IFOSFAMIDE
Clinical safety rating: avoid
Contraindicated (not allowed)
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.
| 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. |
| Molecular Weight | 261.09 |
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. |
| 1st trimester | Contraindicated: high teratogenicity; associated with major malformations and fetal loss. |
| 2nd trimester | Contraindicated: fetal toxicity including growth retardation and CNS abnormalities. |
| 3rd trimester | Contraindicated: risk of neonatal myelosuppression and immunosuppression. |
Clinical note
Other bone marrow suppressants may have additive effects Can cause hemorrhagic cystitis (requires Mesna) and neurotoxicity.
| Placental transfer | Extensive; crosses placenta rapidly and achieves fetal concentrations comparable to maternal levels. |
| Breastfeeding | Excreted into breast milk; potential for severe adverse effects including myelosuppression in the infant. Breastfeeding is not recommended during therapy and for at least 1 week after last dose. |
■ FDA Black Box Warning
Hemorrhagic cystitis (requires mesna prophylaxis), myelosuppression (dose-limiting), CNS toxicity (encephalopathy), and nephrotoxicity (Fanconi syndrome, renal tubular acidosis).
| Common Effects | Myelosuppression |
| Serious Effects |
Hypersensitivity to ifosfamide or other alkylating agentsSevere bone marrow suppressionSevere renal impairment (CrCl <30 mL/min)Active infectionPregnancy
| 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. |
| Food/Dietary |
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| Lactation Rating |
| L5 (Contraindicated) |
| 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. |
| Fetal Monitoring | Monitor complete blood count, renal function, liver enzymes, urinalysis for hemorrhagic cystitis, and fetal ultrasound for growth and amniotic fluid volume. Consider fetal echocardiography. |
| Fertility Effects | May cause ovarian failure, premature menopause, and azoospermia or oligospermia in males due to gonadal toxicity. Fertility preservation counseling recommended. |
| Avoid grapefruit and grapefruit juice during treatment as they inhibit CYP3A4 and may increase ifosfamide toxicity. St. John's Wort should be avoided as it can reduce ifosfamide effectiveness. No specific dietary restrictions other than maintaining adequate hydration. Avoid alcohol as it may exacerbate hepatotoxicity or central nervous system depression. |
| Clinical Pearls | Ifosfamide is a prodrug requiring hepatic activation via CYP3A4. Always co-administer with mesna for uroprotection to prevent hemorrhagic cystitis. Ensure adequate hydration (≥2 L/m²/day) and monitor urine output. Concurrent use of aprepitant or other CYP3A4 inducers may reduce efficacy; strong CYP3A4 inhibitors increase toxicity. Neurotoxicity (encephalopathy) is dose-dependent and may be reversed with methylene blue. Monitor renal function and electrolytes; ifosfamide can cause Fanconi syndrome (renal tubular acidosis, hypophosphatemia, glycosuria). Use with caution in patients with prior cisplatin nephrotoxicity. Administer antiemetics aggressively (NK1 receptor antagonist + 5-HT3 antagonist ± dexamethasone). Accumulation of chloroacetaldehyde metabolite causes nephro- and neurotoxicity. |
| Patient Advice | This medication is a chemotherapy drug called ifosfamide; it works by slowing or stopping the growth of cancer cells. · You will receive another medication called mesna before and after ifosfamide to protect your bladder from irritation and bleeding. · Drink plenty of fluids (at least 8-10 glasses per day) to flush your kidneys and bladder, unless told otherwise by your doctor. · Call your doctor immediately if you see blood in your urine, have burning or pain during urination, or cannot urinate. · Report any confusion, drowsiness, hallucinations, or unusual behavior to your healthcare team right away; these may be signs of a serious side effect affecting the brain. · You may experience nausea, vomiting, hair loss, or loss of appetite; medications are available to help manage these symptoms. · This drug can lower your ability to fight infections; avoid contact with people who are sick and wash hands frequently. · Do not take any other medications, including over-the-counter drugs, herbs, or supplements, without consulting your doctor. · If you miss a dose, call your healthcare provider for instructions; do not double up on doses. · Women should not become pregnant and men should not father a child while on this treatment; use effective contraception during and for at least 6 months after therapy. |