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Pronunciation |
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(MEL
fa
lan) |
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U.S. Brand
Names |
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Alkeran® |
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Generic
Available |
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No |
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Synonyms |
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L-PAM; L-Sarcolysin; Phenylalanine Mustard |
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Pharmacological Index |
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Antineoplastic Agent, Alkylating Agent |
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Use |
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Palliative treatment of multiple myeloma and nonresectable epithelial ovarian
carcinoma; neuroblastoma, rhabdomyosarcoma, breast cancer |
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Pregnancy Risk
Factor |
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D |
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Contraindications |
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Hypersensitivity to melphalan or any component; severe bone marrow
suppression; patients whose disease was resistant to prior
therapy |
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Warnings/Precautions |
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The U.S. Food and Drug Administration (FDA) currently recommends that
procedures for proper handling and disposal for antineoplastic agents be
considered. Is potentially mutagenic, carcinogenic, and teratogenic; produces
amenorrhea. Reduce dosage or discontinue therapy if leukocyte count
<3000/mm3 or platelet count <100,000/mm3; use with
caution in patients with bone marrow suppression, impaired renal function, or
who have received prior chemotherapy or irradiation; will cause amenorrhea.
Toxicity to immunosuppressives is increased in elderly. Start with lowest
recommended adult doses. Signs of infection, such as fever and WBC rise, may not
occur. Lethargy and confusion may be more prominent signs of
infection. |
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Adverse
Reactions |
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>10%:
Hematologic: Myelosuppressive: Leukopenia and thrombocytopenia are the most
common effects of melphalan. Irreversible bone marrow failure has been reported.
WBC: Moderate
Platelets: Moderate
Onset (days): 7
Nadir (days): 8-10 and 27-32
Recovery (days): 42-50
Second malignancies: Reported are melphalan more frequently
1% to 10%:
Cardiovascular: Vasculitis
Dermatologic: Vesiculation of skin, alopecia, pruritus, rash
Endocrine & metabolic: SIADH, sterility and amenorrhea
Gastrointestinal: Nausea and vomiting are mild; stomatitis and diarrhea are
infrequent
Genitourinary: Bladder irritation, hemorrhagic cystitis
Hematologic: Anemia, agranulocytosis, hemolytic anemia
Respiratory: Pulmonary fibrosis, interstitial pneumonitis
Miscellaneous: Hypersensitivity |
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Overdosage/Toxicology |
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Symptoms of overdose include hypocalcemia, pulmonary fibrosis, nausea and
vomiting, bone marrow suppression |
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Drug
Interactions |
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Decreased effect: Cimetidine and other H2-antagonists: The
reduction in gastric pH has been reported to decrease bioavailability of
melphalan by 30%
Increased toxicity: Cyclosporine: Increased incidence of nephrotoxicity
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Stability |
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Tablets/injection: Protect from light, store at room temperature
(15°C to 30°C)
The time between reconstitution/dilution and administration of parenteral
melphalan must be kept to a minimum (<60 minutes) because reconstituted and
diluted solutions are unstable
Injection: Preparation:
Dissolve powder initially with 10 mL of diluent to a concentration of 5
mg/mL. This solution is chemically and physically stable for at least 90 minutes
when stored at 25°C (77°F).
Immediately dilute dose in 0.9% sodium chloride to a concentration of
0.1-0.45 mg/mL. This solution is physically and chemically stable for at least
60 minutes at 25°C (77°F). HIGHLY
UNSTABLE SOLUTION - administration should occur within one hour of dissolution.
Do not refrigerate solution - precipitation occurs.
Standard I.V. dilution:
Dose/250-500 mL NS (concentration of 0.1-0.45 mg/mL)
MUST BE PREPARED FRESH - solution is stable for 1 hour after dilution and
must be administered within that time period |
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Mechanism of
Action |
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Alkylating agent which is a derivative of mechlorethamine that inhibits DNA
and RNA synthesis via formation of carbonium ions; cross-links strands of
DNA |
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Pharmacodynamics/Kinetics |
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Absorption: Oral: Variable and incomplete from the GI tract; food interferes
with absorption
Distribution: Vd: 0.5-0.6 L/kg throughout total body water
Bioavailability: Unpredictable, decreasing from 85% to 58% with repeated
doses
Half-life, terminal: 1.5 hours
Time to peak serum concentration: Reportedly within 2 hours
Elimination: 10% to 30% of a dose excreted unchanged in the urine; 20% to 50%
excreted in the stool after oral administration |
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Usual Dosage |
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Oral (refer to individual protocols); dose should always be adjusted to
patient response and weekly blood counts:
Children: 4-20 mg/m2/day for 1-21 days
Adults:
Multiple myeloma: 6 mg/day initially adjusted as indicated or 0.15
mg/kg/day for 7 days or 0.25 mg/kg/day for 4 days; repeat at 4- to
6-week intervals
Ovarian carcinoma: 0.2 mg/kg/day for 5 days, repeat every 4-5 weeks
Intravenous (refer to individual protocols):
Children:
Pediatric rhabdomyosarcoma: 10-35 mg/m2/dose every 21-28 days
High-dose melphalan with bone marrow transplantation for neuroblastoma:
70-100 mg/m2/day on day 7 and 6 before BMT or 140-220
mg/m2 single dose before BMT or 50 mg/m2/day for 4
days or 70 mg/m 2/day for 3 days
Adults:
Multiple myeloma: 16 mg/m2 administered at 2-week intervals for 4
doses, then repeat monthly as per protocol for multiple myeloma
Dosing adjustment in renal impairment:
Clcr 10-50 mL/minute: Administer at 75% of normal dose
Clcr <10 mL/minute: Administer at 50% of normal dose
or
BUN >30 mg/dL: Reduce dose by 50%
Serum creatinine >1.5 mg/dL: Reduce dose by 50%
Hemodialysis: Unknown
CAPD effects: Unknown
CAVH effects: Unknown |
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Dietary
Considerations |
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Food interferes with oral absorption |
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Monitoring
Parameters |
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CBC with differential and platelet count, serum electrolytes, serum uric
acid |
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Test
Interactions |
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False-positive Coombs' test [direct] |
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Mental Health: Effects
on Mental Status |
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None reported |
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Mental Health:
Effects on Psychiatric
Treatment |
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Myelosuppression is common; avoid concurrent use with clozapine and
carbamazepine |
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Dental Health: Local
Anesthetic/Vasoconstrictor
Precautions |
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No information available to require special precautions |
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Dental Health:
Effects on Dental Treatment |
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No effects or complications reported |
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Patient
Information |
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Infusion: Report promptly any pain, irritation, or redness at infusion site.
Oral: Preferable to take on an empty stomach, 1 hour prior to or 2 hours after
meals. Do not take alcohol, aspirin or aspirin-containing medications, and OTC
medications without consulting prescriber. Inform prescriber of all prescription
medication you are taking. Maintain adequate fluid balance (2-3 L/day of fluids
unless instructed to restrict fluid intake). May cause hair loss (reversible);
easy bleeding or bruising (use soft toothbrush or cotton swabs and frequent
mouth care, use electric razor, avoid sharp knives or scissors); increased
susceptibility to infection (avoid crowds or exposure to infection - do not have
any vaccinations unless approved by prescriber). Report unusual bleeding or
bruising or persistent fever or sore throat; blood in urine, stool, or vomitus;
delayed healing of any wounds; skin rash; yellowing of skin or eyes; changes in
color of urine or black stool; pain or burning on urination; respiratory
difficulty; or other severe adverse reactions. Pregnancy/breast-feeding
precautions: Inform prescriber if you are pregnant. Do not get pregnant
during or for 1 month following therapy. Male: Do not cause a female to become
pregnant. Male/female: Consult prescriber for instruction on appropriate barrier
contraceptive measures. This drug may cause severe fetal defects. Breast-feeding
is not recommended. |
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Nursing
Implications |
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Avoid skin contact with I.V. formulation |
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Dosage Forms |
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Powder for injection: 50 mg
Tablet: 2 mg |
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References |
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Alberts DS, Chang SY, Chen HS, et al, "Oral Melphalan Kinetics," Clin
Pharmacol Ther, 1979, 26(6):737-45.
Berg SL, Grisell DL, DeLaney TF, et al,
"Principles of Treatment of Pediatric Solid Tumors," Pediatr Clin North
Am, 1991, 38(2):249-67.
Coates TD, "Survival From Melphalan Overdose," Lancet, 1984,
2(8410):1048.
Hutchins LF and Lipschitz DA, "Cancer, Clinical Pharmacology, and Aging,"
Clin Geriatr Med, 1987, 3(3):483-503.
Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure.
Position Statement.
"The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding,"
January 12, 1987.
Kaplan HG, "Use of Cancer Chemotherapy in the Elderly," Drug Treatment in
the Elderly, Vestal RE, ed, Boston, MA: ADIS Health Science Press, 1984,
338-49.
Kellie SJ and Kingston JE,
"Ovarian Failure After High-Dose Melphalan in Adolescents," Lancet, 1987,
1(8547):1425.
Pole JG, Casper J, Elfenbein G, et al,
"High-Dose Chemoradiotherapy Supported by Marrow Infusions for Advanced Neuroblastoma: A Pediatric Oncology Group Study,"
J Clin Oncol, 1991, 9(1):152-8.
Schroeder H, Pinkerton CR, Powles RL, et al,
"High-Dose Melphalan and Total Body Irradiation With Autologous Marrow Rescue in Childhood Acute Lymphoblastic Leukemia After Relapse,"
Bone Marrow Transplant, 1991, 7(1):11-15.
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