cyclophosphamide
alkylating agent· Brands: Endoxan, Cytoxan, Neosar, ProcytoxIVPO
Mechanism of action
Cyclophosphamide is a prodrug that requires hepatic activation by cytochrome P450 enzymes to form the active alkylating metabolite phosphoramide mustard. This metabolite forms cross-links with DNA, interfering with replication and transcription, leading to cell death. Acrolein, another metabolite, is responsible for the urothelial toxicity seen with this drug.
Pharmacokinetics
Cyclophosphamide is well absorbed after oral administration and is also given intravenously. It is metabolised in the liver by CYP2B6, CYP3A4 and other enzymes to active and inactive metabolites. The active metabolites have a half-life of several hours, but the parent drug has a half-life of 4 to 6 hours. Elimination is primarily renal, so dose adjustment may be needed in renal impairment.
Indications & dosing
Non-Hodgkin lymphoma (part of CHOP regimen)
Typically administered with doxorubicin, vincristine, and prednisolone.
- adult · IV: 750 mg/m² every 2-3 weeks · Typically administered with doxorubicin, vincristine, and prednisolone.
Breast cancer (part of AC regimen)
Given with doxorubicin.
- adult · IV: 600 mg/m² every 3 weeks · Given with doxorubicin.
Ovarian cancer
- adult · IV: 1000 mg/m² every 3-4 weeks
Severe rheumatoid arthritisoff-label
Off-label; often used in refractory cases.
- adult · PO: 1–2 mg/kg/day daily · Off-label; often used in refractory cases.
Nephrotic syndrome (pediatric)off-label
For steroid-resistant or frequently relapsing disease.
- pediatric · PO: 2–3 mg/kg/day daily · For steroid-resistant or frequently relapsing disease.
Contraindications & precautions
- Hypersensitivity to cyclophosphamide or any excipient · Anaphylaxis or severe allergic reactions.
- Severe bone marrow suppression · May be used with caution if the benefit outweighs the risk (e.g., in haematological malignancies).
- Active infection · Immunosuppression may exacerbate infection; treat infection before starting if possible.
- Pregnancy · Teratogenic; use only if benefit to mother outweighs fetal risk.
- Ensure adequate hydration to reduce the risk of haemorrhagic cystitis; consider mesna with high-dose regimens.
- Monitor full blood count regularly and adjust dose as necessary.
- Avoid live vaccines in immunocompromised patients.
- Use effective contraception in men and women of childbearing potential.
- Monitor for infections and treat promptly.
Adverse effects
- Bone marrow suppression (leucopenia, neutropenia, thrombocytopenia, anaemia)serious
- Alopecia
- Nausea and vomiting
- Haemorrhagic cystitisserious
- Infertility (gonadal dysfunction)serious
- Cardiotoxicity (including cardiomyopathy and heart failure)serious
- Secondary malignancy (e.g., leukaemia, bladder cancer)serious
- SIADH (syndrome of inappropriate antidiuretic hormone secretion)serious
Renal & hepatic adjustment
- eGFR 10–30: Reduce dose to 75% of normal (25% reduction) for moderate renal impairment.
- eGFR 0–10: Reduce dose to 50% of normal (50% reduction) or consider alternative agent for severe renal impairment.
- Hepatic impairment (severe): Reduce dose or consider alternative agent in severe hepatic impairment.
Monitoring, pregnancy & toxicity
- Full blood count (neutrophils and platelets) · Before each dose, then weekly or as clinically indicated
- Liver function tests · Before treatment and at regular intervals
- Renal function (serum creatinine/eGFR) · Before treatment and at regular intervals
- Urinalysis for haematuria · Before and after each dose (or as per local protocol)
- Adequate hydration and urine output · Monitor during treatment
- Pregnancy: Contraindicated in pregnancy. Cyclophosphamide is teratogenic; effective contraception is required for both men and women during treatment and for at least 3 months after the last dose.
- Toxicity: Myelosuppression (neutropenia, thrombocytopenia, anaemia) · Monitor FBC; reduce dose or delay treatment if neutrophil count <1.5×10^9/L or platelets <100×10^9/L; consider G-CSF if symptomatic; treat infections promptly.
- Toxicity: Haemorrhagic cystitis · Ensure adequate hydration (e.g., 2-3 L/day), frequent voiding, and consider mesna prophylaxis; if haematuria develops, stop cyclophosphamide and consider IV fluids and bladder irrigation in severe cases.
- Toxicity: Nausea and vomiting · Use antiemetics (e.g., 5-HT3 antagonists) before and after administration; consider aprepitant for delayed emesis; maintain hydration.
- Toxicity: Cardiotoxicity (at high doses) · Monitor cardiac function; reduce total dose or use alternative regimen in patients with cardiac disease; treat heart failure if occurs.
Clinical notes
Cyclophosphamide is used in the treatment of various cancers including lymphoma, leukaemia and breast cancer, and as an immunosuppressant in autoimmune diseases such as systemic lupus erythematosus and vasculitis. The main dose-limiting toxicity is myelosuppression, particularly neutropenia. Haemorrhagic cystitis is a significant adverse effect caused by acrolein, prevented by adequate hydration and the use of mesna. Patients require regular monitoring of full blood count and urinalysis. The drug is teratogenic and should be avoided in pregnancy.
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BNF; local formulary