MELPHALAN: 16,061 Adverse Event Reports & Safety Profile

DESCRIPTION Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent that is active against selected human neoplastic diseases. It is known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine monohydrochloride. The molecular formula is C 13 H 18 C l2 N 2 O 2 . HCl and the molecular weight is 341.67. The structural formula is: Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active against certain animal tumors, and the dose needed to produce effects on chromosomes is larger than that required with the L-isomer. The racemic (DL-) form is known as merphalan or sarcolysin. Melphalan is practically insoluble in water and has a pKa1 of∼2.5. Melphalan salt is practically insoluble in acetone and chlorinated organic solvents. Slightly soluble in methanol and ethanol. Soluble in water, 0.1 N HCl and 0.1 N NaOH. Melphalan hydrochloride for injection is supplied as a sterile,nonpyrogenic, freeze-dried powder. Each single-dose vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg povidone. Melphalan hydrochloride for injection is reconstituted using the sterile diluent provided. Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6 mL, ethanol (96%) 0.52 mL, and Water for Injection toa total of 10 mL. Melphalan hydrochloride for injection is administered intravenously.

AND 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 AND ADMINISTRATION The usual IV dose is 16 mg/m 2 . Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ≥30 mg/dL) (see PRECAUTIONS: General ). The drug is administered as a single infusion over 15 to 20 minutes. Melphalan hydrochloride for injection is administered at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. Available evidence suggests about one third to one half of the patients with multiple myeloma show a favorable response to the drug. Experience with oral melphalan suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned prematurely. Dose adjustment on the basis of blood cell counts at the nadir and day of treatment should be considered.

Administration

Precautions As with other toxic compounds, caution should be exercised in handling and preparing the solution of melphalan hydrochloride for injection. Skin reactions associated with accidental exposure may occur. The use of gloves is recommended. If the solution of melphalan hydrochloride for injection contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not use this product. Care should be taken to avoid possible extravasation of melphalan and in cases of poor peripheral venous access, consideration should be given to use of a central venous line (see WARNINGS) . Preparation for Administration/Stability 1.Melphalan hydrochloride for injection must be reconstituted by rapidly injecting 10 mL of the supplied diluent directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. This provides a 5 mg/mL solution of melphalan. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. 2. Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater than 0.45 mg/mL. 3. Administer the diluted product over a minimum of 15 minutes. 4. Complete administration within 60 minutes of reconstitution. The time between reconstitution/dilution and administration of melphalan hydrochloride for injection should be kept to a minimum because reconstituted and diluted solutions of melphalan hydrochloride for injection are unstable. Over as short a time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted material from the reaction of melphalan hydrochloride for injection with Sterile Diluent for melphalan hydrochloride for injection. Upon further dilution with saline, nearly 1% label strength of melphalan hydrolyzes every 10 minutes. A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.

CONTRAINDICATIONS Melphalan hydrochloride for injection should not be used in patients whose disease has demonstrated prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan hydrochloride for injection should not be given the drug.

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%).

WARNINGS Melphalan Hydrochloride for Injection may cause local tissue damage should extravasation occur, and consequently it should not be administered by direct injection into a peripheral vein. It is recommended that Melphalan Hydrochloride for Injection be administered by injecting slowly into a fast-running intravenous infusion via an injection port, or via a central venous line (see DOSAGE AND ADMINISTRATION: Administration Precautions ).

Melphalan

Hydrochloride for Injection should be administered in carefully adjusted dosage by or under the supervision of experienced physicians who are familiar with the drug's actions and the possible complications of its use. As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression. Bone marrow suppression is the most significant toxicity associated with Melphalan Hydrochloride for Injection in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent dose of Melphalan Hydrochloride for Injection: platelet count, hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity. Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered. Hypersensitivity reactions including anaphylaxis have occurred in approximately 2% of patients who received the intravenous formulation (see ADVERSE REACTIONS ). These reactions usually occur after multiple courses of treatment. Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of volume expanders, pressor agents, corticosteroids, or antihistamines at the discretion of the physician. If a hypersensitivity reaction occurs, intravenous or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan.

Carcinogenesis

Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after oral melphalan therapy was 19.5% for cumulative doses ranging from 730 to 9,652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after oral melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy. 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/m 2 ) and in mice (2.25 to 4.5 mg/m 2 ) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively.

Mutagenesis

Melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 and 60 mg/m 2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats. Impairment of Fertility Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.

Pregnancy Pregnancy

Category D.

Melphalan

Hydrochloride for Injection may cause fetal harm when administered to a pregnant woman. While adequate animal studies have not been conducted with intravenous melphalan, oral (6 to 18 mg/m 2 /day for 10 days) and IP (18 mg/m 2 ) administration in rats was embryolethal and teratogenic. Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly). There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS General In all instances where the use of Melphalan Hydrochloride for Injection is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events.

Melphalan

Hydrochloride for Injection should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy or whose marrow function is recovering from previous cytotoxic therapy. Dose reduction should be considered in patients with renal insufficiency receiving intravenous melphalan. In one trial, increased bone marrow suppression was observed in patients with BUN levels ≥30 mg/dL. A 50% reduction in the intravenous melphalan dose decreased the incidence of severe bone marrow suppression in the latter portion of this study. Administration of live vaccines to immunocompromised patients should be avoided. Information for Patients Patients should be informed that the major acute toxicities of melphalan are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Patients should never be allowed to take the drug without close medical supervision and should be advised to consult their physicians if they experience skin rash, signs or symptoms of vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant.

Laboratory Tests

Periodic complete blood counts with differentials should be performed during the course of treatment with Melphalan Hydrochloride for Injection. At least 1 determination should be obtained prior to each dose. Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see WARNINGS ).

Drug Interactions

The development of severe renal failure has been reported in patients treated with a single dose of intravenous melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. Intravenous melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic acid and intravenous melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section.

Pregnancy Teratogenic Effects Pregnancy

Category D: See WARNINGS section.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Intravenous melphalan should not be given to nursing mothers.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Melphalan Hydrochloride for Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Drug Interactions The development of severe renal failure has been reported in patients treated with a single dose of IV melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. IV melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section.

Pregnancy Teratogenic Effects

See WARNINGS section.

Nursing

Mothers It is not known whether this drug is excreted in human milk. IV melphalan should not be given to nursing mothers.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Melphalan Hydrochloride for Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.