PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Nitrogen Mustard Analogs

    BOXED WARNING

    Anemia, bone marrow suppression, herpes infection, immunosuppression, infection, leukopenia, thrombocytopenia, varicella

    Use ifosfamide with caution in patients with an active infection, severe immunosuppression, or compromised bone marrow reserve (e.g., bone marrow suppression, leukopenia, granulocytopenia, thrombocytopenia, extensive bone marrow metastases, prior radiation, or prior chemotherapy); latent infections (e.g., varicella, herpes infection) can also be reactivated. Severe myelosuppression has occurred with ifosfamide treatment, which can cause leukopenia, neutropenia, thrombocytopenia (increased risk of bleeding), anemia, and fatal infections. The risk is dose-dependent, and is increased with administration of a single high dose compared with fractionated administration; it is also higher when given in combination with other chemotherapeutic or hematotoxic agents, and/or radiation. The leukocyte nadir tends to be reached approximately during the second week after administration. Closely monitor complete blood counts prior to each dose of ifosfamide and at appropriate intervals during treatment; do not administer ifosfamide to patients with a white blood cell (WBC) count less than 2,000 cells/mm3 and/or a platelet count less than 50,000 cells/mm3. 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. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the physician.

    Hematuria, hemorrhagic cystitis, urinary tract infection (UTI)

    Ifosfamide is metabolized to acrolein, which is urotoxic and is eliminated renally; the duration of exposure of acrolein to the bladder wall should be minimized. Manifestations of urotoxicity include hemorrhagic cystitis. The risk of hemorrhagic cystitis is dose-dependent, and can be reduced with the prophylactic administration of mesna. Use ifosfamide with caution, if at all, in patients with urinary tract infection (UTI). Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis. Administer mesna concurrently with ifosfamide treatment to decrease the incidence of hemorrhagic cystitis. Obtain a urinalysis prior to each dose of ifosfamide; hold ifosfamide if microscopic hematuria (greater than 10 red blood cells per high power field) is present, until complete resolution.

    Bladder obstruction, nephrotoxicity, renal failure, renal impairment, urinary tract obstruction

    Ifosfamide is contraindicated in patients with urinary outflow obstruction, including patients with bladder obstruction and urinary tract obstruction due to the risk of nephrotoxicity. Before starting treatment with ifosfamide, it is necessary to exclude or correct any urinary tract obstructions. Carefully weigh the risks and benefits of therapy with ifosfamide when considering treatment in patients with baseline renal impairment, renal failure, or reduced nephron reserve, as it is excreted by the kidneys and may accumulate in patients with decreased renal function which increases the risk of myelosuppression, central nervous system (CNS) toxicity, and cardiac toxicity. Closely monitor these patients as they may also experience worsening of renal function during or following ifosfamide treatment and consider a dose reduction if clinically appropriate. Ifosfamide is both nephrotoxic and urotoxic; fatal outcomes have been reported. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Administer adequate amounts of fluid during or immediately after administration of ifosfamide to force diuresis and reduce the risk of nephrotoxicity. Evaluate glomerular and tubular kidney function before starting therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity. Monitor serum and urine chemistries regularly, including phosphorus and potassium, administering appropriate replacement therapy as indicated. Tubular damage may become apparent during therapy, months, or even years after cessation of treatment.

    Encephalopathy, females, hypoalbuminemia, neurotoxicity

    Ifosfamide can cause severe neurotoxicity resulting in encephalopathy and death. Risk factors for the development of CNS toxicity include the following: oral route of administration utilized, high ifosfamide dosing regimen, short IV infusions, poor performance status prior to treatment, hypoalbuminemia, renal dysfunction, and females. Manifestations consist of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma. Monitor for central nervous system (CNS) toxicity and discontinue ifosfamide if encephalopathy occurs. Neurotoxicity can occur within a few hours to a few days after the first administration of ifosfamide; most cases resolve within 48 to 72 hours of discontinuation, but symptoms can last for longer periods of time. Supportive therapy should be maintained until complete resolution; occasionally, recovery has been incomplete. Recurrence of CNS toxicity has been reported after several uneventful treatment courses. Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide-induced encephalopathy. Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery. The use of methylene blue may reduce the risk of ifosfamide-induced.

    DEA CLASS

    Rx

    DESCRIPTION

    Alkylating agent; synthetic analog of cyclophosphamide
    Used for the treatment of advanced testicular cancer, along with several off-label uses
    Black box warnings for myelosuppression, neurotoxicity, nephrotoxicity, and hemorrhagic cystitis

    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.

    Adults

    FDA approved: 1,200 mg/m2 IV on days 1 through 5, every 21 days.
    Off-label: Single doses up to 5,000 mg/m2 IV (see regimen for specific information).

    Geriatric

    FDA approved: 1,200 mg/m2 IV on days 1 through 5, every 21 days.
    Off-label: Single doses up to 5,000 mg/m2 IV (see regimen for specific information).

    Adolescents

    FDA labeling: Safety and efficacy have not been established.
    Off-label: Single doses up to 3,000 mg/m2 IV (see regimen for specific information).

    Children

    FDA labeling: Safety and efficacy have not been established.
    Off-label: Single doses up to 3,000 mg/m2 IV (see regimen for specific information).

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use ifosfamide with caution in patients with impaired hepatic function. No formal studies have been conducted in these patients, and ifosfamide is extensively metabolized in the liver to both efficacious and toxic metabolites.

    Renal Impairment

    Closely monitor patients with renal impairment for toxicity; consider a dose reduction if appropriate. Formal studies have not been conducted in patients with renal impairment; however, ifosfamide and its metabolites are excreted by the kidneys and may accumulate in patients with decreased renal function. Ifosfamide and its metabolites are dialyzable.

    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

    Patients should be well hydrated with at least 2 liters per day of oral or IV fluids to prevent bladder toxicity during therapy. Ifosfamide must also be given in combination with mesna to prevent hemorrhagic cystitis.
     
    Reconstitution, Powder for Injection:
    1 g vial: Reconstitute with 20 mL, of sterile water for injection or bacteriostatic water for injection containing parabens or benzyl alcohol, for a concentration of 50 mg/mL.
    3 g vial: Reconstitute with 60 mL of sterile water for injection or bacteriostatic water for injection containing parabens or benzyl alcohol, for a concentration of 50 mg/mL.
    Storage after reconstitution: Refrigerate reconstituted solutions and use within 24 hours; solutions containing benzyl alcohol can reduce the stability of ifosfamide.
     
    Dilution (solution for injection or reconstituted powder):
    Further dilute to a final concentration of 0.6 mg/mL to 20 mg/mL in one of the following solutions: 5% dextrose for injection, 0.9% sodium chloride for injection, lactated ringer's injection, or sterile water for injection; intermediate concentrations or mixtures of excipients (e.g., 2.5% dextrose injection, 0.45% sodium chloride injection, 5% dextrose and 0.9% sodium chloride injection) are also acceptable.
    Storage after dilution: Refrigerate diluted solutions and use within 24 hours; solutions containing benzyl alcohol can reduce the stability of ifosfamide. Infuse over a minimum of 30 minutes.

    STORAGE

    Generic:
    - Diluted product if not used immediately can be stored at 36 to 46 degrees F for up to 24 hours
    - 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

    Anemia, bone marrow suppression, herpes infection, immunosuppression, infection, leukopenia, thrombocytopenia, varicella

    Use ifosfamide with caution in patients with an active infection, severe immunosuppression, or compromised bone marrow reserve (e.g., bone marrow suppression, leukopenia, granulocytopenia, thrombocytopenia, extensive bone marrow metastases, prior radiation, or prior chemotherapy); latent infections (e.g., varicella, herpes infection) can also be reactivated. Severe myelosuppression has occurred with ifosfamide treatment, which can cause leukopenia, neutropenia, thrombocytopenia (increased risk of bleeding), anemia, and fatal infections. The risk is dose-dependent, and is increased with administration of a single high dose compared with fractionated administration; it is also higher when given in combination with other chemotherapeutic or hematotoxic agents, and/or radiation. The leukocyte nadir tends to be reached approximately during the second week after administration. Closely monitor complete blood counts prior to each dose of ifosfamide and at appropriate intervals during treatment; do not administer ifosfamide to patients with a white blood cell (WBC) count less than 2,000 cells/mm3 and/or a platelet count less than 50,000 cells/mm3. 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. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the physician.

    Hematuria, hemorrhagic cystitis, urinary tract infection (UTI)

    Ifosfamide is metabolized to acrolein, which is urotoxic and is eliminated renally; the duration of exposure of acrolein to the bladder wall should be minimized. Manifestations of urotoxicity include hemorrhagic cystitis. The risk of hemorrhagic cystitis is dose-dependent, and can be reduced with the prophylactic administration of mesna. Use ifosfamide with caution, if at all, in patients with urinary tract infection (UTI). Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for hemorrhagic cystitis. Administer mesna concurrently with ifosfamide treatment to decrease the incidence of hemorrhagic cystitis. Obtain a urinalysis prior to each dose of ifosfamide; hold ifosfamide if microscopic hematuria (greater than 10 red blood cells per high power field) is present, until complete resolution.

    Bladder obstruction, nephrotoxicity, renal failure, renal impairment, urinary tract obstruction

    Ifosfamide is contraindicated in patients with urinary outflow obstruction, including patients with bladder obstruction and urinary tract obstruction due to the risk of nephrotoxicity. Before starting treatment with ifosfamide, it is necessary to exclude or correct any urinary tract obstructions. Carefully weigh the risks and benefits of therapy with ifosfamide when considering treatment in patients with baseline renal impairment, renal failure, or reduced nephron reserve, as it is excreted by the kidneys and may accumulate in patients with decreased renal function which increases the risk of myelosuppression, central nervous system (CNS) toxicity, and cardiac toxicity. Closely monitor these patients as they may also experience worsening of renal function during or following ifosfamide treatment and consider a dose reduction if clinically appropriate. Ifosfamide is both nephrotoxic and urotoxic; fatal outcomes have been reported. Manifestations include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glycosuria as well as tubular acidosis. Administer adequate amounts of fluid during or immediately after administration of ifosfamide to force diuresis and reduce the risk of nephrotoxicity. Evaluate glomerular and tubular kidney function before starting therapy as well as during and after treatment. Monitor urinary sediment regularly for the presence of erythrocytes and other signs of uro/nephrotoxicity. Monitor serum and urine chemistries regularly, including phosphorus and potassium, administering appropriate replacement therapy as indicated. Tubular damage may become apparent during therapy, months, or even years after cessation of treatment.

    Encephalopathy, females, hypoalbuminemia, neurotoxicity

    Ifosfamide can cause severe neurotoxicity resulting in encephalopathy and death. Risk factors for the development of CNS toxicity include the following: oral route of administration utilized, high ifosfamide dosing regimen, short IV infusions, poor performance status prior to treatment, hypoalbuminemia, renal dysfunction, and females. Manifestations consist of somnolence, confusion, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma. Monitor for central nervous system (CNS) toxicity and discontinue ifosfamide if encephalopathy occurs. Neurotoxicity can occur within a few hours to a few days after the first administration of ifosfamide; most cases resolve within 48 to 72 hours of discontinuation, but symptoms can last for longer periods of time. Supportive therapy should be maintained until complete resolution; occasionally, recovery has been incomplete. Recurrence of CNS toxicity has been reported after several uneventful treatment courses. Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of ifosfamide-induced encephalopathy. Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other heavy machinery. The use of methylene blue may reduce the risk of ifosfamide-induced.

    Children

    Children may be at increased risk for ifosfamide-induced nephrotoxicity. Risk factors in children have included age younger than 5 years, total cumulative dose of ifosfamide received greater than 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.

    Cardiac disease, cardiotoxicity

    Use ifosfamide with caution in patients with risk factors for cardiotoxicity, in patients with pre-existing cardiac disease, and in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region. Ifosfamide is associated with dose-dependent cardiotoxicity, including some fatalities. Manifestations of cardiotoxicity include supraventricular or ventricular arrhythmias, decreased QRS voltage and ST-segment or T-wave changes, toxic cardiomyopathy leading to heart failure with congestion and hypotension, pericardial effusion, fibrinous pericarditis, and epicardial fibrosis.

    Radiation therapy

    Use ifosfamide with caution, if at all, in patients who have received radiation therapy, as they are at an increased risk of severe myelosuppression and resultant immunosuppression, as well as cardiotoxicity. Past or concomitant radiation of the bladder may increase the risk of hemorrhagic cystitis.

    Chronic lung disease (CLD), pulmonary disease, pulmonary toxicity

    Use ifosfamide with caution in patients with pre-existing pulmonary disease or chronic lung disease (CLD). Interstitial pneumonitis, pulmonary fibrosis, and other forms of pulmonary toxicity have been reported with ifosfamide treatment. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated.

    Geriatric

    Monitor geriatric patients for an increased incidence of treatment-related adverse reactions. Ifosfamide and its metabolites are substantially excreted by the kidney; the risk of toxic reactions is increased in patients with impaired renal function. In general, dose selection for elderly patients should be cautious, as they have a greater frequency of decreased renal, hepatic, or cardiac function. The elimination half-life and volume of distribution (Vd) of ifosfamide appear to increase with age. However, no significant changes in total plasma clearance or renal or non-renal clearance were noted with age in a study of patients age 40 to 71 years.

    Infertility

    Ifosfamide interferes with oogenesis and spermatogenesis, which may result in infertility; sterility in both males and females has been reported. Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment; sterility may be irreversible in some patients. Amenorrhea has been reported in postmarketing experience with ifosfamide; the risk of permanent chemotherapy-induced amenorrhea increases with age. Pediatric patients treated with ifosfamide during prepubescence subsequently may not conceive, and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause. Males treated with ifosfamide may develop oligospermia or azoospermia. Pediatric patients treated with ifosfamide during prepubescence might not develop secondary sexual characteristics normally, but may have oligospermia or azoospermia. Azospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children. Additionally, ovarian failure, premature menopause, ovarian disorder, ovulation disorder, impairment of spermatogenesis, decreased blood estrogen, and increased blood gonadotropin were reported in postmarketing experience with humans treated with ifosfamide.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during ifosfamide treatment; men should not father a child during treatment and for up to 6 months after the last dose. Although there are no adequately controlled studies in pregnant humans, ifosfamide can cause fetal harm and death including fetal growth retardation and neonatal anemia when administered during pregnancy based on its mechanism of action and animal studies. Fetal growth retardation has been reported in postmarketing experience with human treatment with ifosfamide. In animal studies, ifosfamide was genotoxic and mutagenic in male and female germ cells, with embryo-toxic and teratogenic effects observed in mice, rats, and rabbits and doses 0.05 to 0.075 times the human dose. Women who are pregnant or who become pregnant while receiving ifosfamide should be apprised of the potential hazard to the fetus. When administered to pregnant mice during the gestation period, increased resorptions and anomalies were reported at doses of 30 mg/m2. Embryo-lethal effects were observed in rats receiving ifosfamide 54 mg/m2 during the gestational period, and embryotoxic effects were apparent in dams receiving 18 mg/m2 during the same dosing period. Ifosfamide was also embryotoxic to rabbits receiving ifosfamide 88 mg/m2 per day, with the number of anomalies significantly increased over the control group.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ifosfamide treatment. Ifosfamide can be teratogenic if taken by the mother during pregnancy or if a male patient fathers a child during treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during ifosfamide therapy. Males with female partners of reproductive potential should use effective contraception and not father a child during therapy and for at least 6 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of ifosfamide. Women who become pregnant while receiving ifosfamide should be apprised of the potential hazard to the fetus.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from ifosfamide, advise women to discontinue breast-feeding during treatment. Ifosfamide is excreted in breast milk.

    Vaccination

    Vaccination with live vaccines should be avoided due to myelosuppression and potential risk of fatal infections during ifosfamide therapy.

    ADVERSE REACTIONS

    Severe

    hemorrhagic cystitis / Delayed / 0-44.1
    hepatotoxicity / Delayed / 1.8-1.8
    cardiotoxicity / Delayed / 0.5-0.5
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    ileus / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    renal tubular acidosis (RTA) / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    anuria / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    Fanconi syndrome / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    acute cerebellar syndrome / Early / Incidence not known
    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    atrial flutter / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    heart failure / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    atrial tachycardia / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    pericarditis / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    hepatic failure / 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
    hearing loss / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    capillary leak syndrome / Early / Incidence not known
    vasculitis / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    pulmonary toxicity / Early / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    hemolytic anemia / Delayed / Incidence not known

    Moderate

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

    Mild

    alopecia / Delayed / 89.6-89.6
    vomiting / Early / 46.8-46.8
    nausea / Early / 46.8-46.8
    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
    hyperhidrosis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    rash / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    cylindruria / Delayed / Incidence not known
    polyuria / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    headache / Early / Incidence not known
    dizziness / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    tremor / Early / Incidence not known
    agitation / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    drowsiness / Early / Incidence not known
    asterixis / Delayed / Incidence not known
    lethargy / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    premature atrial contractions (PACs) / Early / Incidence not known
    flushing / Rapid / Incidence not known
    malaise / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    paranoia / Early / Incidence not known
    vertigo / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    polydipsia / Early / Incidence not known
    cough / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    fever / Early / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with butalbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; butalbital is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with butalbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; butalbital is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with butalbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; butalbital is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Amiodarone: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with amiodarone is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Amiodarone is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Amobarbital: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with amobarbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; amobarbital is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with clarithromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Clarithromycin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with clarithromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Clarithromycin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Apalutamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with apalutamide is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; apalutamide is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Aprepitant, Fosaprepitant: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with aprepitant, fosaprepitant is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Aprepitant is a moderate CYP3A4 inhibitor when administered as a 3-day regimen. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. Coadministration may decrease plasma concentrations of ifosfamide active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with butalbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; butalbital is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with butalbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; butalbital is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Atazanavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with atazanavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Atazanavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Atazanavir; Cobicistat: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with atazanavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Atazanavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with phenobarbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; phenobarbital is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with phenobarbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; phenobarbital is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Bexarotene: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with bexarotene is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; bexarotene is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Bosentan: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with bosentan is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; bosentan is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Brigatinib: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with brigatinib is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; in vitro data suggest brigatinib is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as ifosfamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Butabarbital: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with butabarbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; butabarbital is a CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Carbamazepine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with carbamazepine is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; carbamazepine is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Ceritinib: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ceritinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. In vitro data suggest ceritinib is a CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Chloramphenicol: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with chloramphenicol is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Chloramphenicol is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Ciprofloxacin: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ciprofloxacin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    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: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with clarithromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Clarithromycin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Cobicistat: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Conivaptan: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with conivaptan is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Conivaptan is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Crizotinib: (Moderate) Monitor for a decrease in the 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 plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Dabrafenib: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with dabrafenib is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; dabrafenib is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Dalfopristin; Quinupristin: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with quinupristin; dalfopristin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Quinupristin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Danazol: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with danazol is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Danazol is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Darunavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with darunavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Darunavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Darunavir; Cobicistat: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with darunavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Darunavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with darunavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Darunavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ritonavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ritonavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Delavirdine: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with delavirdine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Delavirdine is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Dexamethasone: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with dexamethasone is necessary. The significance of this interaction is unknwon, however, as dexamethasone is widely used as an antiemetic with chemotherapy such as ifosfamide. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; dexamethasone is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Diltiazem: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with diltiazem is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Diltiazem is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    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) Monitor for a decrease in the efficacy of ifosfamide if coadministration with dronedarone is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Dronedarone is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Duvelisib: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with duvelisib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Duvelisib is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Efavirenz: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with efavirenz is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; efavirenz is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with efavirenz is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; efavirenz is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with efavirenz is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; efavirenz is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Enzalutamide: (Moderate) 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 may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Erythromycin: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with erythromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Erythromycin is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with erythromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Erythromycin is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Eslicarbazepine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with eslicarbazepine is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; eslicarbazepine is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Etravirine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with etravirine is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; etravirine is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Fluconazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluconazole is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Fluoxetine: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluoxetine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluoxetine is a weak CYP3A4 inhibitor, but its metabolite norfluoxetine is a moderate inhibitor of CYP3A4. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Fluoxetine; Olanzapine: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluoxetine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluoxetine is a weak CYP3A4 inhibitor, but its metabolite norfluoxetine is a moderate inhibitor of CYP3A4. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Fluvoxamine: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluvoxamine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Fosamprenavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fosamprenavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fosamprenavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Fosphenytoin: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with fosphenytoin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; fosphenytoin is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Grapefruit juice: (Moderate) Advise patients that consumption of grapefruit products may decrease the efficacy of ifosfamide treatment. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Grapefruit juice is a strong CYP3A4 inhibitor.
    Idelalisib: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with idelalisib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Idelalisib is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Imatinib: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with imatinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Imatinib is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Indinavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with indinavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Indinavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Isavuconazonium: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with isavuconazonium is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Isavuconazole, the active moiety of isavuconazonium, is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Isoniazid, INH: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with isoniazid is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Isoniazid is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with rifampin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; rifampin is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with isoniazid is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Isoniazid is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Isoniazid, INH; Rifampin: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with rifampin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; rifampin is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with isoniazid is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Isoniazid is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Itraconazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with itraconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Itraconazole is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Ketoconazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ketoconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ketoconazole is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Letermovir: (Moderate) Closely monitor for reduced ifosfamide efficacy if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Metabolism of ifosfamide, a CYP3A4 substrate, to its active alkylating metabolite may be decreased during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as ifosfamide, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lopinavir; Ritonavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with lopinavir; ritonavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ritonavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ritonavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Lumacaftor; Ivacaftor: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with lumacaftor; ivacaftor is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; lumacaftor is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Mephobarbital: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with mephobarbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; mephobarbital is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Mitotane: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with mitotane is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; mitotane is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Modafinil: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with modafinil is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; modafinil is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Nafcillin: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with nafcillin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; nafcillin is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Nefazodone: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with nefazodone is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Nefazodone is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Nelfinavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with nelfinavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Nelfinavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with netupitant is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Netupitant is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Nevirapine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with nevirapine is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; nevirapine is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Nilotinib: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with nilotinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Nilotinib is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ritonavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ritonavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenobarbital: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with phenobarbital is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; phenobarbital is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Phenytoin: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with phenytoin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; phenytoin is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Posaconazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with posaconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Posaconazole is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Primidone: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with primidone is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; primidone is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Quinine: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with quinine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Quinine is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Ribociclib: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ribociclib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ribociclib is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Ribociclib; Letrozole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ribociclib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ribociclib is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Rifabutin: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with rifabutin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; rifabutin is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Rifampin: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with rifampin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; rifampin is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Rifapentine: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with rifapentine is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; rifapentine is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Ritonavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ritonavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ritonavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Saquinavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with saquinavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Saquinavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    St. John's Wort, Hypericum perforatum: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with St. John's Wort is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4. St. John's Wort is a strong CYP3A4 inducer; however, the amount of individual constituents in various products of St. John's Wort may alter the inducing effects, making drug interactions unpredictable. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Streptogramins: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with quinupristin; dalfopristin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Quinupristin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Telithromycin: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with telithromycin is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Telithromycin is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Tipranavir: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with tipranavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Tipranavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Trandolapril; Verapamil: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with verapamil is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Verapamil is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    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.
    Verapamil: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with verapamil is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Verapamil is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Voriconazole: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with voriconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Voriconazole is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during ifosfamide treatment; men should not father a child during treatment and for up to 6 months after the last dose. Although there are no adequately controlled studies in pregnant humans, ifosfamide can cause fetal harm and death including fetal growth retardation and neonatal anemia when administered during pregnancy based on its mechanism of action and animal studies. Fetal growth retardation has been reported in postmarketing experience with human treatment with ifosfamide. In animal studies, ifosfamide was genotoxic and mutagenic in male and female germ cells, with embryo-toxic and teratogenic effects observed in mice, rats, and rabbits and doses 0.05 to 0.075 times the human dose. Women who are pregnant or who become pregnant while receiving ifosfamide should be apprised of the potential hazard to the fetus. When administered to pregnant mice during the gestation period, increased resorptions and anomalies were reported at doses of 30 mg/m2. Embryo-lethal effects were observed in rats receiving ifosfamide 54 mg/m2 during the gestational period, and embryotoxic effects were apparent in dams receiving 18 mg/m2 during the same dosing period. Ifosfamide was also embryotoxic to rabbits receiving ifosfamide 88 mg/m2 per day, with the number of anomalies significantly increased over the control group.

    Due to the potential for serious adverse reactions in nursing infants from ifosfamide, advise women to discontinue breast-feeding during treatment. Ifosfamide is excreted in breast milk.

    MECHANISM OF ACTION

    Ifosfamide is an oxazaphosphorine alkylating agent related to the nitrogen mustards. It is a prodrug requiring activation by cytochrome P450 3A4 for its cytotoxic activity; activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein, an alkylating isophosphoramide mustard, and multiple nontoxic products. The exact mechanism of action has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation of the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intrastrand crosslinks in the DNA results in cell death.

    PHARMACOKINETICS

    Ifosfamide is administered intravenously. Ifosfamide shows little protein binding, but it and its active metabolites are extensively bound by red blood cells. It exhibits both dose-dependent and time-dependent pharmacokinetics. At single doses ranging from 3.8 to 5 g/m2, plasma concentrations decay biphasically and the mean terminal half-life is about 15 hours; however at lower doses (1.6 to 2.4 g/m2 per day), plasma decay is monoexponential and the terminal elimination half-life is about 7 hours. When administered intravenously over 30 minutes once daily for 5 days, the median elimination half-life decreased from 7.2 hours on day 1 to 4.6 hours on day 5; median clearance increased from 66 mL/minute on day 1 to 115 mL/minute on day 5. There was no significant change in volume of distribution on day 5 (0.72 L/kg) compared with day 1 (0.64 L/kg). The volume of distribution (Vd) of ifosfamide is approximates the total body water volume, suggesting minimal tissue binding.
     
    Ifosfamide is extensively metabolized through 2 metabolic pathways: ring oxidation to form the active metabolite (4-hydroxy-ifosfamide), and side-chain oxidation to form the inactive metabolites (3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde). Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism is required for generation of biologically active species and while metabolism is extensive, it is also variable. After administration of radiolabeled ifosfamide at a dose of 5 g/m2, 70% to 86% of the dosed radioactivity was recovered in urine as metabolites, with about 61% of the dose excreted as parent compound. At lower doses (1.6 to 2.4 g/m2), only 12% to 18% of the dose was excreted as unchanged drug within 72 hours. Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present.
     
    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.