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melphalan
Melphalan is a phenylalanine derivative of mechlorethamine. Alkylation of DNA results in breaks in the DNA molecules as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA. Like other alkylators, melphalan is cell cycle phase non-specific
Rapid distribution into total body water. Pharmacokinetics are linear and similar in adults and children.
| Cross blood brain barrier? | Limited; plasma to CNS ratio 10:1. |
| PPB | 55-60% serum albumin; some irreversible (20% α-acid glycoprotein) |
Chemical hydrolysis to mono and dihydroxy products; primary means of elimination.
| Active metabolites | No |
| Inactive metabolites | Yes |
Biphasic; mainly feces; renal excretion low.
| Feces | 20-50% within 6 days (PO). |
| Urine | 20-35% within 24 hours (PO); 10% as intact drug. |
| Half-life | (terminal) : 75 minutes (IV) |
- Malignant melanoma (hyperthermic isolated limb perfusion, as an adjuvant to surgery)
- Multiple myeloma
- Ovarian cancer (palliative)
Other Uses:
- Hodgkin's lymphoma
- Non-Hodgkin's lymphomas
Emetogenic Potential:
Minimal – No routine prophylaxis; PRN recommended (PO)
Extravasation Potential: Vesicant
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Flushing (high doses) | I E | |||
| Dermatological | Alopecia (BMT doses) | E | |||
| Rash | E | ||||
| Gastrointestinal | Diarrhea (especially with high-dose regimens) | E | |||
| Mucositis (with high doses) | E | ||||
| Nausea (or vomiting - PO: up to 30%; IV: up to 50%) | I | ||||
| Vomiting | I | ||||
| General | Wound complication (reduced wound healing - limb perfusion) | I E | |||
| Hematological | Hemolysis | ||||
| Myelosuppression | E | ||||
| Hepatobiliary | Hepatitis | E | |||
| Jaundice | E | ||||
| ↑ LFTs | E | ||||
| Veno-occlusive disease | E | ||||
| Hypersensitivity | Anaphylaxis (2%) (Type I anaphylactoid) | I | |||
| Injection site | Injection site reaction (50%) (transient; mild pain, irritation, warmth, tingling) | I | |||
| Necrosis (rare; or ulceration) | I E | ||||
| Metabolic / Endocrine | Hyperuricemia | ||||
| Musculoskeletal | ↑CPK (with perfusion) | I | |||
| Rhabdomyolysis (with perfusion) | I | ||||
| Neoplastic | Leukemia (secondary) | L | |||
| MDS | L | ||||
| Secondary malignancy | L | ||||
| Renal | ↑ BUN | E | |||
| Creatinine increased | E | ||||
| Reproductive and breast disorders | Infertility | L | |||
| Irregular menstruation (amenorrhea) | D | ||||
| Respiratory | Pneumonitis | E | |||
| Pulmonary fibrosis (chronic, rare) | D | ||||
| Vascular | Vasculitis | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most frequent dose-limiting toxicity is dose-related, cumulative myelosuppression.
Hypersensitivity reactions, including anaphylaxis, have been reported. Cardiac arrest has rarely been associated with such events. If a hypersensitivity reaction occurs, melphalan treatment should be discontinued.
Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g. some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.
The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected.
Nausea and vomiting occur rarely with chronic low-dose treatment, but may be more severe with single high oral or IV doses. With high dose therapy gastrointestinal toxicity (mucositis, esophagitis, and diarrhea) becomes dose-limiting.
Pulmonary fibrosis and interstitial pneumonitis have been reported. Signs and symptoms are dry cough, dyspnea, tachypnea, fever and cyanosis. Melphalan pulmonary toxicity is not related to dose or to duration of therapy. There are no identifiable risk factors. Patients either recover with complete resolution of all signs and symptoms of pulmonary toxicity or die from progressive pulmonary disease.
Alkylating agents cause gonadal suppression; therefore melphalan may cause amenorrhea or azoospermia, which may be irreversible. Second malignancies may occur in up to 20% of patients with prolonged exposure (over 600mg)
- Discontinue if hypersensitivity or pneumonitis / pulmonary fibrosis occurs.
Dosage with myelosuppression:
- Do not retreat until platelets > 100 x 109/L and neutrophils > 1.5 x 109/L. Reduce melphalan after grade 4 neutropenia or grade 3 thrombocytopenia.
- Modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Hematologic and Non-Hematologic Toxicities."
Increased incidence of severe myelosuppression has been observed in patients with BUN ≥ 10.7 mmol/L. Dose reduction should be considered in patients with renal insufficiency receiving melphalan.
| Creatinine clearance (mL/min) | % usual dose |
| 10-50 | 75% and monitor |
| <10 | 50% and monitor |
No adjustment required, but caution should be exercised.
IV MELPHALAN
- Slow push through sidearm of free-flowing IV (Normal Saline).
- For reconstitution, rapid addition of the supplied diluent to the drug vial followed by immediate vigorous shaking is important for proper dissolution.
- May dilute in Normal Saline to a concentration between 0.1 to 0.45 mg/mL; Infuse over 15-30 minutes.
- Should be administered within 50 minutes of reconstitution. Reconstituted product is stable for 2 hours at 30°C. Precipitate forms if refrigerated.
ORAL MELPHALAN
- Oral self-administration; drug available by outpatient prescription.
- Keep refrigerated.
- Take on an empty stomach.
Melphalan is contraindicated in patients whose disease has demonstrated a prior resistance to this agent, or have demonstrated hypersensitivity to melphalan or to any of its excipients. There is cross-sensitivity between melphalan and chlorambucil, which is manifested as a rash. Avoid the use of live vaccines.
Melphalan should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior radiation or chemotherapy, or whose marrow function is recovering from previous chemotherapy. Melphalan should not be administered concurrently with radiotherapy.
Melphalan is carcinogenic, mutagenic and teratogenic; it should not be used in pregnancy. Adequate contraception should be used by both sexes during melphalan treatment and for at least 6 months after treatment cessation. Breast feeding is not recommended due to the potential secretion into breast milk.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Cimetidine (and H2 receptor antagonists) | ↓ bioavailability of melphalan | Inhibit GI absorption | Monitor for ↓ melphalan activity |
| cyclosporine | ↑ nephrotoxicity | Unknown | Monitor renal function |
| Nalidixic acid | ↑ hemorrhagic enterocolitis | Unknown | Avoid concurrent treatment |
| Cisplatin | ↑ melphalan levels and toxicity | ↓ clearance | Caution |
| BCNU | ↑ risk of interstitial pneumonitis | Unknown | Caution |
| Interferon | ↓ levels of melphalan | ↑ melphalan elimination | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
| CBC | Baseline and regular |
Clinical assessment for bleeding, infection, hematologic, pulmonary, GI, local toxicity. |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
| Uric acid levels | Baseline and regular |
| Liver and renal function tests | Baseline and regular |
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1159-62.
Product Monograph: Alkeran® (melphalan). GlaxoSmithKline Inc., October 18, 2007.
June 2019 Updated emetic risk category.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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