Professional Drug Information > L-PAM

Melphalan (Systemic)

VA CLASSIFICATION
Primary: AN100

Commonly used brand name(s): Alkeran.

Other commonly used names are
L-PAM and phenylalanine mustard .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, ovarian, epithelial (treatment) ^{{01} {08}} or
[Carcinoma, breast (treatment)]¹—Melphalan is indicated for the palliative treatment of nonresectable epithelial carcinoma of the ovary ^{{01} {08}}. It is also indicated for treatment of breast carcinoma ^{{10} {11} {12}}.

[Melanoma, malignant (treatment)]—Melphalan is indicated for regional limb perfusion as an adjuvant to surgery to treat metastatic melanoma of the extremity ^{08}.

Multiple myeloma (treatment) ^{{01} {08} {09}} or
[Waldenström's macroglobulinemia (treatment)]¹—Melphalan is indicated for the palliative treatment of multiple myeloma ^{{01} {08} {09}} and Waldenström's macroglobulinemia ^{06}.

[Lymphomas, Hodgkin's (treatment) ]¹—Melphalan is indicated as a component of conventional-dose salvage combination therapy for relapsed, resistant Hodgkin's lymphomas ^{13}.

[Leukemia, chronic myelocytic (treatment) ]¹—Melphalan, as part of a high-dose chemotherapy regimen prior to bone marrow transplantation, is considered reasonable medical therapy at some point in the management of chronic myelocytic leukemia (Evidence rating: IIID) ^{{37} {38} {39} {40} {41} {42}}.

[Carcinoma, endometrial (treatment) ]¹—Melphalan, in combination with other agents, is considered reasonable medical therapy at some point in the management of endometrial carcinoma (Evidence rating: IIA) ^{{43} {44} {45} {46} {47}}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    305.21 ^{14}

Mechanism of action/Effect:

Melphalan is an alkylating agent of the nitrogen mustard type. Melphalan is a bifunctional alkylating agent and is cell cycle–phase nonspecific. Activity occurs as a result of formation of an unstable ethylenimmonium ion, which alkylates or binds with many intracellular molecular structures including nucleic acids. Its cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis.

Absorption:

Variably and incompletely absorbed from the gastrointestinal tract ^{{01} {08} {09}}. Absorption is decreased in the presence of food ^{{20} {21}}.

Distribution:

Apparent volume of distribution (Vol _D)—steady-state: 0.5 liter per kg of body weight (L/kg) ^{{01} {09} {16}}.

Protein binding:

Moderate to high (60 to 90%), primarily to albumin and alpha ₁-acid glycoprotein; 30% is irreversibly bound to plasma proteins ^{{01} {08} {09}}.

Biotransformation:

Deactivated in plasma by hydrolysis ^{{01} {08} {09} {15}}.

Half-life:

Distribution—Approximately 10 minutes ^{{01} {09}}.

Terminal—Approximately 90 minutes ^{33}; the average terminal half-life of melphalan in the perfusion circuit during regional hyperthermic perfusion is 26 to 53 minutes ^{{30} {31}}.

Elimination:
    Primarily nonrenal ^{{01} {09}}.
    In dialysis—Not removable by hemodialysis or hemoperfusion ^{{01} {09}}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to chlorambucil may also be sensitive (in form of skin rash) to melphalan ^{08}.

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The risk may increase with increasing dose and duration of therapy. In one study, the 10-year risk of developing secondary acute leukemia or myeloproliferative syndrome was less than 2% for cumulative doses under 600 mg, but 19.5% for cumulative doses of 730 to 9652 mg ^{{01} {08} {09}}. Although information is limited, available data seem to indicate that the highest carcinogenic risk is with the alkylating agents.

Melphalan has been associated with an increased risk of development of secondary malignancies, including acute nonlymphocytic leukemia and myeloproliferative syndrome, in humans ^{{01} {08} {09}}. The risk of development of secondary leukemia may be increased by increased cumulative dose of melphalan ^{01}.

Melphalan produces chromosomal aberrations in human cells both in vitro and in vivo ^{{01} {09}}.

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking melphalan ^{{01} {09} {17} {18}}. These effects may be related to the dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

Pregnancy—
Adequate and well-controlled studies in humans have not been done. However, melphalan is believed to be potentially harmful to the fetus ^{{01} {09}}.

In a study in rats, oral administration of melphalan at a dose of 6 to 18 mg per square meter of body surface area per day (mg/m ²/day) resulted in abnormalities in the development of the brain, eyes, mandible, and tail ^{{01} {09}}.

FDA Pregnancy Category D ^{01}.

In general, use of a contraceptive is recommended during cytotoxic drug therapy ^{01}.

Breast-feeding

It is not known whether melphalan is distributed into breast milk. Breast-feeding is not recommended while melphalan is being administered, because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity) ^{{01} {09}}.

Pediatrics

Appropriate studies on the relationship of age to the effects of melphalan have not been performed in the pediatric population. Safety and efficacy in pediatric patients have not been established ^{{01} {09}}.


Geriatrics


No information is available on the relationship of age to the effects of melphalan in geriatric patients. However, geriatric patients are more likely to have age-related renal function impairment, which may require adjustment of dosage ^{{02} {09}}.


Dental

The bone marrow depressant effects of melphalan may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Melphalan may cause stomatitis, especially when high doses are used.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of melphalan may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of melphalan, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Carmustine    (intravenous melphalan may be synergistic with carmustine in causing lung toxicity ^{09})


Cimetidine    (reduced serum concentration of melphalan may result, perhaps due to decreased absorption ^{23})


Cyclosporine    (increased risk of nephrotoxicity ^{22})


Interferons, alpha    (increased elimination of melphalan may occur, perhaps due to fever induced by alpha interferons ^{19})


Nalidixic acid    (increased incidence of hemorrhagic necrotic enterocolitis in pediatric patients ^{09})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by melphalan therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by melphalan therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the melphalan therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. Oral poliovirus vaccine should not be administered to persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Uric acid concentrations in blood and urine^{24}    (may be increased)


Urinary 5-hydroxyindoleacetic acid (5-HIAA) concentrations    (may be increased, possibly as a result of tumor cell destruction with accompanying release of metabolites)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to melphalan^{01}{08}{09}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression^{01}{08}{09}
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Gout, history of or
Urate renal stones, history of    (risk of hyperuricemia)


» Infection
» Renal function impairment^{{01}{08}{09}{15}{27}}    (effect on toxicity difficult to predict; possible increased risk of bone marrow depression)


» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy within 3 to 4 weeks.

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Blood counts, complete (CBC), including
Hematocrit
Hemoglobin
Platelet count    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to the patient's condition, the dose of melphalan administered, and other drugs being administered concurrently ^{{01} {08} {09}})


Blood urea nitrogen (BUN) concentrations and
Serum creatinine concentrations    (recommended prior to initiation of therapy and at periodic intervals during therapy)


Serum uric acid concentrations    (recommended prior to initiation of therapy and at periodic intervals during therapy)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible cause in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
—dose-related    
Neutropenia, with or without infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic; uncommon after limb perfusion^{08}
    
thrombocytopenia^{01}{08}{09} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Note: Myelosuppression usually occurs within 2 to 3 weeks of initiation of therapy, although neutropenia may occur within 5 days in a few patients. The nadir of leukocyte and platelet counts usually occurs within 3 to 5 weeks ^{01}, and leukocyte and platelet counts usually return to normal within 4 to 8 weeks ^{01}.


Incidence less frequent or rare
    
Hypersensitivity reactions, including anaphylaxis^{01}{08}{09} (fast or irregular heartbeat; shortness of breath; sudden skin rash or itching; troubled breathing)
    
hyperuricemia or uric acid nephropathy (joint pain; lower back or side pain; swelling of feet or lower legs)
    
mucositis^{36} (diarrhea; difficulty in swallowing)—dose-related
    
pulmonary fibrosis^{01}{08}{09} (shortness of breath)
    
skin or soft tissue injury^{08} (redness and/or soreness in arm or leg)—with isolated limb perfusion
    
stomatitis^{01}{08}{09} (sores in mouth and on lips)
    
vasculitis, severe, recurrent^{08} (redness and/or soreness at the infusion site)

Note: Hypersensitivity reactions have occurred in approximately 2% of patients receiving multiple courses of intravenous melphalan ^{09}.
Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown which leads to elevated serum uric acid concentrations ^{24}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Nausea and vomiting^{01}{08}{09} —dose-related



Those indicating the need for medical attention if they occur after medication is discontinued
    
Bone marrow depression^{01}{08}{09} (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising)

Note: Cumulative myelosuppression may occur with repeated dosing.





Overdose
For specific information on the agents used in the management of melphalan overdose, see the Colony Stimulating Factors (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
    
Anemia^{01}{08}{09} (unusual bleeding or bruising; unusual tiredness or weakness)
    
colitis^{01}{08}{09} (abdominal cramping and pain)
    
mucositis, severe^{01}{08}{09} (difficulty in swallowing; diarrhea^{01}{08}{09})
    
nausea and vomiting^{01}{08}{09}
    
neutropenia, possibly with infection^{01}{08}{09} (chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
    
stomatitis^{01}{08}{09} (painful sores in the mouth)
    
thrombocytopenia^{01}{08}{09} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)


Supportive care
There is no specific antidote to melphalan ^{{01} {08} {09}}; care of patients with melphalan overdose should be supportive. One pediatric patient who was inadvertently administered a dose of 254 mg per square meter of body surface area (mg/m ²) of melphalan survived with standard supportive care ^{28}. Melphalan can not be removed from the plasma by hemodialysis or hemoperfusion ^{{01} {08} {09}}.

The patient's blood count parameters should be monitored closely for 3 to 6 weeks following the overdose, and supportive therapy should be given as needed ^{{01} {08} {09}}. Severe bone marrow depression may require transfusion of needed blood components ^{{01} {08} {09}}. Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required ^{{01} {08} {09}}. Treatment with colony stimulating factors may shorten the duration of pancytopenia. Nutritional support with parenteral nutrition may be used in cases of overdose if mucositis prevents the oral intake of nutrition ^{28}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Melphalan (Systemic) .

» Consider advising the patient on the following ( = major clinical significance):

Before using this medication
  Conditions affecting use, especially:
Hypersensitivity to melphalan



Carcinogenicity—
Increased risk of secondary malignancies

Pregnancy—Advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of the potential risk to the infant
Other medications, especially other bone marrow depressants and live virus vaccines, or previous cytotoxic drug therapy or radiation therapy within 3 to 4 weeks
Other medical problems, epecially bone marrow depression, chickenpox or recent exposure, herpes zoster, infection, or renal function impairment

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

Caution in taking combination chemotherapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

» Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

Checking with physician if vomiting occurs shortly after dose is taken

» Proper dosing
Missed dose: Not taking at all; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding immunizations unless approved by physician;" other persons in patients household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever, chills, cough, hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
May cause adverse effects such as blood problems and cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially neutropenia, with or without infection; thrombocytopenia; hypersensitivity reactions, including anaphylaxis; hyperuricemia or uric acid nephropathy; mucositis; pulmonary fibrosis; skin or soft tissue injury; stomatitis; severe, recurrent vasculitis




General Dosing Information
Patients receiving melphalan should be under the supervision of a physician experienced in cancer chemotherapy.

Although systemic complications are less common with isolated limb perfusion of melphalan compared with orally or intravenously administered melphalan, severe local reactions, rarely requiring amputation, are possible ^{08}. Isolated limb perfusion should be used only by physicians well trained in the technique ^{08}.

A variety of dosage schedules and regimens of melphalan, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response and degree of bone marrow depression. This is especially important because of unreliable absorption of orally administered melphalan.

Although melphalan is eliminated primarily by nonrenal mechanisms, increased bone marrow toxicity has been observed in patients with renal function impairment who receive melphalan ^{27}. The manufacturer recommends consideration of dosage reduction in patients with renal function impairment receiving melphalan intravenously, and careful observation of patients with renal function impairment receiving melphalan orally ^{{01} {02} {03}}.

Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration and, in some cases, administration of allopurinol. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated.

It is recommended that melphalan therapy be discontinued if marked leukopenia (particularly granulocytopenia) or thrombocytopenia occurs. Therapy may be resumed at a lower dosage when the clinical and laboratory examinations are satisfactory ^{08}.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of melphalan. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required.

Development of a hypersensitivity reaction requires immediate discontinuation of infusion and initiating symptomatic treatment. It is recommended that melphalan (oral and intravenous formulations) not be readministered if a hypersensitivity reaction occurs ^{09}.

Safety considerations for handling this medication
There is evidence that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
Detailed guidelines for the handling of cytotoxic and hazardous antineoplastic agents have been developed by various groups, including the American Society of Health-System Pharmacists (ASHP) and the Office of Occupational Medicine, Occupational Safety and Health Administration (OSHA) ^{{25} {26}}.

Direct contact of skin or mucosa with melphalan requires immediate washing with soap and water or thoroughly flushing with water, respectively ^{{01} {08} {09}}.


Combination chemotherapy
Melphalan may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages may be used. For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.

For treatment of adverse effects
Recommended treatment consists of the following:    • Controlling hypersensitivity reactions with antihistamines and/or corticosteroids ^{09}.



Oral Dosage Forms

MELPHALAN TABLETS USP

Usual adult dose
Multiple myeloma
Oral, 150 mcg (0.15 mg) per kg of body weight a day for seven days, followed by a rest period of at least three weeks, during which time the leukocyte count will fall. When white cell and platelet counts are rising, a maintenance dose of 50 mcg (0.05 mg) per kg of body weight a day may be instituted, or

Oral, 100 to 150 mcg (0.1 to 0.15 mg) per kg of body weight a day for two to three weeks, or 250 mcg (0.25 mg) per kg of body weight a day for four days, followed by a rest period of two to four weeks ^{{01} {08}}. When leukocyte counts rise above 3000 to 4000 per cubic millimeter and platelet counts above 100,000 per cubic millimeter, a maintenance dose of 2 to 4 mg a day may be instituted, or

Oral, 7 mg per square meter of body surface area or 250 mcg (0.25 mg) per kg of body weight a day for five days every five to six weeks, adjusted to produce mild leukopenia and thrombocytopenia.

Ovarian carcinoma, epithelial
Oral, 200 mcg (0.2 mg) per kg of body weight a day for five days, repeated every four to five weeks if blood counts return to normal ^{01}.

[Carcinoma, endometrial (treatment)]¹
Consult medical literature and manufacturer's literature for specific dosage.


Usual pediatric dose
Children up to 12 years of age—Safety and efficacy have not been established.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


2 mg (Rx) [Alkeran (scored) (lactose ) (sucrose)]

Canada—


2 mg (Rx) [Alkeran (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Note: Dispense in a glass container.




Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

MELPHALAN HYDROCHLORIDE FOR INJECTION

Usual adult dose
Multiple myeloma ^{32}
Intravenous infusion, 16 mg per square meter of body surface area (mg/m ²) administered over 15 to 20 minutes at two-week intervals for four doses; then at four-week intervals after recovery from toxicity. Dosage adjustments may be made, based on blood cell counts at the nadir.

[Malignant melanoma ^{{08} {29}}]


Upper extremity:
Arterial infusion, by hyperthermic isolated limb perfusion technique, 1 mg per kg of body weight, not to exceed 80 mg, in three equally divided doses at five-minute intervals ^{08}, or



Lower extremity:
Arterial infusion, by hyperthermic isolated limb perfusion technique, 1.5 mg per kg of body weight, not to exceed 120 mg, in three equally divided doses at five-minute intervals ^{08}.


Note: The following perfusion guidelines are recommended by the manufacturer ^{08}:    • Temperature of the perfusate should not exceed 42.5 °C (108.5 °F)
   • Temperature of the limb should not exceed 42 °C (107.6 °F)
   • Flow-rate—250 to 600 mL per minute (mL/min)
   • Perfusate—650 to 750 mL of heparinized whole blood or an equal mixture of lactated Ringer's solution and washed packed red blood cells
   • Perfusion duration—Not to exceed one hour



[Leukemia, chronic myelocytic (treatment)]¹
Consult medical literature and manufacturer's literature for specific dosage.


Usual pediatric dose
Safety and efficacy have not been established. ^{01}

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


50 mg (Rx) [Alkeran (lyophilized powder) (povidone 20 mg)]

Canada—


50 mg (Rx) [Alkeran (lyophilized powder) (povidone 20 mg)]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF). Protect from light.

Preparation of dosage form:
For intravenous infusion ^{{08} {09}}—



• Reconstitute the vial of melphalan with 10 mL of the diluent supplied by the manufacturer, for a concentration of 5 mg per mL (mg/mL).


• Immediately dilute the dose to be administered in 0.9% sodium chloride injection, USP, to a final concentration no greater than 0.45 mg/mL.^{48}
For isolated limb perfusion ^{08}—



• Reconstitute the vial of melphalan with 10 mL of the diluent supplied by the manufacturer, for a concentration of 5 mg per mL (mg/mL).

Stability:
Melphalan reconstituted as directed to a concentration of 5 mg/mL is stable for up to two hours at 30 ºC (86 ºF). The reconstituted solution should not be refrigerated because refrigeration will cause a precipitate to form ^{{08} {09}}.

Melphalan infusions prepared to a final concentration of 0.1 to 0.45 mg/mL in 0.9% sodium chloride injection are stable for up to 50 minutes when stored at 30 ºC (86 ºF) ^{{08} {09}}, and up to four hours at 20 ºC (68 ºF) ^{33}.

Unused portions of melphalan should be discarded ^{{08} {09}}.

Incompatibilities:
Melphalan 0.1 mg per mL (mg/mL) in 0.9% sodium chloride injection is incompatible for Y-site administration with amphotericin B, chlorpromazine hydrochloride, daunorubicin hydrochloride, idarubicin hydrochloride, lorazepam, methylprednisolone sodium succinate, and prochlorperazine edisylate. ^{35}

Auxiliary labeling:
   • Do not refrigerate.
   • Protect from light.

Revised: 01/29/2003

References

Note: References used in the development and subsequent revisions of this monograph have not yet been incorporated into the database and, therefore, are not listed below.

1. Alkeran tablets package insert (GlaxoWellcome—US), Rev 2/96, Rec 7/30/97; Rev 9/97, Rec 1/99.
   

2. General concept per Geriatrics Advisory Panel (1985-1990), 1990 revision.
   

3. Reviewer comment, 11/10/88.
   

4. Reviewer comment, 10/4/88.
   

5. Dorr RT, Fritz WL. Cancer chemotherapy handbook. New York: Elsevier; 1980. p. 507-12.
   

6. Salmon S, Cassady J. Plasma cell neoplasms. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 2376.
   

7. Hold.
   

8. Alkeran package insert (GlaxoWellcome—Canada), Rev 4/96, Rec 8/05/97.
   

9. Alkeran for injection package insert (GlaxoWellcome—US), Rev 1/96, Rec 7/30/97; Rev 8/97, Rec 3/99.
   

10. Harris J, Morrow M, Norton L. Malignant tumors of the breast. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 1603.
    

11. Vincent M, Powles T, Coombes R, et al. Late intensification with high dose melphalan and autologous bone marrow support in breast cancer patients responding to conventional chemotherapy. Cancer Chemother Pharmacol 1988; 21: 255-60.
    

12. Somlo G, Doroshow J, Forman S, et al. Double cycle high dose melphalan and cisplatin followed by peripheral stem cell rescue. Proc Am Soc Clin Oncol 1994; 13: 104.
    

13. DeVita VT, Mauch P, Harris N. Hodgkin"s disease. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 2272.
    

14. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1997. p. 448.
    

15. Chang S, Alberts D, Farquhar D, et al. Hydrolysis and protein binding of melphalan. J Pharm Sci 1978; 67: 682-4.
    

16. Woodhouse K, Hamilton P, Lennard A, et al. The pharmacokinetics of melphalan in patients with multiple myeloma: an intravenous/oral study using a conventional dose regimen. Eur J Clin Pharmacol 1983; 24: 283-5.
    

17. Rose D, David P. Ovarian function in patients receiving adjuvant chemotherapy for breast cancer. Lancet 1977; 1: 1174-6.
    

18. Ahmann D. Repeated adjuvant chemotherapy with phenylalanine mustard or 5-fluorouracil, cyclophosphamide and prednisone with or without radiation. Lancet 1978; 1: 893-6.
    

19. Ehrsson H, Eksborg S, Wallin I, et al. Oral melphalan pharmacokinetics: influence of interferon-induced fever. Clin Pharmacol Ther 1990; 47: 86-90.
    

20. Bosanquet A, Gilby E. Comparison of the fed and fasting states on the absorption of melphalan in multiple myeloma. Cancer Chemother Pharmacol 1984; 12: 183-6.
    

21. Reece P, Kotasek D, Morris R, et al. The effect of food on oral melphalan absorption. Cancer Chemother Pharmacol 1986; 16: 194-7.
    

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