Class: Antineoplastic Agents
VA Class: AN100
CAS Number: 148-82-3
Brands: Alkeran
- 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
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 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
Compatible |
Acyclovir sodium |
Amikacin sulfate |
Aminophylline |
Ampicillin sodium |
Aztreonam |
Bleomycin sulfate |
Bumetanide |
Buprenorphine HCl |
Butorphanol tartrate |
Calcium gluconate |
Carboplatin |
Carmustine |
Cefazolin sodium |
Cefepime HCl |
Cefotaxime sodium |
Cefotetan disodium |
Ceftazidime |
Ceftizoxime sodium |
Ceftriaxone sodium |
Cefuroxime sodium |
Cimetidine HCl |
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 phosphate |
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 |
ActionsActions
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 2 mg | Alkeran (with povidone; scored) | Celgene |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection | 50 mg (of melphalan) | Alkeran (with povidone and with diluent containing alcohol 0.52 mL, propylene glycol, and sodium citrate) | Celgene |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Alkeran 2MG Tablets (CELGENE CORP): 50/$245.98 or 150/$719.94
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2008. 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.
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