Introduction

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^{† [off-label]} 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^{† [off-label]}.

Melanoma

Has been used alone and in combination regimens in isolated limb perfusion^{† [off-label]} for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma^{† [off-label]} of the extremities.

Amyloidosis

Has been used with prednisone in the treatment of amyloidosis^{† [off-label]}.

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.

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

Administration

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.

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.

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

Dilution

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.

Dosage

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.

Adults

Multiple Myeloma

Oral

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.

IV

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

Oral

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

Oral

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

IV

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.

Contraindications

• Prior resistance to melphalan therapy.

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

Warnings/Precautions

Warnings

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.

Fertility

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).

Cross-Sensitivity

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

General Precautions

Immunization.

Avoid administration of live vaccines to immunocompromised patients.

Pulmonary Toxicity

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

Specific Populations

Pregnancy

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

Lactation

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.

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.

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

Administration

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.

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.

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

Dilution

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.

Dosage

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.

Adults

Multiple Myeloma

Oral

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.

IV

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

Oral

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

Oral

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

IV

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.

Specific Drugs