Evomela

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.

1.1Multiple 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.

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).

2.1Recommended 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 .

2.2Preparation 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.

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.

5.1Bone 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.

5.2Gastrointestinal 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. .

5.3Hepatotoxicity 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.

5.4Hypersensitivity 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.

5.5Secondary 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.

5.6Embryo-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 .

5.7Infertility 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 .

History of serious allergic reaction to melphalan. History of serious allergic reaction to melphalan

8.1Pregnancy 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).

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. 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 • Gastrointestinal Toxicity • Hepatotoxicity • Hypersensitivity • Secondary Malignancies

6.1Clinical 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). . 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%).