Melphalan Hydrochloride

Description

DESCRIPTION Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent that is active against selected human neoplastic diseases. It is known chemically as 4-[bis(2-chloroethyl)amino]- L- phenylalanine. The molecular formula is C 13 H 18 Cl 2 N 2 O 2 and the molecular weight is 305.20. The structural formula is: Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active against certain animal tumors, and the dose needed to produce effects on chromosomes is larger than that required with the L-isomer. The racemic (DL-) form is known as merphalan or sarcolysin. Melphalan is practically insoluble in water and has a pKa 1 of ~2.5. Melphalan hydrochloride for injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single-dose vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg povidone. Melphalan hydrochloride for injection is reconstituted using the sterile diluent provided. Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6 mL, ethanol (96%) 0.52 mL, and water for injection to a total of 10 mL. Melphalan hydrochloride for injection is administered intravenously. structural formula

What Is Melphalan Hydrochloride Used For?

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

Dosage and Administration

DOSAGE AND ADMINISTRATION The usual intravenous dose is 16 mg/m 2 . Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ≥30 mg/dL) (see PRECAUTIONS: General ). The drug is administered as a single infusion over 15 to 20 minutes. Melphalan is administered at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. 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 and day of treatment should be considered. 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 for injection 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 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 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 per mL solution of melphalan. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater than 0.45 mg per mL. 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 for injection should be kept to a minimum because reconstituted and diluted solutions of melphalan hydrochloride for injection are unstable. Over as short a time as 30 minutes, a citrate derivative of melphalan has been detected in...

Side Effects (Adverse Reactions)

ADVERSE REACTIONS (SEE OVERDOSAGE ) The following information on adverse reactions is based on data from both oral and intravenous 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 for myeloma (see WARNINGS ). These reactions were characterized by urticaria, pruritus, edema, skin rashes, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid therapy. If a hypersensitivity reaction occurs, intravenous or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been reported rarely in association with such reports. 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. To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions

Drug Interactions The development of severe renal failure has been reported in patients treated with a single dose of intravenous melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. Intravenous melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic acid and intravenous melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients.

Contraindications

CONTRAINDICATIONS 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.

Pregnancy and Breastfeeding

Pregnancy Teratogenic Effects See WARNINGS section.

Nursing Mothers It is not known whether this drug is excreted in human milk. Intravenous melphalan should not be given to nursing mothers.

Overdosage

OVERDOSAGE Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m 2 , have produced the following symptoms: severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, and cholinomimetic effects. Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (>100 mg/m 2 ). Elevations in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia caused by an associated inappropriate secretion of ADH syndrome has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely. The principal toxic effect is bone marrow suppression. Hematologic parameters should be closely followed for 3 to 6 weeks. An uncontrolled study suggests that administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, filgrastim) may shorten 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. A pediatric patient survived a 254-mg/m 2 overdose treated with standard supportive care.

How Supplied

HOW SUPPLIED Melphalan hydrochloride for injection is supplied as follows: NDC Melphalan hydrochloride for injection Kit Package Factor 71288- 132 -90 One 50 mg Single-Dose Clear Glass Vial of Freeze-Dried melphalan hydrochloride for injection and One 10 mL Clear Glass Vial of Sterile Diluent 1 vial per carton 1 vial per carton Storage Conditions Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Discard unused portion. Lyophilized. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.