ALKERAN

Melphalan is a nitrogen mustard or bischloroethylamine type alkylating agent.

It was first synthesized in the early 1950s by substituting L-phenylalanine for the methyl group on nitrogen mustard. 4, 5 Melphalan is used in the treatment of multiple myeloma and ovarian carcinoma.

It is also used for high-conditioning before hematopoietic stem cell transplant.

It is also used to treat uveal melanoma with unresectable hepatic metastases.

Melphalan is indicated for use as a high-dose conditioning treatment prior to hematopoietic stem cell transplantation in patients with multiple myeloma.

It is also indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary.

Melphalan is a component of HEPZATO

KIT, a liver-directed therapy indicated for the treatment of adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.

Melphalan possesses cytotoxic, immunosuppressive, and myeloablative activities. 4, 7 Melphalan produces chromosomal aberrations in vitro and in vivo; thus, it is considered to be potentially leukemogenic in humans.

It also causes dose-limiting bone marrow suppression.

The peak mean heart rate increased by 20 bpm from baseline following melphalan 100 mg/m for two consecutive days in multiple myeloma patients undergoing autologous stem cell transplantation.

The absorption of oral melphalan is highly variable concerning both the time to the first appearance of the drug in plasma (range: 0-6 hours) and peak plasma concentration (C max ).

The average absolute bioavailability of melphalan ranges from 56% to 93%.

High variability in bioavailability may be due to incomplete intestinal absorption, variable first-pass hepatic metabolism, or rapid hydrolysis.

T max was one hour in patients who received single oral doses of 0.2 mg/kg to 0.25 mg/kg of melphalan.

Oral administration of melphalan with a high-fat meal may reduce melphalan exposure (AUC) by 36% to 54%.

Mean (± SD) C max and AUC 0-inf were 5.8 ± 1.5 mcg/mL and 451 ± 109 mcg x min/mL, respectively, following intravenous administration of 100 mg/m in multiple myeloma patients.

The volume of distribution of melphalan ranges from approximately 35.5-185.7 L/m 2.

Penetration into cerebrospinal fluid is low.

Melphalan primarily undergoes chemical hydrolysis to inactive metabolites, monohydroxymelphalan and dihydroxymelphalan. 7, 8 No other melphalan metabolites have been observed in humans.

Hover over products below to view reaction partners Melphalan Monohydroxymelphalan Dihydroxymelphalan.

About 5.8% to 21.3% of melphalan is excreted in urine.

In patients given a single oral dose of 0.6 mg/kg of melphalan, the terminal elimination plasma half-life (± SD) was 1.5 ± 0.83 hours.

Following intravenous administration, the terminal elimination half-life is approximately 75 minutes.

Average total body clearance (CL) ranges from approximately 250-325 mL/min/m 2.

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The oral and intraperitoneal

LD in rats is 4484 µg/kg and 11200 µg/kg, respectively.

The subcutaneous

LD in mice is 32 mg/kg.

Overdoses resulting in death have been reported with melphalan.

Overdoses, including intravenous doses up to 290 mg/m and oral doses up to 50 mg/day for 16 days, have been reported.

Symptoms of overdose include severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, cholinomimetic effects, mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract.

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.

Melphalan is not removed from plasma via hemodialysis, and overdose is typically managed by general supportive measures, with appropriate blood transfusions and antibiotics. 7, 8.

Melphalan Hydrochloride for

Injection 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's actions and the possible complications of its use.

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 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 Hydrochloride for Injection: 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.

These reactions usually occur after multiple courses of treatment.

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.

If a hypersensitivity reaction occurs, IV or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan.

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 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 ) and in mice (2.25 to 4.5 mg/m 2 ) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively.

Melphalan has been shown to cause chromatid or chromosome damage in humans.

Intramuscular administration of melphalan at and 60 mg/m 2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats.

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.

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 /day for 10 days) and IP (18 mg/m 2 ) administration in rats was embryolethal and teratogenic.

Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly).

There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid becoming pregnant.

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.

The usual

IV dose is 16 mg/m 2.

Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ≥30 mg/dL) .

The drug is administered as a single infusion over 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.

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 ormucosa, 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/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/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 reconstituted material from the reaction of Melphalan Hydrochloride for Injection 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.

Melphalan Hydrochloride for Injection is supplied as follows: NDC Melphalan Hydrochloride for Injection (Kit) Package Factor 84679-001-01 50 mg Single-Dose Vial of Melphalan Hydrochloride for Injection and 10 mL Vial of Sterile Diluent 1 vial per carton 1 vial per carton Each carton contains one single-dose clear glass vial of freeze-dried melphalan hydrochloride equivalent to 50 mg melphalan and one 10 mL clear glass vial of sterile diluent.

Store at 20° to 25°C (68° to 77°F).

Protect from light.

Discard unused portion.

The container closure is not made with natural rubber latex.

Store at 20° to 25°C (68° to 77°F).

Protect from light.

Discard unused portion.

The container closure is not made with natural rubber latex.

See WARNINGS section.

It is not known whether this drug is excreted in human milk.

IV melphalan should not be given to nursing mothers.

The safety and effectiveness in pediatric patients have not been established.

Clinical studies of Melphalan Hydrochloride for

Injection did not include sufficient numbers of subjects aged 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.