Usage
Ifosfamide is an alkylating antineoplastic agent primarily indicated, in combination with other approved antineoplastic agents, for third-line treatment of germ cell testicular cancer. It is also used, though not always FDA-approved, for the treatment of soft tissue sarcomas, pancreatic carcinoma, and advanced or recurrent cervical carcinoma. It’s classified as an alkylating agent.
Ifosfamide works by interfering with DNA replication and RNA transcription, ultimately leading to cell death. It requires hepatic activation to its active metabolites.
Alternate Names
Ifosfamide is also known as Ifosphamidum (Latin). Brand names for ifosfamide include Ifex and Mitoxana.
How It Works
Pharmacodynamics: Ifosfamide’s cytotoxic effects are primarily due to its alkylating properties. It crosslinks DNA strands, preventing DNA replication and RNA transcription, which induces cell death. This process impacts rapidly dividing cells, such as cancer cells, more significantly than normal cells.
Pharmacokinetics:
- Absorption: Administered intravenously, thus achieving 100% bioavailability.
- Metabolism: Requires hepatic bioactivation to its active metabolites, isophosphoramide mustard and acrolein.
- Elimination: Primarily renal excretion. The elimination half-life ranges from 4 to 7 hours in adults, and it exhibits time-dependent pharmacokinetics. Clearance increases with repeated dosing, while the volume of distribution increases with age and obesity. Dose adjustments may be necessary in patients with renal or hepatic dysfunction.
Mode of Action: Ifosfamide’s alkylating metabolites bind to DNA, forming crosslinks that disrupt DNA replication and RNA transcription.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Ifosfamide does not directly interact with receptors or neurotransmitters. Its primary effect is mediated through DNA alkylation and disruption of nucleic acid function. Hepatic enzymes are essential for its activation to cytotoxic metabolites.
Elimination Pathways: Ifosfamide and its metabolites are primarily excreted renally.
Dosage
Standard Dosage
Adults:
The standard dose is 1.2 g/m² per day, administered as a slow intravenous infusion (over at least 30 minutes) for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity (platelets ≥ 100,000/μL, WBC ≥ 4,000/μL).
Children:
Safety and efficacy in children haven’t been fully established in registration trials. Dosing in children is based on protocols and typically ranges between 0.8 to 3 g/m²/day for 2-5 days, resulting in a total dose of 4-12 g/m² per course. Uroprotection with mesna is mandatory.
Special Cases:
- Elderly Patients: Dose selection should be cautious, considering potential age-related decline in hepatic, renal, or cardiac function.
- Patients with Renal Impairment: Dosage adjustments are necessary based on creatinine clearance.
- Patients with Hepatic Dysfunction: Dose reduction may be required based on liver function tests.
- Patients with Comorbid Conditions: Dose adjustments may be needed based on the specific comorbidity.
Clinical Use Cases
Ifosfamide dosing remains consistent across the listed clinical settings (intubation, surgical procedures, mechanical ventilation, ICU use, emergency situations) and follows the standard adult dosage guidelines mentioned above. Adjustments should be made for renal and hepatic function, as well as other comorbid conditions.
Dosage Adjustments
Dose adjustments are required based on renal function, hepatic function, and hematological toxicity. Consult specific guidelines for detailed dosage adjustment recommendations based on creatinine clearance and liver function tests.
Side Effects
Common Side Effects:
Nausea, vomiting, diarrhea, loss of appetite, temporary hair loss (alopecia), bladder irritation, fatigue, and injection site reactions (redness, pain, swelling).
Rare but Serious Side Effects:
Hemorrhagic cystitis, myelosuppression (neutropenia, thrombocytopenia), neurotoxicity (encephalopathy, seizures, peripheral neuropathy), nephrotoxicity, cardiotoxicity, secondary malignancies.
Long-Term Effects:
Infertility, secondary malignancies (leukemia, lymphoma), renal insufficiency.
Adverse Drug Reactions (ADR):
Severe myelosuppression, hemorrhagic cystitis, encephalopathy, anaphylaxis, nephrotoxicity.
Contraindications
- Absolute: Known hypersensitivity to ifosfamide, urinary tract outflow obstruction.
- Relative: Severe myelosuppression, severe renal impairment, severe hepatic impairment.
Drug Interactions
Ifosfamide interacts with numerous medications, including:
- Live vaccines: Concurrent use is contraindicated due to immunosuppression.
- CYP450 substrates: Interactions may occur, requiring dosage adjustments.
- Nephrotoxic agents: Increased risk of nephrotoxicity.
- Myelosuppressive agents: Increased risk of myelosuppression.
- Anticoagulants: Increased risk of bleeding.
Consult a comprehensive drug interaction database for detailed information.
Pregnancy and Breastfeeding
Pregnancy Safety Category: D. Ifosfamide is contraindicated during pregnancy due to its teratogenic potential.
Breastfeeding: Ifosfamide is excreted in breast milk. Breastfeeding is contraindicated during treatment and for 1 week after the last dose.
Drug Profile Summary
- Mechanism of Action: Alkylating agent, crosslinks DNA, inhibits DNA replication and RNA transcription.
- Side Effects: Myelosuppression, hemorrhagic cystitis, neurotoxicity, nausea, vomiting, alopecia.
- Contraindications: Hypersensitivity, urinary outflow obstruction, severe myelosuppression, severe renal/hepatic impairment.
- Drug Interactions: Live vaccines, nephrotoxic agents, myelosuppressive agents, anticoagulants.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 1.2 g/m² IV daily for 5 days, repeated every 3 weeks.
- Monitoring Parameters: CBC, renal function tests, liver function tests, urinalysis.
Popular Combinations
Ifosfamide is often combined with other antineoplastic agents, like cisplatin and etoposide, for testicular cancer treatment. Mesna is co-administered to prevent hemorrhagic cystitis.
Precautions
- General Precautions: Monitor for myelosuppression, hemorrhagic cystitis, and neurotoxicity. Ensure adequate hydration and administer mesna for uroprotection.
- Specific Populations: See “Dosage - Special Cases” and “Pregnancy and Breastfeeding.”
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ifosfamide?
A: The recommended dosage is 1.2 g/m² IV daily for 5 days, repeating every 3 weeks. Dosage adjustments are based on renal and hepatic function and hematologic toxicity. Pediatric dosing varies by protocol.
Q2: What are the most common side effects of Ifosfamide?
A: Common side effects include nausea, vomiting, alopecia, myelosuppression, and hemorrhagic cystitis.
Q3: How is hemorrhagic cystitis managed in patients receiving Ifosfamide?
A: Hemorrhagic cystitis is managed with aggressive hydration and co-administration of mesna.
Q4: Is Ifosfamide safe to use during pregnancy or breastfeeding?
A: No, Ifosfamide is contraindicated during pregnancy and breastfeeding.
Q5: What are the major drug interactions with Ifosfamide?
A: Major drug interactions include live attenuated vaccines, nephrotoxic drugs, and myelosuppressive agents.
A: Ifosfamide requires hepatic activation to its active metabolites.
Q7: What monitoring parameters are important for patients on Ifosfamide?
A: Important monitoring parameters include complete blood counts (CBC), renal function tests, liver function tests, and urinalysis.
Q8: How is Ifosfamide administered?
A: Ifosfamide is administered intravenously as a slow infusion over at least 30 minutes.
Q9: What is the mechanism of action of Ifosfamide?
A: Ifosfamide is an alkylating agent. Its active metabolites crosslink DNA, preventing DNA replication and transcription, leading to cell death.
Q10: What are the signs of ifosfamide neurotoxicity?
A: Signs include encephalopathy, seizures, peripheral neuropathy, and other central nervous system effects. If these occur, the drug should be discontinued.
