Evomela Drug Information

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

Preparation and Administration Evomela is a hazardous drug

Follow applicable special handling and disposal procedures 1. Evomela is light sensitive. Retain in original carton until use.

Do not mix Evomela with other melphalan hydrochloride for injection drug products. Reconstitution and Infusion Instructions: 1. The reconstituted Evomela drug product is stable for 24 hours at refrigerated temperature (5 o C) without any precipitation due to the high solubility.

The reconstituted Evomela drug product is stable for 1 hour at room temperature. 2. Calculate the required volume of Evomela needed for a patient’s dose and withdraw that volume from the vial(s). 3. Add the required volume of Evomela to the appropriate volume of 0.9% Sodium Chloride Injection, USP to a final concentration of 0.45 mg/mL.

The Evomela admixture solution is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution. 4. Infuse over 30 minutes via an injection port or central venous catheter. Evomela may cause local tissue damage should extravasation occur.

Do not administer by direct injection into a peripheral vein. Administer Evomela by injecting slowly into a fast-running IV infusion via a central venous access line. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of Evomela may not reflect the rates observed in practice. The most common adverse reactions observed in at least 50% of patients with multiple myeloma treated with Evomela were neutrophil count decreased, white blood cell count decreased, lymphocyte count decreased, platelet count decreased, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting. Table 1 summarizes the adverse reactions from the single-arm trial in patients with multiple myeloma.

Severe myelosuppression is expected and these adverse reactions are not listed below. Table 1 Non-hematologic Adverse Reactions in≥ 25% of Patients with Multiple Myeloma Who Received Evomela Conditioning for ASCT Twelve (20%) patients experienced a treatment emergent serious adverse reaction while on study. The most common serious adverse reactions (>1 patient, 1.6%) were pyrexia, hematochezia, febrile neutropenia, and renal failure.

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.

Pregnancy Risk Summary 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. 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.

Data Animal Data Adequate animal studies have not been conducted with intravenous melphalan. Malformations resulting from melphalan administration included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, and hepatocele (exomphaly).

Pediatric Use Pediatric patients were not included in clinical trials. Safety and effectiveness have not been established in pediatric patients.

History of serious allergic reaction to melphalan.

Overdoses resulting in death have been reported with melphalan. Overdoses, including doses up to 290 mg/m 2, 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/m 2 ).

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/m 2 overdose treated with standard supportive care.