LYOPHILIZED CYTOXAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LYOPHILIZED CYTOXAN (LYOPHILIZED CYTOXAN).
Cyclophosphamide is an alkylating agent that interferes with DNA replication and RNA transcription by cross-linking DNA strands. It requires hepatic activation via cytochrome P450 (CYP2B6, CYP3A4, CYP2C9) to form active metabolites (e.g., phosphoramide mustard), which alkylate DNA and induce apoptosis preferentially in rapidly dividing cells.
| Metabolism | Hepatic metabolism via cytochrome P450 enzymes, primarily CYP2B6, CYP3A4, and CYP2C9, to form active metabolites (4-hydroxycyclophosphamide, phosphoramide mustard) and inactive metabolites (e.g., acrolein). Acrolein is responsible for urotoxicity. |
| Excretion | Renal elimination accounts for 50-70% of the dose, primarily as metabolites. Fecal excretion is minor (<5%). Unchanged drug is <20% of renal excretion. |
| Half-life | Terminal elimination half-life is 3-12 hours (mean 6 hours) for the parent drug; prolonged with hepatic impairment. Active metabolites (e.g., 4-hydroxycyclophosphamide) have a half-life of 4-8 hours. |
| Protein binding | Approximately 60% bound to plasma proteins, primarily albumin; minimal binding to other proteins. |
| Volume of Distribution | Apparent volume of distribution is 30-50 L/kg (0.4-0.7 L/kg), indicating extensive tissue distribution; penetrates CNS poorly. |
| Bioavailability | Oral bioavailability is 70-90% (mean 85%) when administered as tablets or lyophilized powder reconstituted for oral use. |
| Onset of Action | IV: Onset of antineoplastic effect within 2-4 hours after administration, correlating with metabolite formation. Oral: Onset delayed to 4-8 hours. |
| Duration of Action | Duration of immunosuppressive effect is 4-6 weeks; cytotoxic effect on bone marrow lasts 7-14 days. Recovery of normal cells begins after 2-3 weeks. |
| Molecular Weight | 261.08 Da (cyclophosphamide monohydrate; anhydrous: 243.07 Da). |
500-1500 mg/m² IV every 2-4 weeks
| Dosage form | INJECTABLE |
| Renal impairment | GFR 10-50 mL/min: reduce dose by 25%; GFR <10 mL/min: reduce dose by 50% |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25%; Child-Pugh C: reduce dose by 50% |
| Pediatric use | 60-75 mg/kg IV every 2-4 weeks |
| Geriatric use | Reduce initial dose by 25-50% due to increased myelosuppression risk |
| 1st trimester | Contraindicated due to teratogenicity (malformations, miscarriage). |
| 2nd trimester | Contraindicated; associated with fetal growth restriction and myelosuppression. |
| 3rd trimester | Contraindicated; risks of neonatal myelosuppression, immune suppression, and potential long-term effects. |
Clinical note
Comprehensive clinical and safety monograph for LYOPHILIZED CYTOXAN (LYOPHILIZED CYTOXAN).
| Placental transfer | Cyclophosphamide crosses the placenta rapidly and is metabolized to active alkylating species. Maternal exposure can cause fetal DNA alkylation. |
| Breastfeeding | Cyclophosphamide is excreted into breast milk. Due to potential for serious adverse reactions (e.g., neutropenia, carcinogenesis) in the nursing infant, breastfeeding is contraindicated during therapy and for at least 36 hours after the last dose. |
■ FDA Black Box Warning
Cyclophosphamide may cause myelosuppression, immunosuppression, hemorrhagic cystitis, cardiac toxicity, and secondary malignancies (e.g., bladder cancer, myelodysplasia). It is excreted in breast milk; breastfeeding should be discontinued during therapy. Should be administered under supervision of a physician experienced in chemotherapy.
| Serious Effects |
Hypersensitivity to cyclophosphamide or any componentSevere bone marrow suppression (e.g., leukopenia, thrombocytopenia)Active infection (especially viral)PregnancyLactation
| Precautions | Hemorrhagic cystitis: Urinary frequency, urgency, hematuria; ensure adequate hydration and frequent voiding; consider mesna prophylaxis in high-dose regimens., Myelosuppression: Dose-dependent leukopenia, thrombocytopenia, anemia; monitor CBC regularly., Cardiotoxicity: High doses can cause myocarditis, pericarditis, cardiac tamponade; risk increased in patients with prior anthracycline exposure or mediastinal radiation., Secondary malignancies: Increased risk of bladder cancer and myelodysplastic syndrome, especially with prolonged therapy., Immunosuppression and infection risk., Gonadal suppression: May cause amenorrhea, azoospermia, infertility., Renal and hepatic impairment: Dose adjustment may be required., Pregnancy: Can cause fetal harm; effective contraception recommended. |
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| Lactation Rating | L5 (Avoid) - Hazardous. |
| Teratogenic Risk | Cyclophosphamide is a known human teratogen. First trimester exposure is associated with major congenital malformations including craniofacial, limb, and central nervous system defects, with a reported malformation rate of approximately 18%. Second and third trimester exposure may cause fetal growth restriction, myelosuppression, and neonatal pancytopenia. Use is contraindicated in pregnancy unless clearly necessary. |
| Fetal Monitoring | Monitor maternal complete blood count, renal and hepatic function, and urinalysis for hemorrhagic cystitis. Perform fetal ultrasound for growth and anatomy. Consider fetal echocardiogram if exposure in first trimester. Monitor for neonatal myelosuppression and infection after delivery. |
| Fertility Effects | Cyclophosphamide causes dose-dependent gonadal toxicity with potential for permanent infertility. In females, it leads to ovarian failure, amenorrhea, and loss of fertility; risk increases with age. In males, it may cause oligospermia or azoospermia, often irreversible. Pre-treatment fertility preservation options (e.g., oocyte or sperm cryopreservation) should be discussed. |
| Food/Dietary | Avoid grapefruit and grapefruit juice due to potential CYP3A4 interaction. Limit alcohol intake as it may increase hepatotoxicity. No specific food restrictions otherwise; maintain adequate hydration. |
| Clinical Pearls | Lyophilized Cytoxan (cyclophosphamide) requires reconstitution with sterile water or bacteriostatic water; use within 24 hours if refrigerated. Administer with ample hydration (at least 2-3 L/day) to prevent hemorrhagic cystitis. Monitor for neutropenia, especially nadir at days 10-14. Mesna is often co-administered to reduce bladder toxicity. Assess for cardiotoxicity at high doses (>1.5 g/m²). Adjust dose in renal impairment (CrCl <20 mL/min). |
| Patient Advice | Drink plenty of water (at least 8-10 glasses daily) to protect your bladder. · Report any blood in urine or painful urination immediately. · Avoid live vaccines and contact with people who have recently received oral polio vaccine. · Use effective contraception during treatment and for at least 1 year after. · Monitor for signs of infection (fever, chills, sore throat) and bleeding (easy bruising, petechiae). · Do not take aspirin or NSAIDs without consulting your doctor. · Inform your doctor if you are pregnant or breastfeeding. |