IFOSFAMIDE/MESNA KIT
Clinical safety rating: safe
No significant drug interactions Used to prevent hemorrhagic cystitis caused by ifosfamide.
Ifosfamide is an alkylating agent that requires metabolic activation by hepatic cytochrome P450 enzymes to form active metabolites (e.g., ifosforamide mustard). These metabolites cross-link DNA, inhibiting DNA synthesis and transcription, leading to cell death. Mesna is a thiol compound that binds to and detoxifies acrolein, a urotoxic metabolite of ifosfamide, preventing hemorrhagic cystitis.
| Metabolism | Hepatic via CYP3A4 and CYP2B6 to active metabolites (4-hydroxyifosfamide, ifosforamide mustard) and inactive metabolites (chloroacetaldehyde, acrolein). Autoinduction of CYP3A4 with repeated dosing. |
| Excretion | Ifosfamide: ~50-60% excreted unchanged in urine; metabolites (e.g., 4-hydroxyifosfamide, ifosforamide mustard) also renally eliminated. Mesna: ~30% excreted unchanged in urine; remainder as dimesna (reduced form) via renal and biliary routes. |
| Half-life | Ifosfamide: Terminal half-life 7-15 hours (biphasic: distribution ~3-4 hours, elimination ~7-15 hours). Higher doses and autoinduction shorten half-life over multiple cycles. Mesna: Terminal half-life 0.5-1.5 hours for reduced form; dimesna half-life ~2-4 hours. |
| Protein binding | Ifosfamide: Minimal (≈20%) binding to plasma proteins (primarily albumin). Mesna: Approximately 90% bound to albumin (reduced form); dimesna unbound. |
| Volume of Distribution | Ifosfamide: Approximately 0.5-0.7 L/kg (widely distributed including CNS; crosses blood-brain barrier). Mesna: Total Vd 0.9-1.4 L/kg (largely extracellular; does not enter cells significantly). |
| Bioavailability | Ifosfamide: Oral bioavailability ~90-100% (not used orally due to GI toxicity; IV only in clinical practice). Mesna: Oral bioavailability ~50-70% (used IV or oral as part of regimen; oral doses are higher to compensate). IV administration yields 100% bioavailability for both agents. |
| Onset of Action | Ifosfamide: IV administration – cytotoxic effect begins within 1-2 hours (requires hepatic activation). Mesna: IV – uroprotective effect occurs within 1 hour (must be given concurrently and continue after ifosfamide). |
| Duration of Action | Ifosfamide: Duration of antineoplastic activity extends several days; clinical dosing is typically fractionated over 3-5 days to allow recovery. Mesna: Uroprotection lasts for the duration of infusion and several hours post; given on schedule covering ifosfamide excretion. |
1.2 g/m2 IV daily for 5 consecutive days, or 5 g/m2 as a 24-hour continuous IV infusion every 3-4 weeks. Mesna is administered IV at 20% of the ifosfamide dose (w/w) at 0, 4, and 8 hours after ifosfamide, or as a continuous infusion at 100% of the ifosfamide dose.
| Dosage form | INJECTABLE |
| Renal impairment | Ifosfamide: GFR 30-60 mL/min: reduce dose by 25-50%; GFR 10-29 mL/min: administer 50% of normal dose; GFR <10 mL/min: administer 25% of normal dose. Mesna: No specific renal adjustment required, but monitor for urinary toxicity. |
| Liver impairment | Ifosfamide: Child-Pugh Class A: no adjustment; Class B: reduce dose by 25%; Class C: reduce dose by 50% or avoid use. Mesna: No specific hepatic adjustment. |
| Pediatric use | Ifosfamide: 1.2-1.8 g/m2 IV daily for 5 days every 3-4 weeks. Mesna: IV bolus at 20% of ifosfamide dose at 0, 4, and 8 hours, or continuous infusion at 100% of ifosfamide dose. Reduce ifosfamide dose by 25-50% for GFR <60 mL/min/1.73m2. |
| Geriatric use | Elderly patients may have reduced renal function; adjust ifosfamide dose based on creatinine clearance. No specific age-related dose modifications established; use caution and monitor renal function closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
No significant drug interactions Used to prevent hemorrhagic cystitis caused by ifosfamide.
| FDA category | Animal |
| Breastfeeding | Contraindicated during breastfeeding. Ifosfamide and its metabolites are excreted in human milk; M/P ratio not reported. Potential for severe adverse reactions in nursing infants, including immunosuppression and carcinogenesis. Discontinue nursing or drug. |
| Teratogenic Risk | Pregnancy Category D. First trimester: High risk of major congenital malformations including craniofacial, skeletal, and CNS defects. Second and third trimesters: Fetal growth restriction, premature birth, and neonatal myelosuppression. Avoid during pregnancy unless benefit outweighs risk. |
■ FDA Black Box Warning
Myelosuppression (severe leukopenia, thrombocytopenia, anemia); hemorrhagic cystitis (can be severe, requiring discontinuation); neurotoxicity (confusion, coma, seizures); urotoxicity requires administration with mesna for prophylaxis; renal toxicity (especially in patients with compromised renal function); acute encephalopathy.
| Common Effects | Eye pain Eye irritation Abnormal eye sensation Eye discomfort Sleepiness Weakness Dryness in mouth |
| Serious Effects |
Absolute: Hypersensitivity to ifosfamide or mesna; severe bone marrow depression. Relative: Active urinary tract infection; renal impairment (CrCl <30 mL/min); hepatic impairment; pre-existing neurotoxicity.
| Precautions | Myelosuppression (monitor CBC); hemorrhagic cystitis (use with mesna, hydrate); neurotoxicity (discontinue if occurs); nephrotoxicity (monitor renal function); secondary malignancies (acute leukemia); impaired fertility; infections; vaccination with live vaccines; patients with renal impairment (dose reduction); hepatic impairment; concomitant use with warfarin (enhanced anticoagulation). |
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| Fetal Monitoring | Complete blood count with differential prior to each cycle; monitor for neutropenia, thrombocytopenia. Renal function tests (serum creatinine, BUN) and urinalysis for hematuria. Hepatic function tests. Fetal ultrasound for growth and anatomy if exposure occurs. Monitor for hemorrhagic cystitis. |
| Fertility Effects | Gonadal suppression leading to oligospermia or azoospermia in males; ovarian failure and premature menopause in females. May cause irreversible infertility. Discuss fertility preservation options prior to treatment. |