BLACK BOX WARNING
- myelosuppression
- bladder toxicity (hemorrhagic cystitis)
- cardiac toxicity (at high doses)
- secondary malignancies
- serious infections
- severe immunosuppression
cyclophosphamide
Brand: Cytoxan
⚠ BBW ISMP High Alert Prototype Drug
Drug Class: nitrogen mustard alkylating agent
Drug Family: antineoplastic
Subclass: prodrug alkylating agent
Organ Systems: hematology-oncologyimmunology
Mechanism of Action
Prodrug activated by hepatic CYP2B6/CYP3A4 to active metabolites phosphoramide mustard and acrolein; phosphoramide mustard alkylates and cross-links DNA (both interstrand and intrastrand), preventing DNA replication and transcription; acrolein causes hemorrhagic cystitis.
DNA (N-alkylation of guanine, cross-linking)
Indications
- non-Hodgkin lymphoma
- Hodgkin lymphoma
- breast cancer
- ovarian cancer
- small cell lung cancer
- nephrotic syndrome
- lupus nephritis
- ANCA-associated vasculitis (immunosuppression)
- hematopoietic stem cell transplant conditioning
Contraindications
- cyclophosphamide hypersensitivity
- active urinary tract obstruction
- severely compromised bone marrow
Adverse Effects
Common
- nausea/vomiting
- alopecia
- myelosuppression
Serious
- hemorrhagic cystitis (from acrolein metabolite)
- bladder transitional cell carcinoma (long-term risk)
- myelosuppression
- gonadal toxicity (ovarian failure, azoospermia)
- SIADH/hyponatremia (at high doses)
- pulmonary fibrosis
- cardiotoxicity (at very high HSCT doses)
Pharmacokinetics (ADME)
| Absorption | oral bioavailability ~75%; IV also common |
| Distribution | widely distributed; crosses BBB |
| Metabolism | hepatic prodrug activation (CYP2B6/CYP3A4) to active phosphoramide mustard and toxic acrolein |
| Excretion | renal (active metabolites and acrolein) |
| Half-life | 3–12 hours |
| Onset | prodrug — hours |
| Peak | 1–2 hours (oral) |
| Duration | varies |
| Protein Binding | 20% (parent); metabolites higher |
| Vd | moderate |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| CYP inducers (rifampin) | increase activation to phosphoramide mustard and acrolein; greater toxicity | major |
| allopurinol | may increase cyclophosphamide toxicity by inhibiting metabolism | moderate |
| succinylcholine | cyclophosphamide inhibits pseudocholinesterase, prolonging neuromuscular blockade | major |
Nursing Considerations
- MESNA (sodium 2-mercaptoethanesulfonate) must be co-administered with high-dose cyclophosphamide to prevent hemorrhagic cystitis; MESNA binds acrolein in the bladder, neutralizing its urotoxic effect.
- Maintain vigorous hydration (2–3 L/day) and encourage frequent voiding during and for 24 hours after administration to flush acrolein from the bladder.
- Monitor CBC with differential; nadir typically occurs 7–14 days after administration — WBC nadir guides neutropenic precautions.
- Administer antiemetics before and after each dose; late nausea may require extended antiemetic coverage.
Clinical Pearls
- The toxic bladder metabolite of cyclophosphamide is acrolein (not the antitumor phosphoramide mustard); MESNA selectively inactivates acrolein in the urinary tract by conjugation without affecting systemic antitumor activity — a pharmacological masterpiece of selective detoxification.
- Long-term cyclophosphamide use for autoimmune diseases (e.g., SLE nephritis, vasculitis) is associated with bladder transitional cell carcinoma risk, typically 5–10 years after exposure; cumulative dose is the primary risk factor.
Safety Profile
Pregnancy contraindicated
Lactation avoid
Renal Adjustment Required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.