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Brand name: Alkeran
Drug class: Antineoplastic Agents
- Alkylating Agents
VA class: AN100
CAS number: 148-82-3

Medically reviewed by on Jun 30, 2022. Written by ASHP.


Special Alerts:

[Posted 07/28/2021]

FDA is alerting patients and health care professionals that a clinical trial (OCEAN, Study OP-103) evaluating Pepaxto (melphalan flufenamide) with dexamethasone to treat patients with multiple myeloma showed an increased risk of death.

The trial compared Pepaxto with low-dose dexamethasone to pomalidomide with low-dose dexamethasone in patients with relapsed or refractory (resistant) multiple myeloma following 2-4 lines of prior therapy and in patients who were resistant to lenalidomide in the last line of therapy.

FDA encourages health care professionals to review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments. Patients currently receiving Pepaxto should also discuss with their health care professional the risks and benefits of receiving Pepaxto.

In February 2021, FDA approved Pepaxto under Accelerated Approval for use in combination with dexamethasone to treat adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody. The manufacturer, Oncopeptides AB, was required to conduct the OCEAN trial as a post-approval requirement under the accelerated approval program.

Due to the detrimental effect on overall survival in the OCEAN trial, FDA is requiring the manufacturer suspend enrollment in the trial. FDA has also suspended enrollment in other ongoing Pepaxto clinical trials. Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.

FDA continues to evaluate the OCEAN trial results and may hold a future public meeting to discuss these safety findings and explore the continued marketing of Pepaxto. The agency will update patients and health care professionals when new information is available.

For more information visit the FDA website at: [Web] and [Web].


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

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

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

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

      Hypersensitivity Reactions
    • Hypersensitivity reactions, including anaphylaxis, reported.


Antineoplastic agent; nitrogen mustard derivative; alkylating agent.

Uses for Melphalan

Multiple Myeloma

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

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

Ovarian Cancer

Palliative treatment of nonresectable epithelial ovarian cancer.

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

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.


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.


Has been used with prednisone in the treatment of amyloidosis.

Melphalan Dosage and Administration


  • 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.

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


Administer orally or by IV infusion.

Has been administered by regional isolation perfusion (e.g., for melanoma) and intraperitoneally (e.g., for advanced ovarian cancer).

Usually administered orally; however, can also be administered IV in the palliative treatment of multiple myeloma in patients in whom oral therapy is not feasible.

Oral Administration

Administer orally on an empty stomach.

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

IV Administration

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

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

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

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

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


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.

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


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

Rate of Administration

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


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

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

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

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


Multiple Myeloma

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

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

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

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.


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

Ovarian Cancer

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

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment


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


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

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.

Cautions for Melphalan


  • Prior resistance to melphalan therapy.

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



Adequate Patient Evaluation and Monitoring

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

Hematologic Effects

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

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

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

Careful hematologic monitoring required. 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). Withhold therapy until leukocyte count is >3000/mm3 and platelet count is >100,000/mm3.

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

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

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

Mutagenicity and Carcinogenicity

Possible leukemia or secondary malignancies; assess risk/benefits of therapy.

Causes chromatid or chromosome damage in humans.

Fetal/Neonatal Morbidity and Mortality

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


Reversible and irreversible testicular suppression reported.

Ovarian suppression and amenorrhea reported in premenopausal females.

Local Effects

Extravasation may produce severe local tissue necrosis.

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.

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.

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


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

General Precautions


Avoid administration of live vaccines to immunocompromised patients.

Pulmonary Toxicity

Pulmonary embolism, sometimes fatal, and fibrosis have been reported.

Specific Populations


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


Not known whether melphalan is distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

Renal Impairment

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

Common Adverse Effects

Bone marrow suppression, mild nausea.

Interactions for Melphalan

Specific Drugs





Possible reduced threshold for carmustine-induced pulmonary toxicity with IV melphalan


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

Monitor for decreased melphalan activity


Possible decreased clearance of melphalan secondary to cisplatin-induced renal impairment


Possible increased risk of cyclosporine-induced nephrotoxicity

Monitor renal function

Consider reducing cyclosporine dosage in patients receiving high-dose melphalan

Interferon alfa

Interferon alfa-induced fever may increase plasma elimination of melphalan

Nalidixic acid

Possible increased incidence of severe hemorrhagic necrotic enterocolitis in pediatric patients

Melphalan Pharmacokinetics



Absorption from the GI tract is incomplete and extremely variable.


Food decreases bioavailability by about 35%.



Rapidly distributed throughout total body water; distributes into CSF in low concentrations.

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

Plasma Protein Binding

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



Undergoes spontaneous hydrolysis in plasma to monohydroxymelphalan and dihydroxymelphalan.

Elimination Route

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

Not removed by hemodialysis.


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

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







Powder for Injection

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

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

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


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


Solution CompatibilityHID

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


Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%1

Drug Compatibility
Y-Site CompatibilityHID


Acyclovir sodium

Amikacin sulfate


Ampicillin sodium


Bleomycin sulfate


Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate



Caspofungin acetate

Cefazolin sodium

Cefotaxime sodium

Cefotetan disodium


Ceftriaxone sodium

Cefuroxime sodium


Clindamycin phosphate






Daunorubicin HCl

Dexamethasone sodium phosphate

Diphenhydramine HCl

Doxorubicin HCl

Doxycycline hyclate








Fludarabine phosphate



Gallium nitrate

Ganciclovir sodium

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Idarubicin HCl


Imipenem–cilastatin sodium



Mechlorethamine HCl

Meperidine HCl


Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl



Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Ondansetron HCl


Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate




Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate



Amphotericin B

Chlorpromazine HCl


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

  • Active against both resting and rapidly dividing tumor cells.

  • Possesses some immunosuppressive activity.

Advice to Patients

  • Risk of bone marrow suppression, hypersensitivity reactions, infertility, pulmonary toxicities, and secondary malignancies.

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

  • Importance of close medical supervision of patients receiving melphalan.

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

  • 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.

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

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


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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.



Dosage Forms


Brand Names




2 mg

Alkeran (scored)


Melphalan Hydrochloride


Dosage Forms


Brand Names



For injection

50 mg (of melphalan)



AHFS DI Essentials™. © Copyright 2022, Selected Revisions July 10, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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