Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 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 single-dose vial containing 50 mg melphalan free base. 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. 1; PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Evomela Carton Label NDC 72893-001-01 Evomela ® (melphalan) for Injection 50 mg per vial* For Intravenous Infusion Only Single-Use Vial Discard Unused Portion Sterile *Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride. Acrotech Biopharma Inc. Evomela Vial Label NDC 72893-001-01 Evomela ® (melphalan) for Injection 50 mg per vial* For Intravenous Infusion Only Single-Use Vial Discard Unused Portion Sterile *Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride. Rx only image-03 image-02
- 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 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 single-dose vial containing 50 mg melphalan free base. 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. 1
- PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Evomela Carton Label NDC 72893-001-01 Evomela ® (melphalan) for Injection 50 mg per vial* For Intravenous Infusion Only Single-Use Vial Discard Unused Portion Sterile *Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride. Acrotech Biopharma Inc. Evomela Vial Label NDC 72893-001-01 Evomela ® (melphalan) for Injection 50 mg per vial* For Intravenous Infusion Only Single-Use Vial Discard Unused Portion Sterile *Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride. Rx only image-03 image-02
Overview
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 C 13 H 18 Cl 2 N 2 O 2 • 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 1N 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. Sodium hydroxide and if necessary, hydrochloric acid are added as a pH adjuster. melphalan structure
Indications & 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. ( 1.1 ) 1.1 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
For Conditioning Treatment , the recommended dose of Evomela 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). ( 2.1 ) 2.1 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 [see Warnings and Precautions ( 5.2 )] . 2.2 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.
Warnings & Precautions
Gastrointestinal toxicity: Nausea, vomiting, diarrhea or oral mucositis may occur; provide supportive care using antiemetic and antidiarrheal medications as needed. ( 2.1 , 5.2 ) 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. ( 5.6 , 8.1 , 8.3 ) Infertility: Melphalan may cause ovarian function suppression or testicular suppression. ( 5.7 ) 5.1 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. 5.2 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. [see Dosage and Administration ( 2.1 ) and Adverse Reactions ( 6.1 )] . 5.3 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. 5.4 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. 5.5 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. 5.6 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 [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.7 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 [see Use in Specific Populations ( 8.3 )].
Boxed Warning
SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY, and LEUKEMOGENICITY Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) melphalan to oral melphalan have shown more myelosuppression with the IV formulation. Monitor hematologic laboratory parameters. [see Warnings and Precautions ( 5.1 )] Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Discontinue treatment with Evomela for serious hypersensitivity reactions. [see Warnings and Precautions ( 5.4 )] Melphalan produces chromosomal aberrations in vitro and in vivo. Evomela should be considered potentially leukemogenic in humans. [see Warnings and Precautions ( 5.5 )] WARNING: SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY, AND LEUKEMOGENICITY See full prescribing information for complete boxed warning. Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) melphalan to oral melphalan have shown more myelosuppression with the IV formulation. Monitor hematologic laboratory parameters. ( 5.1 ) Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Discontinue treatment with Evomela for serious hypersensitivity reactions. ( 5.4 ) Melphalan produces chromosomal aberrations in vitro and in vivo . Evomela should be considered potentially leukemogenic in humans. ( 5.5 )
Contraindications
History of serious allergic reaction to melphalan. History of serious allergic reaction to melphalan
Adverse Reactions
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%).
Drug Interactions
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.
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