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:

• Ifosfamide is a medicine used to treat cancer.
• To avoid harming the bladder, it's given along with another medicine called mesna and you need to drink a lot of fluids (at least 2 liters a day).
• Ifosfamide can sometimes make you feel like vomiting, so doctors suggest taking anti-nausea medicines to prevent that.

Ifosfamide Dose in the treatment of Testicular cancer: IV:

• Manufacturer's guidelines:
  • Given with mesna (a medicine to protect the bladder).
  • Dosage: 1,200 mg/m^2 each day, for 5 days. This is repeated every 3 weeks or after the blood counts have recovered.
• VIP regimen:
  • This combines Ifosfamide with three other drugs: etoposide, mesna, and cisplatin.
  • Dosage: 1,200 mg/m^2 each day for 5 days. This is done for 4 cycles, every 3 weeks.
• VeIP regimen:
  • This combines Ifosfamide with vinblastine, mesna, and cisplatin.
  • Dosage: 1,200 mg/m^2 each day for 5 days. This is done for 4 cycles, every 3 weeks.

Off-label dosing/combinations (not officially approved but sometimes used):

• TIP regimen:
  • Ifosfamide is used with paclitaxel, mesna, and cisplatin.
  • Dosage: 1,500 mg/m^2 each day for 4 days (from day 2 to day 5). This is repeated for 4 cycles, every 3 weeks.
• TICE regimen:
  • This combines Ifosfamide with paclitaxel and mesna. After this, carboplatin and etoposide are given.
  • Dosage: 2,000 mg/m^2 each day for 3 days (from day 2 to day 4), and this is given over 4 hours. This treatment is done for 2 cycles, every 2 weeks.

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

For treating advanced bladder cancer (not the standard use but based on some studies), the dose of Ifosfamide is:

• Dosage: 1,500 mg/m^2 each day for 5 days.
• Frequency: This is repeated every 3 weeks.
• Duration: Continue this treatment until the cancer gets worse.

Note: It's important to also take mesna with Ifosfamide to protect the bladder.

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

For treating recurrent or metastatic cervical cancer (which is an off-label use), the dose of Ifosfamide is:

• Dosage: 1,500 mg/m^2 each day for 5 days.
• Frequency: This treatment is repeated every 3 weeks.

Note: Mesna should be taken along with Ifosfamide to protect the bladder.

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

Ifosfamide dosage in the treatment of Ewing sarcoma (an off-label use):

• VAC/IE regimen (for adults 30 years or younger):
  • IE: 1,800 mg/m^2 each day for 5 days.
  • This is combined with mesna (to protect the bladder) and etoposide.
  • Alternated with VAC (vincristine, doxorubicin, and cyclophosphamide) every 3 weeks.
  • This treatment continues for 17 courses.
• VAIA regimen:
  • Option 1: 3,000 mg/m^2 on days 1, 2, 22, 23, 43, and 44. This lasts for 4 courses and is combined with vincristine, doxorubicin, dactinomycin, and mesna.
  • Option 2 (for adults 35 years or younger): 2,000 mg/m^2 each day for 3 days, repeated every 3 weeks for 14 courses. This is also combined with vincristine, doxorubicin, dactinomycin, and mesna.
• VIDE regimen (for adults 50 years or younger):
  • Dose: 3,000 mg/m^2 daily, given over 1 to 3 hours, for 3 days.
  • This treatment is repeated every 3 weeks for 6 courses.
  • Used in combination with vincristine, doxorubicin, etoposide, and mesna.
• IE regimen:
  • Dose: 1,800 mg/m^2 daily, given over 1 hour, for 5 days.
  • This is repeated every 3 weeks for 12 cycles.
  • Combined with etoposide and mesna.
• ICE regimen (for adults 22 years or younger):
  • Dose: 1,800 mg/m^2 each day for 5 days.
  • This treatment is repeated every 3 weeks for up to 12 cycles.
  • Used in combination with carboplatin, etoposide, and mesna.

Always make sure to consult with an oncologist for precise and specific treatment plans.

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

Ifosfamide dosage for treating relapsed or refractory Hodgkin lymphoma (an off-label use):

1. ICE regimen:
   • Dose: 5,000 mg/m^2 given over 24 hours, starting on the 2nd day.
   • Frequency: Every 2 weeks.
   • Duration: For 2 cycles.
   • Combined with: mesna (to protect the bladder), carboplatin, and etoposide.
2. IGEV regimen:
   • Dose: 2,000 mg/m^2 each day, for 4 consecutive days.
   • Frequency: Every 3 weeks.
   • Duration: For 4 cycles.
   • Combined with: mesna, gemcitabine, vinorelbine, and prednisolone.

It's vital to consult with a hematologist or oncologist when considering these treatments.

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

Burkitt lymphoma (using the CODOX-M/IVAC regimen):

• For adults 65 years old or younger:
  • During Cycles 2 and 4 (referred to as IVAC): 1,500 mg/m^2 each day for 5 days. This is used in combination with cytarabine, mesna, and etoposide. IVAC is alternated with CODOX-M.
• For adults older than 65:
  • During Cycles 2 and 4 (IVAC): 1,000 mg/m^2 each day for 5 days. This also combines cytarabine, mesna, and etoposide, and IVAC is alternated with CODOX-M.

Diffuse large B-cell lymphoma (using the RICE regimen):

• Dose: 5,000 mg/m^2 given over 24 hours, starting on the 4th day.
• Frequency: Every 2 weeks.
• Duration: For 3 cycles.
• Combined with: mesna, carboplatin, etoposide, and rituximab.

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

Ifosfamide dosage for treating Osteosarcoma (an off-label use):

Ifosfamide/cisplatin/doxorubicin/HDMT regimen (for adults under 40 years):

1. Dose: 3,000 mg/m^2 given as a continuous infusion each day for 5 days.
2. When: During weeks 4 and 10 (before surgery) and weeks 16, 25, and 34 (after surgery).
3. Combined with: cisplatin, doxorubicin, high-dose methotrexate, and mesna.

Ifosfamide/cisplatin/epirubicin regimen:

• Dose: 2,000 mg/m^2, given over 4 hours, for 3 days (specifically on days 2, 3, and 4).
• Frequency: Every 3 weeks for 3 cycles before surgery, and every 4 weeks for 3 cycles after surgery.
• Combined with: cisplatin, epirubicin, and mesna.

ICE regimen (for adults 22 years or younger):

• Dose: 1,800 mg/m^2 each day for 5 days.
• Frequency: Every 3 weeks.
• Duration: Up to 12 cycles.
• Combined with: carboplatin, etoposide, and mesna.

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

For treating advanced ovarian cancer (specifically those that don't respond well to platinum-based treatments):

• Dosage: 1,000 to 1,200 mg/m^2 each day for 5 days.
• Frequency: Every 28 days.
• Duration: Up to 6 cycles.

Note: Patients should also take mesna with Ifosfamide to protect the bladder.

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

Single-agent ifosfamide:

• Dose: 3,000 mg/m^2 each day for 3 days.
• Frequency: Every 3 weeks.
• Duration: For at least 2 cycles or until the cancer worsens.

EIA regimen:

• Dose: 1,500 mg/m^2 each day for 4 days.
• Frequency: Every 3 weeks.
• Duration: Until the cancer worsens or side effects become unacceptable.
• Combined with etoposide, doxorubicin, and regional hyperthermia.

MAID regimen:

• Dose Option 1: 2,000 mg/m^2 each day for 3 days (or 2,500 mg/m^2 if no prior pelvic radiation).
• Dose Option 2: 1,500 mg/m^2 each day for 3 days (if prior pelvic radiation).
• Frequency: Every 3 weeks.
• Continuous infusion for 3 days.
• Combined with mesna, doxorubicin, and dacarbazine.

Ifosfamide/epirubicin:

• Dose: 1,800 mg/m^2 each day for 5 days.
• Frequency: Every 3 weeks.
• Duration: For 5 cycles.
• Combined with mesna and epirubicin.

AIM regimens:

• Dose Option 1: 1,500 mg/m^2 each day for 4 days.
• Dose Option 2: 2,000 to 3,000 mg/m^2 each day for 3 days.
• Frequency: Every 3 weeks.
• Duration: For 4 to 6 cycles.
• Combined with mesna and doxorubicin.

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

Ifosfamide dosage for treating advanced thymomas and thymic cancers (an off-label use):

• Dosage Option 1: 1,200 mg/m^2 each day for 4 days.
  • Frequency: Every 3 weeks.
  • Duration: For 4 cycles.
  • Combined with: mesna, cisplatin, and etoposide.
  • Also, growth factor support was given on days 5 to 15, or until white blood cell count (WBC) reached a certain level.
• Dosage Option 2: 1,500 mg/m^2 each day for 5 days.
  • Frequency: Every 3 weeks.
  • Duration: For up to 9 cycles.
  • Also, mesna should be taken with Ifosfamide.

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Ifosfamide Dose in Childrens:

Note:

• When using Ifosfamide, it's important to protect the bladder from harm. So, adults and kids should take another medicine called mesna, which acts like a shield for the bladder. Besides this, drinking lots of water is crucial.
• For adults: Drink at least 2 liters of water daily, either by mouth or through an IV.
• For kids: The amount of water varies. Some places recommend double the usual amount or 3 liters for each square meter of body surface.

Note:

• Sometimes, Ifosfamide dosage is decided based on either body size or weight. It's very important to be really careful when calculating the right dose. Always double-check the numbers.
• Each treatment plan might have its own rules about how much to take, how often, and what other medicines to use with it.

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

Ifosfamide doses for treating Ewing sarcoma in kids and teenagers:

IE regimen:

• Dose: 1,800 mg/m^2 given over an hour, every day for 5 days.
• Combined with: mesna (for bladder protection) and etoposide.
• How often: Every 3 weeks.
• For how long: 12 rounds.
• Alternatively: Can be switched with another treatment called VAC every 3 weeks, making it a total of 17 rounds.

HD-IE regimen:

• Dose: 2,800 mg/m^2 given over an hour, every day for 5 days.
• Combined with: mesna and etoposide.
• How often: Every 3 weeks.
• Alternate with: VAC treatment.

ICE regimen:

• Dose: 1,800 mg/m^2 every day for 5 days.
• Combined with: carboplatin, etoposide, and mesna.
• How often: Every 3 to 4 weeks.
• For how long: Up to 12 rounds.
• Can also be followed by: 2 rounds of another treatment called CAV.

VAIA regimen (two different ways):

• First way: 3,000 mg/m^2 on specific days across 4 rounds, combined with vincristine, doxorubicin, dactinomycin, and mesna.
• Second way: 2,000 mg/m^2 every day for 3 days, every 3 weeks for 14 rounds, combined with vincristine, doxorubicin, and dactinomycin.

VIDE regimen:

• Dose: 3,000 mg/m^2 given over 1 to 3 hours, every day for 3 days.
• Combined with: vincristine, doxorubicin, etoposide, and mesna.
• How often: Every 3 weeks.
• For how long: 6 rounds.

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

Ifosfamide doses for treating recurrent or refractory Hodgkin and Non-Hodgkin lymphomas:

ICE regimen:

• Cairo 2005:
  • Children and Adolescents.
  • Dose: 1,800 mg/m^2 once daily for 5 days.
  • Frequency: Every 3 weeks.
  • Combined with etoposide, carboplatin, and mesna.
  • Duration: 6 courses.
• Moskowitz 2001:
  • Children 12 years and older, and Adolescents.
  • Dose: Continuous infusion of 5,000 mg/m^2 over 24 hours, starting on day 2.
  • Frequency: Every 2 weeks.
  • Combined with mesna, carboplatin, and etoposide.
  • Duration: 2 cycles.

IE regimen:

• Children and Adolescents:
  • Dose: 1,800 mg/m^2 once daily for 5 days.
  • Alternated with other treatments.
  • Frequency: Every 3 weeks.
  • Combined with etoposide and mesna.
  • Duration: For 4 cycles.

MIED regimen:

• Children and Adolescents:
  • Sandlund 2011:
    • Dose: 2,000 mg/m^2 over 2 hours on days 2 to 4.
    • Combined with high-dose methotrexate, etoposide, and dexamethasone (and mesna).
    • Patients with NHL also received intrathecal methotrexate, hydrocortisone, and cytarabine.
  • Griffin 2009:
    • Dose: 3,000 mg/m^2 over 2 hours on days 3 to 5.
    • Combined with rituximab and ICE (carboplatin, etoposide, and mesna).
    • Frequency: Every 23 days.
    • Duration: Up to 3 courses.

Remember, the treatments can be quite varied based on the individual, the type of lymphoma, and other factors.

Ifosfamide Dose in the treatment of Osteosarcoma:

For treating Osteosarcoma in children and teenagers:

IE regimen:

• Dose: Between 1,800 to 3,000 mg/m^2 over 4 to 5 days.
• How often and how long they get this treatment can vary, it depends on the specific plan the doctor chooses.
• This treatment is combined with etoposide (another cancer drug) and mesna (to protect the bladder).

ICE regimen:

• Dose: 1,800 mg/m^2 once daily for 5 days.
• How often: Every 3 weeks.
• For how long: Up to 12 rounds or cycles.
• This is combined with three other drugs: carboplatin, etoposide, and mesna.

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

Ifosfamide doses for treating newly diagnosed high-grade osteosarcoma with metastases in children and adolescents:

Bacci 2003:

• Dose: 3,000 mg/m^2 each day for 5 days as a continuous infusion.
• When: During weeks 4 and 10 before surgery, and weeks 16, 25, and 34 after surgery.
• Combined with: cisplatin, doxorubicin, high-dose methotrexate, and mesna.

Basaran 2007:

• Dose: 2,000 mg/m^2 over 4 hours each day for 3 days (on days 2, 3, and 4).
• Pre-Surgery: Every 3 weeks for 3 cycles.
• Post-Surgery: Every 4 weeks for 3 cycles.
• Combined with: cisplatin, epirubicin, and mesna.

Le Deley 2007:

• Dose: 3,000 mg/m^2 over 3 hours each day for 4 days.
• When: During weeks 4 and 9 (with three additional post-surgery rounds for good responders).
• Combined with: high-dose methotrexate, etoposide, and mesna.

Ifosfamide Dose in the treatment of refractory or relapsed Neuroblastoma:

Ifosfamide dose for treating refractory or relapsed neuroblastoma in children and adolescents:

HD-ICE regimen:

• Dose: 2,000 mg/m^2 over 2 hours each day for 5 days.
• When: Given as part of a treatment plan.
• Combined with: mesna (for bladder protection), carboplatin, and etoposide.
• Additional Info: Depending on how well the bone marrow is doing, peripheral blood stem cell support might be included. This part helps the bone marrow recover.
• Source: Information from Kushner 2013.

Ifosfamide Dose in the treatment of Rhabdomyosarcoma:

Interval-compressed I/E regimen (Weigel 2016):

• Infants:
  • Dose: 900 mg/m^2 daily for 5 days.
  • Combo: Given with mesna and etoposide.
  • When: During weeks 9, 13, 17, 26, and 30, which is 2 weeks after treatment with vincristine, doxorubicin, and cyclophosphamide.
  • Note: The infant dose is half of what older kids get. If infants handle the dose well, doctors might increase it step by step to the full dose.
• Children and Adolescents:
  • Dose: 1,800 mg/m^2 daily for 5 days.
  • Combo: Given with mesna and etoposide.
  • When: During weeks 9, 13, 17, and 30, 2 weeks after the other treatment mentioned above.

VAI (IRS-IV) regimen (Baker 2000):

• Infants:
  • Dose: 900 mg/m^2 daily for 5 days.
  • Combo: Given with mesna, vincristine, and dactinomycin.
  • Frequency: Every 21 days, for 8 rounds. (During radiation, dactinomycin is skipped).
  • Note: Same as above regarding dose increases.
• Children and Adolescents:
  • Dose: 1,800 mg/m^2 daily for 5 days.
  • Combo and Frequency: Same as infants.

VIE (IRS-IV; Baker 2000) regimen:

• Infants:
  • Dose: 900 mg/m^2 daily for 5 days.
  • Combo: Given with mesna, vincristine, and etoposide.
  • Frequency: Every 21 days, for 8 rounds. (During radiation, etoposide is skipped).
  • Note: Same as above regarding dose increases.
• Children and Adolescents:
  • Dose: 1,800 mg/m^2 daily for 5 days.
  • Combo and Frequency: Same as infants.

This is a general guide and may vary based on individual needs.

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

For treating non-Rhabdomyosarcoma soft tissue sarcomas in children and teenagers:

Dose:

• Amount: 3,000 mg/m^2 each day.
• Duration: For 3 days.
• How often: Every 21 days.
• Total number of treatment rounds: 4 cycles.
• Combined with: mesna (to protect the bladder) and doxorubicin (another cancer drug).

Ifosfamide Dose in the treatment of relapsed Wilms tumor:

Ifosfamide dosage for treating relapsed Wilms tumor in children and teenagers:

ICE regimen:

• Dose: 1,800 mg/m^2 each day.
• Duration: For 5 days.
• How often: Every 21 days.
• Total number of treatment rounds: At least 2 cycles, but on average, 4 cycles were given as per the study.
• Combined with: mesna (to protect the bladder), carboplatin, and etoposide (both are cancer drugs).

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Ifosfamide Pregnancy Category: D

• Ifosfamide, a medicine used in some treatments, can cause issues if taken during pregnancy, like slow baby growth and low blood levels in newborns.
• It can also affect the ability of both men and women to have children.
• The effects on having children, like causing women to miss periods or men to have no sperm, can sometimes be permanent.
• Women should avoid getting pregnant while on this medicine, and men should avoid fathering a child both during treatment and for 6 months afterward.

Use of Ifosfamide while breastfeeding

• Ifosfamide can be found in breast milk.
• It's not advised to breastfeed while taking this medication because it could cause harmful effects to the baby.
• The manufacturer suggests either stopping the medication or not breastfeeding.
• This decision should consider the benefits of the treatment for the mother.

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Ifosfamide Dose in Kidney Disease:

If someone has kidney problems, they might need a smaller dose of Ifosfamide because the drug and its byproducts, which are processed by the kidneys, can build up in the body. While the manufacturer doesn’t provide specific dosage changes, Ifosfamide can be removed from the body using dialysis.

Based on certain studies:

• Aronoff 2007:
  • If the kidneys are still working fairly well (CrCl ≥10 mL/minute): No change in dosage.
  • If the kidneys are working at a low capacity (CrCl <10 mL/minute): Use 75% of the normal dose.
  • For those on hemodialysis: No additional dose is needed.
• Kintzel 1995:
  • Kidney function at a moderate level (CrCl 46 to 60 mL/minute): Use 80% of the normal dose.
  • Kidney function a bit lower (CrCl 31 to 45 mL/minute): Use 75% of the normal dose.
  • Kidney function is quite low (CrCl <30 mL/minute): Use 70% of the normal dose.

Ifosfamide Dose in Liver disease:

The manufacturer doesn't give specific dosage changes for people with liver issues, even though Ifosfamide is processed in the liver and can become active or inactive there. Still, be cautious.

Based on a study by Floyd in 2006:

• If a substance called bilirubin is high in the blood (more than 3 mg/dL), only use 25% of the usual 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:

People should not take Ifosfamide if they:

• Are allergic to it or any of its ingredients.
• Have a blockage that stops urine from flowing out.

In Canada, there are extra reasons why someone shouldn't take Ifosfamide (these aren't listed in the US instructions):

• Very low white blood cell or platelet count.
• Serious kidney or liver problems.
• Bladder inflammation.
• An ongoing infection.
• Advanced hardening of the brain's arteries.

Warnings and precautions

Suppression of bone marrow: [US Boxed Warning]

• A strong warning is given because Ifosfamide can make the bone marrow less active, which might be serious and lead to dangerous infections.
• Doctors need to check blood counts before and after each treatment cycle.
• Ifosfamide can cause low white blood cells, low neutrophils, low platelets, and anemia.
• The bone marrow effect is linked to the dose and kidney function.
• Using high single doses and having kidney problems can make it worse.
• Using Ifosfamide with other treatments like chemotherapy or radiation can also lead to severe bone marrow problems.
• It's used carefully in people with weaker bone marrow.
• If white blood cells are very low (<2,000/mm^3) or platelets are very low (<50,000/mm^3), Ifosfamide should be avoided unless it's really needed.
• Sometimes, antibiotics or antifungal drugs are given to prevent infection in people with low white blood cells.

Cardiotoxicity

• Ifosfamide can harm the heart, and in some cases, it might be deadly.
• Some people on Ifosfamide have had heart rhythm issues, changes in ECG readings, heart muscle diseases, fluid around the heart, and heart inflammation.
• The higher the dose of Ifosfamide, the bigger the risk of heart problems.
• The risk also goes up if someone takes other heart-damaging drugs (like anthracyclines), has radiation near the heart, or has kidney issues.
• People with heart problems or risks should be careful when using Ifosfamide.
• According to the American Heart Association, Ifosfamide can directly harm the heart or make existing heart issues worse.
• The impact on the heart is considered moderate to major.

CNS toxicities: [US Boxed Warning]

• A strong warning is given because Ifosfamide can affect the brain, which could be very serious, leading to a condition called encephalopathy and even death.
• Watch out for signs of brain problems such as feeling very sleepy, confused, dizzy, seeing or hearing things that aren't there, odd behaviors, muscle twitching, seizures, and issues with vision or controlling urine.
• These symptoms can appear shortly after starting the drug and usually get better in a few days after stopping it.
• However, some symptoms might last longer.
• It's rare, but these brain issues can come back even after multiple safe uses of the drug.
• Factors that may increase the risk of these brain problems include having low protein levels in the blood, kidney problems, and taking high doses of drugs to prevent nausea.
• Drugs that act on the brain can increase these risks when taken with Ifosfamide.
• Some people also experience nerve damage.

Gastrointestinal toxicities:

• Ifosfamide can cause stomach issues, making people feel like throwing up.
• It's a good idea to take medications that prevent nausea and vomiting when on Ifosfamide.

Hemorrhagic cystitis - [US Boxed Warning]

• A strong warning is given because Ifosfamide can cause a serious bladder problem where there's bleeding inside the bladder, known as hemorrhagic cystitis.
• To reduce this risk, it's advised to take a medicine called mesna alongside Ifosfamide.
• Drinking plenty of water (at least 2 liters a day for adults), spreading out doses of Ifosfamide, and taking mesna can help prevent blood in the urine and protect the bladder.
• Before each Ifosfamide dose, a urine test should be done.
• If the test shows even tiny amounts of blood, the treatment should be paused until the issue clears up.
• Ensure there are no blockages in the urinary system before treatment, and be extra careful using Ifosfamide if there's a current urinary infection.
• The risk of this bladder issue goes up with higher doses of Ifosfamide, especially if given all at once.
• Prior treatments like radiation to the bladder or a drug called busulfan can also raise the risk.

Hepatic effects

• Ifosfamide can affect the liver.
• There's a specific liver problem called sinusoidal obstruction syndrome (SOS), which was previously known as venoocclusive disease (VOD).
• This condition has been noticed in some people taking treatments that include Ifosfamide.

Hypersensitivity reactions

• Some people can have severe allergic reactions, like anaphylaxis, when taking Ifosfamide.
• If you're allergic to medicines similar to Ifosfamide, you might also be allergic to Ifosfamide itself.

Infection

• Ifosfamide can weaken your immune system, making you more likely to get serious infections.
• This includes infections from bacteria, viruses, fungi, and parasites.
• It can even bring back old viral infections that were inactive.
• If you're taking other drugs that also weaken the immune system, or if you currently have an infection, be extra careful when using Ifosfamide.

Toxicity in the lungs:

• Ifosfamide can cause lung problems.
• Some people have experienced inflammation in the lungs, scarring, and other harmful lung effects that can make it hard to breathe and could even lead to death.
• If you notice any breathing issues or symptoms related to the lungs while on this medication.

Renal toxicities: [US Boxed Warning]

• There's a strong warning about Ifosfamide because it can seriously harm the kidneys.
• This damage can lead to kidney failure and might even cause death.
• Some people experience both short-term and long-term kidney problems after using this drug.
• The damage can happen right away or can show up much later, even years after treatment.
• Common kidney-related issues include a slower rate of filtering waste, higher creatinine levels, protein in the urine, and various other signs of kidney stress.
• The medicine can also cause a condition where the body holds onto too much water due to an imbalance in a hormone.
• Rare conditions like renal rickets and Fanconi syndrome have also been reported.
• It's essential to check kidney function before starting the medicine and to keep checking it while on treatment.
• If there's blood in the urine or other signs of kidney problems, it should be reported immediately.

Secondary malignancy

• Using Ifosfamide might increase the risk of getting another type of cancer in the future.
• This can take time to develop after the treatment is over.
• Specifically, there's a higher chance of developing a condition called myelodysplastic syndrome, which can eventually turn into a type of blood cancer called acute leukemia.

Wound healing

• Ifosfamide can slow down or affect the body's ability to heal wounds.

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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:

Blood Tests:

• CBC with Differential: Check this before each treatment cycle and whenever needed based on your health.

Kidney and Urine Tests:

• Urine Output: Monitor how much you're peeing.
• Urinalysis: Check your urine before each dose to ensure kidney health.

Liver Tests:

• Regularly check the health of your liver with tests.

Look Out For Signs of:

• Neurotoxicity: Watch for unusual nervous system symptoms.
• Pulmonary Toxicity: Monitor for lung or breathing issues.
• Hemorrhagic Cystitis: Check for blood in urine and other bladder problems.

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How to administer Ifosfamide?

Nausea and Vomiting:

• When given through an IV, Ifosfamide might make you feel nauseous.
• It's a good idea to take anti-nausea medicines to avoid feeling sick (Hesketh 2017; Roila 2016).

How to Administer:

• Give Ifosfamide through an IV, slowly, over at least 30 minutes.
• Different treatments might have different timings, so always check your specific instructions.

Protecting the Bladder:

• Ifosfamide can be tough on the bladder.
• To keep the bladder safe, always take it with another medicine called mesna and make sure you're drinking enough fluids.

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Mechanism of action of Ifosfamide:

• Ifosfamide does its job by connecting parts of your cell's genetic material called DNA together.
• This makes it hard for the cell to work properly, causing it to stop growing and eventually die.
• It also affects the cell's ability to make proteins and copy its DNA.
• All of these actions together help to stop the cancer cells from growing and spreading.

Distribution:

• Ifosfamide spreads throughout the body, resembling the water in your body.
• It can enter the brain, but not in amounts needed for treatment.

Protein Binding:

• Ifosfamide doesn't stick much to proteins in the blood.

Metabolism:

• The liver changes ifosfamide into active and inactive forms.
• Active forms include isofosforamide mustard and 4-hydroxy-ifosfamide.
• Acrolein is another active form; it's linked to causing bladder issues like hemorrhagic cystitis.
• Inactive forms include dichloroethylated and carboxy metabolites.

Half-life Elimination (Time in the Body):

• For high doses (3,800 to 5,000 mg/m²), ifosfamide takes around 15 hours to leave the body.
• For lower doses (1,600 to 2,400 mg/m²), it takes around 7 hours.

Excretion (Leaving the Body):

• For high doses (5,000 mg/m²), about 70% to 86% of ifosfamide exits through urine (with 61% as the unchanged drug).
• For lower doses (1,600 to 2,400 mg/m²), about 12% to 18% is unchanged and leaves through urine.

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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.