FDA label 310ae23f-9f49-206d-e063-6394a90a6ce2

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IVRA sfety and effectively. See full prescribing information for IVRA IVRA (melphalan) injection for intravenous use Initial U.S. Approval: 1964 FULL PRESCRIBING INFORMATION 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 melphalan to oral melphalan have shown more myelosuppression with the intravenous formulation. Monitor hematologic laboratory parameters (5.1). Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the intravenous formulation of melphalan. Discontinue treatment with IVRA for serious hypersensitivity reactions (5.4). Melphalan produces chromosomal aberrations in vitro and in vivo. IVRA should be considered potentially leukemogenic in humans (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 melphalan to oral melphalan have shown more myelosuppression with the intravenous formulation. Monitor hematologic laboratory parameters (5.1). Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the intravenous formulation of melphalan. Discontinue treatment with IVRA for serious hypersensitivity reactions (5.4). Melphalan produces chromosomal aberrations in vitro and in vivo. IVRA should be considered potentially leukemogenic in humans (5.5).

<table border="1" cellpadding="0" cellspacing="0"><tbody><tr><td><paragraph><content styleCode="bold">WARNING: SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY and LEUKEMOGENICITY</content></paragraph><paragraph><content styleCode="bold">See full prescribing information for complete boxed warning.</content></paragraph><paragraph/><list listType="unordered"><item><content styleCode="bold">Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous melphalan to oral melphalan have shown more myelosuppression with the intravenous formulation. Monitor hematologic laboratory parameters (5.1).</content></item><item><content styleCode="bold">Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the intravenous formulation of melphalan. Discontinue treatment with IVRA for serious hypersensitivity reactions (5.4).</content></item><item><content styleCode="bold">Melphalan produces chromosomal aberrations in vitro and in vivo. IVRA should be considered potentially leukemogenic in humans (5.5).</content></item></list></td></tr></tbody></table>

<table border="1" cellpadding="0" cellspacing="0"><tbody><tr><td><paragraph><content styleCode="bold">WARNING: SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY and LEUKEMOGENICITY</content></paragraph><paragraph><content styleCode="bold">See full prescribing information for complete boxed warning.</content></paragraph><paragraph/><list listType="unordered"><item><content styleCode="bold">Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous melphalan to oral melphalan have shown more myelosuppression with the intravenous formulation. Monitor hematologic laboratory parameters (5.1).</content></item><item><content styleCode="bold">Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the intravenous formulation of melphalan. Discontinue treatment with IVRA for serious hypersensitivity reactions (5.4).</content></item><item><content styleCode="bold">Melphalan produces chromosomal aberrations in vitro and in vivo. IVRA should be considered potentially leukemogenic in humans (5.5).</content></item></list></td></tr></tbody></table>

5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression IVRA causes bone marrow suppression in most patients. Obtain complete blood counts with differential at the start of therapy and prior to each subsequent dose of IVRA. Withhold treatment for grade 3 thrombocytopenia and/ or leukopenia until blood counts have returned to grade 2 [see Dosage and Administration (2.2)]. Consider dose adjustment on the basis of blood counts at the nadir and day of treatment. 5.2 Gastrointestinal Toxicity Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration can occur with melphalan treatment. Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (greater than 100 mg/m2 6 times the recommended approved dose). Use prophylactic antiemetics [see Dosage and Administration (2.1)]. Provide supportive care for nausea, vomiting, diarrhea, and mucositis. 5.3 Hepatotoxicity Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported during treatment with melphalan. Hepatic veno- occlusive disease has been reported. Monitor liver enzymes as clinically indicated. 5.4 Hypersensitivity Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving melphalan injection for myeloma. These reactions were characterized by urticaria, pruritus, edema, skin rashes, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid therapy. If a hypersensitivity reaction occurs, intravenous or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been reported in association with such reports. Discontinue treatment with IVRA for serious hypersensitivity reactions. 5.5 Secondary Malignancies Melphalan has been shown to cause chromatid or chromosome damage in humans. 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. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy. 5.6 Embryo-Fetal Toxicity Based on its mechanism of action, IVRA can cause fetal harm when administered to a pregnant woman. Melphalan is genotoxic, targets actively dividing cells, and was embryolethal and teratogenic in rats. While adequate animal studies have not been conducted with intravenous melphalan, oral (6 to 18 mg/m2/day for 10 days) and IP (18 mg/m2) 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). If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, advise a pregnant woman of the of potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with IVRA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IVRA and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, advise a pregnant woman of the of potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with IVRA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IVRA and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 5.7 Infertility 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 [see Use in Specific Populations (8.3)]. Gastrointestinal toxicity: Nausea, vomiting, diarrhea, or oral mucositis may occur; provide supportive care using antiemetic and antidiarrheal medications as needed. (5.2) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to fetus and to use effective contraception. (5.6, 8.1) Infertility: Melphalan may cause ovarian function suppression or testicular suppression. (5.7)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: 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 melphalan 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 melphalan were neutrophil count decreased, white blood cell count decreased, lymphocyte count decreased, platelet count decreased, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting. Palliative Treatment of Patients with Multiple Myeloma The safety of melphalan was evaluated in 295 patients with multiple myeloma in the randomized clinical trial [see Clinical Studies (14)]. One hundred and ninety-five patients were administered intravenous melphalan at a dosage of 16 mg/m2 q 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks. One hundred patients were administered oral melphalan at a dosage of 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC counts began to rise. Severe myelotoxicity (WBC ≤1,000 and/or platelets ≤25,000) was more common in the intravenous melphalan arm (28%) than in the oral melphalan arm (11%). Most common adverse reactions (≥50%) 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 Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .