MELPHALAN HYDROCHLORIDE- melphalan hydrochloride

CLINICAL PHARMACOLOGY
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 Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 minutes and 75 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 mL/min/kg to 9 mL/min/kg (250 mL/min/m2 to 325 mL/min/m2) 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 mg/m2 or 20 mg/m2 were 1. 4 mcg/mL and 2. 9 mcg/mL, respectively. The steady-state volume of distribution of melphalan is 0. 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. 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 Doses of melphalan were adjusted according to the following criteria: 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 0 107 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 Response rates at week 22 are shown in the following table: Table 2. Response Rates at Week 22 Initial Arm Evaluable Patients Responders n (%) P Oral melphalan 100 44 (44%) P Intravenous 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 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 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.
Pharmacokinetics
Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 minutes and 75 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 mL/min/kg to 9 mL/min/kg (250 mL/min/m2 to 325 mL/min/m2) 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 mg/m2 or 20 mg/m2 were 1.2 +/- 0.4 mcg/mL 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 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.
Mutagenesis
Melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 mg/m 2 2

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

The usual intravenous dose is 16 mg/m 2 PRECAUTIONS: General 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 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 hydrochloride for injection and in cases of poor peripheral venous access, consideration should be given to use of a central venous line (see WARNINGS 1. Immediately 3. 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 A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.

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. 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 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.
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.

CONTRAINDICATIONS
Melphalan hydrochloride for injection 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.
Hypersensitivity
Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving melphalan hydrochloride for injection for myeloma (see WARNINGS

Pregnancy
Pregnancy Category D. Melphalan may cause fetal harm when administered to a pregnant woman. While adequate animal studies have not been conducted with intravenous melphalan, oral (6 mg/m 2 2 2
Pregnancy: Teratogenic Effects
Pregnancy Category D: See WARNINGS
Nursing Mothers
It is not known whether this drug is excreted in human milk. Intravenous 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.

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.

Clinical Trial
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 Doses of melphalan were adjusted according to the following criteria: 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 0 107 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 Response rates at week 22 are shown in the following table: Table 2. Response Rates at Week 22 Initial Arm Evaluable Patients Responders n (%) P Oral melphalan 100 44 (44%) P Intravenous 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 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 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.
WARNINGS
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 intravenous infusion via an injection port, or via a central venous line (see DOSAGE AND ADMINISTRATION: Administration Precautions Melphalan hydrochloride for injection 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 intravenous formulation (see ADVERSE REACTIONS 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 mg 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 administration of melphalan in rats (5. 4 mg/m 2 2 2 2 Melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 mg/m 2 2 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 Category D. Melphalan may cause fetal harm when administered to a pregnant woman. While adequate animal studies have not been conducted with intravenous melphalan, oral (6 mg/m 2 2 2.
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 mg 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 administration of melphalan in rats (5.4 mg/m 2 2 2 2
Carcinogenesis,Mutagenesis, Impairment of Fertility
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.
OVERDOSAGE
Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m 2 2 2
Preparation for Administration/Stability
1. 2. Immediately 3. 4. 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 A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.
REFERENCES
1. 2. 3. Am J Health-Syst Pharm. 4. nd

Almaject, Inc.

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