CYTOXAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CYTOXAN (CYTOXAN).
Cyclophosphamide is an alkylating agent that crosslinks DNA, leading to cell cycle nonspecific cytotoxicity. It requires hepatic activation by cytochrome P450 enzymes to form active metabolites, primarily phosphoramide mustard.
| Metabolism | Hepatic activation via cytochrome P450 enzymes (CYP2B6, CYP3A4, CYP2C9, CYP2C19) to form 4-hydroxycyclophosphamide, which tautomerizes to aldophosphamide. Aldophosphamide is further metabolized to phosphoramide mustard (active) and acrolein (urotoxic). Also undergoes metabolism by aldehyde dehydrogenase to inactive carboxyphosphamide. |
| Excretion | Renal elimination of unchanged cyclophosphamide (5-30%) and metabolites (primarily 4-ketocyclophosphamide and carboxyphosphamide) accounts for approximately 80% of total clearance; fecal excretion is minimal (<5%). |
| Half-life | Terminal elimination half-life of cyclophosphamide is 3-12 hours (range 2-19 h) in adults; the half-life of active metabolites (e.g., 4-hydroxycyclophosphamide) is approximately 8-10 hours. Half-life is prolonged in hepatic impairment (up to 20 h) and reduced in dose adjustments. |
| Protein binding | Cyclophosphamide is 10-30% bound to plasma proteins; active metabolite 4-hydroxycyclophosphamide is approximately 50-60% bound to albumin and other proteins. |
| Volume of Distribution | Volume of distribution (Vd) for cyclophosphamide is 0.6-0.7 L/kg (range 0.5-1.0 L/kg), indicating distribution throughout total body water; higher Vd suggests extensive tissue binding. |
| Bioavailability | Oral bioavailability of cyclophosphamide is >90% (range 75-100%), with peak plasma concentrations reached in 1-2 hours; intravenous administration yields complete bioavailability. |
| Onset of Action | Onset of immunosuppressive/antineoplastic effect: 2-8 weeks for oral or IV administration; hemopoietic suppression begins 3-5 days after therapy, with nadir at 7-14 days. |
| Duration of Action | Duration of immunosuppression: 2-6 weeks after a single dose; myelosuppression recovery begins 7-10 days post-nadir. Therapeutic effect on autoimmune conditions may persist for weeks to months. |
| Molecular Weight | 261.1 |
500-1500 mg/m² IV every 2-4 weeks or 1-5 mg/kg/day PO for 10-14 days.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl 10-50 mL/min: reduce dose by 25%; CrCl <10 mL/min: reduce dose by 50%. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25%; Child-Pugh C: avoid use. |
| Pediatric use | IV: 300-600 mg/m² every 2-4 weeks; PO: 2.5-5 mg/kg/day (50-150 mg/m²/day). |
| Geriatric use | Start at lower end of dosing range; monitor renal function and myelosuppression. |
| 1st trimester | Contraindicated due to teratogenicity; risk of fetal malformations (e.g., cleft palate, skeletal anomalies) and spontaneous abortion. |
| 2nd trimester | Contraindicated; may cause fetal growth restriction, myelosuppression, and organ damage. |
| 3rd trimester | Contraindicated; risk of neonatal myelosuppression, pancytopenia, and potential long-term effects. |
Clinical note
Comprehensive clinical and safety monograph for CYTOXAN (CYTOXAN).
| Placental transfer | Cyclophosphamide and its active metabolites cross the placenta extensively; fetal plasma concentrations are approximately 50% of maternal levels. |
| Breastfeeding | Cyclophosphamide is excreted into breast milk in clinically significant amounts; breast-feeding is not recommended during therapy and for at least 24-48 hours after last dose. |
■ FDA Black Box Warning
WARNING: CARDIOTOXICITY, SECONDARY MALIGNANCIES, HEMORRHAGIC CYSTITIS, AND MYELOSUPPRESSION. CYCLOPHOSPHAMIDE CAN CAUSE CARDIOTOXICITY, INCLUDING FATAL MYOCARDITIS AND PERICARDITIS. SECONDARY MALIGNANCIES (E.G., BLADDER CANCER, LEUKEMIA) HAVE BEEN REPORTED. HEMORRHAGIC CYSTITIS CAN OCCUR; INCREASE FLUID INTAKE AND VOID FREQUENTLY. SIGNIFICANT MYELOSUPPRESSION MAY OCCUR.
| Serious Effects |
Hypersensitivity to cyclophosphamideSevere myelosuppression (e.g., leukocyte count <2,000/mm³)Active infection (especially varicella-zoster)Pregnancy
| Precautions | Cardiotoxicity: Risk increases with high doses; monitor cardiac function, Hemorrhagic cystitis: Hydrate and ensure frequent voiding; use mesna for prophylaxis, Myelosuppression: Monitor blood counts; dose adjust for neutropenia or thrombocytopenia, Secondary malignancies: Especially bladder cancer and acute leukemia, Gonadal suppression: May cause infertility, Pulmonary toxicity: Interstitial pneumonitis, Hepatotoxicity: Monitor liver function, Urinary tract obstruction: Use caution in patients with compromised renal function |
| Food/Dietary |
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| Lactation Rating |
| L5 - Contraindicated |
| Teratogenic Risk | Pregnancy Category D. First trimester: High risk of major malformations (neural tube defects, craniofacial, limb anomalies) and fetal loss. Second and third trimesters: Risk of intrauterine growth restriction, myelosuppression, and neonatal pancytopenia. All trimesters: Avoid unless maternal benefit outweighs risk. |
| Fetal Monitoring | Monitor complete blood count with differential, liver function tests, renal function, and urinalysis regularly. Perform fetal ultrasound for growth and anomaly assessment. Consider amniocentesis for karyotyping if exposure in first trimester. Monitor for hemorrhagic cystitis with urinalysis and symptom assessment. |
| Fertility Effects | Causes dose-dependent ovarian failure, amenorrhea, and premature menopause in females; oligospermia, azoospermia, and testicular atrophy in males. Fertility preservation options (e.g., egg/sperm cryopreservation) should be discussed prior to therapy. |
| Avoid grapefruit and grapefruit juice; maintain adequate hydration; no other specific food restrictions. |
| Clinical Pearls | Hydrate aggressively to prevent hemorrhagic cystitis; monitor CBC closely for myelosuppression; antiemetic premedication recommended; dose adjust in renal impairment; avoid live vaccines during therapy. |
| Patient Advice | Drink plenty of fluids to protect your bladder. · Report any blood in urine or painful urination immediately. · Use effective contraception during treatment and for at least 1 year after. · Do not receive live vaccines while on this medication. · Avoid grapefruit and grapefruit juice as they may interact. |