EVOMELA (melphalan) for injection
Evomela contains melphalan hydrochloride, an alkylating drug, as the active ingredient. The chemical name of melphalan hydrochloride is 4-[bis(2-chloroethyl)amino]-L-phenylalanine hydrochloride. Its molecular formula is C13H18Cl2N2O2 • HCl and the molecular weight is 341.67.
Melphalan hydrochloride is a white to off-white powder, with a melting range of 199°C − 201°C. It is practically insoluble in water, but freely soluble in 1N HCl and methanol.
Indications and usage
Evomela is an alkylating drug indicated for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma.
Mechanism of Action
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 N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
Dosage and administration
For Conditioning Treatment, the recommended dose of Evomela 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)
History of serious allergic reaction to melphalan
Warnings and precautions
- Gastrointestinal toxicity: Nausea, vomiting, diarrhea or oral mucositis may occur; provide supportive care using antiemetic and antidiarrheal medications as needed.
- Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception.
- Infertility: Melphalan may cause ovarian function suppression or testicular suppression
Most common adverse reactions observed in at least 50% of patients treated with Evomela are neutrophil count decreased, white blood cell count decreased, lymphocyte count decreased, platelet count decreased, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting.
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/m2 followed by standard oral doses of cyclosporine. Intravenous melphalan may also reduce the threshold for BCNU lung toxicity.
Use in specific populations
Pregnancy: Based on its mechanism of action, Evomela 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.
Lactation: 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 Evomela and for one week after the last dose.
Females and Males of Reproductive Potential
Evomela can cause fetal harm when administered to a pregnant woman.
Contraception: Advise females of reproductive potential to use effective contraception during treatment with Evomela and for 6 months after the last dose.
Evomela administration may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Advise males with female partners of reproductive potential to use effective contraception during treatment with Evomela and for 3 months after the last dose.
Infertility: Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients.
Reversible and irreversible testicular suppression has been reported in male patients after administration of melphalan.
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 Evomela, 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.
Overdoses resulting in death have been reported with melphalan. Overdoses, including doses up to 290 mg/m2 , have produced the following symptoms: severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, and cholinomimetic effects. Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (>100 mg/m2 ). Elevations in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia, caused by an associated inappropriate secretion of ADH syndrome, has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely.
The principal toxic effect is bone marrow suppression leading to leucopenia, thrombocytopenia and anemia. Hematologic parameters should be closely followed for 3 to 6 weeks. An uncontrolled study suggests that administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, filgrastim) may shorten the period of pancytopenia. General supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis or hemoperfusion. A pediatric patient survived a 254 mg/m2 overdose treated with standard supportive care.
Storage and Handling
Store Evomela at room temperature 25°C (77°F). Temperature excursions are permitted between 15- 30°C (59-86°F). [see USP Controlled Room Temperature]
Evomela is light sensitive. Retain in original carton until use. Melphalan is a hazardous drug. Follow applicable special handling and disposal procedures.