Melphalan 50 mg/vial

INDICATIONS

Multiple Myeloma-Conditioning Treatment: Melphalan is indicated for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma.

PHARMACOLOGY

Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N 7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.

DOSAGE & ADMINISTRATION

Recommended Dosage for Conditioning Treatment: The recommended dose of Melphalan for conditioning treatment is 100 mg/m2/day administered over 30 minutes by intravenous infusion for 2 consecutive days (Day-3 and Day-2) prior to autologous stem cell transplantation (ASCT, Day 0). For patients who weigh more than 130% of their ideal body weight, body surface area should be calculated based on adjusted ideal body weight.

INTERACTION

No formal drug interaction studies have been conducted. The development of severe renal impairment has been reported in patients treated with a single dose of intravenous melphalan 140-250 mg/m 2 followed by standard oral doses of cyclosporine. Intravenous melphalan may also reduce the threshold for BCNU lung toxicity.

SIDE EFFECTS

Most common adverse reactions observed in at least 50% of patients treated with Melphalan are neutrophil count decreased, white blood cell count decreased, lymphocyte count decreased, platelet count decreased, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting.

PREGNANCY & LACTATION

Based on its mechanism of action, Melphalan can cause fetal harm when administered to a pregnant woman,including teratogenicity and/or embryo-fetal lethality. Melphalan is a genotoxic drug and can cause chromatid or chromosome damage in humans. In animal studies, melphalan was embryolethal and teratogenic in rats at doses below the recommended clinical doses. Advise a pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.It is not known whether melphalan is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing children from melphalan, breastfeeding is not recommended during treatment with Melphalan and for 1 week after the last dose.

PRECAUTIONS & WARNINGS

Bone Marrow Suppression: For patients receiving Melphalan as part of a conditioning regimen, myeloablation occurs in all patients. Do not begin the conditioning regimen if a stem cell product is not available for rescue. Monitor complete blood counts, provide supportive care for infections, anemia and thrombocytopenia until there is adequate hematopoietic recovery.Gastrointestinal Toxicity: For patients receiving Melphalan as part of a conditioning regimen, nausea, vomiting, mucositis, and diarrhea may occur in over 50% of patients. Use prophylactic antiemetic medication. Provide supportive care for nausea, vomiting, diarrhea, and mucositis. The frequency of grade 3/4 mucositis in clinical studies was 13%. Provide nutritional support and analgesics for patients with severe mucositis.Hepatotoxicity: Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported after treatment with melphalan. Hepatic veno-occlusive disease has also been reported. Monitor liver chemistries.Hypersensitivity: Acute hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received an intravenous formulation of melphalan. Symptoms may include urticaria, pruritus, edema, and skin rashes and, in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. Discontinue treatment with Melphalan for serious hypersensitivity reactions.Secondary Malignancies: Melphalan has been shown to cause chromatid or chromosome damage in humans. Secondary malignancies such as myeloproliferative syndrome or acute leukemia have been reported in multiple myeloma patients treated with melphalan-containing chemotherapy regimens. The potential benefit of Melphalan therapy must be considered against the possible risk of the induction of a secondary malignancy.Embryo-Fetal Toxicity: Based on its mechanism of action, Melphalan can cause fetal harm when administered to a pregnant woman. Melphalan is genotoxic, targets actively dividing cells, and was embryolethal and teratogenic in rats. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Melphalan and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Melphalan and for 3 months after the last dose.Infertility: Melphalan-based chemotherapy regimens have been reported to cause suppression of ovarian function in premenopausal women, resulting in persistent amenorrhea in approximately 9% of patients. Reversible or irreversible testicular suppression has also been reported.

USE IN SPECIAL POPULATIONS

Pediatric Use: Pediatric patients were not included in clinical trials. Safety and effectiveness have not been established in pediatric patients.Geriatric Use: Of the total number of subjects in the single-arm pivotal study of melphalan, 30% were 65 and over, but no patients were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. A greater incidence of engraftment syndrome was observed in older patients; 7% (3 of 43) of patients younger than 65 years old versus 28% (5 of 18) of patients 65 years old and over.

THERAPEUTIC CLASS

Cytotoxic Chemotherapy

STORAGE CONDITIONS

Store melphalan at room temperature 25°C. Temperature excursions are permitted between 15-30°C. Melphalan is light-sensitive. Retain in original carton until use. Melphalan is a hazardous drug. Follow applicable special handling and disposal procedures.