Melphalan (AHFS DI (Adult and Pediatric))

U.S. Brand Names

Alkeran®

Synonyms
l-PAM; l-Sarcolysin; Phenylalanine Mustard

Therapeutic Class
10:00 Antineoplastic Agents

Introduction

Melphalan, a nitrogen mustard-derivative alkylating agent, is an antineoplastic agent.

Uses
Multiple Myeloma

Melphalan is used alone and as a component of various chemotherapeutic regimens in the treatment of multiple myeloma. The drug
usually is used orally;Ref however, melphalan hydrochloride also can be used IV in the palliative treatment of multiple myelomaRef in
patients in whom oral therapy is not feasible,Ref and melphalan injection is designated an orphan drug by the US Food and Drug
Administration (FDA) for use in this condition.Ref Comparative studies have shown the efficacy of IV melphalan hydrochloride in
combination with prednisone in the treatment of multiple myeloma to be equivalent to that of orally administered melphalan in
combination with prednisone.Ref

Although not curative, melphalan can prolong the survival of patients with multiple myeloma. Although melphalan is used mainly in
combination chemotherapy, about one-third of patients who receive the drug alone have an objective response, which may be
characterized by a decrease in the amount of abnormal proteins present in urine or serum, a decrease in the number of myeloma cells in
the bone marrow, an increase in hemoglobin, improved renal function, a decreased frequency of infection due in part to an increased
concentration of normal immunoglobulins, normalization of serum calcium, and/or lack of progression and, rarely, recalcification of bone
lesions. Subjective response, which occurs in most patients who receive melphalan alone, is characterized by relief of pain and increased
mobility and performance status. Response to melphalan may occur gradually over several months; therefore, it is important that
repeated courses or continuous therapy be administered in order that maximum benefit from the drug may be obtained. Many clinicians
believe that 3–12 months of therapy with melphalan may be necessary to evaluate the response to the drug.

Comparative studies have shown the effectiveness of melphalan in the treatment of multiple myeloma to be equivalent to that of
cyclophosphamide, and most experts consider melphalan or cyclophosphamide to be the drug of choice for the treatment of multiple
myeloma. Some experts prefer cyclophosphamide to melphalan in patients with severe thrombocytopenia because of the relative platelet-
sparing effect of cyclophosphamide. In some patients resistant to melphalan, cyclophosphamide in high doses may be useful. Controlled
trials of intermittent regimens of melphalan with prednisone have shown this combination to be superior in most patients to the use of
intermittent or daily regimens of melphalan alone for remission induction; the median duration of survival is apparently increased
compared to that produced by melphalan alone. In patients who achieve a remission, continued maintenance therapy after the first year
of treatment does not appear to prolong the duration of remission or survival; however, some clinicians continue therapy because most
patients relapse and some of these patients may become unresponsive to further chemotherapy. Melphalan also has been used in other
combination regimens with agents such as carmustine, cyclophosphamide, fluoxymesterone, lomustine, procarbazine hydrochloride,
testosterone, and vincristine sulfate, but the best combination or sequential therapy to achieve the maximum response and duration of
survival has not been established.

Ovarian Cancer

Melphalan may be used in the palliative treatment of nonresectable epithelial carcinoma of the ovary.Ref An objective response occurs
in 30–50% of patients who receive melphalan alone. Response rates, including complete response rates, are higher for cisplatin-based
combination therapy; however, the best combination or sequential therapy in the treatment of advanced ovarian tumors has not been
established, and the comparative safety and efficacy of various regimens are continually being evaluated.Ref Tumor regression has
occurred in some patients receiving intraperitoneal† administration of melphalan for the treatment of advanced ovarian cancer confined
to the peritoneal cavity and/or associated with malignant ascites.Ref

Breast Cancer
 Melphalan has been used alone or with other antineoplastic agents as an adjunct to surgery in the treatment of breast cancer † .
Melphalan appears to increase disease-free survival principally in patients younger than 50 years of age with 1–3 involved axillary lymph
nodes; however, combination therapy containing melphalan and/or other agents appears to be more effective in these and other
subgroups of patients. Some clinicians have recommended that melphalan no longer be used alone as adjunctive therapy.

Combination chemotherapy used as an adjunct to surgery has been shown to increase both disease-free (i.e., decreased recurrence)
and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast
cancer.Ref Adjuvant combination chemotherapy has produced overall reductions in the annual rates of recurrence and death of 28 and
16%, respectively, with overall 5-year disease-free survival rates of 58.8 versus 49.6% for patients with early breast cancer receiving
combination chemotherapy versus those who did not.Ref Although adjuvant combination chemotherapy that includes cyclophosphamide,
methotrexate, and fluorouracil has been used most extensively and is considered a regimen of choice,Ref several melphalan-containing
regimens appear to produce similar outcomes in early breast cancer but have been used less commonly and/or studied less extensively.Ref
Melphalan has been used for adjunctive treatment of early breast cancer in combination with fluorouracil for premenopausal women and
in combination with fluorouracil and tamoxifen for postmenopausal women with estrogen-receptor-positive/progestin-receptor-positive
tumors.Ref Melphalan also has been used in combination with doxorubicin and fluorouracil, since the addition of doxorubicin to an
adjuvant regimen of melphalan and fluorouracil (without tamoxifen) has been shown to improve outcome in women younger than 50
years of age with hormone-receptor-negative disease and in those 50–59 years of age with progestin-receptor-negative disease.Ref
Melphalan also has been used as a component of these and other regimens for the treatment of locally advanced (stage III) disease.Ref

Melanoma

Melphalan is used in isolated limb perfusion † for palliative treatment of locally recurrent or unresectable in-transit metastatic
melanoma † of the extremities.Ref Use of melphalan in combination regimens (e.g., melphalan, tumor necrosis factor, and interferon
gamma) for perfusion therapy of limb melanoma is being investigated.Ref No survival benefit has been shown for use of isolated limb
perfusion with melphalan as adjuvant therapy for melanoma of the extremities.Ref

Other Uses

Melphalan has been used in the treatment of polycythemia vera†; its effect is reportedly about equivalent to that of chlorambucil, but
faster in onset.

Melphalan has been used with prednisone in the treatment of amyloidosis † . In a randomized study in patients with primary
amyloidosis, combined therapy with melphalan and prednisone produced an objective response (as measured by disappearance or a
reduction of at least 50% in serum or urinary monoclonal protein concentration) in about 29% of patients compared with 28% of patients
receiving combined therapy with melphalan, prednisone, and colchicine and 3% of patients receiving colchicine alone.Ref A median survival
duration of 18 months was reported in patients receiving melphalan with prednisone compared with 17 months in those receiving
melphalan, prednisone, and colchicine and 8.5 months in those receiving colchicine monotherapy.Ref Objective response has been
observed within 1 year following initiation of chemotherapy in about 70% of those who responded, while 21% of patients who responded
required an additional year of chemotherapy.Ref Patients with cardiac amyloidosis had a much shorter survival (about 5 months) after
randomization than those with amyloidosis associated with nephrotic syndrome (16 months), or peripheral neuropathy (about 34
months).Ref In addition, at 12 months following initiation of chemotherapy, patients who showed an objective response had a median
overall survival of about 50 months compared with 36 months for those without an objective response.Ref Additional studies are needed to
evaluate the efficacy of high-dose melphalan therapy and other agents in the management of primary amyloidosis.Ref

Melphalan has also been used in the treatment of scleromyxedema † , chronic myelogenous leukemia † , osteogenic sarcoma † ,
advanced prostatic carcinoma†, and testicular seminoma†.

Melphalan also has been administered by regional isolation perfusion† in the treatment of certain sarcomas†.

Dosage and Administration

Reconstitution and Administration

Melphalan is administered orally, and melphalan hydrochloride is administered by IV injection. Melphalan hydrochloride also has been
administered intra-arterially†, intraperitoneally†,Ref and by regional isolation perfusion† (e.g., for melanoma).

Melphalan hydrochloride powder for injection is reconstituted by adding 10 mL of the diluent provided by the manufacturer to a vial
labeled as containing 50 mg of melphalan using a 20-gauge or larger needle to provide a solution containing 5 mg/mL.Ref The diluent should
be added rapidly and the vial should be shaken vigorously until a clear solution is obtained.Ref Reconstituted solutions of melphalan
hydrochloride should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container
permit.Ref The reconstituted solution should not be refrigerated, since a precipitate may form at 5°C.Ref The reconstituted solution of
melphalan hydrochloride should be diluted further with 0.9% sodium chloride injection to provide a solution with a concentration not
exceeding 0.45 mg/mL.Ref Dilution of reconstituted solutions of the drug should be performed immediately because a citrate derivative of
melphalan has been detected in the solution within 30 minutes of reconstitution of melphalan hydrochloride for injection.Ref Because
approximately 1% of the labeled strength of melphalan hydrolyzes every 10 minutes following dilution with 0.9% sodium chloride, the
solution of melphalan hydrochloride should be administered soon after dilution.Ref Melphalan is administered by IV infusion, usually over 15–
20 minutes.Ref Administration of melphalan hydrochloride should be completed within 60 minutes of reconstitution.Ref

The manufacturer recommends that procedures for proper handling and disposal of antineoplastic drugs (e.g., use of gloves) be used,
since adverse dermatologic effects associated with exposure to the drug may occur.Ref If melphalan solution comes in contact with the skin
or mucous membranes, the affected area should be washed thoroughly with soap and water.Ref For further information on the handling of
cytotoxic drugs, see the guidelines at the end of Antineoplastic Agents 10:00 and consult special references on the handling and disposal of
cytotoxic drugs.Ref

Dosage

Dosage of melphalan must be adjusted carefully according to the clinical and hematologic response and tolerance of the patient in order
to obtain optimum therapeutic results with minimum adverse effects. It is usually necessary to maintain some degree of myelosuppression.
The leukocyte count generally serves as a guide to dosage adjustments and is usually maintained between 3000–4000/mm3. Dosage
adjustments based on the blood cell nadir and blood counts taken on the day of melphalan therapy should be considered.Ref

Dosage of melphalan hydrochloride is expressed in terms of melphalan.Ref

Multiple Myeloma

For the treatment of multiple myeloma, various dosage schedules for oral melphalan or IV melphalan hydrochloride have been used.
The drug may be administered continually or intermittently. The clinician should consult published protocols for the dosage of melphalan
and other chemotherapeutic agents and the method and sequence of administration.

Oral Dosage

The manufacturer recommends a usual initial oral dosage of melphalan of 6 mg given as a single daily dose. Subsequent dosage
should be adjusted as required based on blood counts performed approximately weekly. After 2–3 weeks, the drug should be
discontinued for up to 4 weeks until the leukocyte and platelet counts increase, at which time an oral maintenance dosage of 2 mg daily
may be instituted. Alternatively, most clinicians recommend an intermittent oral melphalan dosage schedule of 0.15 mg/kg daily for 7
successive days or 0.25 mg/kg daily for 4 successive days, administered at intervals of 4–6 weeks, usually with prednisone.

Other clinicians have used oral melphalan dosages of 10 mg daily for 7–10 days.Ref In these patients, maximum suppression of
leukocyte and platelet counts occurred within 3–5 weeks while recovery reportedly occurred within 4–8 weeks.Ref When platelet and
leukocyte counts exceeded 100,000 and 4000, respectively, a continuous maintenance therapy of 2 mg daily was initiated; dosage was
adjusted at 1–3 mg daily depending on hematologic response.Ref The manufacturer states that it is desirable to maintain a substantial
degree of bone marrow depression in order to keep the leukocyte count at 3000–3500.Ref

IV Dosage

The manufacturer states that an exact dosage conversion from oral to parenteral melphalan cannot be made.Ref Clinicians should
consult published protocols for specific information on parenteral dosage regimens using IV melphalan hydrochloride for specific
diseases.Ref

The manufacturer states that the usual IV dosage of melphalan is 16 mg/m2 given by IV infusion once at 2-week intervals for 4
doses; then, after satisfactory recovery from toxicity, the same dose should be repeated at 4-week intervals.Ref In some controlled
clinical studies in patients with multiple myeloma, dosage reductions of 25% were employed when platelet counts were 75,000–99,999 or
leukocyte counts were 3000–3999 and dosage reductions of 50% were used when platelet counts were 50,000–74,999 or leukocyte counts
were 2000–2999; IV melphalan was discontinued when platelet or leukocyte counts fell below these values.Ref

Ovarian Cancer

For the treatment of ovarian carcinoma, the usual dosage of melphalan is 0.2 mg/kg daily for 5 successive days, administered at
intervals of 4–5 weeks.Ref

Dosage in Renal Impairment

 Dosage reduction should be considered in patients with renal impairment who are receiving IV melphalan hydrochloride therapy,
since increased bone marrow suppression was observed in patients with BUN concentrations of 30 mg/dL or more.Ref When dosage of IV
melphalan hydrochloride is reduced by 50% in these patients, the risk of severe leukopenia and drug-related death may be reduced from
about 50 to 11% and 10 to 3% of patients, respectively.Ref

Cautions

Adverse systemic effects reported with IV melphalan hydrochloride usually are similar to those reported with oral melphalan;Ref
however, results of controlled clinical studies indicate that the incidence of severe myelosuppression was higher in patients receiving the
drug IV compared with those receiving the drug orally.Ref

Hematologic Effects

Hematologic toxicity is the major and dose-limiting adverse effect of both oral and IV melphalan and is manifested principally by
leukopenia and thrombocytopenia. Anemia, hemolytic anemia, pancytopenia, and agranulocytosis may also occur. Myelosuppression
usually occurs after 2–3 weeks of melphalan therapy, but leukopenia may occur after 5 days in a few patients. Leukocyte and platelet
counts usually return to normal levels during the fifth week, but leukopenia or thrombocytopenia may persist for 6 weeks or longer after
the drug is discontinued. However, irreversible bone marrow depression has been reported in some patients receiving the drug.Ref The
patient’s hematologic status must be carefully monitored. (See Cautions: Precautions and Contraindications.) Melphalan has reportedly
caused positive direct Coombs’ test results and concurrent hemolytic anemia. Severe leukopenia may occur in patients with renal
impairment receiving IV melphalan hydrochloride therapy; dosage reduction (i.e., by 50%) should be considered in these patients.Ref(See
Dosage and Administration: Dosage in Renal Impairment.)

Cardiovascular Effects

Arterial or venous thrombosis,Ref or pulmonary embolism, sometimes fatal,Ref has been reported in patients receiving melphalan
administered by regional isolation perfusion.

Nervous System Effects

Adverse neurologic effects, including transient paralysis,Ref limb pain,Ref nerve injury, and peripheral neuritis,Ref have been associated
with administration of melphalan by regional isolation perfusion.

Local Effects

Phlebitis and extravasation have been reported in patients receiving IV melphalan hydrochloride.Ref

Administration of melphalan by regional isolation perfusion may cause erythemaRef and/or edemaRef of the perfused area,
thrombophlebitis, necrotizing fasciitis, and varying degrees of vesiculation and tissue necrosis; amputationRef sometimes has been
necessary.

GI Effects

Mild nausea and vomiting occur infrequently after usual doses but may be common after large doses of melphalan. Occasional
diarrhea, stomatitis, and oral ulceration also have been reported.

Dermatologic and Hypersensitivity Reactions

Dermatologic reactions including maculopapular and urticarial rashes, dermatitis, skin hypersensitivity, allergic reactions, pruritus,
and, rarely, alopecia have been reported in patients receiving melphalan. Anaphylaxis has also been reported. Hypersensitivity reactions
including urticaria, pruritus, exanthema, rash, edema, tachycardia, bronchospasm, dyspnea, hypotension, and anaphylaxis have been
reported in about 2% of patients receiving the drug IV; in several patients, rechallenge with oral melphalan produced rash, pruritus, and
chest pain. Hypersensitivity reactions occur most commonly after several courses of IV therapy with the drug.Ref If a hypersensitivity
reaction to IV melphalan hydrochloride occurs, the drug should be discontinued and appropriate symptomatic treatment initiated (e.g.,
plasma volume expanders, vasopressors, corticosteroids, antihistamines) at the discretion of the clinician.Ref

Skin ulceration at the injection site and skin necrosis (rarely requiring skin grafting) have been reported in patients receiving IV
melphalan therapy.Ref

Other Adverse Effects

 Vasculitis, pulmonary fibrosis, and interstitial pneumonitis have been reported in patients receiving melphalan.Ref Hepatotoxicity (e.g.,
hepatic veno-occlusive disease) has been reported in patients receiving IV melphalan hydrochloride.Ref Hepatotoxicity also has been
reported in patients receiving oral melphalan.Ref Rarely, menstrual irregularities and bronchopulmonary dysplasia have occurred following
prolonged melphalan therapy.

Precautions and Contraindications

Melphalan is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence
of toxicity. The drug must be used only under constant supervision by physicians experienced in therapy with cytotoxic agents. Melphalan
should be used only when the possible benefits outweigh the possible risks.Ref Patients should be advised that the major toxicities
associated with melphalan are bone marrow depression, hypersensitivity reactions, infertility, nonlymphocytic leukemia,
myeloproliferative syndrome, and GI and pulmonary toxicities.Ref Patients who receive myelosuppressive drugs experience an increased
frequency of infections as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient
should be instructed to notify the physician if fever, sore throat, persistent cough, or unusual bleeding or bruising occurs. The patient’s
hematologic status must be carefully monitored and blood counts performed approximately weekly in patients receiving oral melphalan
therapy. The manufacturer states that complete blood counts (leukocyte count with differential, platelet count, hemoglobin) should be
performed prior to initiation of IV melphalan hydrochloride therapy and before each subsequent IV dose.Ref Therapy should be
discontinued temporarily or dosage decreased at the first sign of abnormal bone marrow depression (specifically, if the leukocyte count
falls below 3000/mm3 or the platelet count falls below 100,000/mm3); when blood counts have returned to acceptable levels, therapy may
be resumed if indicated.Ref Treatment of severe hematologic toxicity may consist of supportive therapy, antibiotics for complicating
infections, and transfusions with blood components. Melphalan should be used with extreme caution in patients whose bone marrow
reserve may have been compromised by prior irradiation or chemotherapy, or whose bone marrow function is recovering from previous
cytotoxic therapy. Patients also should be instructed to notify the physician if rash, signs or symptoms of vasculitis, nausea, vomiting,
amenorrhea, weight loss, or unusual lumps/masses occur.Ref

The manufacturer states that there may be cross-sensitivity between melphalan and chlorambucil manifested by rash.

Melphalan is contraindicated in patients with known hypersensitivity to the drug or in patients whose disease was resistant to prior
therapy with the drug. It has not been clearly determined whether dosage of oral melphalan should routinely be reduced in patients with
impaired renal function; the manufacturer states that patients with azotemia should be closely monitored in order to make dosage
reductions, if necessary, at the earliest possible time. The manufacturer states that although renal elimination of melphalan appears to be
low dosage reduction should be considered in patients with renal impairment who are receiving melphalan hydrochloride IV, since
increased bone marrow suppression was observed in patients with BUN concentrations of 30 mg/dL or more.Ref A 50% reduction in IV
melphalan dosage was associated with a decreased risk of leukopenia and drug-related death.Ref(See Dosage and Administration: Dosage
in Renal Impairment.)

Pediatric Precautions

Safety and efficacy of melphalan in pediatric patients have not been established.Ref

Geriatric Precautions

In clinical studies, the responses to melphalan in geriatric patients did not differ substantially from those observed in younger
patients.Ref However, dosage of melphalan should be selected carefully in geriatric patients and the greater frequency of decreased
hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.Ref

Mutagenicity and Carcinogenicity

Melphalan is potentially mutagenic.Ref The drug has caused chromatid or chromosome damage in humans.Ref Structural chromosomal
and chromatid aberrations also have been observed in bone marrow cells of Wistar rats receiving IM doses of 6 and 60 mg/m2.Ref
Melphalan is potentially carcinogenic and has been associated with the development of acute myelogenous (nonlymphocytic) leukemia,
myeloproliferative syndrome, and carcinoma in patients with multiple myeloma, ovarian carcinoma, or breast cancer, especially with
prolonged continuous dosing of the drug. Evidence from clinical studies suggests that the estimated 10-year cumulative risk of developing
acute leukemia or myeloproliferative syndrome following melphalan therapy is 19.5 or less than 2% in patients receiving cumulative doses
of 730–9652 or less than 600 mg of the drug, respectively.Ref However, a cumulative dose below which there is no risk of melphalan-
induced secondary malignancy has not been established to date.Ref Although the benefits of melphalan therapy in the palliative treatment
of multiple myeloma and ovarian carcinoma are generally believed to outweigh the potential risks, the possibility of development of a
secondary malignancy must be considered. There are no adequate and controlled carcinogenicity studies in animals; however,
intraperitoneal administration of melphalan dosages of 5.4–10.8 mg/m2 in rats and 2.25–4.5 mg/m2 in mice 3 times a week for 6 months
were associated with peritoneal sarcomas and lung tumors, respectively.Ref

Pregnancy, Fertility, and Lactation

 Pregnancy

Melphalan can cause fetal harm when administered to pregnant women.Ref Although there are no adequate and controlled studies
to date using melphalan in pregnant women, the drug has been shown to be teratogenic and embryotoxic in rats.Ref In rats given oral
melphalan dosages of 6–18 mg/m2 daily for 10 days or intraperitoneal dosages of 18 mg/m2, teratogenic effects, including anomalies of
the brain (e.g., meningocele, encephalocele, deformation, underdevelopment) and eyes (e.g., anophthalmia, microphthalmia),
hepatocele (exomphalos), and reduction in size of mandibles and tails occurred.Ref If melphalan is administered during pregnancy or if
the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.Ref Women
of childbearing potential should be advised to avoid becoming pregnant while receiving melphalan.Ref

Fertility

Ovarian suppression and amenorrhea may occur during melphalan therapy in premenopausal women.Ref Reversible and
irreversible suppression of testicular function also have been reported in patients receiving the drug.Ref

Lactation

It is not known whether melphalan is distributed into milk.Ref Because of the potential for serious adverse reactions to melphalan in
nursing infants if the drug were distributed into milk, a decision should be made whether to discontinue nursing or the drug, taking into
account the importance of the drug to the woman.Ref The manufacturer states that IV melphalan should not be administered to nursing
women.Ref

Drug Interactions
Food

Food appears to decrease the bioavailability of melphalan.Ref Following oral administration of melphalan, bioavailability of the drug
was about 85–93 and 49–58% in the fasted and nonfasted state, respectively.Ref Some clinicians state that oral melphalan should not be
administered with food.Ref

Cyclosporine

Melphalan may increase cyclosporine-induced nephrotoxicity.Ref Severe renal failure has been reported in patients receiving a single
dose of IV melphalan followed by usual dosages of cyclosporine.Ref Renal function should be monitored carefully in patients receiving
cyclosporine and melphalan concomitantly;Ref dosage reduction of cyclosporine may be necessary in patients receiving high-dose
melphalan therapy.Ref

Other Drugs

Plasma elimination of melphalan may be enhanced by interferon alfa-induced fever, resulting in a decreased area under the plasma
concentration-time curve (AUC) of melphalan.Ref The clinical importance of this interaction remains to be determined.Ref

Concomitant administration of cisplatin may affect pharmacokinetics of melphalan secondary to cisplatin-induced renal impairment,
which may result in decreased clearance of melphalan.Ref IV melphalan may reduce the threshold for carmustine-induced pulmonary
toxicity.Ref Concomitant nalidixic acid and melphalan use in children may result in an increased incidence of severe hemorrhagic necrotic
enterocolitis.Ref

Cimetidine appears to inhibit GI absorption of melphalan resulting in reduced serum concentrations of melphalan;Ref patients
receiving cimetidine and melphalan concomitantly should be monitored for decreased melphalan activity.Ref

Pharmacology

Melphalan, as an alkylating agent, interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of
nucleic acid function. Melphalan also possesses some immunosuppressive activity.

Acute Toxicity
Pathogenesis

The oral LD50 of melphalan is 21 mg/kg in mice.Ref

 Manifestations

Overdosage with melphalan doses up to 290 mg/m2 was associated with severe nausea, vomiting, ulceration of the mouth, decreased
consciousness, seizures, muscular paralysis, and cholinomimetic effects.Ref In addition, overdosage with melphalan dosages up to 50 mg
daily for 16 days may be associated with vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the GI tract.Ref Several fatalities
following melphalan overdosage have been reported to date.Ref One child who received standard supportive care survived a single
melphalan dose of 254 mg/m2.Ref In patients receiving high doses of melphalan (i.e., greater than 100 mg/m2), severe mucositis,
stomatitis, colitis, diarrhea, and GI bleeding have been reported.Ref Elevations in liver enzymes, hepatic veno-occlusive disease,
nephrotoxicity, and adult respiratory distress syndrome have occurred rarely.Ref In some patients, severe hyponatremia caused by
inappropriate antidiuretic hormone secretion (SIADH) has been reported.Ref The principal toxic effect of melphalan is bone marrow
suppression.Ref The patient’s hematologic status should be monitored carefully for 3–6 weeks following melphalan overdosage.Ref

Treatment

Treatment of severe hematologic toxicity may consist of supportive therapy, anti-infectives for complicating infections, and blood
product transfusions, at the discretion of the clinician.Ref Results of an uncontrolled study suggest that administration of autogenous
(autologous) bone marrow or a biosynthetic hematopoietic agent (e.g., filgrastim, sargramostim) may shorten the period of melphalan-
induced pancytopenia.Ref Melphalan is not removed by hemodialysis or hemoperfusion.Ref

Pharmacokinetics

The pharmacokinetics of orally administered melphalan have been studied extensively in adults.Ref

Absorption

Absorption of melphalan from the GI tract is incomplete and extremely variable. In a crossover study of single 0.6 mg/kg IV and oral
doses of melphalan, the areas under the plasma concentration-time curves (AUCs) following oral administration were 25–89% of those
following IV administration. In one study in fasting patients given a single oral melphalan dose of 0.6 mg/kg, average peak plasma
melphalan concentrations of 280 ng/mL were reached within 2 hours. In adult patients with myeloma who received single IV melphalan
doses of 10 or 20 mg/m2, mean peak plasma concentrations of the drug were 1.2 or 2.8 ng/mL, respectively.Ref Monohydroxy and
dihydroxy derivatives of melphalan are present in plasma within 30 minutes after oral administration of the drug.

Distribution

Melphalan is rapidly distributed throughout total body water. Melphalan distributes into CSF in low concentrations.Ref The volume of
distribution of melphalan at steady state (Vss) has been reported to be approximately 0.5 L/kg.Ref The drug reportedly is 60–90% bound to
plasma proteins, mainly albumin and to a lesser extent (about 20%) to α1-acid glycoprotein (α1-AGP).Ref About 30% of melphalan is
irreversibly bound to plasma proteins.Ref Interactions of melphalan with immunoglobulins have been found to be negligible.Ref
Experimental evidence indicates that melphalan may alkylate plasma proteins. It is not known whether melphalan crosses the placenta. It
is also not known whether melphalan or its metabolites are distributed into milk.

Elimination

Following a single oral dose in one study, the terminal plasma half-life of melphalan was 1.5 hours. Monohydroxy and dihydroxy
derivatives of melphalan have apparent terminal plasma half-lives 2–3 times longer than unchanged melphalan. Plasma concentrations of
melphalan appear to decline in a biphasic manner following IV administration of the drug.Ref Following IV administration of melphalan
hydrochloride in adult patients, the half-life of melphalan is about 10 minutes in the initial distribution phase (t½α) and about 75 minutes in
the terminal elimination phase (t½β).Ref

Melphalan is apparently eliminated from plasma mainly by spontaneous hydrolysis, forming the monohydroxy and dihydroxy
derivatives of the drug; no other metabolites have been identified in humans. In vitro in human plasma, melphalan undergoes first-order
hydrolysis. Following IV administration of melphalan hydrochloride, total body clearance of the drug averages 7–9 mL/minute per kg in
adult patients, although considerable interindividual variation in body clearance exists.Ref In adult patients, total body clearance of
melphalan may be decreased following multiple IV doses (e.g., 0.5 mg/kg every 6 weeks).Ref Total body clearance decreased from 8.1
mL/minute per kg after the first course of therapy to 5.5 mL/minute per kg after the third course of therapy; body clearance did not
decrease appreciably after the third course of therapy with melphalan.Ref About 20–35% of an oral dose is excreted in urine as the drug
and its metabolites within 24 hours. Approximately 10% of a single oral dose of melphalan is excreted in urine unchanged within 24 hours.
Although renal elimination of melphalan appears to be low, results of one pharmacokinetic study indicate that there may be a direct
correlation between renal function and elimination rate constant of the drug, while a negative correlation may exist between the area
under the plasma concentration-time curve (AUC) of the drug and renal function.Ref In one study using orally administered melphalan C
14, 20–50% of the dose was excreted in feces within 6 days.
Chemistry and Stability
Chemistry

Melphalan, a nitrogen mustard derivative, is a bifunctional alkylating agent. The drug is the l-isomer of the phenylalanine derivative of
mechlorethamine. Melphalan occurs as an off-white to buff powder that has a faint odor and is practically insoluble in water and slightly
soluble in alcohol. Melphalan hydrochloride for injection is commercially available as a sterile, nonpyrogenic, lyophilized powder.Ref The
powder for injection also contains povidone.Ref A sterile diluent containing water for injection, sodium citrate, propylene glycol, and alcohol
is provided by the manufacturer for reconstitution.Ref The reconstituted injection has a pH of about 7;Ref the pKa of melphalan is
approximately 2.5.Ref

Stability

Melphalan tablets should be stored in well-closed, light-resistant, glass containers at a temperature less than 40°C, preferably between
15–30°C. Following reconstitution with sterile diluent, melphalan hydrochloride solution containing 5 mg of melphalan per mL is stable for up
to 90 minutes at room temperature; this reconstituted solution should not be refrigerated since a precipitate may form at 5°C.Ref The
reconstituted solution should be diluted further with 0.9% sodium chloride injection to provide a solution with a concentration not exceeding
0.45 mg/mL.Ref This diluted solution is stable for 60 minutes at room temperature.Ref

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at
http://www.ahfsdruginformation.com.

Preparations

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.
Melphalan

RoutesDosage Forms StrengthsBrand Names Manufacturer

Oral Tablets, film-coated2 mg Alkeran® GlaxoSmithKline

Melphalan Hydrochloride

Routes Dosage Forms Strengths Brand Names Manufacturer

Parenteral For injection 50 mg (of melphalan) Alkeran® GlaxoSmithKline

References
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