Melphalan

A to Z Drug Facts

Actions Melphalan is a bifunctional, alkylating agent of the bischloroethylamine type. Its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA. Like other bifunctional alkylating agents, it is active against resting and rapidly dividing tumor cells. Plasma melphalan levels vary after oral dosing with respect to the time of first detectable levels (0 to 336 min) and to the peak concentrations achieved (0.166 to 3741 mcg/mL). These results may be because of incomplete intestinal absorption, a variable “first-pass” hepatic metabolism, or to rapid hydrolysis. Following injection, mean peak plasma levels were 1.2 and 2.8 ng/mL after 10 and 20 mg/m² doses. The steady-state volume of distribution is 0.5 L/kg. Plasma protein binding of melphalan ranges from 60% to 90% with » 30% being covalently (irreversibly) bound. Plasma half-life after oral dosing is » 90 min. Following injection, drug plasma concentrations showed a distribution phase and terminal elimination phase half-lives of » 10 and 75 min. Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxy and dihydroxy melphalan; no other metabolites have been seen. The contribution of renal elimination to melphalan clearance appears to be low; » 10% is excreted unchanged in urine within 24 hr.

 Indications Palliative therapy of multiple myeloma (oral and IV) and non-resectable epithelial carcinoma of the ovary (oral).

Breast carcinoma, testicular carcinoma, bone marrow transplantation.

 Contraindications Standard considerations.

 Route/Dosage

Multiple Myeloma

ADULTS: PO 6 mg/day for 2 to 3 wk as a single daily dose. Resume therapy with 2 mg/day PO after a rest period £ 4 wk and increase dose as necessary.

Alternate regimens: PO 0.25 mg/kg/day for 4 to 7 days or 0.15 mg/kg/day for 7 days. Either regimen can be repeated at 4- to 6-wk intervals after toxicity has resolved. Continuous daily dosing may increase the risk of severe bone marrow depression and secondary malignancy.

ADULTS: IV 16 mg/m² q 2 wk for 4 doses, then as tolerated every 4 wk. The dose should be decreased 50% in patients with BUN ³ 30 mg/dL (or serum creatinine ³ 1.5 mg/dL).

Epithelial Ovarian Cancer

ADULTS: PO 0.2 mg/kg/day for 5 days q 4 to 5 wk.

Dosage Adjustments

ADULTS: PO, IV All doses should be adjusted based on hematological parameters at nadir. If WBC ³ 4000 cells/mm³ and platelet count ³ 100,000 cells/mm³, administer 100% of prior dose. If WBC ³ 3000 cells/mm³ and platelet count ³ 75,000 cells/mm³, administer 75% of prior dose. If WBC ³ 2000 cells/mm³ and platelet count ³ 50,000 cells/mm³, administer 50% of prior dose. If WBC < 2000 cells/mm³ and platelet count ³ 50,000 cells/mm³, no prior dose is to be given. The manufacturer recommends discontinuing drug for leukocyte count < 3000/mm³ or platelet count < 100,000/mm.³.

Interactions

Carmustine

Melphalan may increase the likelihood of carmustine pulmonary toxicity.

Cimetidine and interferon alfa

May decrease serum concentrations of melphalan.

Cisplatin

May alter melphalan clearance, resulting in renal dysfunction.

Cyclosporine

Bone marrow transplant patients receiving melphalan followed by cyclosporine had a high frequency of severe renal dysfunction in 1 study.

Lab Test Interferences None well documented.

 Adverse Reactions

DERMATOLOGIC: Alopecia. ENDOCRINE: Syndrome of inappropriate antidiuretic hormone secretion with high IV doses. GI: Very low potential for nausea and vomiting with oral use; moderate potential for nausea and vomiting when used IV in bone marrow transplantation; diarrhea, mucositis; hepatic veno-occlusive disease after bone marrow transplantation. GU: Ovarian and testicular suppression. HEMATOLOGIC: Bone marrow suppression, nadir at 2 to 3 wk. HYPERSENSITIVITY: Anaphylactoid reaction (2.4% frequency) after IV administration may require stopping the infusion and giving fluids, corticosteroids, antihistamines, or pressors. RESPIRATORY: Pulmonary fibrosis, interstitial pneumonitis. OTHER: Increased risk of acute leukemia or myeloproliferative syndrome with high cumulative doses and long duration of therapy.

 Precautions

Pregnancy: Category D. Lactation: Undetermined. Children: Safety and efficacy in children have not been established. Bone marrow suppression: Excessive dosage will produce marked bone marrow suppression, which is the most significant toxicity associated with IV melphalan in most patients. Hypersensitivity reactions: Hypersensitivity reactions including anaphylaxis have occurred with both oral and injection. Renal function impairment (IV): Consider dose reduction in patients with renal insufficiency receiving IV melphalan. Renal function impairment (oral): Whether routine dosage reductions are needed in impaired Ccr is unknown. Carcinogenesis: Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, occurred in cancer patients following therapy with alkylating agents. Fertility impairment: Melphalan causes chromatid or chromosome damage in humans. Suppression of ovarian function may occur in premenopausal women, resulting in amenorrhea. Extravasation: IV melphalan is a vesicant; extravasation can cause severe local necrosis. Prior radiation and chemotherapy: Use with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy or whose marrow function is recovering from previous cytotoxic therapy.

 Administration/Storage

• Store at room temperature and protect from light. Store tablets in glass containers.
• Reconstitute by rapidly injecting 10 mL of supplied diluent into the vial and shaking vigorously until the solution is clear (final concentration is 5 mg/mL). The dose can be diluted with 0.9% Sodium Chloride to a concentration £ 0.45 mg/mL. It can also be given undiluted through a central venous catheter.
• Melphalan injection is rapidly hydrolyzed. The undiluted solution is stable for 90 min. With further dilution immediately after reconstitution, it is stable for 60 min.
• Administer PO or IV.
• Give oral melphalan on an empty stomach. Food markedly reduces bioavailability.
• IV melphalan degrades rapidly; give as soon as possible after reconstitution. Give over 15 to 20 min by IV push injection or IV side arm into a running IV infusion. Protection from light during infusion is not necessary. Bolus doses of undiluted solution are also tolerated via a central venous catheter.
• Follow procedures for proper handling and disposal of anticancer drugs. Wear gloves and avoid skin exposure and inhalation of fumes.

 Assessment/Interventions

• For patients receiving melphalan for bone marrow ablation, hydration with IV fluids may begin 12 hr before the dose and continue for 24 hr after the dose. Furosemide may also be given to induce diuresis.
• Hyperuricemia may occur because of rapid cell lysis; monitor serum uric acid. Minimize effects of hyperuricemia with hydration, urinary alkalinization, and allopurinol.
• Perform the following tests at the start of therapy and prior to each subsequent dose: Platelet count, hemoglobin, WBC count, and differential. Thrombocytopenia or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Discontinue the drug or decrease the dosage upon evidence of bone marrow suppression. Consider dose adjustment on the basis of blood counts at the nadir and day of treatments. If leukocyte count falls to < 3000/mm³ or platelet count to < 100,000/mm³, discontinue drug until peripheral blood cell counts have recovered.

 Patient/Family Education

• Inform patients that the major toxicities are related to myelosuppression, hypersensitivity, GI toxicity, pulmonary toxicity, infertility, and non-lymphocytic leukemia. Do not take without close medical supervision.
• Notify health care provider of unusual bleeding or bruising, fever, chills, sore throat, shortness of breath, yellow discoloration of skin or eyes, persistent cough, flank or stomach pain, joint pain, mouth sores, black tarry stools, skin rash, vasculitis, amenorrhea, nausea, vomiting, weight loss, or unusual lumps or masses.
• Contraceptive measures are recommended during therapy.

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Copyright © 2003 Facts and Comparisons
David S. Tatro
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