IFEX/MESNEX KIT

Clinical safety rating: caution

Comprehensive clinical and safety monograph for IFEX/MESNEX KIT (IFEX/MESNEX KIT).

How it works

Ifosfamide is an alkylating agent that requires metabolic activation by cytochrome P450 (CYP3A4) to active metabolites (e.g., ifosfamide mustard) that crosslink DNA, leading to cell cycle arrest and apoptosis. Mesna is a thiol compound that binds to and detoxifies urotoxic ifosfamide metabolites (e.g., acrolein) in the urinary tract, preventing hemorrhagic cystitis.

What the body does with it

Metabolism	Ifosfamide is extensively metabolized by hepatic CYP3A4 to active metabolites (ifosfamide mustard, 4-hydroxyifosfamide) and inactive metabolites (e.g., 2- and 3-dechloroethylifosfamide). Mesna is oxidized in the blood to dimesna and then reduced back to mesna in the kidneys.
Excretion	Ifosfamide: Renal excretion of unchanged drug (12-18%) and metabolites (primarily 4-hydroxyifosfamide, ifosforamide mustard, and chloroacetaldehyde). Biliary/fecal elimination is minimal (<2%). Mesna: Renal excretion as mesna and its disulfide dimer (dimesna), with >80% recovered in urine within 24 hours.
Half-life	Ifosfamide: Terminal elimination half-life of 4-7 hours at standard doses (1.2-2 g/m²), increasing to 10-15 hours at high doses (5 g/m²) due to saturable metabolism; clinically significant for dosing intervals and toxicity monitoring. Mesna: Terminal half-life of approximately 0.36 hours (22 minutes) for mesna and 1.17 hours for dimesna.
Protein binding	Ifosfamide: Minimal protein binding (<20%) and not concentration-dependent. Mesna: Approximately 69-75% bound to plasma proteins, primarily to albumin via disulfide bonds.
Volume of Distribution	Ifosfamide: Mean Vd of 0.6-0.8 L/kg, indicating extensive tissue distribution; crosses blood-brain barrier with CSF levels 20-60% of plasma. Mesna: Vd of 0.65 L/kg, limited to extracellular fluid; does not penetrate cells due to hydrophilic nature.
Bioavailability	Ifosfamide: Oral bioavailability is close to 100%, but intravenous administration is standard due to gastrointestinal toxicity; oral use is rare. Mesna: Oral bioavailability is 40-50% due to first-pass metabolism; oral mesna is available but typically used intravenously for this indication.
Onset of Action	Intravenous ifosfamide: Clinical antineoplastic effect is delayed, but distribution and metabolism begin immediately; peak plasma concentrations achieved at end of infusion. Intravenous mesna: Onset of uroprotective effect is immediate, as it binds acrolein in the urine.
Duration of Action	Ifosfamide: Antineoplastic effect persists for days, but dosing is typically given over 3-5 days per cycle; prolonged exposure increases cumulative toxicity. Mesna: Uroprotective effect lasts 8-12 hours; repeated doses are required (e.g., 0, 4, 8 hours post-ifosfamide) to maintain protection.

Classification & Brands

Dosing & administration

IFEX (ifosfamide) 1.2 g/m2 intravenously daily for 5 consecutive days every 3 weeks, with MESNEX (mesna) given as 20% of the ifosfamide dose intravenously at the time of ifosfamide administration and 4 and 8 hours after each ifosfamide dose (total daily mesna dose = 60% of ifosfamide dose).

Dosage form	INJECTABLE
Renal impairment	CrCl > 60 mL/min: no adjustment; CrCl 30-60 mL/min: reduce ifosfamide dose by 25%; CrCl 10-29 mL/min: reduce ifosfamide dose by 50%; CrCl < 10 mL/min: use is not recommended.
Liver impairment	No specific dose adjustments provided for Child-Pugh classification in prescribing information; caution advised in severe hepatic impairment.
Pediatric use	For children, IFEX dose is 1.2-1.8 g/m2/day intravenously for 5 days every 3-4 weeks, with mesna dosing as per adult ratio (60% of ifosfamide daily dose divided into 3 doses).
Geriatric use	No specific dose adjustments; use with caution due to increased risk of renal and neurological toxicity; consider renal function for dose adjustment.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for IFEX/MESNEX KIT (IFEX/MESNEX KIT).

Breastfeeding	Contraindicated: Ifosfamide and mesna are excreted into breast milk. M/P ratio not established. Risk of severe neonatal immunosuppression, growth retardation. Do not breastfeed during therapy and for at least 1 week after last dose.
Teratogenic Risk	First trimester: Contraindicated due to major teratogenic effects (craniofacial, skeletal, visceral anomalies) and fetal loss. Second/third trimesters: Risk of fetal growth restriction, neurodevelopmental impairment, and neonatal myelosuppression. No effective chemotherapeutic alternative; if unavoidable, use only with maternal life-threatening condition.

Warnings & precautions

■ FDA Black Box Warning

Ifosfamide can cause severe myelosuppression (leukopenia, thrombocytopenia, anemia) and dose-dependent hemorrhagic cystitis. Mesna is indicated to reduce the incidence of hemorrhagic cystitis. Ifosfamide is also associated with neurotoxicity (e.g., encephalopathy, confusion, coma) and nephrotoxicity (e.g., renal tubular acidosis, acute renal failure).

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to ifosfamide, mesna, or any component; severe bone marrow suppression (e.g., leukopenia, thrombocytopenia); severe renal impairment (creatinine clearance <30 mL/min); acute urinary tract obstruction; pregnancy (can cause fetal harm); breastfeeding (discontinue nursing during treatment).

Clinical Precautions

Precautions

Myelosuppression (monitor blood counts), hemorrhagic cystitis (use mesna, adequate hydration, monitor urinalysis), neurotoxicity (discontinue if severe), nephrotoxicity (monitor renal function, avoid in pre-existing renal impairment), urotoxicity (ensure mesna administration), embryofetal toxicity (can cause fetal harm), and vaccination risks (avoid live vaccines during treatment).

Clinical Tips & Counseling

Drug interactions

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IFEX/MESNEX KIT

Clinical safety rating: caution

Comprehensive clinical and safety monograph for IFEX/MESNEX KIT (IFEX/MESNEX KIT).

How it works

What the body does with it

Metabolism	Ifosfamide is extensively metabolized by hepatic CYP3A4 to active metabolites (ifosfamide mustard, 4-hydroxyifosfamide) and inactive metabolites (e.g., 2- and 3-dechloroethylifosfamide). Mesna is oxidized in the blood to dimesna and then reduced back to mesna in the kidneys.
Excretion	Ifosfamide: Renal excretion of unchanged drug (12-18%) and metabolites (primarily 4-hydroxyifosfamide, ifosforamide mustard, and chloroacetaldehyde). Biliary/fecal elimination is minimal (<2%). Mesna: Renal excretion as mesna and its disulfide dimer (dimesna), with >80% recovered in urine within 24 hours.
Half-life	Ifosfamide: Terminal elimination half-life of 4-7 hours at standard doses (1.2-2 g/m²), increasing to 10-15 hours at high doses (5 g/m²) due to saturable metabolism; clinically significant for dosing intervals and toxicity monitoring. Mesna: Terminal half-life of approximately 0.36 hours (22 minutes) for mesna and 1.17 hours for dimesna.
Protein binding	Ifosfamide: Minimal protein binding (<20%) and not concentration-dependent. Mesna: Approximately 69-75% bound to plasma proteins, primarily to albumin via disulfide bonds.
Volume of Distribution	Ifosfamide: Mean Vd of 0.6-0.8 L/kg, indicating extensive tissue distribution; crosses blood-brain barrier with CSF levels 20-60% of plasma. Mesna: Vd of 0.65 L/kg, limited to extracellular fluid; does not penetrate cells due to hydrophilic nature.
Bioavailability	Ifosfamide: Oral bioavailability is close to 100%, but intravenous administration is standard due to gastrointestinal toxicity; oral use is rare. Mesna: Oral bioavailability is 40-50% due to first-pass metabolism; oral mesna is available but typically used intravenously for this indication.
Onset of Action	Intravenous ifosfamide: Clinical antineoplastic effect is delayed, but distribution and metabolism begin immediately; peak plasma concentrations achieved at end of infusion. Intravenous mesna: Onset of uroprotective effect is immediate, as it binds acrolein in the urine.
Duration of Action	Ifosfamide: Antineoplastic effect persists for days, but dosing is typically given over 3-5 days per cycle; prolonged exposure increases cumulative toxicity. Mesna: Uroprotective effect lasts 8-12 hours; repeated doses are required (e.g., 0, 4, 8 hours post-ifosfamide) to maintain protection.

Classification & Brands

Dosing & administration

Dosage form	INJECTABLE
Renal impairment	CrCl > 60 mL/min: no adjustment; CrCl 30-60 mL/min: reduce ifosfamide dose by 25%; CrCl 10-29 mL/min: reduce ifosfamide dose by 50%; CrCl < 10 mL/min: use is not recommended.
Liver impairment	No specific dose adjustments provided for Child-Pugh classification in prescribing information; caution advised in severe hepatic impairment.
Pediatric use	For children, IFEX dose is 1.2-1.8 g/m2/day intravenously for 5 days every 3-4 weeks, with mesna dosing as per adult ratio (60% of ifosfamide daily dose divided into 3 doses).
Geriatric use	No specific dose adjustments; use with caution due to increased risk of renal and neurological toxicity; consider renal function for dose adjustment.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for IFEX/MESNEX KIT (IFEX/MESNEX KIT).

Breastfeeding	Contraindicated: Ifosfamide and mesna are excreted into breast milk. M/P ratio not established. Risk of severe neonatal immunosuppression, growth retardation. Do not breastfeed during therapy and for at least 1 week after last dose.
Teratogenic Risk	First trimester: Contraindicated due to major teratogenic effects (craniofacial, skeletal, visceral anomalies) and fetal loss. Second/third trimesters: Risk of fetal growth restriction, neurodevelopmental impairment, and neonatal myelosuppression. No effective chemotherapeutic alternative; if unavoidable, use only with maternal life-threatening condition.