Usage
Ifosfamide, in combination with Mesna, is prescribed for the treatment of various cancers, including:
- Germ cell testicular cancer (third-line treatment in combination with other antineoplastic agents)
- Soft tissue sarcomas
- Advanced or recurrent cervical cancer
- Relapsed or refractory pancreatic cancer
Ifosfamide is classified as an alkylating antineoplastic agent. Mesna is a chemoprotectant specifically used to prevent ifosfamide-induced hemorrhagic cystitis.
Ifosfamide’s mechanism of action involves its activation in the liver to metabolites that alkylate DNA, leading to DNA cross-linking and hindering DNA replication and transcription, ultimately resulting in cell death. Mesna binds to and detoxifies acrolein, a toxic metabolite of ifosfamide responsible for hemorrhagic cystitis.
Alternate Names
Ifosfamide is also known as ifosfamidum. Mesna is also known as sodium 2-mercaptoethane sulfonate.
Brand names for Ifosfamide include Ifex®. Brand names for Mesna include Mesnex®. Ifosfamide is often administered with Mesna, but there are no brand names for the combination product.
How It Works
Pharmacodynamics (Ifosfamide): Ifosfamide itself is inactive and requires hepatic activation to form alkylating metabolites that disrupt DNA function, leading to cell death.
Pharmacokinetics (Ifosfamide):
- Absorption: Administered intravenously.
- Metabolism: Hepatically activated.
- Elimination: Renally excreted.
Pharmacodynamics (Mesna): Mesna binds to and inactivates acrolein in the urinary bladder, thereby preventing hemorrhagic cystitis.
Pharmacokinetics (Mesna):
- Absorption: Administered intravenously or orally.
- Metabolism: Hepatically metabolized to dimesna.
- Elimination: Primarily renal excretion.
Mode of Action (Ifosfamide): Ifosfamide metabolites cause DNA cross-linking, primarily at the N7 position of guanine. This inhibits DNA replication and transcription, inducing apoptosis and cell death.
Elimination Pathways (Ifosfamide): Ifosfamide is predominantly eliminated via renal excretion.
Elimination Pathways (Mesna): Mesna is primarily renally excreted, both as the parent compound and its disulfide metabolite, dimesna.
Dosage
Standard Dosage
Adults:
Ifosfamide: 1.2 g/m² IV daily for 5 consecutive days, repeated every 3 weeks or after hematologic recovery. Other regimens use higher doses over fewer days.
Mesna: Dosage is dependent on ifosfamide dose. Commonly, Mesna is administered at a dose equivalent to 20% of the ifosfamide dose IV bolus at time of ifosfamide administration, followed by oral Mesna at a dose equivalent to 40% of the ifosfamide dose at 2 and 6 hours following ifosfamide administration.
The patient should be well hydrated and maintain a fluid balance.
Administration of Ifosfamide must be done by slow IV infusion over at least 30 minutes.
Children:
Dosing should be based on body surface area (BSA) and adjusted according to specific protocols.
Special Cases:
- Elderly Patients: Dose adjustments are based on renal function and overall health status.
- Patients with Renal Impairment: Dose reduction is necessary.
- Patients with Hepatic Dysfunction: Close monitoring for toxicity is necessary.
- Patients with Comorbid Conditions: Individualized dosing adjustments based on the specific comorbid conditions.
Clinical Use Cases
Dosing is generally consistent across different clinical settings and is determined by the underlying malignancy, patient-specific factors, and concurrent therapies. Refer to specific protocols and guidelines for detailed instructions.
Dosage Adjustments
Dose modifications are necessary based on hematologic toxicity, renal function, hepatic function, and other patient-specific factors.
Side Effects
Common Side Effects
- Alopecia
- Nausea and vomiting
- Leukopenia
- Anemia
- Hemorrhagic cystitis (reduced with Mesna)
- Central nervous system toxicity (e.g., confusion, somnolence, hallucinations)
Rare but Serious Side Effects
- Myelosuppression (neutropenia, thrombocytopenia)
- Nephrotoxicity
- Cardiotoxicity (arrhythmias, cardiomyopathy)
- Pulmonary toxicity
- Secondary malignancies
- Anaphylactic reactions
Long-Term Effects
- Infertility
- Increased risk of secondary malignancies
Adverse Drug Reactions (ADR)
- Severe encephalopathy
- Severe hemorrhagic cystitis
- Renal failure
- Cardiac arrest
Contraindications
- Hypersensitivity to Ifosfamide or Mesna
- Urinary outflow obstruction
- Severe bone marrow suppression
- Severe renal or hepatic impairment
- Pregnancy and lactation
Drug Interactions
- CYP450 interactions: Ifosfamide is metabolized by CYP3A4. Concomitant use with CYP3A4 inducers or inhibitors may alter ifosfamide metabolism.
- Other drug interactions include those with anticoagulants, immunosuppressants, and other antineoplastic agents.
- Alcohol should be avoided during Ifosfamide therapy.
Pregnancy and Breastfeeding
Ifosfamide is contraindicated during pregnancy and breastfeeding. Mesna is not recommended in these situations.
Drug Profile Summary
- Mechanism of Action: DNA alkylation leading to cell death (Ifosfamide); Inactivation of acrolein, preventing hemorrhagic cystitis (Mesna).
- Side Effects: Myelosuppression, nephrotoxicity, neurotoxicity, hemorrhagic cystitis (reduced with Mesna), alopecia, nausea, and vomiting.
- Contraindications: Hypersensitivity, urinary outflow obstruction, severe bone marrow dysfunction, severe renal or hepatic impairment, pregnancy, breastfeeding.
- Drug Interactions: CYP3A4 inducers/inhibitors, anticoagulants, immunosuppressants, other antineoplastic agents.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Ifosfamide: 1.2 g/m²/day x 5 days; Mesna: dose is dependent on the ifosfamide dose.
- Monitoring Parameters: Complete blood counts, renal and hepatic function, urinalysis.
Popular Combinations
Ifosfamide is frequently used in combination with other chemotherapeutic agents like etoposide and cisplatin (VIP regimen) or vinblastine and cisplatin (VeIP regimen) for treating testicular cancer.
Precautions
- Monitor for myelosuppression, neurotoxicity, nephrotoxicity, and cardiotoxicity.
- Administer with adequate hydration and Mesna to minimize urotoxicity.
- Avoid alcohol.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ifosfamide + Mesna?
A: Ifosfamide is commonly given at 1.2 g/m²/day x 5 days. Mesna is usually given as 20% of the ifosfamide dose IV bolus followed by 40% of the ifosfamide dose orally at 2 and 6 hours after each ifosfamide dose. Other dose regimens are possible.
Q2: What are the major side effects of Ifosfamide?
A: Myelosuppression, nephrotoxicity, neurotoxicity (including encephalopathy), hemorrhagic cystitis (reduced by Mesna use), alopecia, nausea, and vomiting.
Q3: How does Mesna prevent hemorrhagic cystitis?
A: Mesna binds to and inactivates acrolein, a urotoxic metabolite of ifosfamide, in the urine.
Q4: Are there any contraindications to Ifosfamide + Mesna?
A: Yes. Contraindications include hypersensitivity to either drug, urinary outflow obstruction, severe myelosuppression, severe renal or hepatic impairment, pregnancy, and breastfeeding.
Q5: What are the key monitoring parameters during Ifosfamide + Mesna therapy?
A: Complete blood counts, renal function tests, hepatic function tests, and urinalysis. Patients should also be closely monitored for neurologic signs and symptoms.
Q6: Can Ifosfamide be given to patients with renal impairment?
A: Yes, but dosage adjustments are necessary. Careful monitoring for toxicity is essential.
Q7: What is the role of hydration in Ifosfamide administration?
A: Extensive hydration helps dilute the concentration of urotoxic metabolites in the urine and minimize the risk of hemorrhagic cystitis.
A: Encephalopathy is a rare but serious side effect and may be fatal. Dose limiting side effects include myelosuppression and nephrotoxicity. Hemorrhagic cystitis is a significant concern, though it can be effectively mitigated with Mesna.
A: Ifosfamide is metabolized in the liver by hepatic microsomal enzymes, including CYP3A4.
Q10: How should Ifosfamide be administered?
A: Ifosfamide should be administered as a slow intravenous infusion over at least 30 minutes. It should not be given as an IV bolus or push.
