DOXIL

2 DOSAGE AND ADMINISTRATION Administer DOXIL liposomal infusion at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related reactions occur, increase rate of infusion to complete administration over 1 hour. Do not administer as bolus injection or undiluted solution ( 2 ). • Ovarian cancer: 50 mg/m 2 intravenously every 4 weeks ( 2.2 ) • AIDS-related Kaposi’s Sarcoma: 20 mg/m 2 intravenously every 3 weeks ( 2.3 ) • Multiple Myeloma: 30 mg/m 2 intravenously on day 4 following bortezomib ( 2.4 ) 2.1 Important Use Information Do not substitute DOXIL liposomal infusion for other doxorubicin hydrochloride products. Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2) ] . 2.2 Ovarian Cancer The recommended dose of DOXIL liposomal infusion is 50 mg/m 2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity. 2.3 AIDS-Related Kaposi’s Sarcoma The recommended dose of DOXIL liposomal infusion is 20 mg/m 2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity. 2.4 Multiple Myeloma The recommended dose of DOXIL liposomal infusion is 30 mg/m 2 intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer DOXIL liposomal infusion after bortezomib on day 4 of each cycle [see Clinical Studies (14.3) ] . 2.5 Dose Modifications for Adverse Reactions Do not increase DOXIL liposomal infusion after a dose reduction for toxicity. Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse Reactions Toxicity Dose Adjustment Hand-Foot Syndrome (HFS) Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities • If no previous Grade 3 or 4 HFS: no dose adjustment. • If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then decrease dose by 25%. Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter • Delay dosing up to 2 weeks or until resolved to Grade 0–1. • Discontinue DOXIL liposomal infusion if no resolution after 2 weeks. • If resolved to Grade 0–1 within 2 weeks: o And no previous Grade 3 or 4 HFS: continue treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing • Delay dosing up to 2 weeks or until resolved to Grade 0–1, then decrease dose by 25%. • Discontinue DOXIL liposomal infusion if no resolution after 2 weeks. Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization • Delay dosing up to 2 weeks or until resolved to Grade 0–1, then decrease dose by 25%. • Discontinue DOXIL liposomal infusion if no resolution after 2 weeks. Stomatitis Grade 1: Painless ulcers, erythema, or mild soreness • If no previous Grade 3 or 4 toxicity: no dose adjustment. • If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%. Grade 2: Painful erythema, edema, or ulcers, but can eat • Delay dosing up to 2 weeks or until resolved to Grade 0–1. • Discontinue DOXIL liposomal infusion if there is no resolution after 2 weeks. • If resolved to Grade 0–1 within 2 weeks: o And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Painful erythema, edema, or ulcers, and cannot eat • Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. • If after 2 weeks there is no resolution, discontinue DOXIL liposomal infusion. Grade 4: Requires parenteral or enteral support • Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. • If after 2 weeks there is no resolution, discontinue DOXIL liposomal infusion. Neutropenia or Thrombocytopenia Grade 1 No dose reduction Grade 2 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 3 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 4 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor Table 2: Recommended Dose Modifications of DOXIL Liposomal Infusion for Toxicity When Administered in Combination With Bortezomib Toxicity DOXIL Liposomal Infusion Fever ≥38°C and ANC <1,000/mm 3 • Withhold dose for this cycle if before Day 4; • Decrease dose by 25%, if after Day 4 of previous cycle. On any day of drug administration after Day 1 of each cycle: • Platelet count <25,000/mm 3 • Hemoglobin <8 g/dL • ANC <500/mm 3 • Withhold dose for this cycle if before Day 4; • Decrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity. Grade 3 or 4 non-hematologic drug related toxicity Do not dose until recovered to Grade <2, then reduce dose by 25%. For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for DOXIL liposomal infusion. Refer to bortezomib manufacturer’s prescribing information. 2.6 Preparation and Administration Preparation Dilute DOXIL liposomal infusion doses up to 90 mg in 250 mL of 5% Dextrose Injection, USP prior to administration. Dilute doses exceeding 90 mg in 500 mL of 5% Dextrose Injection, USP prior to administration. Refrigerate diluted DOXIL liposomal infusion at 2°C to 8°C (36°F to 46°F) and administer within 24 hours. Administration Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. Do not use with in-line filters. Administer the first dose of DOXIL liposomal infusion at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour [see Warnings and Precautions (5.2) ]. Do not rapidly flush the infusion line. Do not mix DOXIL liposomal infusion with other drugs. Management of Suspected Extravasation Discontinue DOXIL liposomal infusion for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows: • Do not remove the needle until attempts are made to aspirate extravasated fluid • Do not flush the line • Avoid applying pressure to the site • Apply ice to the site intermittently for 15 minute 4 times a day for 3 days • If the extravasation is in an extremity, elevate the extremity 2.7 Procedure for Proper Handling and Disposal DOXIL liposomal infusion is a hazardous drug. Follow applicable special handling and disposal procedures. 1 If DOXIL liposomal infusion comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

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1 INDICATIONS AND USAGE DOXIL liposomal infusion is an anthracycline topoisomerase inhibitor indicated for: • Ovarian cancer: After failure of platinum-based chemotherapy ( 1.1 ) • AIDS-related Kaposi’s Sarcoma: After failure of prior systemic chemotherapy or intolerance to such therapy ( 1.2 ) • Multiple Myeloma: In combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy ( 1.3 ) 1.1 Ovarian Cancer DOXIL liposomal infusion is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.