1. Clinical Overview
Melphalan is a bifunctional alkylating agent belonging to the nitrogen mustard family, used primarily as a chemotherapeutic agent. It is a derivative of mechlorethamine and functions by forming covalent bonds with DNA, leading to interstrand and intrastrand cross-links, which inhibit DNA and RNA synthesis, ultimately causing cell death. It is cell cycle phase-nonspecific but is most active in the late G1 and S phases. In the Indian context, it is a critical, cost-effective component in the treatment of multiple myeloma and other hematological malignancies, often used in high-dose conditioning regimens prior to stem cell transplantation.
| Onset | Duration | Bioavailability |
|---|---|---|
| The onset of cytotoxic action is rapid following administration, with DNA alkylation occurring within minutes. However, the clinical therapeutic effect (e.g., reduction in tumor burden) is observed over weeks to months of treatment cycles. | The pharmacological effect is prolonged due to its irreversible binding to DNA. Myelosuppression, the dose-limiting toxicity, typically has a nadir at 2-3 weeks post-administration, with recovery in 4-5 weeks. | Oral bioavailability is highly variable and incomplete, ranging from 25% to 89% (mean approximately 56-65%). Absorption is erratic and can be significantly reduced by food, especially high-fat meals. |
2. Mechanism of Action
Melphalan is a bifunctional alkylating agent. Its active form, a highly reactive aziridinium ion, forms covalent bonds (alkylates) with the N7 position of guanine residues in DNA. This leads to the formation of interstrand and intrastrand cross-links between DNA strands, preventing DNA replication and transcription. It also causes DNA strand breaks and miscoding via depurination. These lesions trigger apoptosis (programmed cell death) in rapidly dividing cells, particularly malignant lymphocytes and plasma cells.
3. Indications & Uses
- Multiple Myeloma (Palliative treatment, Induction therapy, High-dose conditioning prior to autologous stem cell transplant)
- Ovarian Adenocarcinoma (Palliative treatment)
4. Dosage & Administration
Adult Dosage: **Multiple Myeloma (Oral):** 0.15 mg/kg/day for 7 days OR 0.25 mg/kg/day for 4 days, repeated every 4-6 weeks based on blood counts. **High-dose IV (Transplant):** 140-200 mg/m² as a single dose or split over 2 days. **Ovarian Cancer:** 0.2 mg/kg/day for 5 days, repeated every 4-5 weeks.
Administration: **Oral:** Administer on an empty stomach (1 hour before or 2 hours after food). Do not crush or break tablets. Handle tablets with gloves. **IV:** Administer as a slow intravenous infusion over 30-45 minutes. Must be reconstituted and diluted immediately prior to use. Strict aseptic technique and careful avoidance of extravasation is mandatory. Pre- and post-hydration is often used with high-dose therapy.
5. Side Effects
Common side effects may include:
- Nausea and vomiting (mild to moderate)
- Myelosuppression: Leukopenia, Neutropenia, Thrombocytopenia, Anemia (nadir at 2-3 weeks)
- Mucositis/Stomatitis (especially with high-dose IV)
- Alopecia (mild, not always)
- Diarrhea
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Cyclosporine | Increased risk of renal toxicity and possibly enhanced myelosuppression. | Major |
| Nalidixic Acid | Increased risk of severe hemorrhagic necrotic enterocolitis in children. | Contraindicated |
| Live Vaccines (e.g., BCG, MMR, Varicella) | Risk of disseminated vaccine-induced infection due to immunosuppression. | Major |
| Other Myelosuppressants (e.g., Azathioprine, Clozapine) | Additive bone marrow toxicity. | Major |
| Cimetidine | May reduce oral bioavailability of melphalan. | Moderate |
| Interferon Alfa | Possible increased pulmonary toxicity (fibrosis). | Moderate |
7. Patient Counselling
- DO take tablets exactly as prescribed, on an empty stomach.
- DO swallow tablets whole; do not crush, break, or chew.
- DO use gloves or wash hands thoroughly after handling tablets if you are a caregiver.
- DO maintain excellent oral hygiene to reduce risk of mucositis.
- DONT take the drug if you are pregnant, planning pregnancy, or breastfeeding.
- DONT receive live vaccines while on therapy.
- DONT take over-the-counter medications, especially NSAIDs, without consulting your doctor.
- DONT miss scheduled blood tests.
8. Toxicology & Storage
Overdose: Manifestations of severe, potentially fatal myelosuppression (pancytopenia, infection, hemorrhage), severe mucositis, diarrhea, vomiting, and hepatic toxicity. Symptoms may be delayed by 1-3 weeks post-ingestion.
Storage: Store at 2°C to 8°C (refrigerated). Do not freeze. Protect from light. Keep in the original container. For the intravenous formulation: after reconstitution, the solution is unstable; it must be diluted and administered immediately. Keep out of reach of children and pets. Return unused or expired medication to the hospital pharmacy for hazardous waste disposal. Do not flush or throw in household trash.