melphalan (phenylalanine mustard)
Alkeran

Available forms
Available by prescription only
Powder for injection: 50 mg
Tablets (scored): 2 mg

Indications and dosages
Dosage and indications may vary. Check current literature for recommended protocol.
 Multiple myeloma. Adults: 6 mg P.O. daily for 2 to 3 weeks; then stop therapy for 4 weeks. When WBC and platelet count begin to increase, start maintenance dosage of 2 mg P.O. daily. Or, give 0.15 mg/kg daily P.O. for 7 days or 0.25 mg/kg daily P.O. for 4 days at 4- to 6-week intervals, usually with prednisone; monitor patient’s blood counts. Other dosing methods: 10 mg P.O. for 7 to 10 days. When platelet and leukocyte counts exceed 100,000/μL and 4000/μL, respectively, start maintenance therapy at 2 mg P.O. daily. Adjust dosage by 1 to 3 mg based on hematologic response.
 For I.V. use, give 16 mg/m² over 15 to 20 minutes at 2-week intervals for four doses. Monitor patient’s blood counts and reduce dose as necessary. After satisfactory recovery, repeat dose at 4-week intervals.
 Epithelial ovarian cancer. Adults: 200 mcg/kg daily P.O. for 5 days, repeated q 4 to 5 weeks if blood counts return to normal.
≡ Dosage adjustment. Reduce I.V. melphalan dose by 50% in patients with renal impairment to reduce severe leukopenia and drug-related death.

Pharmacodynamics
Antineoplastic action: Melphalan exerts its cytotoxic activity by forming cross-links of strands of DNA and RNA and inhibiting protein synthesis.

Pharmacokinetics
Absorption: Absorption from GI tract is incomplete and variable.
Distribution: Distributes rapidly and widely into total body water. Drug is initially 50% to 60% bound to plasma proteins and eventually increases to 80% to 90% over time.
Metabolism: Extensively deactivated by the process of hydrolysis.
Excretion: Elimination has been described as biphasic, with an initial half-life of 8 minutes and a terminal half-life of 2 hours. Melphalan and its metabolites are excreted primarily in urine, with 10% of an oral dose excreted as unchanged drug.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug and in those whose disease is known to be resistant to drug. Patients hypersensitive to chlorambucil may have cross-sensitivity to melphalan.
  Use cautiously in patients with impaired renal function, severe leukopenia, thrombocytopenia, anemia, or chronic lymphocytic leukemia.

Interactions
Drug-drug. Cimetidine: Inhibits GI absorption. Avoid administration together.
Cisplatin, cyclosporine: May increase nephrotoxicity. Monitor renal function closely.
Interferon alpha: May decrease melphalan levels. Monitor patient carefully.
Drug-food. Any food: Reduces bioavailability of melphalan. Advise patient to take drug on an empty stomach.

Adverse reactions
CNS: transient paralysis, peripheral neuritis.
CV: hypotension, tachycardia, edema, thrombosis, phlebitis, pulmonary embolism.
GI: nausea, vomiting, diarrhea, oral ulceration.
Hematologic: thrombocytopenia, leukopenia, bone marrow suppression, hemolytic anemia.
Hepatic: hepatotoxicity.
Respiratory: pneumonitis, pulmonary fibrosis, dyspnea, bronchospasm.
Skin: pruritus, alopecia, urticaria, vesiculation, and tissue necrosis.
Other: anaphylaxis, hypersensitivity, secondary malignancy.

Effects on lab test results
• May increase nitrogenous compound (urea) level.
• May decrease hemoglobin and RBC, WBC, and platelet counts.

Overdose and treatment
Signs and symptoms of overdose include myelosuppression, hypocalcemia, severe nausea, vomiting, ulceration of the mouth, decreased consciousness, seizures, muscular paralysis, and cholinomimetic effects.
 Treatment is usually supportive and includes transfusion of blood components.

Special considerations
• Fever may enhance elimination of the drug.
• Use anticoagulants, aspirin, and aspirin-containing products cautiously.
• Discontinue therapy temporarily or reduce dosage if WBC count is less than 3,000/mm³ or platelet count is less than 100,000/mm³.
• Increased bone marrow suppression was observed in patients with BUN levels of 30 mg/dl or more.
• Oral dose may be taken all at one time.
• Give drug on an empty stomach because absorption is decreased by food.
• Avoid I.M. injections when platelet count is less than 100,000/mm³.
• For I.V. administration, consider dosage reduction in patients with renal impairment.
• Follow procedure for proper handling and disposal of antineoplastics.
• For I.V. administration, reconstitute powder for injection by adding 10 ml of provided diluent to 50-mg vial using a 20G or larger needle; produces a concentration of 5 mg/ml. Add diluent rapidly and shake vial until solution is clear. Don’t refrigerate because a precipitate may form. Immediately, dilute further in normal saline solution for injection to provide a solution not exceeding 0.45 mg/ml. Give over 15 to 20 minutes; infuse solution within 60 minutes from time of reconstitution.
• Frequent hematologic monitoring, including CBC, is needed for accurate dosage adjustments and prevention of toxicity.
• Monitor renal function, especially if BUN is greater than 30 mg/dL.
Breast-feeding patients
• It isn’t known if melphalan appears in breast milk. However, because of risk of serious adverse reactions, mutagenicity, and carcinogenicity in the infant, breast-feeding isn’t recommended.

Patient education
• Instruct patient to continue taking drug despite nausea and vomiting.
• Tell patient to call immediately if vomiting occurs shortly after taking a dose.
• Explain that adequate fluid intake is important to facilitate excretion of uric acid.
• Instruct patient to avoid exposure to people with infections.
• Reassure patient that hair should grow back after treatment has ended.
• Tell patient to promptly report signs and symptoms of infection or bleeding.
• Advise women of childbearing age to avoid becoming pregnant while receiving drug therapy.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use