Get your patient on Melphalan Hydrochloride - Melphalan Hydrochloride (Melphalan Hydrochloride)

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).

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.
2.000000000000000e+00 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 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.

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 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.

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, 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.

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 BPI Labs, LLC at 1-727-471-0850 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com

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 ) were observed. One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the third course. Mean (±SD) peak melphalan plasma concentrations in myeloma patients given intravenous melphalan at doses of 10 or 20 mg/m ² were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, respectively.

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 α ₁ -acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.

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.

A randomized trial compared prednisone plus intravenous 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 1: Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC began to rise.

Arm 2: Intravenous melphalan 16 mg/m ² q 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks.

Doses of melphalan were adjusted according to the following criteria:

One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the intravenous 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 intravenous arm ( P <0.04). Response rates at week 22 are shown in the following table:

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 intravenous 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 intravenous melphalan dose if the BUN was ≥30 mg/dL. The rate of severe leukopenia in the intravenous arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) before protocol amendment to 11% (3/28) ( P = 0.01) after the amendment.

Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the intravenous 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.