IVRA

IVRA contains melphalan which is an alkylating drug. The chemical name of melphalan hydrochloride is 4-[bis(2-chloroethyl)amino]-L-phenylalanine hydrochloride. The 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 to 201°C. It is practically insoluble in water, but freely soluble in 1N HCl and methanol. IVRA is supplied as a sterile, clear colorless to yellow solution in a multiple-dose vial for intravenous use. Each mL contains 90 mg melphalan free base equivalent to 100.75 mg melphalan hydrochloride, 170 mg propylene glycol, 5 mg monothioglycerol, 0.5 mg (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid dihydrate), and 0.025 mL water for injection in polyethylene glycol 400. May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH of the drug product solution after dilution with 0.9% sodium chloride ranges from 2.4 - 3.5. Each mL contains 90 mg melphalan free base equivalent to 100.75 mg melphalan hydrochloride.

Multiple Myeloma-Palliative Treatment IVRA is indicated for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate. IVRA is an alkylating drug indicated for palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate. ( 1 )

Recommended dosage is 16 mg/m 2 administered intravenously over 15 to 20 minutes at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. ( 2.2 ) See full prescribing information for preparation and administration instructions. ( 2.3 ) 2.1 Recommended Dosage The recommended dosage is 16 mg/m 2 intravenously over 15 to 20 minutes at 2-week intervals for 4 doses, then at 4-week intervals until unacceptable toxicity. Administer prophylactic antiemetics [see Warnings and Precautions ( 5.2 )]. 2.2 Dosage Modifications for Adverse Reactions See Table 1 for dosage modifications for adverse reactions related to bone marrow suppression [see Warnings and Precautions ( 5.1 )]. Table 1. Dosage Modifications for Adverse Reaction: Bone Marrow Suppression Parameter Dosing Recommendations White Blood Cell Count (WBC/mm 3 ) Platelet Count (Per mcL) Greater than or equal to 4,000 Greater than or equal to 100,000 Continue full IVRA dose Greater than or equal to 3,000 Greater than or equal to 75,000 Reduce IVRA to 75% of full dose Greater than or equal to 2,000 Greater than or equal to 50,000 Reduce IVRA to 50% of full dose Less than 2,000 Less than 50,000 Withold IVRA 2.3 Dosage Modifications for Renal Impairment Consider a dosage reduction of up to 50% in patients with renal insufficiency (BUN ≥30 mg/dL) [see Use in Specific Populations ( 8.6 )] . 2.4 Preparation and Administration Preparation IVRA is a hazardous drug. Follow applicable special handling and disposal procedures 1 . 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. IVRA is light sensitive. After first use, store the partially used vial refrigerated at 2°C to 8°C [36°F to 46°F] in the original carton for use within 28 days and then discard the remaining contents. Retain vial in original carton until contents are used. Do not mix IVRA with other melphalan hydrochloride drug products. Dilution Calculate the required volume of IVRA needed for a patient’s dose and withdraw that volume from the vial(s). Add the required volume of IVRA to the appropriate volume of 0.9% Sodium Chloride Injection to obtain a solution with a concentration not greater than 0.45 mg/mL. Immediately mix the contents of infusion vigorously by manual rotation. The diluted product is stable for 1 hour at room temperature. Administration Infuse over 15 to 20 minutes via an injection port or central venous catheter. Complete administration within 60 minutes of dilution. IVRA may cause local tissue damage should extravasation occur. Administer IVRA only by injecting slowly into a fast-running intravenous infusion via an injection port or, central venous access line.

IVRA is contraindicated in patients with a history of severe hypersensitivity to melphalan. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.4 )]. History of severe hypersensitivity to melphalan. ( 4 )

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 )] 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 . ­ 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/m 2 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%).

7.1 Effect of Other Drugs on IVRA Cisplatin Concomitant use with cisplatin may alter melphalan clearance by inducing renal dysfunction. Consider intravenous IVRA dosage reduction in patients with renal insufficiency following concomitant use with cisplatin [see Dosage and Administration ( 2.2 )] . 7.2 Effect of IVRA on Other Drugs BCNU Concomitant use with BCNU may reduce the threshold for lung toxicity. Monitor for increased lung toxicity. 7.3 Cyclosporine Concomitant use with cyclosporine may increase the risk of developing severe renal failure [see Clinical Pharmacology ( 12.3 ) ]. Consider intravenous IVRA dosage reduction in patients with renal insufficiency following concomitant use with cyclosporine [see Dosage and Administration ( 2.2 )] .