Ifosfamide (Ifex) is a chemotherapeutic drug that is used to treat a variety of cancers including testicular tumors, bladder cancers, ovarian, and refractory lymphomas.

Ifosfamide Uses:

• Testicular cancer:

  • • Treatment (third line) of germ cell testicular cancer (in blend with additional chemotherapy drugs and with concomitant mesna for prophylaxis of hemorrhagic cystitis)

• Off Label Use of Ifosfamide in Adults:

  • Bladder cancer, advanced
  • Cervical cancer (recurrent or metastatic)
  • Ewing sarcoma
  • Hodgkin lymphoma, relapsed or refractory
  • Non-Hodgkin lymphomas
  • Osteosarcoma
  • Ovarian cancer, advanced (platinum-resistant)
  • Soft tissue sarcoma
  • Thymomas and thymic cancers, advanced

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Ifosfamide Dose in Adults:

Note:

• To prevent bladder toxicity, ifosfamide must be administered with mesna and hydration (at least 2 L of oral or IV fluid per day).
• Ifosfamide is linked with a mild emetic potential; antiemetics are advocated to prevent nausea and vomiting.

Ifosfamide Dose in the treatment of Testicular cancer: IV:

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

• VIP regimen:

  • 1,200 mg/m²/day for 5 days every 3 weeks for 4 cycles (in combination with etoposide, mesna, and cisplatin).

• VeIP regimen:

  • 1,200 mg/m²/day for 5 days every 3 weeks for 4 cycles (in combination with vinblastine, mesna, and cisplatin).

• Off-label dosing/combinations:

  • TIP regimen (off-label dosing):
    • 1,500 mg/m²/day for 4 days (days 2 to 5) every 3 weeks for 4 cycles (in combination with paclitaxel, mesna, and cisplatin).
  • TICE regimen (off-label dosing):
    • 2,000 mg/m²/day for 3 days (days 2 to 4) over 4 hours every 2 weeks for 2 cycles (in combination with paclitaxel and mesna; followed by carboplatin and etoposide).

Ifosfamide Dose in the treatment of advanced bladder cancer (off-label):

• IV: 1,500 mg/m²/day for 5 days every 3 weeks (with mesna) until disease progression.

Ifosfamide Dose in the treatment of recurrent or metastatic cervical cancer (off-label):

• IV: 1,500 mg/m²/day for 5 days every 3 weeks (with mesna).

Ifosfamide Dose in the treatment of Ewing sarcoma (off-label): IV:

• VAC/IE regimen:

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

• VAIA regimen:

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

• VIDE regimen:

  • Adults ≤50 years: 3,000 mg/m /day over 1 to 3 hours for 3 days every 3 weeks for 6 courses (with vincristine, doxorubicin, etoposide, and mesna).

• IE regimen:

  • 1,800 mg/m²/day over 1 hour for 5 days every 3 weeks for 12 cycles (in combination with etoposide and mesna).

• ICE regimen:

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

Ifosfamide Dose in the treatment of relapsed or refractory Hodgkin lymphoma, (off-label): IV:

• ICE regimen:

  • 5,000 mg/m² (over 24 hours) beginning on day 2 every 2 weeks for 2 cycles (in combination with mesna, carboplatin, and etoposide).

• IGEV regimen:

  • 2,000 mg/m²/day for 4 days every 3 weeks for 4 cycles (in combination with mesna, gemcitabine, vinorelbine, and prednisolone).

Ifosfamide Dose in the treatment of Non-Hodgkin lymphomas (off-label): IV:

• Burkitt lymphoma (CODOX-M/IVAC regimen):

  • Adults ≤65 years:
    • Cycles 2 and 4 (IVAC): 1,500 mg/m²/day for 5 days (IVAC is a combination with cytarabine, mesna, and etoposide; IVAC alternates with CODOX-M).
  • Adults >65 years:
    • Cycles 2 and 4 (IVAC): 1,000 mg/m /day for 5 days (IVAC is a combination with cytarabine, mesna, and etoposide; IVAC alternates with CODOX-M).

• Diffuse large B-cell lymphoma (RICE regimen):

  • 5,000 mg/m² (over 24 hours) starting on day 4 every 2 weeks for 3 cycles (given with mesna, carboplatin, etoposide, and rituximab).

Ifosfamide Dose in the treatment of Osteosarcoma (off-label): IV:

• Ifosfamide/cisplatin/doxorubicin/HDMT regimen:

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

• Ifosfamide/cisplatin/epirubicin regimen:

  • 2,000 mg/m²/day over 4 hours for 3 days (days 2, 3, and 4) every 3 weeks for 3 cycles (preop) and every 4 weeks for 3 cycles (postop) (in combination with cisplatin, epirubicin, and mesna).

• ICE regimen (adults ≤22 years):

  • 1,800 mg/m²/day for 5 days every 3 weeks for up to 12 cycles (in combination with carboplatin and etoposide [and mesna]).

Ifosfamide Dose in the treatment of advanced ovarian cancer, (platinum-resistant):

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

Ifosfamide Dose in the treatment of Soft tissue sarcoma (off-label): IV:

• Single-agent ifosfamide:

  • 3,000 mg/m²/day over 4 hours for 3 days every 3 weeks for at least 2 cycles or until disease progression.

• EIA regimen:

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

• MAID regimen:

  • 2,000 mg/m²/day continuous infusion for 3 days every 3 weeks (in combination with mesna, doxorubicin, and dacarbazine) or 2,500 mg/m²/day continuous infusion for 3 days every 3 weeks (in combination with mesna, doxorubicin, and dacarbazine); reduce ifosfamide to 1,500 mg/m²/day if earlier pelvic irradiation.

• Ifosfamide/epirubicin:

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

• AIM regimens:

  • 1,500 mg/m²/day over 2 hours for 4 days every 3 weeks for 4 to 6 cycles (in combination with mesna and doxorubicin) or 2,000 to 3,000 mg/m²/day over 3 hours for 3 days (in combination with mesna and doxorubicin).

Ifosfamide Dose in the treatment of Thymomas and advanced thymic cancers (off-label):

• IV: 1,200 mg/m²/day for 4 days every 3 weeks for 4 cycles (in combination with mesna, cisplatin, and etoposide);
• Colony-stimulating growth factor support was administered on days 5 to 15 (or until WBC ≥10,000/mm³) or 1,500 mg/m²/day for 5 days (with mesna) every 3 weeks for up to 9 cycles. More trials may be needed to further define the role of ifosfamide in this condition.

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Ifosfamide Dose in Childrens:

Note:

• To avoid bladder toxicity, combination therapy with mesna (bladder protectant or chemo protectant) and hydration in adults and children is essential; in adults, at least 2 L/day of oral or IV fluid.
• In children, certain protocols should be consulted for hydration recommendation; for example, some centers have used 2 times maintenance or 3 L/m²/day.

Note:

• Medicating may be based on either BSA (mg/m²) or weight (mg/kg); use extra safety measures to verify dosing parameters during calculations.
• Protocol-specific details regarding dosing, frequency, and combination regimes should be consulted. Ifosfamide is associated with a mild emetic potential.
• Antiemetics are advocated to prevent nausea and vomiting.

Ifosfamide Dose in the treatment of Ewing sarcoma: dosing regimens and combinations variable:

• Children and Adolescents:

  • IE regimen:
    • IV: 1,800 mg/m² over 1 hour once daily for 5 days in combination with mesna and etoposide every 3 weeks for 12 cycles; or may alternate with VAC (vincristine, doxorubicin, and cyclophosphamide) every 3 weeks for a total of 17 courses.
  • HD-IE regimen:
    • 2,800 mg/m² over 1 hour once daily for 5 days in combination with mesna and etoposide every 3 weeks alternating with VAC (vincristine, doxorubicin, cyclophosphamide).
  • ICE regimen:
    • IV: 1,800 mg/m² once daily for 5 days every 3 to 4 weeks for up to 12 cycles in combination with carboplatin, etoposide, and mesna; or may follow with 2 courses of CAV (cyclophosphamide, doxorubicin, and vincristine).
  • VAIA regimen:
    • Reported dosing variable: IV: 3,000 mg/m² on days 1, 2, 22, 23, 43, and 44 for 4 courses in combination with vincristine, doxorubicin, dactinomycin, and mesna or 2,000 mg/m² once daily for 3 days every 3 weeks for 14 courses in combination with vincristine, doxorubicin, and dactinomycin.
  • VIDE regimen:
    • IV: 3,000 mg/m² over 1 to 3 hours once daily for 3 days every 3 weeks for 6 courses in combination with vincristine, doxorubicin, etoposide, and mesna.

Ifosfamide Dose in the treatment of recurrent or refractory Lymphoma, Hodgkin (HL) and Non-Hodgkin (NHL): dosing regimens and combinations variable:

• ICE regimen:

  • Cairo 2005:

    • Children and Adolescents:
      • IV: 1,800 mg/m² once daily for 5 days every 3 weeks for 6 courses in combination with etoposide, carboplatin, and mesna.

  • Moskowitz 2001:

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

• IE regimen:

  • Children and Adolescents:
    • IV: 1,800 mg/m² once daily for 5 days alternating in combination with etoposide and mesna;
    • Alternate at 3-week intervals with DECAL (dexamethasone, etoposide, cisplatin, cytarabine [high-dose ara-C]), and L asparaginase for 4 cycles.

• MIED regimen:

  • Children and Adolescents:

    • Sandlund 2011:
      • IV: 2,000 mg/m² over 2 hours on days 2 to 4 in combination with high-dose methotrexate, etoposide, and dexamethasone (and mesna); patients with NHL also received intrathecal methotrexate, hydrocortisone, and cytarabine
    • Griffin 2009:
      • IV: 3,000 mg/m² over 2 hours on days 3 to 5 in combination with rituximab and ICE (carboplatin, etoposide, and mensa) every 23 days for up to 3 courses has been used in NHL patients

Ifosfamide Dose in the treatment of Osteosarcoma:

• IE regimen:

  • Children and Adolescents:
    • IV: 1,800 to 3,000 mg/m² for 4 to 5 days; frequency and duration protocol-specific with etoposide and mesna.

• ICE regimen:

  • Children and Adolescents:
    • IV: 1,800 mg/m² once daily for 5 days every 3 weeks for up to 12 cycles in combination with carboplatin, etoposide, and mesna.

Ifosfamide Dose in the treatment of newly diagnosed high-grade osteosarcoma of the extremity with metastases:

• Bacci 2003:

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

• Basaran 2007:

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

• Le Deley 2007:

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

Ifosfamide Dose in the treatment of refractory or relapsed Neuroblastoma:

• HD-ICE regimen:

  • Children and Adolescents:
    • IV: 2,000 mg/m² over 2 hours once a day for 5 days in combination with mesna, carboplatin, and etoposide with or without peripheral blood stem cell support (depending on hematologic reserve.

Ifosfamide Dose in the treatment of Rhabdomyosarcoma:

• Interval-compressed I/E regimen:

  • Infants:
    • IV: 900 mg/m² one time each day for 5 days in combination with mesna and etoposide on weeks 9, 13, 17, 26, and 30 (2 weeks after vincristine, doxorubicin, and cyclophosphamide therapy).
    • Note: Infant dose is half of the full dose in children; if infant tolerates dose (i.e., no delayed count recovery or delayed resolution of other toxicities which delays administration), may consider increasing to 75% and then to 100% calculated full dose.
  • Children and Adolescents:
    • IV: 1,800 mg/m² once daily for 5 days in combination with mesna and etoposide on weeks 9, 13, 17, and 30 (2 weeks after vincristine, doxorubicin, and cyclophosphamide therapy)

• VAI (IRS-IV):

  • Infants:
    • IV: 900 mg/m² once daily for 5 days in combination with mesna, vincristine, and dactinomycin for a 21-day cycle for 8 cycles (omitting dactinomycin during radiation).
    • Note: Infant dose is half of full-dose in children; if infant tolerates dose (i.e., no delayed count recovery or delayed resolution of other toxicities which delays administration), may consider increasing to 75% and then to 100% calculated full dose.
  • Children and Adolescents:
    • IV: 1,800 mg/m² once daily for 5 days in combination with mesna, vincristine, and dactinomycin for a 21-day cycle for 8 cycles (omitting dactinomycin during radiation)

• VIE (IRS-IV; Baker 2000):

  • Infants:
    • IV: 900 mg/m² once daily for 5 days in combination with mesna, vincristine, and etoposide for a 21-day cycle for 8 cycles (omitting etoposide during radiation).
    • Note: Infant dose is 50% of full-dose in children; if infant tolerates dose (ie, no delayed count recovery or delayed resolution of other toxicities which delays administration), may consider increasing to 75% and then to 100% calculated full dose.
  • Children and Adolescents:
    • IV: 1,800 mg/m² one time every time for 5 days in combination with mesna, vincristine, and etoposide for a 21-day cycle for 8 cycles (omitting etoposide during radiation)

Ifosfamide Dose in the treatment of Sarcomas; soft tissue, non-Rhabdomyosarcoma:

• Children and Adolescents:

  • 3,000 mg/m² once daily for 3 days every 21 days for 4 cycles in combination with mesna and doxorubicin.

Ifosfamide Dose in the treatment of relapsed Wilms tumor:

• ICE regimen:

  • Children and Adolescents:
    • IV: 1,800 mg/m² one time every day for 5 days every 21 days for at least 2 cycles (median of 4 cycles reported) in combination with mesna, carboplatin, and etoposide.

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Ifosfamide Pregnancy Category: D

• Exposure to ifosfamide-containing regimens during pregnancy has been linked to neonatal anemia and growth retardation.
• Female and male fertility can be affected. The dose and duration of fertility in males as well as females are important factors.
• Ifosfamide can cause oogenesis and stammogenesis problems; amenorrhea and azoospermia have been reported, which may be permanent.
• Treatment should be completed by women only. Male patients must refrain from having children during or for 6 months after treatment ends.

Use of Ifosfamide while breastfeeding

• Breast milk contains ifosfamide.
• It is recommended not to breastfeed while receiving ifosfamide treatment.
• There are potential side effects that can be severe for breastfed babies.
• The manufacturer suggests discontinuing ifosfamide treatment or terminating breastfeeding.
• This decision should be made taking into consideration the benefits to the mother.

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Ifosfamide Dose in Kidney Disease:

Consider reducing the dosage in patients with renal damage; however, there are no dosage modifications given in the manufacturer’s labeling; ifosfamide (and metabolites) are excreted via the kidneys and may accumulate in patients with renal dysfunction. Ifosfamide and metabolites are dialyzable.

• The following adjustments have also been recommended:
  • Aronoff 2007:
    • CrCl ≥10 mL/minute: No dosage adjustment necessary.
    • CrCl <10 mL/minute: Administer 75% of dose.
    • Hemodialysis (supplement for dialysis): No supplemental dose required.
  • Kintzel 1995:
    • CrCl 46 to 60 mL/minute: Administer 80% of dose.
    • CrCl 31 to 45 mL/minute: Administer 75% of dose.
    • CrCl <30 mL/minute: Administer 70% of dose.

Dose in Liver disease:

There are no dosage alterations given in the manufacturer’s labeling; however, ifosfamide is significantly hepatically metabolized to both active and inactive metabolites; exercise caution.

The following changes have been suggested:

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

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Common Side Effects of Ifosfamide:

• Central Nervous System:

  • Brain Disease
  • Central Nervous System Toxicity

• Dermatologic:

  • Alopecia

• Endocrine & Metabolic:

  • Metabolic Acidosis

• Gastrointestinal:

  • Nausea
  • Vomiting

• Hematologic & Oncologic:

  • Leukopenia
  • Anemia
  • Thrombocytopenia

• Renal:

  • Hematuria

Less Common Side Effects of Ifosfamide:

• Cardiovascular:

  • Localized Phlebitis

• Gastrointestinal:

  • Anorexia

• Hematologic & Oncologic:

  • Febrile Neutropenia

• Hepatic:

  • Hepatic Insufficiency
  • Increased Serum Bilirubin
  • Increased Serum Transaminases

• Infection:

  • Infection

• Renal:

  • Renal Insufficiency

• Miscellaneous:

  • Fever

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Contraindications to Ifosfamide:

• Identified allergic reaction to ifosfamide, or any component of the formulation
• Occupation of urinary outflow
• Canadian labeling: Additional contraindications not in US labeling
  • Severe leukopenia/thrombocytopenia
  • Grave renal and/or liver damage
  • Cystitis;
  • Active infection
  • Advanced cerebral arteriosclerosis

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]

  • It is possible for bone marrow to be destroyed. This can lead to serious infections.
  • Ifosfamide is associated with anemia, leukopenia and neutropenia.
  • Myelosuppression can be dose dependent, and is more common with high single doses than with fractionated doses. It also increases with decreased renal function.
  • Combining chemotherapy with radiation therapy or other drugs can cause severe myelosuppression.
  • Patients with reduced bone marrow reserves should be cautious about using it.
  • Avoid giving WBC >2,000/mm3 to patients with platelets >50,000/mm.
  • Bleeding events may occur due to thrombocytopenia.
  • Some neutropenic patients may require antimicrobial prophylaxis.
  • For this reason, it is important to administer antibiotics and/or antifungal medications for neutropenic fever.
• Cardiotoxicity
  • It has been reported that Ifosfamide-stimulated Cardiotoxicity can be fatal.
  • There have been cases of arrhythmias such as atrial/supraventricular fibrillation, atrial fibrillation and pulseless ventricular rhythmia.
  • Cardiotoxicity can be caused by dose. Other cardiotoxic agents (e.g. anthracyclines), radiation to the cardiac region and kidney damage can also increase the risk.
  • Patients with pre-existing or cardiac disease should be used with caution.
  • According to the American Heart Association's scientific statement, ifosfamide is a drug that can either cause irreversible myocardial toxicities or worsen existing myocardial dysfunction.
• CNS toxicities: [US Boxed Warning]
  • CNS toxicities can be severe and may result in encephalopathy or death.
  • CNS toxic symptoms (somnolence and confusion, faintness and hallucinations), cranial nerve dysfunction and psychotic behavior are usually seen within a few hours or days after the first dose. However, symptoms can last longer so it is important to continue supportive care until they resolve completely.
  • After numerous CNS incidents, there has been a recurrence in CNS toxicities.
  • Hypoalbuminemia, renal dysfunction and high-dose antiemetic therapy may all be risk factors for CNS toxicities.
  • Combining centrally-acting drugs may cause additive CNS effects.
  • Reports of peripheral neuropathy have been made.

• Gastrointestinal toxicities:

  • Ifosfamide has a moderate emetic potency; antiemetics should be used to prevent nausea or vomiting.

• Hemorrhagic cystitis - [US Boxed Warning]

  • Hemorrhagic Cystitis may occur (may even be very severe); concomitant mesna reduces the chance of hemorhagic Cysitis.
  • Hydration (at minimum 2 L/day for adults), dose fractionation and/or mesna will reduce the risk of hemorhagic cystitis and hematuria.
  • Do not wait until the last dose to get a urinalysis.
  • Before you start treatment, eliminate or fix any obstructions in your urinary tract.
  • Patients with active UTI should be treated with caution.
  • Hemorrhagic Cystitis is dose-related. High single doses are more likely than fractionated doses.
  • Concomitant or past bladder radiation, or busulfan treatment can increase hemorhagic risk.

• Hepatic effects

  • Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disorder (VOD), was reported using ifosfamide-containing treatments.

• Hypersensitivity reactions

  • Ifosfamide has been shown to cause anaphylactic/anaphylactoid reactions.
  • Cross-sensitivity may occur with similar agents.

• Infection

  • This may cause significant suppression of immune responses. It can lead to severe infection, sepsis or septic shock.
  • There have been reports of infections that range from bacterial to viral, fungal and parasitic. Latent viral infections could be reactivated.
  • Avoid using immunosuppressants in combination with patients who are ill.

• Toxicity in the lungs:

  • There have been reports of interstitial pneumonitis and pulmonary fibrisis.
  • Pay attention to signs and symptoms of pulmonary toxicities.

• Renal toxicities: [US Boxed Warning]

  • It can cause severe nephrotoxicity that may lead to renal failure.
  • Nephrotoxicity can be fatal.
  • There have been reports of severe and prolonged renal failure.
  • Also, renal parenchymal or tubular necrosis (including acute) has been reported. Tubular damage can be delayed for months to years and may continue.
  • Reduced glomerular rate, increased creatinine and proteinuria are some of the renal manifestations.
  • Reports of syndromes of inappropriate antidiuretic hormone, renal rickets and Fanconi syndrome were made.
  • Before and during treatment, assess renal function; test urine for erythrocytes.

• Secondary malignancy

  • Secondary malignancies can occur (onset could be delayed).
  • Treatment increases the risk of developing myelodysplastic Syndrome (which can lead to serious leukemia).

• Wound healing

  • It can interfere with wound healing.

Ifosfamide: Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of Ifosfamide. Specifically, concentrations of the toxic metabolites of ifosfamide may increase.
Busulfan	May enhance the adverse/toxic effect of Ifosfamide. Specifically, the risk of hemorrhagic cystitis may be increased.
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
CYP2B6 Inducers (Moderate)	May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers).
CYP3A4 Inducers (Moderate)	May decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide.
CYP3A4 Inducers (Strong)	May increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.
CYP3A4 Inhibitors (Moderate)	May decrease serum concentrations of the active metabolite(s) of Ifosfamide.
CYP3A4 Inhibitors (Strong)	May decrease serum concentrations of the active metabolite(s) of Ifosfamide.
Dabrafenib	May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers).
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Fosaprepitant	May increase the serum concentration of Ifosfamide. Specifically, concentrations of the toxic metabolites of ifosfamide may increase.
Lumacaftor	May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers).
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
MiFEPRIStone	May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors).
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Smallpox and Monkeypox Vaccine (Live)	Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live).
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Thiotepa	May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors).
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Vitamin K Antagonists (eg, warfarin)	Ifosfamide may enhance the anticoagulant effect of Vitamin K Antagonists.
Risk Factor D (Consider therapy modification)
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Leflunomide	Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.
Lenograstim	Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Lipegfilgrastim	Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Palifermin	May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
Upadacitinib	Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib.
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live).

 

Monitoring parameters:

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

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How to administer Ifosfamide?

IV:

• Ifosfamide is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.
• Administer IV over at least 30 minutes (infusion times may differ by the institutional protocols; refer to the specific protocol for infusion duration).
• To prevent bladder toxicity, ifosfamide should be given with mesna and hydration.

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Mechanism of action of Ifosfamide:

• Cross-linking of DNA strands occurs when Ifosfamide is bound with nucleic acid and other intracellular structures.
• This causes cell death. It blocks DNA synthesis and protein synthesis. Dose-dependent pharmacokinetics exist.

Distribution:

• It is able to penetrate the central nervous system but not at therapeutic levels

Protein binding

• Negligible

Metabolism:

• Active metabolites are ofosforamide mustard and 4-hydroxy-ifosfamide.
• Hepatic to active metabolites include acrolein and inactive dichloroethylated or carboxy metabolites.
• Acrolein is implicated in the development of hemorhagic cystitis.

Half-life elimination (increased in the elderly):

• High dose (3,800 to 5,000 mg/m²): ~15 hours
• Lower dose (1,600 to 2,400 mg/m²): ~7 hours

Excretion:

• High dose (5,000 mg/m²): Urine (70% to 86%; 61% as unchanged drug)
• Lower dose (1,600 to 2,400 mg/m²): Urine (12% to 18% as unchanged drug)

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International Brand Names of Ifosfamide:

• Ifex
• Alquimid
• Cuantil
• Farmamide
• Fosfa
• Fosfidex
• Holoxan
• Holoxane
• Ifadex
• Ifamide
• Ifo-Cell
• Ifolem
• Ifomida
• Ifomide
• Ifos
• Ipamide
• Iphox
• Isoxan
• Mitoxana
• Tolcamin
• Tronoxal
• Xifox

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Ifosfamide Brand Names in Pakistan:

Ifosfamide Injection 1 G in Pakistan
Fosfamide	Consolidated Chemical Laboratories (Pvt) Ltd.
Ifos	A. J. Mirza Pharma (Pvt) Ltd
Ifosfamin	Pharmedic (Pvt) Ltd.

 

Ifosfamide Injection 2 G in Pakistan
Ifos	A. J. Mirza Pharma (Pvt) Ltd
Ifosfamin	Pharmedic (Pvt) Ltd.