Cyclophosphamide

Alkylating agent Nitrogen mustard derivative

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 50 mg/m² q48h (every other day) Duration: As per protocol (e.g., 6 months for lymphoma)
Notes: For lymphoma, often used in combination protocols (e.g., CHOP). For immune-mediated disease, lower doses (25-50 mg/m²) may be used.
Dog IV 200-250 mg/m² q3 weeks Duration: As per protocol
Notes: Used in high-dose protocols; ensure adequate hydration to prevent cystitis.
Cat PO 50 mg/m² q48h Duration: As per protocol
Notes: Cats may be more sensitive; monitor for myelosuppression.
Cat IV 200 mg/m² q3 weeks Duration: As per protocol
Notes: Use with caution; ensure adequate hydration.
Horse IV 200-400 mg/m² q3 weeks Duration: As per protocol
Notes: Limited data; use with extreme caution.
Cattle IV 200 mg/m² q3 weeks Duration: As per protocol
Notes: Not commonly used; off-label use only.
Small Ruminants IV 200 mg/m² q3 weeks Duration: As per protocol
Notes: Not commonly used; off-label use only.
Rabbit PO 10-20 mg/kg q24h Duration: As per protocol
Notes: Limited data; use with caution.
Bird/Poultry PO 10-20 mg/kg q24h Duration: As per protocol
Notes: Limited data; use with caution.

Clinical Indications & Species Uses

General Indications
  • Antineoplastic agent for various malignancies
  • Immunosuppressive agent for immune-mediated diseases
Dog (Canine)
  • Lymphoma (as part of combination chemotherapy protocols)
  • Leukemia (lymphocytic, granulocytic)
  • Multiple myeloma
  • Mast cell tumors (as adjunctive therapy)
  • Immune-mediated hemolytic anemia (IMHA)
  • Immune-mediated thrombocytopenia (ITP)
  • Systemic lupus erythematosus (SLE)
  • Polyarthritis (immune-mediated)
  • Pemphigus complex
  • Steroid-responsive meningitis-arteritis (SRMA)
Cat (Feline)
  • Lymphoma (as part of combination chemotherapy protocols)
  • Leukemia (lymphocytic)
  • Mammary carcinoma (adjunctive)
  • Immune-mediated hemolytic anemia (IMHA)
  • Immune-mediated thrombocytopenia (ITP)
  • Eosinophilic granuloma complex (refractory cases)
Horse (Equine)
  • Lymphoma (rarely used)
  • Immune-mediated hemolytic anemia (IMHA)
  • Immune-mediated thrombocytopenia (ITP)
  • Chronic inflammatory conditions (off-label)
Cattle (Bovine)
  • Immune-mediated diseases (rarely used)
Small Ruminants (Sheep / Goat)
  • Immune-mediated diseases (rarely used)
Rabbit & Small Mammals
  • Lymphoma (rarely used)
  • Immune-mediated diseases (rarely used)
Avian & Poultry
  • Immune-mediated diseases (rarely used)
Exotic & Other Species
  • Reptiles: lymphoma (rarely used)
  • Small mammals (ferrets, guinea pigs): lymphoma (rarely used)

Pharmacology & Mechanism of Action

Drug Class: Alkylating agent | Pharmacological Group: Nitrogen mustard derivative

Mechanism of Action: Cyclophosphamide is a prodrug that requires hepatic metabolism by cytochrome P450 enzymes (CYP2B6, CYP3A4, CYP2C9) to form 4-hydroxycyclophosphamide, which equilibrates with aldophosphamide. Aldophosphamide diffuses into cells and undergoes β-elimination to produce phosphoramide mustard and acrolein. Phosphoramide mustard forms cross-links between DNA strands, leading to cell cycle arrest and apoptosis. The drug is cell cycle phase-nonspecific, affecting both dividing and resting cells, but is most toxic to rapidly proliferating tissues.

Pharmacodynamics: Cyclophosphamide exerts cytotoxic effects primarily on rapidly dividing cells, including neoplastic cells, bone marrow precursors, and lymphoid cells. It also has immunosuppressive properties by suppressing both humoral and cell-mediated immunity. The drug reduces lymphocyte proliferation, antibody production, and inflammatory cytokine release. In veterinary medicine, it is used for its antineoplastic and immunomodulatory effects, particularly in lymphoproliferative disorders and immune-mediated diseases.

⚡ Pharmacokinetics Summary

Absorption: Cyclophosphamide is well absorbed after oral administration, with bioavailability approaching 100% in most species. Peak plasma concentrations occur within 1-3 hours. In dogs, oral absorption is rapid and complete; in cats, absorption may be slightly slower but still effective. Intravenous administration provides immediate systemic exposure.
Distribution: Cyclophosphamide is widely distributed throughout the body, including the central nervous system, with a volume of distribution of approximately 0.5-1 L/kg. It crosses the blood-brain barrier to a limited extent. Protein binding is low (approximately 20%) in dogs and cats. The drug and its metabolites cross the placenta and are excreted in milk.
Metabolism: Cyclophosphamide is extensively metabolized in the liver via cytochrome P450 enzymes, primarily CYP2B6 and CYP3A4. The active metabolites (4-hydroxycyclophosphamide and phosphoramide mustard) are formed in the liver and then distributed to tissues. Acrolein, a toxic metabolite, is also produced and is responsible for urothelial toxicity. Metabolism is species-dependent; cats may have reduced CYP2B6 activity, leading to slower activation.
Excretion: Cyclophosphamide and its metabolites are primarily excreted in the urine. Approximately 30-60% of the dose is excreted as unchanged drug and metabolites in the urine. The elimination half-life varies by species: dogs approximately 2-4 hours, cats 2-3 hours, horses 1-2 hours, and cattle 2-3 hours. Renal impairment can prolong elimination and increase toxicity.
Half-Life: Dogs: 2-4 hours; Cats: 2-3 hours; Horses: 1-2 hours; Cattle: 2-3 hours
Bioavailability: Oral: ~100% in dogs and cats; IV: 100%.
Protein Binding: Approximately 20% in dogs and cats; minimal in other species.

Available Formulations & Strengths

Oral Tablet 25 mg, 50 mg (PO)
Injectable Solution 500 mg, 1 g, 2 g (powder for reconstitution) (IV)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to cyclophosphamide or other alkylating agents
  • Severe bone marrow suppression (neutropenia, thrombocytopenia)
  • Active infections (due to immunosuppression)
  • Pregnancy (teratogenic)
  • Lactation (excreted in milk)
  • Hepatic or renal insufficiency (use with caution)
  • Hemorrhagic cystitis (active or history)
Warnings & Clinical Precautions:
  • Myelosuppression is dose-limiting; monitor CBC regularly.
  • Urothelial toxicity (hemorrhagic cystitis) is a significant adverse effect; ensure adequate hydration and frequent urination.
  • Immunosuppression may predispose to opportunistic infections.
  • Carcinogenic potential (secondary malignancies) with long-term use.
  • Teratogenic; avoid in pregnant animals.
  • Use with caution in animals with renal or hepatic impairment; adjust dose if necessary.
  • In cats, monitor for signs of toxicity due to potential reduced metabolism.
  • Administer with antiemetics if nausea/vomiting occurs.
  • Wear gloves when handling the drug; avoid skin contact.

Adverse Effects & Reactions

Common:

  • Myelosuppression (neutropenia, thrombocytopenia, anemia)
  • Gastrointestinal signs (nausea, vomiting, diarrhea, anorexia)
  • Hemorrhagic cystitis (sterile, due to acrolein)
  • Alopecia (especially in dogs)
  • Immunosuppression

Serious / Severe:

  • Severe neutropenia with sepsis
  • Hemorrhagic cystitis (can be life-threatening)
  • Secondary malignancies (e.g., transitional cell carcinoma of the bladder)
  • Cardiotoxicity (with high doses)
  • Hepatotoxicity
  • Pulmonary fibrosis (rare)

Rare:

  • Anaphylaxis
  • SIADH (syndrome of inappropriate antidiuretic hormone secretion)
  • Acute pancreatitis
  • Teratogenicity

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Corticosteroids (e.g., prednisone) Additive immunosuppression; may increase risk of infections. Moderate
Doxorubicin Increased cardiotoxicity risk. High
Chloramphenicol May inhibit hepatic metabolism of cyclophosphamide, increasing toxicity. Moderate
Phenobarbital Induces CYP450 enzymes, increasing activation of cyclophosphamide and potential toxicity. Moderate
Allopurinol May increase bone marrow suppression. Moderate
NSAIDs Increased risk of gastrointestinal ulceration and bleeding. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe myelosuppression (pancytopenia)
  • Hemorrhagic cystitis (hematuria, dysuria)
  • Vomiting, diarrhea
  • Cardiotoxicity (arrhythmias, heart failure)
  • Hepatotoxicity
  • Neurotoxicity (seizures, ataxia)

Emergency Treatment Protocol: There is no specific antidote. Treatment is supportive and symptomatic: hospitalize, provide IV fluids to maintain diuresis and reduce urothelial toxicity, administer antiemetics (e.g., maropitant), and consider granulocyte colony-stimulating factor (G-CSF) for severe neutropenia. Monitor CBC, renal, and hepatic function. In severe cases, consider hemodialysis or hemoperfusion (though limited efficacy). Provide broad-spectrum antibiotics if infection develops. For hemorrhagic cystitis, consider mesna (if available) and diuresis.

Food Animal Withdrawal Times

🥩 Meat: 30 days🥛 Milk: 7 days

Cyclophosphamide is not approved for food animals; withdrawal times are extrapolated and may vary. Consult regulatory authorities. Use in food animals is off-label and requires extended withdrawal periods.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature (20-25°C) for tablets; injectable powder should be stored at 2-8°C before reconstitution.

Light Sensitivity: Light-sensitive — protect from direct exposure.

Handling & Special Conditions: Protect from light. Reconstituted solution should be used within 24 hours if stored at room temperature or 48 hours if refrigerated. Discard unused portions.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not FDA-approved for veterinary use; approved for human use.

Extra-Label (Off-Label) Use: Cyclophosphamide is not FDA-approved for veterinary species; use is extra-label under AMDUCA. Requires a valid veterinarian-client-patient relationship. For food animals, a withdrawal time must be established and observed.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Cyclophosphamide is a potent cytotoxic and immunosuppressive agent used in veterinary oncology and immune-mediated diseases. It is most commonly used in dogs and cats for lymphoma, often as part of the CHOP protocol (cyclophosphamide, doxorubicin, vincristine, prednisone). For immune-mediated diseases, it is reserved for cases refractory to corticosteroids or other immunosuppressants. Key clinical considerations: (1) Myelosuppression is dose-limiting; monitor CBC at nadir (7-10 days post-dose). (2) Hemorrhagic cystitis is a significant adverse effect; encourage frequent urination and consider mesna if high-dose IV. (3) Ensure adequate hydration before and after administration. (4) In cats, use lower doses and monitor closely due to potential metabolic differences. (5) Long-term use increases risk of secondary malignancies. (6) Always handle with gloves and dispose of waste properly. (7) For food animals, observe extended withdrawal periods. (8) Consider dose adjustments in renal or hepatic impairment. (9) Use with caution in animals with pre-existing infections. (10) Provide supportive care (antiemetics, appetite stimulants) as needed.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)