Cyclophosphamide
Cyclophosphamide is a potent **antineoplastic** and **immunosuppressive** agent used widely in veterinary medicine for dogs and cats. * **Antineoplastic Use**: Employed in combination protocols for lymphomas, leukemias, carcinomas, and sarcomas. Low-dose metronomic (continuous) therapy is also utilized to prevent sarcoma recurrence. * **Immunosuppressive Use**: Used for severe immune-mediated diseases such as systemic lupus erythematosus (SLE), immune-mediated thrombocytopenia (ITP), immune-mediated hemolytic anemia (IMHA), and pemphigus. > **Clinical Pearl**: Cyclophosphamide is cell-cycle phase nonspecific. Because it is a prodrug requiring hepatic activation, it is not a vesicant and can be given safely via peripheral veins, unlike many other chemotherapy agents.
Mecanismo: Cyclophosphamide is a prodrug that is metabolized in the liver by **cytochrome P450** enzymes into active metabolites, primarily **phosphoramide mustard** and **acrolein**. **Phosphoramide mustard** → acts as an alkylating agent → forms cross-links within and between DNA strands → interferes with DNA replication and RNA transcription → triggers apoptosis and cell death. **Acrolein** is a toxic byproduct that concentrates in the urinary bladder and is responsible for sterile hemorrhagic cystitis. The drug also profoundly suppresses B-cell and T-cell function, leading to its immunosuppressive effects.
Dosificación por especie
- Immunosuppressant (ITP or IMHA) · 50 mg/m2 PO every 2nd day · PO · q48h · Ongoing · Author prefers cyclosporine or chlorambucil in cats.
- To slow progression of FIP · 2-4 mg/kg PO four times a week · PO · 4 times/week · Ongoing
- Chemical shearing agent · Historical use · PO/IV · Single · Single · Historical use only.
- Neoplastic diseases · 200 mg/m2 (usually 1 gram per horse per dose) IV every 1-2 weeks · IV · q1-2 weeks · Protocol dependent · Consult veterinary oncologist.
- Antineoplastic (lymphoma) in rabbits · 50 mg/m2 PO daily for 3 days each week OR 100-200 mg/m2 IV every 7 days · PO/IV · Varies · Protocol dependent · Consider fully implantable vascular access device for IV.
- To inhibit local recurrence in dogs with incompletely resected soft tissue sarcomas · 10 mg/m2 PO once daily with piroxicam at 0.3 mg/kg PO once daily · PO · q24h · Continuous (metronomic) · If unacceptable adverse effects develop, increase interval to every other day.
- Antineoplastic · 50 mg/m2 PO 4 days/week OR 250 mg/m2 PO once every 3 weeks OR 100-300 mg/m2 IV weekly · PO/IV · Varies · Protocol dependent · Consult veterinary oncologist.
Vías de administración
Contraindicaciones
- Prior anaphylactic reactions to the drug
- Severe pre-existing myelosuppression (leukopenia, thrombocytopenia)
- Active infections where immunosuppression may be dangerous
- No specific contraindications available in the monograph, but clinically contraindicated in patients with severe pre-existing myelosuppression or active haemorrhagic cystitis.
- Pre-existing severe myelosuppression
- Active haemorrhagic cystitis
Efectos adversos
- Myelosuppression (leukopenia, thrombocytopenia, anemia)
- Gastroenterocolitis (anorexia, nausea, vomiting, diarrhea)
- Sterile hemorrhagic cystitis (induced by acrolein metabolite)
- Alopecia (especially in continuously growing coats like Poodles and Old English Sheepdogs)
- Pulmonary infiltrates and fibrosis
- Hyponatremia
- Secondary leukemia
- Myelosuppression (nadir usually 5-14 days post-therapy)
- Sterile haemorrhagic cystitis (caused by acrolein metabolite)
- Bladder fibrosis
- Transitional cell carcinoma (secondary to chronic cystitis)
- Vomiting
- Diarrhoea
- Hepatotoxicity
- Nephrotoxicity
Interacciones farmacológicas
- Allopurinol · May increase the myelosuppression caused by cyclophosphamide
- Doxorubicin · Potentiation of cardiotoxicity may occur · major
- Chloramphenicol · May inhibit cyclophosphamide metabolism · moderate
- Phenobarbital · May increase the rate of metabolism to active metabolites, increasing toxicity risk
- Thiazide Diuretics · May increase the myelosuppression caused by cyclophosphamide · major
- Succinylcholine · Metabolism may be slowed, prolonging effects due to decreased pseudocholinesterases
- Digoxin · Absorption of orally administered digoxin may be decreased (may occur several days after dosing) · moderate
- Barbiturates · Increase cyclophosphamide toxicity due to increased rate of conversion to metabolites · major
- Phenothiazines · Reduce cyclophosphamide efficacy · moderate
- Ondansetron · Reduce cyclophosphamide efficacy · moderate
- Insulin · Insulin requirements are altered by concurrent cyclophosphamide · moderate
- cimetidine · Inhibits hepatic cytochrome P450 enzyme pathway, potentially altering the metabolism and increasing toxicity of chemotherapeutics. · major
Monitorización
- Efficacy (tumor response or remission of immune-mediated disease)
- Complete Blood Count (CBC) regularly for myelosuppression (nadir typically 7-14 days)
- Urinalysis regularly for signs of sterile hemorrhagic cystitis (hematuria)
- Uric acid levels (blood and urine)
- White Blood Cell (WBC) count (regular monitoring recommended due to myelosuppression)
- Urinalysis (monitor for haematuria indicating sterile haemorrhagic cystitis)
- Renal and hepatic function panels
- Free-catch urine by dipstick prior to and each week of treatment
- Haematology
- Biochemistry (prior to first treatment and minimum every 6 months)
Sobredosis
Limited information on acute overdoses. The lethal dose in dogs is reported as **40 mg/kg IV**. If an oral overdose occurs, perform gut emptying (emesis/lavage) if indicated and hospitalize the animal for aggressive supportive care, including IV fluids to flush the bladder and prevent hemorrhagic cystitis.
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