Melphalan — Veterinary Vademecum Drug Reference

Dosage & Administration Guidelines

Species	Route	Dose	Frequency	Duration & Clinical Notes
Dog	PO	0.1-0.2 mg/kg	q24h for 7-10 days, then q48h or as maintenance	Duration: Continuous or as per protocol Notes: For multiple myeloma, commonly used at 0.1 mg/kg PO q24h for 10 days, then 0.1 mg/kg q48h. For lymphoma rescue, 0.1-0.2 mg/kg PO q24h for 5-7 days, repeated every 3 weeks.
Dog	IV	0.5-1.0 mg/m²	q21 days	Duration: As per protocol Notes: IV administration is less common; used in high-dose protocols with autologous bone marrow transplant.
Cat	PO	0.1-0.2 mg/kg	q24h for 7-10 days, then q48h	Duration: Continuous or as per protocol Notes: Cats may be more sensitive to myelosuppression; monitor CBC closely.

Clinical Indications & Species Uses

General Indications

Treatment of various neoplasms, particularly multiple myeloma and lymphoma

Dog (Canine)

Multiple myeloma
Lymphoma (as a rescue agent)
Mast cell tumors (as a rescue agent)
Osteosarcoma (adjuvant therapy)

Cat (Feline)

Multiple myeloma
Lymphoma (as a rescue agent)

Pharmacology & Mechanism of Action

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

Mechanism of Action: Melphalan is a bifunctional alkylating agent that forms cross-links between DNA strands, primarily at guanine N7 positions. This leads to inhibition of DNA replication and transcription, resulting in cell cycle arrest and apoptosis. It is cell cycle phase-nonspecific, affecting both dividing and resting cells, but is most toxic to rapidly proliferating tissues.

Pharmacodynamics: Melphalan exhibits cytotoxic activity against a wide range of neoplasms. Its effects are dose-dependent and schedule-dependent, with higher doses producing more profound myelosuppression. It has a steep dose-response curve, and resistance can develop via increased DNA repair mechanisms or decreased drug uptake.

⚡ Pharmacokinetics Summary

Absorption: Oral absorption is variable and incomplete, with bioavailability ranging from 25% to 89% in humans; in dogs, it is approximately 50-60%. Food can reduce absorption. Intravenous administration provides complete bioavailability.

Distribution: Melphalan is widely distributed throughout the body, with a volume of distribution of approximately 0.5 L/kg in humans. It crosses the blood-brain barrier poorly. It is extensively bound to plasma proteins (60-90%), primarily albumin.

Metabolism: Melphalan undergoes spontaneous chemical hydrolysis to monohydroxy and dihydroxy derivatives, which are inactive. It is also metabolized by the liver via cytochrome P450 enzymes, though the extent is limited.

Excretion: Renal excretion is the primary route of elimination, with approximately 30% of the drug excreted unchanged in urine. Biliary excretion is minor. Clearance is reduced in patients with renal impairment.

Half-Life: Dogs: 1-2 hours; Cats: approximately 1 hour; Humans: 1.5-2 hours.

Bioavailability: Oral: 25-89% (variable); in dogs, approximately 50-60%.

Protein Binding: 60-90% bound to plasma proteins, primarily albumin.

Available Formulations & Strengths

Oral Tablet 2 mg (PO)

Injectable Solution 50 mg vial (as powder for reconstitution) (IV)

Contraindications & Clinical Warnings

Contraindications:

Hypersensitivity to melphalan or other nitrogen mustards
Severe bone marrow depression (unless intended as a conditioning regimen)
Pregnancy (teratogenic)
Lactation (may be excreted in milk)

Warnings & Clinical Precautions:

Myelosuppression is dose-limiting; monitor complete blood count regularly.
Renal impairment may require dose reduction.
Hepatic impairment may require dose adjustment.
Use with caution in patients with prior cytotoxic therapy or radiation.
May be carcinogenic; handle with care.
Extravasation can cause tissue damage; administer IV carefully.
In cats, monitor for signs of neurotoxicity (rare).

Adverse Effects & Reactions

Common:

Myelosuppression (neutropenia, thrombocytopenia, anemia)
Gastrointestinal effects (vomiting, diarrhea, anorexia)
Alopecia (in some breeds)

Serious / Severe:

Severe bone marrow suppression leading to infection or bleeding
Secondary malignancies (long-term use)
Pulmonary fibrosis (rare)
Hepatotoxicity

Rare:

Neurotoxicity (especially in cats)
Hypersensitivity reactions
Stevens-Johnson syndrome

Key Drug Interactions

Interacting Drug / Class	Clinical Effect & Mechanism	Severity
Nephrotoxic drugs (e.g., aminoglycosides, NSAIDs)	Increased risk of renal toxicity; may reduce melphalan clearance.	Moderate
Myelosuppressive agents (e.g., cyclophosphamide, doxorubicin)	Additive myelosuppression.	High
Cimetidine	May reduce melphalan absorption.	Mild
Vaccines (live)	Immunosuppression may increase risk of infection from live vaccines.	Moderate

Overdose & Toxicity Management

Signs of Toxicity:

Severe myelosuppression (pancytopenia)
Gastrointestinal toxicity (vomiting, diarrhea)
Hepatotoxicity
Neurotoxicity (seizures, ataxia)

Emergency Treatment Protocol: There is no specific antidote. Treatment is supportive: hospitalization, fluid therapy, blood transfusions, antibiotics for infections, and hematopoietic growth factors (e.g., G-CSF). In severe cases, consider stem cell rescue.

Food Animal Withdrawal Times

Not approved for food animals; no withdrawal times established. Use in food animals is prohibited.

Storage, Handling & Regulatory Information

Storage Temperature: Store at room temperature (15-30°C) in a tightly closed container.

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

Handling & Special Conditions: Protect from light. Keep out of reach of children and pets. Handle with gloves.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Approved for human use; not FDA-approved for veterinary use, but commonly used in veterinary oncology.

Extra-Label (Off-Label) Use: In the US, extra-label use in food animals is prohibited. In companion animals, extra-label use is permitted under AMDUCA with appropriate veterinary oversight.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Melphalan is an important chemotherapeutic agent in veterinary oncology, particularly for multiple myeloma in dogs and cats. It is often used in combination with prednisone. Due to its variable oral bioavailability, therapeutic drug monitoring is not routinely performed, but careful hematologic monitoring is essential. Dose adjustments should be made based on neutrophil and platelet counts. In cats, lower doses are recommended due to increased sensitivity. Clients should be educated on handling and disposal of the drug and its excreta. Prognosis is variable, but melphalan-based protocols can provide prolonged remission in multiple myeloma.

References & Literature

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