Melphalan

Class: Antineoplastic Agents
VA Class: AN100
CAS Number: 148-82-3
Brands: Alkeran

Warning(s)

  • Experience of Supervising Clinician
  • For administration only by individuals experienced in the administration of chemotherapeutic agents.b c

    • Hematologic Toxicity
    • Risk of severe bone marrow suppression (e.g., thrombocytopenia, leukopenia), resulting in bleeding and infection.b c (See Hematologic Effects under Cautions.)

    • Mutagenicity and Carcinogenicity
    • Known carcinogen.b c (See Mutagenicity and Carcinogenicity under Cautions.)

    • Produces chromosomal aberrations in vitro and in vivo; considered potentially mutagenic in humans.b c (See Mutagenicity and Carcinogenicity under Cautions.)

    • Hypersensitivity Reactions
    • Hypersensitivity reactions, including anaphylaxis, reported.c

Introduction

Antineoplastic agent; nitrogen mustard derivative; alkylating agent.a b c

Uses for Melphalan

Multiple Myeloma

Used alone and as a component of various chemotherapeutic regimens in the palliative treatment of multiple myeloma.a b c

As effective as cyclophosphamide; combination of either agent with prednisone is considered treatment of choice.a d

Ovarian Cancer

Palliative treatment of nonresectable epithelial ovarian cancer.113 122 b

Slideshow: The Ferocity of Chemotherapy - Does The End Justify The Means?

Has been administered intraperitoneally for treatment of advanced ovarian cancer confined to the peritoneal cavity and/or associated with malignant ascites.101

Breast Cancer

Has been used alone or as a component of various chemotherapeutic regimens as an adjunct to surgery in the treatment of breast cancer.134 135 136 138 139 a

Melanoma

Has been used alone and in combination regimens in isolated limb perfusion for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma of the extremities.144 145 146 148

Amyloidosis

Has been used with prednisone in the treatment of amyloidosis.141

Melphalan Dosage and Administration

General

  • Adjust dosage carefully according to clinical and hematologic response, based on weekly blood counts, and tolerance of the patient to obtain optimum therapeutic results with minimum adverse effects.a b

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.106 b c

Administration

Administer orally or by IV infusion.b c

Has been administered by regional isolation perfusion (e.g., for melanoma)144 145 146 148 149 and intraperitoneally (e.g., for advanced ovarian cancer).101

Usually administered orally;113 123 124 125 126 127 b however, can also be administered IV in the palliative treatment of multiple myeloma106 114 115 116 117 118 120 in patients in whom oral therapy is not feasible.106 118 120 c

Oral Administration

Administer orally on an empty stomach.108

Administer continuously (as single daily doses) or intermittently (e.g., daily for 7 days every 4–6 weeks).a b

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer IV only by individuals experienced in the administration of the drug.a c

Administer diluted solution slowly into a freely running IV infusion via an injection port or into a central venous line.c

Avoid extravasation; do not administer by direct injection into a peripheral vein.c (See Local Effects under Cautions.)

Handle cautiously (e.g., use protective gloves);c avoid exposure during handling and preparation of IV solution.c If skin or mucosal contact occurs, immediately wash skin or mucosa with soap and water and flush with water.c

Reconstitution

Reconstitute vial containing 50 mg of melphalan by rapidly adding 10 mL of the diluent provided by the manufacturer with a 20-gauge or larger needle to provide a solution containing 5 mg/mL.106 118 119 c

Shake vigorously until a clear solution is obtained.106 118 119 c Must be diluted (immediately after reconstitution) prior to IV infusion.a

Dilution

Immediately dilute reconstituted solution with 0.9% sodium chloride injection to a concentration not >0.45 mg/mL.106 118 119 c

Rate of Administration

Administer by IV infusion over >15 minutes.106 119 120 c Administration should be completed within 60 minutes of reconstitution.106 119 c

Dosage

Available as melphalan and melphalan hydrochloride; dosage expressed in terms of melphalan.106 b c

Consult published protocols for the dosage of melphalan and other chemotherapeutic agents and the method and sequence of administration.a

Consider dosage adjustments based on the blood cell nadir and blood counts taken on the day of therapy.106 113 119 Generally, maintain leukocyte count between 3000–3500/mm3.b

Therapeutic response may occur gradually over several months.b 3–12 months of repeated courses or continuous therapy may be required to evaluate drug response and obtain maximum benefit from the drug.a b

Adults

Multiple Myeloma
Oral

Usual initial and maintenance dosage regimen: 6 mg daily for 2–3 weeks.a b Withhold therapy until leukocyte and platelet counts increase (i.e., up to 4 weeks) and then initiate maintenance therapy of 2 mg daily.a b Adjust dosage, as required, to maintain a degree of bone marrow depression.a b

Alternatively, 10 mg daily for 7–10 days.113 Withhold therapy until platelet and leukocyte counts exceed 100,000/mm3 and 4000/mm3, respectively, and then initiate maintenance therapy of 2 mg daily.113 Adjust dosage, as required, to between 1–3 mg daily, depending on hematologic response.113

Alternatively, 0.15 mg/kg daily for 7 days.a b Withhold therapy until platelet and leukocyte counts increase (i.e., 2–6 weeks), and then initiate maintenance therapy of ≤0.05 mg/kg daily.b Adjust dosage, as required, depending on hematologic response.b

Alternatively, 0.25 mg/kg daily for 4 days or 0.2 mg/kg daily for 5 days, with prednisone; administer at 4–6 week-intervals, if granulocyte and platelet counts are normal.b

IV

Usual dosage: 16 mg/m2 at 2-week intervals for 4 doses.106 118 119 120 After satisfactory recovery from toxicity, initiate maintenance therapy of 16 mg/m2 at 4-week intervals.106 118 119 120

Ovarian Cancer
Oral

Usual dosage: 0.2 mg/kg daily for 5 successive days; administer at intervals of 4–5 weeks.113 b

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.b c

Renal Impairment

Oral

In patients with moderate to severe renal impairment, consider reducing initial dosage; however, no specific dosage recommendations at this time.b

IV

In patients with renal impairment (BUN ≥30 mg/dL), reduce dosage by 50%. 106 118 120 c

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.b c

Cautions for Melphalan

Contraindications

  • Prior resistance to melphalan therapy.a b c

  • Known hypersensitivity to melphalan or any ingredient in the formulation.a b c

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

Administer only under constant supervision by clinicians experienced in therapy with cytotoxic agents.a b c

Hematologic Effects

Risk of dose-limiting myelosuppression, manifested principally by leukopenia and thrombocytopenia; anemia also may occur.a b c d

Severe myelosuppression more common with IV melphalan than with oral melphalan.c

Leukocyte and platelet nadirs generally occur 2–3 weeks after treatment; recovery usually occurs 4–5 weeks after treatment.a c Irreversible bone marrow depression has been reported.106 113 119 c

Careful hematologic monitoring required.a Perform CBCs (leukocyte count with differential, platelet count, hemoglobin) prior to and at periodic intervals during therapy (i.e., prior to each subsequent course of oral melphalan and prior to each subsequent dose of IV melphalan).106 b c Withhold therapy until leukocyte count is >3000/mm3 and platelet count is >100,000/mm3.b

Monitor closely for symptoms of bone marrow suppression (e.g., severe infections, bleeding, symptomatic anemia).b c

Use with caution in patients with compromised bone marrow reserve (i.e., prior radiation therapy or prior therapy with other cytotoxic agents).b c

Positive direct Coombs’ test results and concurrent hemolytic anemia have been reported.a

Mutagenicity and Carcinogenicity

Possible leukemia or secondary malignancies; assess risk/benefits of therapy.106 113 b c d

Causes chromatid or chromosome damage in humans.106 113 b c

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.106 113 b c Avoid pregnancy during therapy.b c If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.106 113 b c

Fertility

Reversible and irreversible testicular suppression reported.b c d

Ovarian suppression and amenorrhea reported in premenopausal females.106 113 b c d

Local Effects

Extravasation may produce severe local tissue necrosis.c

Administration by regional isolation perfusion may cause erythema and/or edema of perfused area, thrombophlebitis, necrotizing fasciitis, and varying degrees of vesiculation and tissue necrosis; amputation sometimes has been necessary.147 148

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, urticaria, pruritus, edema, rashes, tachycardia, bronchospasm, dyspnea, and hypotension reported in 2% of patients receiving IV melphalan and rarely in patients receiving oral melphalan.a b c

If hypersensitivity reaction occurs, discontinue immediately and initiate appropriate therapy as indicated (e.g., plasma volume expanders, vasopressors, corticosteroids, antihistamines).106 b c

Cross-Sensitivity

Potential for cross-sensitivity (rash) between melphalan and other alkylating agents.a

General Precautions

Immunization.

Avoid administration of live vaccines to immunocompromised patients.b c

Pulmonary Toxicity

Pulmonary embolism, sometimes fatal,148 and fibrosis have been reported.106 113 148 d

Specific Populations

Pregnancy

Category D.b c (See Fetal/Neonatal Morbidity and Mortality and also Fertility, under Cautions.)

Lactation

Not known whether melphalan is distributed into milk;106 113 b c discontinue nursing or the drug.106 113 b c

Pediatric Use

Safety and efficacy not established.106 113

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.b c

Renal Impairment

Increased bone marrow suppression and risk of severe leukopenia in patients with renal impairment receiving IV melphalan; dosage reduction should be considered.c Closely monitor patients with azotemia receiving oral melphalan; oral dosage reductions may be required.106 118 b (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Bone marrow suppression, mild nausea.b

Interactions for Melphalan

Specific Drugs

Drug

Interaction

Comments

Carmustine

Possible reduced threshold for carmustine-induced pulmonary toxicity with IV melphalan106 119 c

Cimetidine

Possible reduced serum melphalan concentrations secondary to cimetidine-induced inhibition of GI absorption of melphalan 109

Monitor for decreased melphalan activity109

Cisplatin

Possible decreased clearance of melphalan secondary to cisplatin-induced renal impairment106 119 c

Cyclosporine

Possible increased risk of cyclosporine-induced nephrotoxicity107 112 c

Monitor renal function107 112 c

Consider reducing cyclosporine dosage in patients receiving high-dose melphalan112

Interferon alfa

Interferon alfa-induced fever may increase plasma elimination of melphalan110 111

Nalidixic acid

Possible increased incidence of severe hemorrhagic necrotic enterocolitis in pediatric patients106 119 c

Melphalan Pharmacokinetics

Absorption

Bioavailability

Absorption from the GI tract is incomplete and extremely variable.a b

Food

Food decreases bioavailability by about 35%.108

Distribution

Extent

Rapidly distributed throughout total body water;a distributes into CSF in low concentrations.106 113 119 b c

Not known whether melphalan crosses the placenta or is distributed into milk.a b c

Plasma Protein Binding

About 60–90% (30% irreversibly); mainly albumin and to a lesser extent α1-acid glycoprotein.106 113 119 b c

Elimination

Metabolism

Undergoes spontaneous hydrolysis in plasma to monohydroxymelphalan and dihydroxymelphalan.a b c

Elimination Route

20–35% of oral dose excreted in urine within 24 hours; 20–50% excreted in feces within 6 days.a

Not removed by hemodialysis.106 113

Half-life

Following oral administration, terminal half-life of unchanged drug is 1.5 hours;a terminal half-lives of monohydroxymelphalan and dihydroxymelphalan are 2–3 times longer.a

Following IV administration, terminal half-life is about 75 minutes.106 c

Stability

Storage

Oral

Tablets

2–8°C.b

Parenteral

Powder for Injection

15–30°C; protect unopened vials from light.c

Reconstituted and diluted solutions are unstable; following reconstitution, 1% of label strength hydrolyzed every 10 minutes.c Use within 60 minutes of reconstitution.c

Following reconstitution, do not refrigerate; refrigeration of reconstituted solution may cause precipitation.c

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

1 Incompatible by standard definition; recommended for dilution with use in shorter periods of time.

Incompatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%1

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Amikacin sulfate

Aminophylline

Ampicillin sodium

Aztreonam

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Caspofungin acetate

Cefazolin sodium

Cefotaxime sodium

Cefotetan disodium

Ceftazidime

Ceftriaxone sodium

Cefuroxime sodium

Cisplatin

Clindamycin phosphate

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dacarbazine

Dactinomycin

Daunorubicin HCl

Dexamethasone sodium phosphate

Diphenhydramine HCl

Doxorubicin HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Etoposide

Famotidine

Filgrastim

Floxuridine

Fluconazole

Fludarabine phosphate

Fluorouracil

Furosemide

Gallium nitrate

Ganciclovir sodium

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Idarubicin HCl

Ifosfamide

Imipenem–cilastatin sodium

Lorazepam

Mannitol

Mechlorethamine HCl

Meperidine HCl

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Mitomycin

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Ondansetron HCl

Pentostatin

Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate

Streptozocin

Teniposide

Thiotepa

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Zidovudine

Incompatible

Amphotericin B

Chlorpromazine HCl

Actions

  • Interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of nucleic acid function.a

  • Active against both resting and rapidly dividing tumor cells.b c

  • Possesses some immunosuppressive activity.a

Advice to Patients

  • Risk of bone marrow suppression, hypersensitivity reactions, infertility, pulmonary toxicities, and secondary malignancies.106 113 b c d

  • Advise patients that oral melphalan should be taken on an empty stomach.108

  • Importance of close medical supervision of patients receiving melphalan.a b c

  • Importance of informing clinicians if rash, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps or masses occur.b c

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.b c

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.b c

  • Importance of informing patients of other important precautionary information.b (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Melphalan

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2 mg

Alkeran (scored)

Celgene

Melphalan Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

50 mg (of melphalan)

Alkeran

Celgene

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Alkeran 2MG Tablets (APO PHARMA USA): 50/$425.00 or 150/$1,241.02

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

84. Einhorn N. Acute leukemia after chemotherapy (melphalan). Cancer. 1978; 41:444-7. [IDIS 101911] [PubMed 272946]

100. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983; 2:822-4. [IDIS 176847] [PubMed 6137651]

101. Howell SB, Pfeifle CE, Olshen RA. Intraperitoneal chemotherapy with melphalan. Ann Intern Med. 1984; 101:14-8. [IDIS 188162] [PubMed 6732077]

102. Greene MH, Harris EL, Gershenson DM et al. Melphalan may be a more potent leukemogen than cyclophosphamide. Ann Intern Med. 1986; 105:360-7. [IDIS 220340] [PubMed 3740675]

103. Fisher B, Rockette H, Fisher ER et al. Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience. J Clin Oncol. 1985; 3:1640-58. [PubMed 3906049]

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105. Wadler S, Yeap B, Vogl S et al. Randomized trial of initial therapy with melphalan versus cisplatin-based combination chemotherapy in patients with advanced ovarian carcinoma: initial and long term results—Eastern Cooperative Oncology Group Study E2878. Cancer. 1996; 77:733-42. [IDIS 363630] [PubMed 8616766]

106. Glaxo Wellcome. Alkeran (melphalan hydrochloride) for injection prescribing information. Research Triangle Park, NC; 1998 Aug.

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108. Melphalan (Alkeran) interactions: food. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:411.

109. Melphalan (Alkeran) interactions: H2 receptor antagonists. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:410.

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125. MacLennan ICM, Chapman C, Dunn J et al. Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet. 1992; 339:200-5. [IDIS 290524] [PubMed 1346171]

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128. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.

129. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet. 1992; 339:1-15,71-85. [IDIS 290641] [PubMed 1345950]

130. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976; 294:405-10. [PubMed 1246307]

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132. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994; 330:1253-9. [IDIS 329429] [PubMed 8080512]

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134. Fisher B, Redmond C, Wickerman DL et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989; 7:572-82. [PubMed 2651576]

135. Fisher B, Glass A, Redmond C et al. l-Phenylalanine mustard (l-PAM) in the management of breast cancer: an update of earlier findings and a comparison with those utilizing l-PAM plus fluorouracil (5-FU). Cancer. 1977; 39(Suppl):2883-903. [PubMed 194679]

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137. Fisher B, Redmond C, Brown A et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol. 1986; 4:459-71. [PubMed 2856857]

138. Rivkin SE, Green S, Metch B et al. Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study. J Clin Oncol. 1989; 7:1229-38. [PubMed 2671283]

139. Fisher B, Redmond C, Brown A et al. Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast disease. J Clin Oncol. 1983; 1:227-41. [PubMed 6366135]

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141. Kyle RA, Gertz MA, Greipp PR et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997; 336:1202-7. [IDIS 383378] [PubMed 9110907]

142. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997; 337:898-909. [IDIS 391785] [PubMed 9302305]

143. Skinner M, Anderson JJ, Simms R et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med. 1996; 100:290-8. [IDIS 362735] [PubMed 8629674]

144. Melanoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Aug.

145. Duran Garcia E, Santolaya R, Requena T. Treatment of malignant melanoma. Ann Pharmacother. 1999; 33:730-8. [IDIS 428254] [PubMed 10410188]

146. Houghton A, Coit D, Bloomer W et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology (Huntingt). 1998; 12:153-77.

147. Koops HS, Vaglini M, Suciu S et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol. 1998; 16:2906-12. [IDIS 414236] [PubMed 9738557]

148. Hafstrom L, Rudenstam CM, Blomquist E et al. Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. J Clin Oncol. 1991; 9:2091-4. [PubMed 1960549]

149. Fraker DL, Alexander HR, Andrich M et al. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol. 1996; 14:479-89. [IDIS 362040] [PubMed 8636761]

a. AHFS drug information 2007. McEvoy GK, ed. Melphalan. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1125-8.

b. Glaxo Wellcome. Alkeran (melphalan hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2004 Nov.

c. Glaxo Wellcome. Alkeran (melphalan hydrochloride) for injection prescribing information. Research Triangle Park, NC; 2007 Mar.

d. Treatment Guidelines from the Medical Letter Drugs of Choice for Cancer. Abramowicz M, ed. New Rochelle, NY: The Medical Letter, Inc.; 2003 Mar: 94.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:732-5.

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