MELPHALAN- melphalan hydrochloride

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 N 7 Pharmacokinetics Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 75 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 2 2 The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%). Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while alpha 1 Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one study noted an increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 weeks of therapy. Clinical Trial A randomized trial compared prednisone plus IV melphalan to prednisone plus oral melphalan in the treatment of myeloma. As discussed below, overall response rates at week 22 were comparable; however, because of changes in trial design, conclusions as to the relative activity of the 2 formulations after week 22 are impossible to make. Both arms received oral prednisone starting at 0.8 mg/kg/day with doses tapered over 6 weeks. Melphalan doses in each arm were: Arm 2: IV melphalan 16 mg/m 2 Table 1. Criteria for Dosage Adjustment in a Randomized Clinical Trial WBC/mm 3 Platelets Percent of Full Dose >= 4,000 >= 100,000 100 >= 3,000 >= 75,000 75 >= 2,000 >= 50,000 50 < 2,000 < 50,000 0 One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor load (51% versus 34%) on the oral compared to the IV arm ( P Table 2. Response Rates at Week 22 Initial Arm Evaluable Patients Responders n (%) P Oral melphalan 100 44 (44%) P IV melphalan 195 74 (38%) Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared. Severe myelotoxicity (WBC <= 1,000 and/or platelets <= 25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%). An association was noted between poor renal function and myelosuppression; consequently, an amendment to the protocol required a 50% reduction in IV melphalan dose if the BUN was >= 30 mg/dL. The rate of severe leukopenia in the IV arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) before protocol amendment to 11% (3/28) ( P Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the IV arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1% (1/100) incidence of drug-related death in the oral arm.

Melphalan hydrochloride for injection is indicated for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

The usual IV dose is 16 mg/m 2 PRECAUTIONS, General Administration Precautions As with other toxic compounds, caution should be exercised in handling and preparing the solution of melphalan hydrochloride for injection. Skin reactions associated with accidental exposure may occur. The use of gloves is recommended. If the solution of melphalan hydrochloride contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-4 Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not use this product. Care should be taken to avoid possible extravasation of melphalan and in cases of poor peripheral venous access, consideration should be given to use of a central venous line (see WARNINGS Preparation for Administration/Stability Melphalan hydrochloride for injection must be reconstituted by rapidly injecting 10 mL of the supplied 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. This provides a 5 mg/mL solution of melphalan. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. Immediately Administer the diluted product over a minimum of 15 minutes. Complete administration within 60 minutes of reconstitution. The time between reconstitution/dilution and administration of melphalan hydrochloride should be kept to a minimum because reconstituted and diluted solutions of melphalan hydrochloride are unstable. A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.

(See OVERDOSAGE The following information on adverse reactions is based on data from both oral and IV administration of melphalan as a single agent, using several different dose schedules for treatment of a wide variety of malignancies. Hematologic The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. White blood cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure has been reported. Gastrointestinal Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported. Hepatic veno-occlusive disease has been reported. Hypersensitivity Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving melphalan hydrochloride for myeloma (see WARNINGS Miscellaneous Other reported adverse reactions include skin hypersensitivity, skin ulceration at injection site, skin necrosis rarely requiring skin grafting, maculopapular rashes, vasculitis, alopecia, hemolytic anemia, allergic reaction, pulmonary fibrosis (including fatal outcomes), and interstitial pneumonitis. Temporary significant elevation of the blood urea has been seen in the early stages of therapy in patients with renal damage. Subjective and transient sensation of warmth and/or tingling.

Melphalan should not be used in patients whose disease has demonstrated prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.

WARNINGS:
Melphalan hydrochloride may cause local tissue damage should extravasation occur, and consequently it should not be administered by direct injection into a peripheral vein. It is recommended that melphalan hydrochloride for injection be administered by injecting slowly into a fast-running IV infusion via an injection port, or via a central venous line (see DOSAGE AND ADMINISTRATION , Administration Precautions Melphalan should be administered in carefully adjusted dosage by or under the supervision of experienced physicians who are familiar with the drug ’ 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 hydrochloride in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent dose of melphalan hydrochloride: platelet count, hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity. Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered. Hypersensitivity reactions including anaphylaxis have occurred in approximately 2% of patients who received the IV formulation (see ADVERSE REACTIONS Carcinogenesis 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 acute 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 oral melphalan therapy was 19.5% for cumulative doses ranging from 730 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 oral 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. Adequate and well-controlled carcinogenicity studies have not been conducted in animals. However, intraperitoneal (IP) administration of melphalan in rats (5.4 to 10.8 mg/m 2 2 Mutagenesis Melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 and 60 mg/m 2 Impairment of Fertility 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. Pregnancy Pregnancy Category D Melphalan may cause fetal harm when administered to a pregnant woman. While adequate animal studies have not been conducted with IV melphalan, oral (6 to 18 mg/m 2 2
OVERDOSAGE:
Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m 2 2 2
REFERENCES:
NIOSH Alert: Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings. U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm/_vi/otm_vi_2.html American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. (2nd ed.) Pittsburgh, PA: Oncology Nursing Society.

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