CYTOXAN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for CYTOXAN (CYTOXAN).

How it works

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.

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for CYTOXAN (CYTOXAN).

Breastfeeding	Contraindicated during breastfeeding. Cyclophosphamide is excreted into breast milk with an M/P ratio of approximately 1. Potential for severe adverse effects in the nursing infant, including neutropenia, thrombocytopenia, and immunosuppression. Advise to discontinue nursing or drug.
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.

Warnings & precautions

■ 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.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to cyclophosphamide or any component","Severe bone marrow suppression","Active infections (particularly varicella-zoster)","Pregnancy (causes fetal harm; abortifacient)"]

Clinical Precautions

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"]

Clinical Tips & Counseling

Drug interactions

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CYTOXAN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for CYTOXAN (CYTOXAN).

How it works

What the body does with it

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.

Classification & Brands

Dosing & administration

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.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for CYTOXAN (CYTOXAN).

Breastfeeding	Contraindicated during breastfeeding. Cyclophosphamide is excreted into breast milk with an M/P ratio of approximately 1. Potential for severe adverse effects in the nursing infant, including neutropenia, thrombocytopenia, and immunosuppression. Advise to discontinue nursing or drug.
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.

Warnings & precautions

■ FDA Black Box Warning

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to cyclophosphamide or any component","Severe bone marrow suppression","Active infections (particularly varicella-zoster)","Pregnancy (causes fetal harm; abortifacient)"]