ALKERAN®
Glaxo Wellcome
Melphalan
Antineoplastic
Action And Clinical Pharmacology: Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the Nposition of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
Pharmacokinetics: The pharmacokinetics of melphalan after i.v. administration have been extensively studied in adult patients, and linear pharmacokinetics were observed over a broad dose range (5 to 220 mg/m. Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 70 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m were observed. Mean (±SD) peak melphalan plasma concentrations in myeloma patients given melphalan i.v. at doses of 10 or 20 mg/mwere 1.2±0.4 and 2.8±1.9µg/mL, respectively. Studies in children as young as 1 year showed results similar to adults.
The steady-state volume of distribution of melphalan is 0.5 L/kg and approximates total body water. Penetration into cerebrospinal fluid (CSF) is low, with plasma/CSF concentration ratios reported from 10:1 to greater than 100:1. The extent of melphalan binding to plasma proteins is moderately high with reports ranging from 60 to 90%. Serum albumin is the major binding protein, while a-acid glycoprotein appears to account for about 20% of the plasma protein binding. Interaction with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxy- and dihydroxy-melphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in man. Although the contribution of renal elimination to melphalan clearance is low and most investigators have observed no relationship between renal dysfunction and melphalan pharmacokinetics, one study noted an increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 weeks of therapy.
The pharmacokinetics of melphalan administered by closed circuit limb perfusion have been studied by several investigators. Melphalan concentrations declined rapidly and biexponentially from circulating perfusate with average terminal half-lives reported from 26 min (n=4) to 53 min (n=48). Systemic exposure to melphalan during limb perfusion is generally very low. Peak melphalan concentrations in the closed circuit perfusate are typically 10 to 100 times greater than peak concentrations in plasma observed following standard dose systemic i.v. therapy for multiple myeloma.
Indications And Clinical Uses:
Caution: There are many reports of patients with multiple myeloma who have developed acute, non-lymphatic leukemia or myeloproliferative syndrome following therapy with alkylating agents (including melphalan). Evaluation of published reports strongly suggests that melphalan is leukemogenic in patients with multiple myeloma.
There is a greatly increased incidence of acute, non-lymphatic leukemia in women with ovarian carcinoma treated with alkylating agents (including melphalan).
Melphalan is a carcinogen in animals and must be presumed to be so in humans. Although the palliation to be anticipated from the use of melphalan in multiple myeloma and ovarian carcinoma is generally felt to greatly outweigh the possible induction of a second neoplasm, the potential benefits and the potential risk of carcinogenesis must be evaluated on an individual basis.
Melphalan has been observed to produce chromosomal aberrations in human cells in vitro and in vivo. Melphalan is potentially mutagenic and teratogenic in humans, although the extent of the risk is unknown.
Melphalan is indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary.
Malignant Melanoma: Melphalan for injection has been administered by hyperthermic isolated limb perfusion as an adjuvant to surgery. However, there have been no prospective controlled or uncontrolled trials evaluating dose and its relationship to disease response and/or toxicity.
Contra-Indications: 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. There may be cross-sensitivity (skin rash) between melphalan and chlorambucil.
Melphalan should not be given if other similar chemotherapeutic agents or radiotherapy have been administered to the patient recently or if neutrophil and/or platelet counts are depressed.
Melphalan should not be administered concurrently with radiotherapy.
Manufacturers’ Warnings In Clinical States:
Melphalan should be administered in carefully adjusted dosages by or under the supervision of experienced physicians who are familiar with the drug’s actions and the possible complications of its use.
The major acute toxicities are related to bone marrow suppression, hypersensitivity reactions including anaphylaxis, gastrointestinal disturbances and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Melphalan is leukemogenic and potentially mutagenic in humans.
Careful attention should be paid to the monitoring of blood counts. Patients with renal impairment should be closely observed as they may have uremic marrow suppression.
The drug should not be administered by hyperthermic isolated limb perfusion unless the clinician is experienced and well-trained in this technique.
As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression. Bone marrow suppression is the most significant toxicity associated with melphalan for injection in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent dose of melphalan: platelet count, hemoglobin, WBC count and differential. The occurrence of a platelet count below 50 000/mmor an absolute neutrophil count below 500/mmis an indication to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity.
Acute hypersensitivity reactions, including anaphylaxis, have occurred infrequently (see Adverse Effects). Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of volume expanders, pressor agents, corticosteroids, or antihistamines at the discretion of the physician.
Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of actue leukemia, myeloproliferative syndrome or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was 19.5% cumulative doses ranging from 730 mg to 9 652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.
Melphalan has been shown to cause chromatid or chromosome damage in man. Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.
Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from melphalan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Precautions: General: In all instances where the use of melphalan for injection 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. Dose reduction should be considered in patients with renal insufficiency receiving i.v. melphalan. In one trial, increased bone marrow suppression was observed in patients with BUN levels ³30 mg/dL. A 50% reduction in the i.v. melphalan dose decreased the incidence of severe bone marrow suppression in the later portion of this study.
If the leukocyte count falls below 3 000 cells/µL, or the platelet count below 100 000/µL, the drug should be discontinued until the blood picture has had a chance to recover.
Blood counts may continue to fall for 6 to 8 weeks after initiation of treatment, So, at the first sign of an abnormally large fall in leukocyte or platelet counts, treatment should be temporarily interrupted.
Patients with azotemia should be closely observed, however, in order to make dosage reductions, if required, at the earliest possible time.
Laboratory Tests: 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 dose. Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see Warnings).
Pregnancy: Safe use of melphalan has not been established with respect to adverse effects on fetal development. Therefore, it should be used in women of childbearing potential and particularly during early pregnancy only when, in the judgment of the physician, the potential benefits outweigh the possible hazards.
Children: The safety and effectiveness in children have not been established.
Geriatrics: Clinical experience with melphalan 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.
Adverse Reactions: The following information on adverse reactions is based on data from both oral and i.v. administration of melphalan as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.
Hematologic: Leukopenia, neutropenia and hemolytic anemia were observed. The most common side effect is bone marrow suppression. Irreversible bone marrow failure has been reported. Bone marrow suppression is uncommon after limb perfusion.
Blood Chemistry: Elevation in liver function enzymes is usually mild. An increase in urea and creatinine levels has been observed.
Gastrointestinal: Gastrointestinal effects such as nausea and vomiting occur in up to 30% of patients receiving conventional oral doses of melphalan and in up to 50% of patients receiving i.v. doses of melphalan. Diarrhea is noted to occur 1 week post high dose melphalan therapy. Oral ulceration and hepatic toxicity including veno-occlusive disease have been reported.
Hypersensitivity: Acute hypersensitivity reactions, including anaphylaxis, were reported in 2.4% of 425 patients receiving melphalan for injection for myeloma (see Warnings). These reactions were characterized by urticaria, pruritus, edema, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid therapy. Treatment with melphalan should be discontinued if a hypersensitivity reaction occurs.
Local Reactions: Mild pain and/or irritation at, or near, the site of injection occurred after approximately half of the infusions, resolving within a few hours after the end of the injection, without a need for treatment. Skin ulceration at injection site and flushing were reported.
Miscellaneous: Other reported adverse reactions include: skin hypersensitivity, vasculitis, alopecia, allergic reaction, pulmonary fibrosis, and interstitial pneumonitis. Flushing sensations were reported at high doses of melphalan.
Symptoms And Treatment Of Overdose: Symptoms: Overdose as high as 290 mg/mresulting in death has been reported. It has also been reported that a pediatric patient survived a 254 mg/moverdose treated with standard supportive care. The immediate effects are severe nausea and vomiting. Decreased consciousness, convulsions, muscular paralysis and cholinomimetic effects are less frequently seen. Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high dose (>100 mg/m. Elevations in liver enzymes and veno-occlusive disease occur infrequently. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely. The principal effect is bone marrow suppression.
Treatment: Hematologic parameters should be closely followed for 3 to 6 weeks. Administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, filgrastim) may shortern the period of pancytopenia. General supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis or hemoperfusion.
Dosage And Administration: Oral: Multiple Myeloma: The usual oral dose is 6 mg daily. The entire daily dose may be given at one time. It 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 melphalan dosage 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 and the platelet count is greater than 100 000. 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/µL.
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. 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.
Epithelial Ovarian Cancer: One commonly employed regimen for the treatment of ovarian carcinoma has been to administer melphalan at a dose of 0.2 mg/kg p.o. daily for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance.
I.V.: Multiple Myeloma: The usual i.v. dose is 16 mg/m Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ³30 mg/dL). The drug is administered in one dose and the length of infusion should be from 15 to 90 minutes. Melphalan is repeated at 2-week intervals initially for 4 doses, then at 4-week intervals after adequate recovery from toxicity. Available evidence suggests about one-third to one-half of the patients with multiple myeloma show a favorable response to the drug. Experience with oral melphalan suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned prematurely. Dose adjustment on the basis of blood cell counts at the nadir prior to each dose should be considered.
Perfusion Method: Malignant Melanoma: Only physicians experienced and well-trained in hyperthermic isolated limb perfusion should administer the drug in this fashion. The recommended dose of melphalan for injection for hyperthermic limb perfusion for the treatment of locally advanced malignant melanoma of the extremity is 1.0 mg/kg body weight for upper extremity and 1.5 mg/kg for lower extremity. The total dose for a perfusion should not exceed 80 mg for upper extremity and 120 mg for lower extremity. As soon as hyperthermic conditions are achieved, melphalan for injection is administered into the arterial line of the perfusion in 3 equally divided doses at 5-minute intervals. The hyperthermic perfusion is continued for one hour after the administration of melphalan for injection. The surgical technique and procedure have been well-described. To exclude or minimize perfusion-related complications, the key perfusion variables should be followed: Temperature: perfusate and i.m./s.c. tissue should not exceed 42.5 and 42°C, respectively. Flow Rate: 250 to 400 mL/minute are generally used for auxiliary perfusions, 400 to 600 mL/minute for iliac perfusions. Perfusate: 650 to 750 mL volume consisting of either heparinized whole blood (2 000 units/500 mL) or a heparinized (2 000 units/500 mL) 50:50 mixture of Lactated Ringer’s and washed packed red blood cells. Perfusion Duration: not to exceed 1 hour. Dose: not to exceed 1 mg/kg for upper extremity (total dose £80 mg) and 1.5 mg/kg for lower extremity (total dose£120 mg) of melphalan for injection.
Preparation for Administration/Stability: I.V.: Reconstitute melphalan for injection, as directed, with 10 mL of the supplied diluent. This provides a 5 mg/mL solution of melphalan. Immediately dilute the dose to be administered in 0.9% sodium chloride injection, USP, to a concentration not greater than 2 mg/mL. Administer the diluted product over a minimum of 15 minutes. Complete administration within 50 minutes of reconstitution. Discard any reconstituted and diluted solutions remaining after 50 minutes of reconstitution.
The reconstituted product is stable for up to 2 hours at 30°C. A precipitate forms if the solution is stored at 5°C. Do not refrigerate.
Solutions diluted to a concentration of 0.1 mg/mL to 0.45 mg/mL in 0.9% sodium chloride injection are stable for up to 50 minutes at 30°C and 3 hours at 20°C.
Perfusion: Reconstitute melphalan for injection, as directed, with 10 mL of the supplied diluent. This provides a 5 mg/mL solution of melphalan. Administer the reconstituted melphalan directly into the arterial line of the perfusion in 3 equally divided doses at 5-minute intervals. Complete administration within 2 hours of reconstitution. Discard any portion remaining after 2 hours of reconstitution.
The reconstituted product is stable for up to 2 hours at 30°C. A precipitate forms if the solution is stored at 5°C. Do not refrigerate.
Reconstituted Solutions: Melphalan for injection must be reconstituted, at room temperature, by rapidly transferring 10 mL of the supplied solvent-diluent directly into the vial of lyophilized powder using a sterile needle (20 gauge or larger needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. The pH of resulting solution is approximately 6.5.
Melphalan injection solution has limited stability and should be prepared immediately before use. Any unused solution should be discarded. The reconstituted solution should be used immediately and should not be refrigerated as this will cause precipitation. It is stable for up to 2 hours at 30°C.
Melphalan injection solution has reduced stability when further diluted in an infusion solution and the rate of degradation increases rapidly with rise in temperature. In that case, only Sodium Chloride Infusion, 0.9% w/v should be used. Solutions diluted to a concentration of 0.1 mg/mL to 0.45 mg/mL in 0.9% Sodium Chloride Infusion should be used immediately and are stable for up to 50 minutes at 30°C and 3 hours at 20°C.
Administration Precautions: Parenteral drug products should usually be inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not use this product.
As with other toxic compounds, caution should be exercised when handling and preparing the solution of melphalan. Skin reactions associated with accidental exposure may occur. The use of gloves is recommended. If the solution of melphalan contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
Availability And Storage: Injection: Each vial of sterile, white to cream-colored, freeze-dried powder contains: melphalan HCl equivalent to melphalan 50 mg and povidone 20 mg. Each vial of solvent-diluent provides 10 mL of buffer solution containing sodium citrate 0.20 g, ethanol 0.52 mL, propylene glycol 6 mL and water for injection, q.s. Component packs of 2 comprising a vial containing a freeze-dried powder and a vial of solvent-diluent. Store at controlled room temperature (15 to 30°C). Protect from light.
Tablets: Each white, scored tablet, imprinted ALKERAN and A2A on each side of the score, contains: melphalan 2 mg. Bottles of 50. Nonmedicinal ingredients: lactose, magnesium stearate, potato starch, povidone and sucrose. Store between 15 and 25°C, protected from light. Keep dry and dispense in glass.
ALKERAN® Glaxo Wellcome Melphalan Antineoplastic
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