
    asterixis / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    premature atrial contractions (PACs) / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    paranoia / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    vertigo / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    polydipsia / Early / Incidence not known
    cough / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    fever / Early / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase, tPA: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Aminoglycosides: (Moderate) Nephrotoxic agents, such as the aminoglycosides, can increase the nephrotoxicity of ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, renal toxicity, and bone marrow suppression.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Nephrotoxic agents, such as amphotericin B, can increase the nephrotoxicity of ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, renal toxicity, and bone marrow suppression.
    Amphotericin B lipid complex (ABLC): (Moderate) Nephrotoxic agents, such as amphotericin B, can increase the nephrotoxicity of ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, renal toxicity, and bone marrow suppression.
    Amphotericin B liposomal (LAmB): (Moderate) Nephrotoxic agents, such as amphotericin B, can increase the nephrotoxicity of ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, renal toxicity, and bone marrow suppression.
    Amphotericin B: (Moderate) Nephrotoxic agents, such as amphotericin B, can increase the nephrotoxicity of ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, renal toxicity, and bone marrow suppression.
    Amprenavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, amprenavir and fosamprenavir, both a CYP3A4 inhibitor (strong), inducer, and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Anagrelide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Anticoagulants: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithrombin III: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Apixaban: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aprepitant, Fosaprepitant: (Major) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting and is often used in combination with ifosfamide. However, use caution and monitor for a possible increase in non-emetogenic ifosfamide-related adverse effects for several days after administration of a multi-day aprepitant regimen; ifosfamide-induced neurotoxicity, behavioral changes, and agitation have been reported in clinical trials and in postmarketing experience with aprepitant coadministration. Ifosfamide is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and theoretically could increase plasma concentrations of ifosfamide. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Argatroban: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Atazanavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and atazanavir, a CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Atazanavir; Cobicistat: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and atazanavir, a CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and cobicistat, a moderate CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic ). As a result of this interaction, the risk of ifosfamide toxicity is increased. A case report describes encephalopathy following a single dose of ifosfamide 3 grams/m2 plus mesna, vincristine, and dactinomycin in a 15-year old girl who had been taking long-term phenobarbital. The authors cite a possible interaction with phenobarbital leading to increased formation of the neurotoxic ifosfamide metabolite, chloroacetaldehyde. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Bacitracin: (Moderate) Nephrotoxic agents, such as systemic bacitracin, can increase the nephrotoxicity of ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, renal toxicity, and bone marrow suppression.
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic ). As a result of this interaction, the risk of ifosfamide toxicity is increased. A case report describes encephalopathy following a single dose of ifosfamide 3 grams/m2 plus mesna, vincristine, and dactinomycin in a 15-year old girl who had been taking long-term phenobarbital. The authors cite a possible interaction with phenobarbital leading to increased formation of the neurotoxic ifosfamide metabolite, chloroacetaldehyde. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betrixaban: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Bivalirudin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Boceprevir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and boceprevir, a strong CYP3A4 inhibitor and partial substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Brigatinib: (Moderate) Closely monitor for an increase in ifosfamide-related adverse reactions (e.g., nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection) if coadministration with brigatinib is necessary; consider an ifosfamide dose adjustment if clinically appropriate. Ifosfamide is a CYP3A substrate and brigatinib induces CYP3A in vitro. CYP3A4 inducers may increase the metabolism of ifosfamide to its active alkylating metabolites, and may also increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Carbamazepine: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and carbamazepine, a strong CYP3A4 inducer and substrate, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Celecoxib: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ceritinib: (Moderate) Monitor for decreased efficacy of ifosfamide if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Inhibition of CYP3A4 may decrease the effectiveness of ifosfamide treatment.
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cilostazol: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Ciprofloxacin: (Moderate) The concomitant use of ifosfamide, a CYP3A4 substrate, and ciprofloxacin, a moderate CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Cisplatin: (Moderate) Delayed renal clearance, and additive nephrotoxicity and neurotoxicity may occur in patients who have received cisplatin in the past and are now receiving ifosfamide. This interaction has been reported clinically. In addition, a potential increase risk of hearing loss from cisplatin has been reported when ifosfamide was used concurrently; however, the potential mechanism is not understood. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, hearing loss (ototoxicity), electrolyte loss, kidney toxicity, and bone marrow suppression.
    Clarithromycin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Clopidogrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and cobicistat, a moderate CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and cobicistat, a moderate CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and cobicistat, a moderate CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Conivaptan: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Corticotropin, ACTH: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Crizotinib: (Major) Monitor for a decrease in the clinical efficacy of ifosfamide if coadministration with crizotinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Crizotinib is a moderate CYP3A4 inhibitor. Coadministration may decrease formation of the active metabolites of ifosfamide, decreasing its efficacy.
    Cyclosporine: (Moderate) Delayed renal clearance, and additive nephrotoxicity may occur in patients who have received or who are currently receiving nephrotoxic drugs and are now receiving ifosfamide. These drugs include cyclosporine. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Immunosuppressive effects may also be additive from this combination. Clinicians should be alert for an increased risk of ifosfamide toxicity which may include neurotoxicity, kidney toxicity, and bone marrow suppression.
    Dabigatran: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Daclizumab: (Minor) Concurrent use of ifosfamide with other agents which cause bone marrow or immune suppression such as immunosuppressives like daclizumab may result in additive effects.
    Dalfopristin; Quinupristin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and dalfopristin; quinupristin, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Dalteparin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Danaparoid: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Darunavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and darunavir, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Darunavir; Cobicistat: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and cobicistat, a moderate CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and darunavir, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and ritonavir, a CYP3A4 inhibitor (strong), substrate, and inducer, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. Caution and close monitoring are advised if these drugs are administered together.
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Delavirdine: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and delavirdine, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Desirudin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and ifosfamide together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Docetaxel: (Minor) When docetaxel and ifosfamide are given concurrently or in sequence, an apparent decrease in the AUC of ifosfamide is observed due to an increased ifosfamide clearance when docetaxel (over 1 hour) is followed by ifosfamide (over 24 hours). The reverse sequence (ifosfamide over 24 hours followed by docetaxel over 1 hour) does not cause an AUC alteration. The pharmacokinetics of docetaxel were unchanged in either case.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ifosfamide is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Efavirenz: (Major) The concomitant use of ifosfamide, a substrate of CYP3A4 and CYP2B6, and efavirenz, a CYP3A4 inducer and substrate and a CYP2B6 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Efavirenz; Emtricitabine; Tenofovir: (Major) The concomitant use of ifosfamide, a substrate of CYP3A4 and CYP2B6, and efavirenz, a CYP3A4 inducer and substrate and a CYP2B6 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Elbasvir; Grazoprevir: (Major) Administering ifosfamide with grazoprevir may result in elevated ifosfamide plasma concentrations. Ifosfamide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enoxaparin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Enzalutamide: (Major) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with enzalutamide is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; enzalutamide is a strong CYP3A4 inducer. Concomitant use of enzalutamide may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Eptifibatide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Esomeprazole; Naproxen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Etodolac: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Filgrastim, G-CSF: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, and filgrastim induces the proliferation of neutrophil-progenitor cells, filgrastim, G-CSF and tbo-filgrastim should not be used in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
    Fluconazole: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and fluconazole, a moderate CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fondaparinux: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fosamprenavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, amprenavir and fosamprenavir, both a CYP3A4 inhibitor (strong), inducer, and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Foscarnet: (Moderate) Delayed renal clearance, and additive nephrotoxicity may occur in patients who have received or who are currently receiving nephrotoxic drugs, such as foscarnet, and are now receiving ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, kidney toxicity, and bone marrow suppression.
    Fosphenytoin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and fosphenytoin or phenytoin, strong CYP3A4 inducers, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. A case report describes altered ifosfamide pharmacokinetics during concurrent administration of phenytoin and ifosfamide in a child; however, the child clinically had no alteration in response to chemotherapy. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Grapefruit juice: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and grapefruit juice, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Heparin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Idelalisib: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and idelalisib, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Indinavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and indinavir, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Indomethacin: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Isavuconazonium: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and isavuconazonium, a moderate CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Isoniazid, INH: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and isoniazid, INH, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and isoniazid, INH, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. A small pharmacokinetic trial (n=12) examined the effects of rifampin on the pharmacokinetics of ifosfamide. In a double-randomized, 2-way crossover study, patients received ifosfamide 3 grams/m2/day IV either alone or in combination with 300 mg rifampin twice daily (3 days before and 3 days concurrently). Rifampin increased the clearance of ifosfamide at the start of therapy by 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, but exposure was decreased due to increased metabolism. The exposure to the active metabolite of ifosfamide was not increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Isoniazid, INH; Rifampin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and isoniazid, INH, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. A small pharmacokinetic trial (n=12) examined the effects of rifampin on the pharmacokinetics of ifosfamide. In a double-randomized, 2-way crossover study, patients received ifosfamide 3 grams/m2/day IV either alone or in combination with 300 mg rifampin twice daily (3 days before and 3 days concurrently). Rifampin increased the clearance of ifosfamide at the start of therapy by 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, but exposure was decreased due to increased metabolism. The exposure to the active metabolite of ifosfamide was not increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Itraconazole: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and itraconazole, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and ifosfamide concurrently; the clinical significance of this interaction is unclear. Ivacaftor is an inhibitor of CYP3A, and ifosfamide is a CYP3A4 substrate. Theoretically, co-administration of ivacaftor and ifosfamide could increase ifosfamide exposure leading to increased or prolonged therapeutic effects and adverse events. However, one pharmacokinetic trial found that ketoconazole, a potent CYP3A inhibitor, did not cause a clinically significant interaction with ifosfamide.
    Ketoconazole: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. A small pharmacokinetic trial (n=12) examined the effects of ketoconazole on the pharmacokinetics of ifosfamide. In a double-randomized, 2-way crossover study, patients received ifosfamide 3 grams/m2/day IV either alone or in combination with 200 mg ketoconazole twice daily (1 day prior and 3 days concurrently). Ketoconazole did not affect the fraction of metabolized or the exposure to the dechlorethylated metabolites; however, the metabolism and exposure to the active 4-hydroxyifosfamide metabolite were reduced.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lepirudin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Loop diuretics: (Moderate) Nephrotoxic agents, such as the loop diuretics, can increase the nephrotoxicity of ifosfamide. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, kidney toxicity, and bone marrow suppression.
    Lopinavir; Ritonavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and lopinavir; ritonavir, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and ritonavir, a CYP3A4 inhibitor (strong), substrate, and inducer, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. Caution and close monitoring are advised if these drugs are administered together.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may increase the metabolism of ifosfamide to its active alkylating metabolites and increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. If these agents are used together, monitor patients closely for ifosfamide adverse events including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection, and consider ifosfamide dosage adjustment if clinically appropriate. Ifosfamide is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and ifosfamide concurrently; the clinical significance of this interaction is unclear. Ivacaftor is an inhibitor of CYP3A, and ifosfamide is a CYP3A4 substrate. Theoretically, co-administration of ivacaftor and ifosfamide could increase ifosfamide exposure leading to increased or prolonged therapeutic effects and adverse events. However, one pharmacokinetic trial found that ketoconazole, a potent CYP3A inhibitor, did not cause a clinically significant interaction with ifosfamide.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mephobarbital: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and mephobarbital which is metabolized to phenobarbital, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mitotane: (Major) Avoid the concomitant use of mitotane with ifosfamide; if coadministration cannot be avoided, monitor for decreased efficacy of ifosfamide. Mitotane is a strong CYP3A4 inducer and ifosfamide is a CYP3A4 substrate. Coadministration may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. A small pharmacokinetic trial (n=12) examined the effects of rifampin on the pharmacokinetics of ifosfamide. In a double-randomized, 2-way crossover study, patients received ifosfamide 3 grams/m2/day IV either alone or in combination with 300 mg rifampin twice daily (3 days before and 3 days concurrently). Rifampin increased the clearance of ifosfamide at the start of therapy by 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, but exposure was decreased due to increased metabolism. The exposure to the active metabolite of ifosfamide was not increased.
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mycophenolate: (Minor) Concurrent use of ifosfamide with other agents which cause bone marrow or immune suppression such as immunosuppressives like mycophenolate may result in additive effects.
    Nabumetone: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Although some experts state that pharmacokinetic interactions between paclitaxel and ifosfamide do not appear to be clinically significant, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
    Naproxen: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nefazodone: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Nelfinavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and nelfinavir, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ifosfamide. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
    Nevirapine: (Major) The concomitant use of ifosfamide, a substrate of CYP3A4 and CYP2B6, and nevirapine, a CYP3A4 and CYP2B6 inducer and substrate, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic ). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and ritonavir, a CYP3A4 inhibitor (strong), substrate, and inducer, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. Caution and close monitoring are advised if these drugs are administered together.
    Oritavancin: (Minor) Ifosfamide is metabolized to its active form by CYP3A4 and CYP2B6; oritavancin is a weak CYP3A4 inducer. Enzyme inducers, such oritavancin, a mild CYP3A4 inducer, may alter the clinical and/or toxic effects of ifosfamide.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palbociclib: (Moderate) Monitor for a possible decrease in the efficacy of ifosfamide if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Ifosfamide is a prodrug that is converted to its active alkylating metabolites via CYP3A4. Coadministration of ifosfamide with CYP3A4 inhibitors may reduce the metabolism of ifosfamide to its active metabolites and therefore decrease efficacy.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and ifosfamide, a CYP3A4 substrate, may cause an increase in systemic concentrations of ifosfamide. Use caution when administering these drugs concomitantly.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Moderate) Delayed renal clearance, and additive nephrotoxicity may occur in patients who have received or who are currently receiving nephrotoxic drugs, such as pentamidine, and are now receiving ifosfamide. These drugs include aminoglycosides, amphotericin B, bacitracin injection, foscarnet, loop diuretics, NSAIDs, systemic pentamidine, polymyxin B injection, salicylates, streptozocin, tacrolimus, and IV vancomycin. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, kidney toxicity, and bone marrow suppression.
    Pentosan: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Phenobarbital: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and phenobarbital, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic ). As a result of this interaction, the risk of ifosfamide toxicity is increased. A case report describes encephalopathy following a single dose of ifosfamide 3 grams/m2 plus mesna, vincristine, and dactinomycin in a 15-year old girl who had been taking long-term phenobarbital. The authors cite a possible interaction with phenobarbital leading to increased formation of the neurotoxic ifosfamide metabolite, chloroacetaldehyde. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Phenytoin: (Moderate) The concomitant use of ifosfamide, a CYP3A4 substrate, and fosphenytoin or phenytoin, strong CYP3A4 inducers, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. A case report describes altered ifosfamide pharmacokinetics during concurrent administration of phenytoin and ifosfamide in a child; however, the child clinically had no alteration in response to chemotherapy. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Piroxicam: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Polymyxin B: (Moderate) Nephrotoxic agents, such as polymyxin B injection, can increase the nephrotoxicity of ifosfamide .
    Posaconazole: (Moderate) The concomitant use of ifosfamide, a CYP3A4 substrate, and posaconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Prasugrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Primidone: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and primidone which is metabolized to phenobarbital, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Reteplase, r-PA: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with ifosfamide is necessary, as the metabolism of ifosfamide to its active alkylating metabolites may be decreased, decreasing the effectiveness of ifosfamide treatment. Ribociclib is a CYP3A4 inhibitor and ifosfamide is a prodrug that is activated via CYP3A4.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with ifosfamide is necessary, as the metabolism of ifosfamide to its active alkylating metabolites may be decreased, decreasing the effectiveness of ifosfamide treatment. Ribociclib is a CYP3A4 inhibitor and ifosfamide is a prodrug that is activated via CYP3A4.
    Rifabutin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and rifabutin, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Rifampin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and rifampin, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. A small pharmacokinetic trial (n=12) examined the effects of rifampin on the pharmacokinetics of ifosfamide. In a double-randomized, 2-way crossover study, patients received ifosfamide 3 grams/m2/day IV either alone or in combination with 300 mg rifampin twice daily (3 days before and 3 days concurrently). Rifampin increased the clearance of ifosfamide at the start of therapy by 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, but exposure was decreased due to increased metabolism. The exposure to the active metabolite of ifosfamide was not increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Rifapentine: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and rifapentine, a strong CYP3A4 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
    Ritonavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and ritonavir, a CYP3A4 inhibitor (strong), substrate, and inducer, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Saquinavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sirolimus: (Minor) Concurrent use of ifosfamide with other agents which cause bone marrow or immune suppression such as immunosuppressives like sirolimus may result in additive effects.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort, Hypericum perforatum, is probably best avoided during ifosfamide treatment. The herb appears to induce several CYP450 isoenzymes, including CYP3A4. Coadministration of St. John's wort could decrease the efficacy of some medications. The concomitant use of ifosfamide, a substrate of CYP3A4 and CYP2B6, and St. John's Wort, a CYP3A4 inducer (strong) and a CYP2B6 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased, and there might also be a reduction in chemotherapy efficacy. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection, and for appropriate response to treatment. Consider dose adjustment if toxicities occur.
    Streptogramins: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and dalfopristin; quinupristin, a strong CYP3A4 inhibitor, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Streptokinase: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Streptozocin: (Moderate) Delayed renal clearance, and additive nephrotoxicity may occur in patients who have received or who are currently receiving nephrotoxic drugs, such as streptozocin, and are now receiving ifosfamide. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, kidney toxicity, and bone marrow suppression.
    Sulindac: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tacrolimus: (Minor) Nephrotoxic agents, such as tacrolimus, can increase the nephrotoxicity of ifosfamide.
    Tbo-Filgrastim: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, and filgrastim induces the proliferation of neutrophil-progenitor cells, filgrastim, G-CSF and tbo-filgrastim should not be used in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
    Telaprevir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and telaprevir, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Telithromycin: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and telithromycin, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ifosfamide is necessary, as the metabolism of ifosfamide to its active alkylating metabolites may increase, as well as the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. If these drugs are used together, closely monitor patients for toxicities and consider dose adjustment. Ifosfamide is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tenecteplase, TNK-tPA: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Thrombolytic Agents: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Ticagrelor: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Ticlopidine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Tinzaparin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Tipranavir: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and tipranavir, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Tirofiban: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Tolmetin: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Urokinase: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Vancomycin: (Moderate) Delayed renal clearance, and additive nephrotoxicity and neurotoxicity may occur in patients who have received or who are currently receiving nephrotoxic drugs and are now receiving ifosfamide. These drugs include IV vancomycin. Damaged kidney tubules may be less likely to convert mesna to its active kidney protecting form, which may contribute to the potential for increased ifosfamide toxicity. Clinicians should be alert for an increased risk of ifosfamide toxicity, including neurotoxicity, kidney toxicity, and bone marrow suppression.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vemurafenib: (Minor) Ifosfamide is metabolized in the liver to its active form via CYP3A4 and 2B6; therefore, CYP3A4 inducers, such as vemurafenib, may accelerate the conversion of ifosfamide to its active alkylating metabolites, perhaps increasing the clinical and/or toxic effects of ifosfamide. Use caution, and monitor therapeutic and toxic effects of ifosfamide when coadministered with vemurafenib.
    Vorapaxar: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as ifosfamide.
    Voriconazole: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced.
    Warfarin: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Ifosfamide should not be used during pregnancy and is classified as FDA pregnancy risk category D. Females of childbearing age should avoid becoming pregnant while receiving ifosfamide. Although human studies are not available, animal studies indicate it is capable of causing gene mutations and chromosomal damage in vivo. Embryotoxic and teratogenic effects have been observed in animal models at doses of 0.05—0.075 times the human dose. Ifosfamide can cause fetal damage when administered to a pregnant woman. If it is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

    Ifosfamide should be avoided while breast-feeding. Since ifosfamide passes into breast milk a decision should be made whether to discontinue breast-feeding or to discontinue ifosfamide, taking into account the importance of the drug to the mother.

    MECHANISM OF ACTION

    Ifosfamide is an oxazaphosphorine alkylating agent related to the nitrogen mustards. The activity of an oxazaphosphorine agents is dependent on their ability to alkylate DNA by attaching the N-7 position of guanine with their relative electrophilic groups resulting in intra- and inter strand cross-links and subsequent cell death. Ifosfamide is a prodrug that requires activation by cytochrome P-450 CYP3A4 isoenzyme in order to be cytotoxic. The hepatic microsomal system converts ifosfamide to aldoifosfamide and 4-hydroxyifosfamide, which are in equilibrium with each other. Aldoifosfamide is further converted to acrolein and ifosforamide mustard, the latter being a potent alkylator of DNA. Mechanisms of resistance are poorly understood but appear to be related to increased intracellular content of glutathione, increased aldehyde dehydrogenase activity, and enhanced ability to repair DNA damage.

    PHARMACOKINETICS

    Ifosfamide is administered intravenously and is commercially available only as a parenteral product. It exhibits dose-dependent pharmacokinetics. It is largely distributed into body water with central compartment approximating the vascular and the extracellular space. Protein and tissue binding are negligible. It appears to distribute well into adipose tissue because, in obese patients, the volume of distribution increases by over 25%. Ifosfamide and two of its metabolites (4-hydroxyifosfamide and ifosforamide mustard) reach concentrations in the CSF similar to the plasma concentration.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2B6
    Ifosfamide is metabolized primarily in the liver by the hepatic cytochrome P450 (CYP) 3A4 and 2B6 isoenzymes. It appears to undergo 2-component Michaelis-Menton model pharmacokinetics including both low Km and high Km CYP 4-hydroxylases. Hepatic metabolism is extensive but variable among patients, producing eight possible metabolites. There are two dechloroethylated derivatives that are identified as the inactive major urinary metabolites. A third metabolite is chloroacetaldehyde, which is chemically related to chloral hydrate and explains some adverse effects of ifosfamide. It appears these N-dechloroethylated metabolites are formed via CYP2B6 to a significant degree. Ketone and thiol groups at the 4 position form two more inactive metabolites.The active component is formed via CYP3A4 which transforms ifosfamide to 4-hydroxyifosfamide, an intermediate derivative that appears in equilibrium with aldoifosfamide. Aldoifosfamide breaks down spontaneously to active ifosforamide mustard with the liberation of acrolein. With ifosfamide, only 50% of a dose is metabolized compared with 90% for cyclophosphamide. Autoinduction of ifosfamide metabolism has been observed, but the mechanism is unknown.
     
    At single doses of 3.8—5 g/m2, the plasma concentration decays biphasically and the mean terminal elimination half-life is approximately 15 hours. At doses of 1.6—2.4 g/m2/d, the plasma decay is monophasic and the terminal elimination half-life is 7 hours. Renal elimination of unchanged ifosfamide represents approximately 20% of the administered drug while urinary excretion accounts for 70—86% of the drug, with high proportions of unchanged drug excreted at doses exceeding 5 g/m2. The renal clearance is twice that of cyclophosphamide.

    Oral Route

    Ifosfamide is commercially available only as a parenteral product, but its oral bioavailability is 100%. Excessive neurotoxicity from oral administration makes it an unfeasible route.