`
`(melphalan hydrochloride)
`for Injection
`
`PRESCRIBING INFORMATION
`
` 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.
`
`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 C13H18Cl2N2O2 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 pKa1 of ∼2.5.
`ALKERAN for Injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each
`
`single-use vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg
`povidone. ALKERAN for Injection is reconstituted using the sterile diluent provided. Each vial
`of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6.0 mL, ethanol (96%) 0.52 mL,
`and Water for Injection to a total of 10 mL. ALKERAN for Injection is administered
`intravenously.
`
`
`
`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
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`at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both
`resting and rapidly dividing tumor cells.
`Pharmacokinetics: The pharmacokinetics of melphalan after IV administration has been
`extensively studied in adult patients. 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/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 IV melphalan at
`
`doses of 10 or 20 mg/m2 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 extent of melphalan binding to plasma proteins ranges
`from 60% to 90%. Serum albumin is the major binding protein, while α1-acid glycoprotein
`appears to account for about 20% of the plasma protein binding. Approximately 30% of the drug
`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.
`Clinical Trial: A randomized trial compared prednisone plus IV 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 IV melphalan 16 mg/m2 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:
`
`
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`Table 1. Criteria for Dosage Adjustment in a Randomized Clinical Trial
`
` WBC/mm3
`Platelets
`Percent of Full Dose
`100
`≥4,000
`≥100,000
`75
`≥3,000
`≥75,000
`50
`≥2,000
`≥50,000
`<2,000
`<50,000
`0
`
`
`
`One hundred seven patients were randomized to the oral melphalan arm and 203 patients to
`the IV 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 IV arm (P<0.04). Response rates at
`week 22 are shown in the following table:
`
`Table 2. Response Rates at Week 22
`
`Evaluable
`
`Initial Arm
`Patients
`Oral melphalan
`100
`IV melphalan
`195
`
`Responders
`n (%)
`44 (44%)
`74 (38%)
`
`
`P
`
`P>0.2
`
`
`
`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 IV
`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 IV melphalan dose if the BUN was
`≥30 mg/dL. The rate of severe leukopenia in the IV 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
`IV 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.
`
`
`INDICATIONS AND USAGE
`
`ALKERAN for Injection is indicated for the palliative treatment of patients with multiple
`
`myeloma for whom oral therapy is not appropriate.
`
`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.
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`WARNINGS
`
`ALKERAN 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 ALKERAN 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
`ALKERAN for Injection in most patients. Therefore, the following tests should be performed at
`the start of therapy and prior to each subsequent dose of ALKERAN: 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.
`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 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.
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`
`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/m2) and in
`mice (2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose
`observation produced peritoneal sarcoma and lung tumors, respectively.
`Mutagenesis: Melphalan has been shown to cause chromatid or chromosome damage in
`humans. Intramuscular administration of melphalan at 6 and 60 mg/m2 produced structural
`aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats.
`Impairment of Fertility: 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: Pregnancy Category D. 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/m2/day for 10 days) and IP (18 mg/m2) 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.
`
`PRECAUTIONS
`
`General: In all instances where the use of ALKERAN 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.
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`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 ALKERAN 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 (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 ALKERAN 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
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`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.
`
`OVERDOSAGE
`
`Overdoses resulting in death have been reported. Overdoses, including doses up to
`
`290 mg/m2, 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/m2). 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/m2 overdose treated with standard supportive care.
`
`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 ALKERAN. Skin reactions associated with accidental
`exposure may occur. The use of gloves is recommended. If the solution of ALKERAN contacts
`the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
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`Procedures for proper handling and disposal of anticancer drugs should be considered. Several
`
`guidelines on this subject have been published.1-8 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. ALKERAN 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 ALKERAN should be
`
`kept to a minimum because reconstituted and diluted solutions of ALKERAN 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 ALKERAN with Sterile Diluent for ALKERAN.
`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.
`
`
`
`HOW SUPPLIED
`
`ALKERAN for Injection is supplied in a carton containing one single-use clear glass vial of
`
`freeze-dried melphalan hydrochloride equivalent to 50 mg melphalan and one 10-mL clear glass
`vial of sterile diluent (NDC 59572-301-01).
`Store at controlled room temperature 15° to 30°C (59° to 86°F) and protect from light.
`
`
`
`REFERENCES
`
`1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations
`for Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41.
`2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC:
`Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services,
`National Institutes of Health; 1992. US Dept of Health and Human Services. Public Health
`Service publication NIH 92-2621.
`
`
`
`Reference ID: 2940448
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`Hospira, Exh. 2026, p. 8
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`
`
`
`
`3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics.
`JAMA. 1985;253:1590-1591.
`4. National Study Commission on Cytotoxic Exposure. Recommendations for handling
`cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study
`Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health
`Sciences, 179 Longwood Avenue, Boston, MA 02115.
`
`5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling
`
` of antineoplastic agents. Med J Australia. 1983;1:426-428.
`6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the
`Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.
`7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling
`cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
`8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.)
`Am J Health-Syst Pharm. 1996;53:1669-1685.
`
`
`
`
`ALKERAN manufactured by
`Cardinal Health
`Albuquerque, NM 87107
`for
`GlaxoSmithKline
`Research Triangle Park, NC 27709
`
`Diluent manufactured by
`GlaxoSmithKline
`Research Triangle Park, NC 27709
`
`Distributed by
`
`
`
`Celgene Corporation
`Summit, NJ 07901
`
`June 2007
`
`Reference ID: 2940448
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