Evomela Drug Information
Generic name: MELPHALAN
Uses of Evomela
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.
Dosage & Administration of Evomela
Recommended Dosage for Conditioning Treatment
The recommended dose of Evomela for conditioning treatment is 100 mg/m 2 /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 .
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. Use 0.9% Sodium Chloride Injection, USP (8.6 mL as directed) to reconstitute Evomela and make a 50 mg/10 mL (5 mg/ mL) nominal concentration of melphalan. 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.
Side Effects of Evomela
- 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Acrotech Biopharma Inc. at 1-888-292-9617 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following serious adverse reactions are described in more detail in other sections of the prescribing information.
- Bone Marrow Suppression [see Warnings and Precautions ( 5.1 )]
- Gastrointestinal Toxicity [see Warnings and Precautions ( 5.2 )]
- Hepatotoxicity [see Warnings and Precautions ( 5.3 )]
- Hypersensitivity [see Warnings and Precautions ( 5.4 )]
- Secondary Malignancies [see Warnings and Precautions ( 5.5 )] 6.1 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. Myeloablative Conditioning in Multiple Myeloma Patients Undergoing ASCT 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/m 2 /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 ( 14.1 )]. 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 3or 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 (2%) 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%) Serious Adverse Reactions 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%).
Warnings & Cautions for Evomela
Bone Marrow Suppression 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.
Gastrointestinal Toxicity 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. .
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 Evomela 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 Evomela therapy must be considered against the possible risk of the induction of a secondary malignancy.
Embryo-Fetal Toxicity
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 .
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.
Drug Interactions with Evomela
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 Safety for Evomela
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.
Melphalan was embryolethal and teratogenic in rats following oral administration of 6 to 18 mg/m 2 /day for 10 days (0.06 to 0.18 times the highest recommended clinical dose of 100 mg/m 2 /day) and intraperitoneal administration of 18 mg/m 2 (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).
Pediatric Use of Evomela
Pediatric Use Pediatric patients were not included in clinical trials. Safety and effectiveness have not been established in pediatric patients.
Contraindications for Evomela
History of serious allergic reaction to melphalan. History of serious allergic reaction to melphalan
Overdosage Information for Evomela
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.
Clinical Studies of Evomela
Myeloablative Conditioning in Patients with Multiple Myeloma Undergoing
ASCT 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 × 10 6 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/m 2 /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/m 2 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/mm 3, absolute lymphocyte count < 100/mm 3, or platelet count < 20,000/mm 3 ). Neutrophil engraftment was defined as ANC > 500/mm 3 ×3 consecutive daily assessments. Platelet engraftment was defined as untransfused platelet counts > 20,000/mm 3 ×3 consecutive daily assessments. Nonengraftment was defined as failure to reach an ANC > 500/mm 3 ×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).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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