IFOSFAMIDE

Clinical safety rating: avoid

Contraindicated (not allowed)

How it works

Prodrug activated by cytochrome P450 to cytotoxic metabolites (4-hydroxyifosfamide, acrolein, and ifosforamide mustard) that alkylate DNA by cross-linking guanine bases, inhibiting DNA replication and transcription.

What the body does with it

Metabolism	Hepatic metabolism via CYP3A4 and CYP2B6 to active metabolite 4-hydroxyifosfamide, which tautomerizes to aldofosfamide and decomposes to ifosforamide mustard (active) and acrolein (urotoxic). Also metabolized by alcohol dehydrogenase to chloroacetaldehyde (nephrotoxic and neurotoxic).
Excretion	Primarily renal: 50-60% excreted unchanged in urine. Biliary/fecal excretion is minimal (<5%).
Half-life	Terminal half-life: 4-7 hours for parent drug; active metabolite 4-desulfonate has half-life ~12-15 hours. Clinical context: Prolonged with renal impairment.
Protein binding	<20% bound primarily to albumin.
Volume of Distribution	Vd: 20-30 L/kg, indicating extensive tissue distribution.
Bioavailability	IV: 100% (only route of administration; oral bioavailability is negligible due to first-pass metabolism).
Onset of Action	IV: Rapid, within 30-60 minutes after infusion start.
Duration of Action	Therapeutic effect duration: 2-4 days. Dosing typically repeated every 3-4 weeks to allow recovery from myelosuppression.

Classification & Brands

Dosing & administration

1.2 g/m² IV over 2 hours daily for 5 consecutive days every 3 weeks, or 5 g/m² IV as a 24-hour continuous infusion every 3 weeks. Administer with mesna and vigorous hydration.

Dosage form	INJECTABLE
Renal impairment	For CrCl 30-60 mL/min: reduce dose by 50%. For CrCl <30 mL/min: consider alternative therapy or reduce dose by 75% with close monitoring.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: not recommended or reduce dose by 75% if benefits outweigh risks.
Pediatric use	1.2-1.8 g/m² IV daily for 5 consecutive days every 3-4 weeks, or 3-5 g/m² IV as a 24-hour continuous infusion every 3-4 weeks. Adjust based on renal function; use with mesna.
Geriatric use	No specific dose adjustment; use with caution due to increased risk of nephrotoxicity and myelosuppression. Monitor renal function and reduce dose if CrCl <60 mL/min.

Use during pregnancy

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

Clinical note

Other bone marrow suppressants may have additive effects Can cause hemorrhagic cystitis (requires Mesna) and neurotoxicity.

Breastfeeding	Present in breast milk; M/P ratio not reported. Discontinue breastfeeding or discontinue drug due to potential for serious adverse reactions in nursing infants.
Teratogenic Risk	First trimester: High risk of congenital malformations including craniofacial defects, skeletal abnormalities, and CNS anomalies. Second/third trimester: Risk of fetal growth restriction, oligohydramnios, and myelosuppression. Use only if clearly needed and no safer alternatives.

Warnings & precautions

■ FDA Black Box Warning

Hemorrhagic cystitis (requires mesna prophylaxis), myelosuppression (dose-limiting), CNS toxicity (encephalopathy), and nephrotoxicity (Fanconi syndrome, renal tubular acidosis).

Side Effect Profile

Common Effects	Myelosuppression
Serious Effects

Absolute Contraindications

Hypersensitivity to ifosfamide, severe bone marrow suppression, acute infection (viral, bacterial, fungal), and concomitant live vaccines (due to immunosuppression).

Clinical Precautions

Precautions

Myelosuppression (monitor CBC), hemorrhagic cystitis (use mesna, hydrate), CNS toxicity (confusion, coma; discontinue if severe), nephrotoxicity (monitor renal function), hepatotoxicity, urate nephropathy (tumor lysis), secondary malignancies (acute myeloid leukemia), impaired fertility, and increased toxicity with renal/hepatic impairment.

Clinical Tips & Counseling

Drug interactions

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