Data from FDA - Curated by EPG Health - Last updated 01 January 2018

Indication(s)

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.

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Advisory information

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.
Special warnings and precautions
PRECAUTIONS General In all instances where the use of Melphalan Hydrochloride 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 IV melphalan. In one trial, increased bone marrow suppression was observed in patients with BUN levels ≥30 mg/dL. A 50% reduction in the IV melphalan dose decreased the incidence of severe bone marrow suppression in the latter portion of this study. Administration of live vaccines to immunocompromised patients should be avoided. Information for Patients Patients should be informed that the major acute toxicities of melphalan are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Patients should never be allowed to take the drug without close medical supervision and should be advised to consult their physicians if they experience skin rash, signs or symptoms of vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant. Laboratory Tests Periodic complete blood counts with differentials should be performed during the course of treatment with melphalan. At least 1 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 ). Drug Interactions The development of severe renal failure has been reported in patients treated with a single dose of IV melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. IV melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section. Pregnancy Teratogenic Effects Pregnancy Category D See WARNINGS section. Nursing Mothers It is not known whether this drug is excreted in human milk. IV melphalan should not be given to nursing mothers. Pediatric Use The safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of Melphalan Hydrochloride for Injection 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.
Adverse reactions
ADVERSE REACTIONS (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 Injection 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, IV 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.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION The usual IV dose is 16 mg/m2. 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. 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 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 1.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. 2. Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater than 0.45 mg/mL. 3.Administer the diluted product over a minimum of 15 minutes. 4.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 reconstituted material from the reaction of Melphalan Hydrochloride with Sterile Diluent for Melphalan Hydrochloride for Injection. Upon further dilution with saline, nearly 1% label strength of melphalan hydrolyzes every 10 minutes. A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.
Pregnancy and lactation
Nursing Mothers It is not known whether this drug is excreted in human milk. IV melphalan should not be given to nursing mothers.

Interactions

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

More information

Category Value
Authorisation number ANDA090270
Orphan designation No
Product NDC 67457-579
Date Last Revised 15-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 311487
Marketing authorisation holder Mylan Institutional LLC
Warnings WARNING Melphalan should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation. Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation. Melphalan is leukemogenic in humans. Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans.