In Treatment of:
It is used to treat multiple myeloma and ovarian cancer, and occasionally malignant melanoma.
The agent was first investigated as a possible drug for use in melanoma. It was not found to be effective, but has been found to be effective in the treatment of myeloma.
Common side effects include:
1. Nausea and vomiting, and oral ulceration.
2. Bone marrow suppression, including
3. Decreased white blood cell count causing increased risk of infection
4. Decreased platelet count causing increased risk of bleeding
5. Less common side effects include:
6. Severe allergic reactions
7. Pulmonary fibrosis (scarring of lung tissue) including fatal outcomes (usually only with prolonged use)
8. Hair loss
9. Interstitial pneumonitis
12. Irreversible bone marrow failure due to melphalan not being withdrawn early enough.
13. Cardiac arrest.
MELPHALAN should not be used in patients whose disease has demonstrated a prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.
In all instances where the use of MELPHALAN is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. MELPHALAN should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from previous cytotoxic therapy. If the leukocyte count falls below 3,000 cells/mcL, or the platelet count below 100,000 cells/mcL, MELPHALAN should be discontinued until the peripheral blood cell counts have recovered.
A recommendation as to whether or not dosage reduction should be made routinely in patients with renal insufficiency cannot be made because:
There is considerable inherent patient-to-patient variability in the systemic availability of melphalan in patients with normal renal function.
Only a small amount of the administered dose appears as parent drug in the urine of patients with normal renal function.
Patients with azotemia should be closely observed, however, in order to make dosage reductions, if required, at the earliest possible time.
Administration of live vaccines to immunocompromised patients should be avoided.
Periodic complete blood counts with differentials should be performed during the course of treatment with MELPHALAN. At least one determination should be obtained prior to each treatment course. Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy Category D
It is not known whether this drug is excreted in human milk. MELPHALAN should not be given to nursing mothers.
The safety and effectiveness of MELPHALAN in pediatric patients have not been established.
Clinical studies of MELPHALAN Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
There are no known drug/drug interactions with oral Melphalan
The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at one time. The dose is adjusted, as required, on the basis of blood counts done at approximately weekly intervals. After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood count should be followed carefully. When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted. Because of the patient-to-patient variation in melphalan plasma levels following oral administration of the drug, several investigators have recommended that the dosage of ALKERAN (melphalan) be cautiously escalated until some myelosuppression is observed in order to assure that potentially therapeutic levels of the drug have been reached.
Other dosage regimens have been used by various investigators. Osserman and Takatsuki have used an initial course of 10 mg/day for 7 to 10 days. They report that maximal suppression of the leukocyte and platelet counts occurs within 3 to 5 weeks and recovery within 4 to 8 weeks. Continuous maintenance therapy with 2 mg/day is instituted when the white blood cell count is greater than 4,000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. Dosage is adjusted to between 1 and 3 mg/day depending upon the hematological response. It is desirable to try to maintain a significant degree of bone marrow depression so as to keep the leukocyte count in the range of 3,000 to 3,500 cells/mcL.
Hoogstraten et al have started treatment with 0.15 mg/kg/day for 7 days. This is followed by a rest period of at least 14 days, but it may be as long as 5 to 6 weeks. Maintenance therapy is started when the white blood cell and platelet counts are rising. The maintenance dose is 0.05 mg/kg/day or less and is adjusted according to the blood count.
Available evidence suggests that about one third to one half of the patients with multiple myeloma show a favorable response to oral administration of the drug.
One study by Alexanian et al has shown that the use of ALKERAN (melphalan) in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. One regimen has been to administer courses of ALKERAN (melphalan) at 0.25 mg/kg/day for 4 consecutive days (or, 0.20 mg/kg/day for 5 consecutive days) for a total dose of 1 mg/kg/course. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte count and the platelet count have returned to normal levels.
It is to be emphasized that response may be very gradual over many months; it is important that repeated courses or continuous therapy be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned too soon.
In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially.
Epithelial Ovarian Cancer: One commonly employed regimen for the treatment of ovarian carcinoma has been to administer ALKERAN (melphalan) at a dose of 0.2 mg/kg daily for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance.
Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.