CYTOXAN (LYOPHILIZED)
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CYTOXAN (LYOPHILIZED) (CYTOXAN (LYOPHILIZED)).
Cyclophosphamide is an alkylating agent that cross-links DNA, inhibiting DNA replication and transcription. It also has immunosuppressive effects by suppressing B and T lymphocyte function.
| Metabolism | Hepatic metabolism primarily via cytochrome P450 enzymes (CYP2B6, CYP3A4, CYP2C9, CYP2C19) to active metabolites phosphoramide mustard and acrolein. Also undergoes oxidation to inactive metabolites. |
| Excretion | Renal: 30-60% of unchanged drug and metabolites (primarily phosphoramide mustard and acrolein). Biliary/fecal: minor (<10%). |
| Half-life | Cyclophosphamide: 4-8 hours (dose-dependent, prolonged in hepatic impairment). Active metabolites (e.g., phosphoramide mustard): 6-12 hours. |
| Protein binding | Cyclophosphamide: 10-20% bound; metabolites: 50-70% bound (primarily albumin). |
| Volume of Distribution | 0.6-0.8 L/kg (total body water); larger Vd (up to 1.0 L/kg) due to tissue binding. |
| Bioavailability | Oral: >75% (well-absorbed, but first-pass metabolism reduces to ~50% of parent drug; metabolite formation is extensive). |
| Onset of Action | IV: Days to weeks for immunosuppression and antineoplastic effect (myelosuppression nadir at 7-14 days). Oral: Similar to IV, with therapeutic effects delayed by absorption. |
| Duration of Action | Myelosuppression: 7-14 days for leukocyte nadir, recovery typically within 21 days. Immunosuppressive effects may persist for weeks. |
| Molecular Weight | 279.1 |
500-1000 mg/m² IV every 2-4 weeks, or 60-120 mg/m² IV daily for 2-3 days, or 500-750 mg/m² IV every 3 weeks. Oral: 50-200 mg daily as continuous therapy.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl 10-50 mL/min: reduce dose by 25%; CrCl <10 mL/min: reduce dose by 50%. Dialysis: administer after hemodialysis; no specific adjustment for peritoneal dialysis. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25%; Child-Pugh C: reduce dose by 50% or contraindicated. |
| Pediatric use | 30-50 mg/kg IV every 2-4 weeks, or 200-400 mg/m² IV daily for 3-5 days, or 2-8 mg/kg daily orally. |
| Geriatric use | Start at lower end of dosing range (e.g., 400-500 mg/m² IV every 3-4 weeks) due to decreased renal function and increased myelosuppression risk. |
| 1st trimester | Cyclophosphamide is teratogenic in humans. Major congenital malformations including craniofacial, limb, and CNS defects occur in 30-50% of exposed fetuses. Use contraindicated in first trimester unless maternal life-threatening condition. |
| 2nd trimester | Fetal risk remains high. May cause growth restriction, developmental delay. Use only if no alternatives and maternal benefit outweighs risks. |
| 3rd trimester | Third trimester exposure can cause neonatal myelosuppression, pancytopenia, and immunosuppression. Avoid near term; if necessary, monitor neonate for cytopenias. |
Clinical note
Comprehensive clinical and safety monograph for CYTOXAN (LYOPHILIZED) (CYTOXAN (LYOPHILIZED)).
| Placental transfer | Cyclophosphamide crosses the placenta efficiently. Fetal concentrations reach maternal levels; active metabolites also cross. Evidence of significant transfer with documented teratogenicity. |
| Breastfeeding |
■ FDA Black Box Warning
Hemorrhagic cystitis, myelosuppression, cardiotoxicity (especially at high doses), secondary malignancies (e.g., bladder cancer, myelodysplasia, acute leukemia), and embryo-fetal toxicity.
| Serious Effects |
Hypersensitivity to cyclophosphamide or any componentSevere bone marrow suppression (e.g., leukopenia, thrombocytopenia)Active infection (particularly viral)Obstructive uropathy (due to hemorrhagic cystitis risk)Pregnancy (especially first trimester) - absolute unless life-savingLactation (nursing infant)
| Precautions | Hemorrhagic cystitis (increase fluid intake, monitor urinalysis), myelosuppression (dose adjustments based on blood counts), cardiotoxicity (especially with high doses or prior anthracyclines), secondary malignancies, impaired fertility, veno-occlusive hepatic disease, and embryo-fetal toxicity. Monitor for infections, tumor lysis syndrome, and SIADH. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may inhibit CYP450 activation and reduce efficacy. No other significant food interactions. Maintain adequate hydration; avoid alcohol due to risk of hepatotoxicity and dehydration. |
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| Cyclophosphamide is excreted into breast milk in clinically significant amounts (up to 20% of maternal dose). It can cause neutropenia, thrombocytopenia, and immunosuppression in the nursing infant. Breastfeeding is not recommended during therapy and for 36-72 hours after last dose due to potential harm. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | First trimester exposure is associated with major congenital malformations including craniofacial, skeletal, cardiac, and neural tube defects; second and third trimester exposure increases risk of intrauterine growth restriction, preterm birth, and fetal myelosuppression. |
| Fetal Monitoring | Monitor maternal complete blood count, renal function, and hepatic function; fetal ultrasound for growth and anomalies; consider prenatal diagnosis for aminopterin-like syndrome. |
| Fertility Effects | Cyclophosphamide causes dose-dependent gonadal toxicity with risk of premature ovarian failure in females and oligospermia or azoospermia in males; risk is higher with cumulative dose and age. |
| Clinical Pearls | Cyclophosphamide is a prodrug activated by hepatic CYP450 enzymes; its active metabolites (phosphoramide mustard and acrolein) cause urotoxicity. Hemorrhagic cystitis is a dose-limiting toxicity; aggressive hydration (oral or IV) and frequent voiding are mandatory. Mesna is co-administered to bind acrolein in urine. Administer in the morning to reduce overnight bladder exposure. Monitor urine output and dipstick for hematuria. Use antiemetic premedication (e.g., aprepitant, 5-HT3 antagonist). Cardiac toxicity can occur at high doses; consider dose adjustment in renal impairment (CrCl <10 mL/min). |
| Patient Advice | Drink plenty of fluids (8-10 glasses per day) on the day of treatment and for 24 hours after to prevent bladder damage. · Urinate frequently, especially at night; empty your bladder every 2-3 hours. · Report any blood in urine, burning with urination, or change in urine color immediately. · This drug may cause nausea and vomiting; take anti-nausea medications as prescribed. · Avoid taking NSAIDs like ibuprofen or aspirin unless approved by your doctor to reduce bleeding risk. · Avoid vaccinations with live viruses; consult your doctor before any immunizations. · Use effective contraception during treatment and for at least 12 months after completion. · Do not breastfeed during treatment. · Report signs of infection (fever, chills, sore throat) or unusual bleeding/bruising. · Do not handle crushed or broken tablets without protection; if a dose is missed, contact your healthcare team. |