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WARNING
SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY, and LEUKEMOGENICITY
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. The structural formula is:
 |
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 1 N HCl and methanol.
Evomela (melphalan) for injection is supplied as a sterile white to off-white lyophilized powder in a single-dose vial for intravenous use. Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride and 2700 mg Betadex Sulfobutyl Ether Sodium, NF.
Evomela is indicated for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma.
The recommended dose of Evomela 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.
Administer prophylactic antiemetics [see WARNINGS AND PRECAUTIONS].
Evomela is a hazardous drug. Follow applicable special handling and disposal procedures1. Evomela is light sensitive. Retain in original carton until use. Do not mix Evomela with other melphalan hydrochloride for injection drug products.
The reconstituted Evomela drug product is stable for 24 hours at refrigerated temperature (5°C) without any precipitation due to the high solubility.
The reconstituted Evomela drug product is stable for 1 hour at room temperature.
The Evomela admixture solution is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution.
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.
For injection: 50 mg, white to off-white lyophilized powder in single-dose vial for reconstitution (after reconstitution the solution is clear and colorless to light yellow). Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalanhydrochloride.
Evomela is supplied in a single carton containing one (1) vial. Each 50 mg vial contains a white to off-white lyophilized powder in single-dose vial for reconstitution (after reconstitution the solution is clear and coloress to light yellow). Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride.
NDC 72893-001-01: Individual carton of Evomela 20 mL single-dose vial containing 50 mg melphalan free base.
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.1
REFERENCES
1. OSHA Hazardous Drugs. OSHA. [Accessed on 9 December 2014, from https://www.osha.gov/SLTC/hazardousdrugs/index.html].
Manufactured For: Acrotech Biopharma LLC 279 Princeton Hightstown Rd. East Windsor, NJ 08520. Revised: Aug 2021
The following serious adverse reactions are described in more detail in other sections of the prescribing information.
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.
The safety of Evomela was evaluated in 61 patients with multiple myeloma in a single arm clinical trial in which patients were administered Evomela at a dosage of 100 mg/m²/day administered over ~30 minutes (range: 24-48 minutes) by intravenous (IV) infusion for 2 consecutive days (Day -3 and Day -2) prior to autologous stem cell transplant (ASCT, Day 0) [see Clinical Studies].
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
| Adverse Reactions | Number (%) of Patients (N=61) |
|
| All Grades | Grade 3 or 4 | |
| All Adverse Reactions | 61 | 61 |
| Diarrhea | 57 (93%) | 2 (3%) |
| Nausea | 55 (90%) | 1 (2%) |
| Fatigue | 47 (77%) | 1 (2%) |
| Hypokalemia | 45 (74%) | 17 (28%) |
| Vomiting | 39 (64%) | 0 (0%) |
| Hypophosphatemia | 30 (49%) | 29 (48%) |
| Decreased Appetite | 30 (49%) | 0 (0%) |
| Pyrexia | 29 (48%) | 2 (3%) |
| Constipation | 29 (48%) | 0 (0%) |
| Febrile Neutropenia | 25 (41%) | 17 (28%) |
| Mucosal Inflammation | 23 (38%) | 6 (10%) |
| Dizziness | 23 (38%) | 0 (0%) |
| Edema Peripheral | 20 (33%) | 0 (0%) |
| Stomatitis | 17 (28%) | 3 (5%) |
| Abdominal Pain | 17 (28%) | 0 (0%) |
| Dysgeusia | 17 (28%) | 0 (0%) |
| Dyspepsia | 16 (26%) | 0 (0%) |
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. Treatment-related serious adverse reactions reported in >1 patient were pyrexia (n=2, 3%), febrile neutropenia (n=2, 3%), and hematochezia (n=2, 3%).
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.
Included as part of the PRECAUTIONS section.
For patients receiving Evomela 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.
For patients receiving Evomela 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 [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].
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.
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 Evomela for serious hypersensitivity reactions.
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 Evomela therapy must be considered against the possible risk of the induction of a secondary malignancy.
Based on its mechanism of action, Evomela 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 Evomela and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Evomela and for 3 months after the last dose [see Use In Specific Populations].
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 [see Use In Specific Populations].
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Advise patients or their caregivers of the following:
Adequate and well-controlled carcinogenicity studies have not been conducted in animals. However, intraperitoneal (IP) administration of melphalan in rats (5.4 to 10.8 mg/m²) and in mice (2.25 to 4.5 mg/m²) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcomasand lung tumors, respectively.
Intramuscular administration of melphalan at 6 and 60 mg/m² produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats.
Based on its mechanism of action, Evomela can cause fetal harm when administered to a pregnant woman, including teratogenicity and/or embryo-fetal lethality [see CLINICAL PHARMACOLOGY]. Melphalan is a genotoxic drug and can cause chromatid or chromosome damage in humans [see Nonclinical Toxicology]. In animal studies, melphalan was embryolethal and teratogenic in rats at doses below the recommended clinical doses [see Data]. 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.
Animal Data
Adequate animal studies have not been conducted with intravenous melphalan. Melphalan was embryolethal and teratogenic in rats following oral administration of 6 to 18 mg/m²/day for 10 days (0.06 to 0.18 times the highest recommended clinical dose of 100 mg/m²/day) and intraperitoneal administration of 18 mg/m² (0.18 times the highest recommended clinical dose). 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).
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.
Evomela can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations].
Females
Advise females of reproductive potential to use effective contraception during treatment with Evomela and for 6 months after the last dose.
Males
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 [see Nonclinical Toxicology].
Females
Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients.
Males
Reversible and irreversible testicular suppression has been reported in male patients after administration of melphalan.
Pediatric patients were not included in clinical trials. Safety and effectiveness have not been established in pediatric patients.
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 associatedinappropriate secretion of ADH syndrome, has been observed. Nephrotoxicity and adult respiratorydistress 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.
History of serious allergic reaction to melphalan.
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 tumorcells.
The peak mean heart rate increased 20 bpm from baseline following melphalan 100 mg/m² for 2 consecutive days in multiple myeloma patients undergoing autologous stem cell transplantation.
No large mean increase in QTc (i.e. > 20 ms) was detected following melphalan 100 mg/m².
Mean (± SD) peak plasma concentrations and AUC0-inf were 5.8 ± 1.5 mcg/mL and 451 ± 109 mcg*min/mL, respectively, following administration of melphalan 100 mg/m² in multiple myeloma patients.
The volume of distribution of melphalan ranges from approximately 35.5 to 185.7 L/m². Melphalan penetrates into cerebrospinal fluid (CSF). Protein binding of melphalan ranges from approximately 50% to 90%, primarily to serum albumin (40% to 60%) and to a lesser extent to α1-acid glycoprotein (20%). Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins.
Melphalan terminal elimination half-life is approximately 75 minutes. Average total body clearance (CL) ranges from approximately 250 to 325 mL/min/m².
Melphalan primarily undergoes chemical hydrolysis to inactive metabolites.
Mean values of melphalan excreted in urine range from 5.8% to 21.3%.
Melphalan clearance changes with ideal body weight (IBW), which decreased by 28% and increased by 31% with IBW of 45 kg and 100 kg compared to 70 kg IBW, respectively.
A decrease in estimated creatinine CL from 100 mL/min to 30 mL/min results in 28.2% reduction in CL for a typical person with an IBW of 70 kg.
An open-label, single-arm, non-randomized trial of Evomela was conducted at 5 US centers (NCT 01660633). The 61 patients enrolled had symptomatic multiple myeloma and had at least 2 × 106 CD34+ cells/kg cryopreserved stem cells available. The median age was 62 years (range 32 to 73); 57% male, 80% white, 18% black, 2% Asian. Evomela was administered at 100 mg/m²/day over 30 minutes by IV infusion for two consecutive days (Day -3 and Day -2) prior to ASCT (Day 0).
The objective of the trial was to determine the overall safety and toxicity profile of 200 mg/m² of Evomela in patients with multiple myeloma undergoing ASCT. The efficacy was evaluated by the International Myeloma Working Group response criteria comparing the disease response immediately prior to the ASCT procedure to the disease response assessed 90 to 100 days post-transplant. In addition, successful myeloablation, and time to engraftment were evaluated.
The overall response rate (partial response or better) improved from 79% (48 of 61) prior to the ASCT procedure to 95% (58 of 61) at 90 to 100 days post-transplant. There was also an increase in the number of patients with a stringent complete response from 0 patients prior to the ASCT procedure to 16% (10 of 61) at 90 to 100 days post-transplant.
Myeloablation and engraftment were evaluated by complete blood cell count tests daily until neutrophil and platelet engraftment, and then weekly until Day 30, and at Day 60 and Day 90-100. Myeloablation was defined as any of the following: absolute neutrophil count (ANC) < 500/mm³, absolute lymphocyte count < 100/mm³, or platelet count < 20,000/mm³). Neutrophil engraftment was defined as ANC > 500/mm³ ×3 consecutive daily assessments. Platelet engraftment was defined as untransfused platelet counts > 20,000/mm³ ×3 consecutive daily assessments. Nonengraftment was defined as failure to reach an ANC > 500/mm³ ×3 consecutive daily assessments by Day 90-100.
Myeloablation, neutrophil engraftment and platelet engraftment were achieved by all 61 patients. Myeloablation occurred on ASCT Day 5 (range ASCT days -1 to 6) with the median time to myeloablation from dosing of 8 days. The median time to neutrophil engraftment was 12 days (range ASCT days 10 to 16). The median time to platelet engraftment was 13 days (range ASCT days 10 to 28).
EVOMELA
(ev-o-meh-lah)
(melphalan) for injection, for intravenous use
What is Evomela?
Evomela is a prescription medicine used in people with a type of cancer called multiple myeloma before receiving a stem cell transplant (conditioning treatment).
It is not known if Evomela is safe and effective in children.
Do not receive Evomela if you are allergic to melphalan or any of the ingredients in Evomela. See the end of this leaflet for a complete list of ingredients in Evomela.
Before receiving Evomela, tell your healthcare provider about all of your medical conditions, including if you:
Females who can become pregnant:
Males with female partners who can become pregnant:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive Evomela?
What are the possible side effects of Evomela?
Evomela may cause serious side effects, including:
Your healthcare provider may need to discontinue treatment with Evomela if you have a serious allergic reaction.
The most common side effects of Evomela include: tiredness and low potassium level.
These are not all of the possible side effects of Evomela.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Evomela.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Evomela that is written for health professionals.
What are the ingredients in Evomela?
Active ingredient: melphalan hydrochloride
Inactive ingredient: Betadex Sulfobutyl Ether Sodium
This Patient Information has been approved by the U.S. Food and Drug Administration.
