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Drug Monographs
Treatment Regimens

Scientific Name:
MELPHALAN IV
Brand Name(s):
Alkeran®

Drug Monograph

Pharmacology

Mechanism of Action

Alkylating Agent which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA.

Pharmacokinetics

Oral Absorption:
incomplete, variable, 25-89% post oral dose; AUC decreased by 39% when taken with food.
Distribution:
rapid distribution into total body water; excretion in breast-milk unknown
cross blood brain barrier? no information
Vd:  0.5-0.6 L/kg; 14.6±5.1 L/m2
PPB: 90±5%
Metabolism:
not actively metabolised, spontaneously degrades to mono and dihydroxy products; primary means of elimination
metabolite(s): active- no inactive- no
Excretion:
mainly feces (20-50% within 6 days) and urine
feces: 20-50% within 6 days
t½a  8 minutes (IV) t½ b 1.8 hours (IV)
Urine: 10-30% as intact drug in 24 hours
Cl:  5.2±2.9 mL/min/kg; 0.438±0.178 L/min/m2

Side Effects

IMMEDIATE ONSET (hours to days)
• anaphylaxis (rare)
• nausea and vomiting (rare with chronic low doses)

EARLY ONSET (days to weeks)
• low WBC, RBC, platelets (myelosuppression nadir 10-21 days, recovery 18-40
   days)
• mouth sores (stomatitis)
• diarrhea
• darkening of skin (hyperpigmentation)
• skin rash
• hair loss (alopecia, BMT doses)

DELAYED/LATE ONSET (weeks to years)
• loss of menstruation (amenorrhea)
• infertility
• lung problems (chronic fibrosis, rare)
• acute leukemia

Therapeutics

Approved Indications

• Multiple myeloma
• Ovarian cancer

OTHER ONCOLOGY USES (Not Approved)
Acute lymphoblastic leukemia (ALL)
Breast cancer       
Ewing’s sarcoma       
Hodgkin’s disease
Malignant melanoma       
Neuroblastoma
Non-Hodgkin’s lymphomas

Routes

• Direct IV  (over 5 minutes)
• Intermittent IV  (in 100 mL over 15 minutes)
• Intraperitoneal  (refer to monograph)

Administration

• Slow push through sidearm of free flowing IV (Normal Saline) over 1-4 minutes (administering nurse should be certified to administer IV push chemotherapy agents)
• Reconstitute powder with 10mL of diluent solution, then immediately dilute dose in Normal Saline to a concentration >0.45mg/mL- Infuse within 1 hour of reconstitution
• Mix in 50-100mL bag (Normal Saline); Infuse over 15-30 minutes
• Protect from light

IV Compatibility

Normal saline only.

Dosing

Intravenous injection:
• Single IV administration of 1 mg/kg.
• Refractory Multiple Myeloma: 50 - 100 mg/m2.
Adequate trial:
• response may be gradual over many months

Intra-arterial perfusion:
• q3w: 70-100 mg x 2-3 cycles

Bone marrow transplant:
• much higher doses are used for tumour ablation prior to marrow transplant than for standard treatment regimens; eg, 100 mg/m2 IV (range 40-200 mg/m2 IV) may be used alone or in combination with other cytotoxic drugs.

Pediatric
Intravenous:
• q3-4w: 30-45 mg/m²

Bone marrow transplant:
• 40-70 mg/m²/day IV x 3 days or 110-180 mg/m² IV x 1 day

Dose Adjustment Criteria

Renal failure
Reduce to 75% dose if CrCl = 0.2-0.8mL/sec;
Reduce to 50% dose if CrCl < 0.2mL/sec (intravenous doses only)
 (Suggested action)

Antiemetic Risk

IV Doses- HIGH RISK (30-90% of patients) 
• Use a serotonin receptor antagonist PLUS dexamethasone pre-chemotherapy and post-chemotherapy

Contraindications

• Known hypersensitivity to melphalan • Pregnancy and breast feeding • Low WBC, RBC, platelets (myelosuppression)

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC), serum electrolytes and serum uric acid levels before each cycle of treatment

SUGGESTED CRITERIA
• Baseline renal function tests- intravenous doses only [serum creatinine, electrolytes & BUN]

Extravasation Hazard

VESICANT (tissue damage on extravasation). Management- stop IV, aspirate, elevate limb, cold intermittent compresses. Follow Extravasation Guidelines.

Significant Interactions

Cimetidine, cyclosporine, food, interferon alfa, nalidixic acid prednisolone, other antineoplastic agents. With high dose melphalan; avoid other quinolones such as ciprofloxacin, norfloxacin and ofloxacin.

Product Information

Commercial Product Description

Vials with 50mg for reconstitution with 10mL. Solvent diluent provided.

Pharmaceutical Considerations

Injection:
Package of one vial containing melphalan 50 mg with 20 mg povidone K12 and one vial containing 10 mL of buffer solution (60% w/v propylene glycol with sodium citrate and ethanol); store at room temperature; protect from light. Refrigeration of the package may result in incomplete dissolution of the melphalan.
Reconstitute powder with 10 mL of the diluent provided to a final concentration of 5 mg/mL. Do not use any other diluent.

Reconstituted solution for injection:
Reconstituted solution should be used as soon as possible. Trissel reports a 10% potency loss approximately 3 hours after reconstitution. Storage of the reconstituted solution in the refrigerator will result in precipitation. Solutions that appear turbid or contain crystals should be discarded.

Diluted solution for infusion:
The manufacturer states that further dilution of the reconstituted solution results in decreased stability and that, if necessary to dilute further, only NS should be used. Administration should be completed within 1.5 hours of reconstitution. Trissel recommends a maximum concentration of 2 mg/mL in NS and states that dilution in NS, D5W, or lactated Ringer’s at 25°C resulted in 10% decomposition in 2.4, 0.6 and 1.5 hours, respectively. Storage at temperatures greater than 25°C will increase the rate of degradation of melphalan. Freezing a 20 mcg/mL solution of melphalan in NS and storing at -20°C for 6 months resulted in insignificant decomposition (2-4% loss). Trissel recommends filtration of the reconstituted solution through a 0.45 micron solution during the dilution step and reports that filtration of a 20 mcg/mL solution in NS through a 0.2 micron cellulose acetate filter delivered 99% of the initial concentration.
Melphalan injection has reduced stability and the rate of degradation increases rapidly with rise in temperature.
It is recommended that melphalan not be mixed with other drugs.

Handling Risk Level

Pregnancy D/Carcinogen 1KNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor D
IARC Carcinogen Risk Group 1 (Known Carcinogen)

  • This drug must be handled using precautions outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:

HAZARD RISK LEVEL 1
FDA Pregnancy Risk Factor D
IARC Carcinogen Risk Group 1 (Known Carcinogen)
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Injection- Advanced Level; • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Formulary • NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety



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