DOXIL

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiomyopathy [see Warnings and Precautions (5.1) ] • Infusion-Related Reactions [see Warnings and Precautions (5.2) ] • Hand-Foot Syndrome [see Warnings and Precautions (5.3) ] • Secondary Oral Neoplasms [see Warnings and Precautions (5.4) ] Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia ( 6 ). To report SUSPECTED ADVERSE REACTIONS contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The safety data reflect exposure to DOXIL liposomal infusion in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma, and 318 patients with multiple myeloma. The most common adverse reactions (>20%) observed with DOXIL liposomal infusion are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The following tables present adverse reactions from clinical trials of single-agent DOXIL liposomal infusion in ovarian cancer and AIDS-Related Kaposi’s sarcoma. Patients With Ovarian Cancer The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with DOXIL liposomal infusion 50 mg/m 2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received DOXIL liposomal infusion for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other. Table 3 presents the hematologic adverse reactions from Trial 4. Table 3: Hematologic Adverse Reactions in Trial 4 DOXIL Liposomal Infusion Patients (n=239) Topotecan Patients (n=235) Neutropenia 500 – <1000/mm 3 8% 14% <500/mm 3 4.2% 62% Anemia 6.5 – <8 g/dL 5% 25% < 6.5 g/dL 0.4% 4.3% Thrombocytopenia 10,000 – <50,000/mm 3 1.3% 17% <10,000/mm 3 0.0% 17% Table 4 presents the non-hematologic adverse reactions from Trial 4. Table 4: Non-Hematologic Adverse Reactions in Trial 4 Non-Hematologic Adverse Reaction 10% or Greater DOXIL Liposomal Infusion (%) treated (n=239) Topotecan (%) treated (n=235) All grades Grades 3–4 All grades Grades 3–4 Body as a Whole Asthenia 40 7 52 8 Fever 21 0.8 31 6 Mucous Membrane Disorder 14 3.8 3.4 0 Back Pain 12 1.7 10 0.9 Infection 12 2.1 6 0.9 Headache 11 0.8 15 0 Digestive Nausea 46 5 63 8 Stomatitis 41 8 15 0.4 Vomiting 33 8 44 10 Diarrhea 21 2.5 35 4.2 Anorexia 20 2.5 22 1.3 Dyspepsia 12 0.8 14 0 Nervous Dizziness 4.2 0 10 0 Respiratory Pharyngitis 16 0 18 0.4 Dyspnea 15 4.1 23 4.3 Cough increased 10 0 12 0 Skin and Appendages Hand-foot syndrome 51 24 0.9 0 Rash 29 4.2 12 0.4 Alopecia 19 N/A 52 N/A The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4). Incidence 1% to 10% Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hematologic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi’s Sarcoma The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma (KS) enrolled in four open-label, uncontrolled trials of DOXIL liposomal infusion administered at doses ranging from 10 to 40 mg/m 2 every 2 to 3 weeks. Demographics of the population were: median age 38.7 years (range 24–70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m 2 of DOXIL liposomal infusion every 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/m 2 (range 3.3 to 798.6 mg/m 2 ); 3% received cumulative doses of greater than 450 mg/m 2 . Disease characteristics were: 61% poor risk for KS tumor burden, 91% poor risk for immune system, and 47% poor risk for systemic illness; 36% were poor risk for all three categories; median CD4 count 21 cells/mm 3 (51% less than 50 cells/mm 3 ); mean absolute neutrophil count at study entry approximately 3,000 cells/mm 3 . Of the 693 patients with concomitant medication information, 59% were on one or more antiretroviral medications [35% zidovudine (AZT), 21% didanosine (ddI), 16% zalcitabine (ddC), and 10% stavudine (D4T)]; 85% received PCP prophylaxis (54% sulfamethoxazole/trimethoprim); 85% received antifungal medications (76% fluconazole); 72% received antivirals (56% acyclovir, 29% ganciclovir, and 16% foscarnet) and 48% patients received colony-stimulating factors (sargramostim/filgrastim) during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS-related Kaposi’s sarcoma and included myelosuppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 5 and Table 6 summarize adverse reactions reported in patients treated with DOXIL liposomal infusion for AIDS-related Kaposi’s sarcoma in a pooled analysis of the four trials. Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n=74 This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. ) Total Patients With AIDS-Related Kaposi’s Sarcoma (n=720 This includes only subjects with AIDS-KS who had available data from the 4 pooled trials. ) Neutropenia < 1000/mm 3 46% 49% < 500/mm 3 11% 13% Anemia < 10 g/dL 58% 55% < 8 g/dL 16% 18% Thrombocytopenia < 150,000/mm 3 61% 61% < 25,000/mm 3 1.4% 4.2% Table 6: Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi’s Sarcoma Adverse Reactions Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n=77 This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. ) Total Patients With AIDS-Related Kaposi’s Sarcoma (n=705 This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials. ) Nausea 18% 17% Asthenia 7% 10% Fever 8% 9% Alopecia 9% 9% Alkaline Phosphatase Increase 1.3% 8% Vomiting 8% 8% Diarrhea 5% 8% Stomatitis 5% 7% Oral Moniliasis 1.3% 6% The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5% Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1% Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma The safety data described are from 318 patients treated with DOXIL liposomal infusion (30 mg/m 2 ) administered on day 4 following bortezomib (1.3 mg/m 2 i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the DOXIL liposomal infusion + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with DOXIL liposomal infusion in combination with bortezomib for multiple myeloma. Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in ≥10% Patients Treated for Multiple Myeloma With DOXIL Liposomal Infusion in Combination With Bortezomib Adverse Reaction DOXIL Liposomal Infusion + bortezomib (n=318) Bortezomib (n=318) Any (%) Grade 3–4 Any (%) Grade 3–4 Blood and lymphatic system disorders Neutropenia 36 32 22 16 Thrombocytopenia 33 24 28 17 Anemia 25 9 21 9 General disorders and administration site conditions Fatigue 36 7 28 3 Pyrexia 31 1 22 1 Asthenia 22 6 18 4 Gastrointestinal disorders Nausea 48 3 40 1 Diarrhea 46 7 39 5 Vomiting 32 4 22 1 Constipation 31 1 31 1 Mucositis/Stomatitis 20 2 5 <1 Abdominal pain 11 1 8 1 Infections and infestations Herpes zoster 11 2 9 2 Herpes simplex 10 0 6 1 Investigations Weight decreased 12 0 4 0 Metabolism and Nutritional disorders Anorexia 19 2 14 <1 Nervous system disorders Peripheral Neuropathy Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. 42 7 45 11 Neuralgia 17 3 20 4 Paresthesia/dysesthesia 13 <1 10 0 Respiratory, thoracic and mediastinal disorders Cough 18 0 12 0 Skin and subcutaneous tissue disorders Rash Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. 22 1 18 1 Hand-foot syndrome 19 6 <1 0 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of DOXIL liposomal infusion. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: muscle spasms Respiratory, Thoracic and Mediastinal Disorders: pulmonary embolism (in some cases fatal) Hematologic Disorders: Secondary acute myelogenous leukemia Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens‑Johnson syndrome, toxic epidermal necrolysis, lichenoid keratosis Secondary Oral Neoplasms: [see Warnings and Precautions (5.4) ].

4 CONTRAINDICATIONS DOXIL liposomal infusion is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions (5.2) ]. • Hypersensitivity reactions to doxorubicin hydrochloride or the components of DOXIL liposomal infusion ( 4 , 5.2 )

11 DESCRIPTION The active ingredient in DOXIL liposomal infusion is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in STEALTH liposomes for intravenous use. The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6‑trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11‑trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C27-H29 -NO11•HCl and the molecular weight is 579.99. The structural formula is: DOXIL liposomal infusion is a sterile, translucent, red liposomal dispersion. Each single- dose vial contains 20 mg or 50 mg doxorubicin hydrochloride at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin). The STEALTH liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine, 1.55 mg as a buffer; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0); and sucrose, 94 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH liposomes. MPEG-DSPE has the following structural formula: HSPC has the following structural formula: Representation of a STEALTH liposome: Structural Formula MPEG-DSPE Structural Formula HSPC Structural Formula Representation of a STEALTH liposome

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: • And no previous Grade 3 or 4 HFS: continue treatment at previous dose. • 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: • And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose. • 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 cytotoxic 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.

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. 1.2 AIDS-Related Kaposi’s Sarcoma DOXIL liposomal infusion is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. 1.3 Multiple Myeloma DOXIL liposomal infusion, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

10 OVERDOSAGE Acute overdosage with doxorubicin hydrochloride causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.

7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with DOXIL liposomal infusion.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active ingredient of DOXIL liposomal infusion is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations. 12.3 Pharmacokinetics The pharmacokinetic parameters for total doxorubicin following a single dose of DOXIL infused over 30 minutes are presented in Table 8 . Table 8: Pharmacokinetic Parameters of Total Doxorubicin from DOXIL Liposomal Infusion in Patients With AIDS-Related Kaposi’s Sarcoma Dose Parameter (units) 10 mg/m 2 20 mg/m 2 N=23 Mean ± Standard Error Peak Plasma Concentration (µg/mL) 4.12 ± 0.215 8.34 ± 0.49 Plasma Clearance (L/h/m 2 ) 0.056 ± 0.01 0.041 ± 0.004 Steady State Volume of Distribution (L/m 2 ) 2.83 ± 0.145 2.72 ± 0.120 AUC (µg/mL∙h) 277 ± 32.9 590 ± 58.7 First Phase (λ 1 ) Half-Life (h) 4.7 ± 1.1 5.2 ± 1.4 Second Phase (λ 1 ) Half-Life (h) 52.3 ± 5.6 55.0 ± 4.8 DOXIL liposomal infusion displayed linear pharmacokinetics over the range of 10 to 20 mg/m 2 . Relative to DOXIL liposomal infusion doses at or below 20 mg/m 2 , the pharmacokinetics of total doxorubicin following a 50 mg/m 2 DOXIL liposomal infusion dose are nonlinear. At this dose, the elimination half-life of DOXIL liposomal infusion is longer and the clearance lower compared to a 20 mg/m 2 dose. Distribution Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5–10% free doxorubicin) remains liposome-encapsulated during circulation. In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/m 2 ), the small steady state volume of distribution of liposomal doxorubicin suggests that DOXIL liposomal infusion is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of DOXIL liposomal infusion has not been determined; the plasma protein binding of doxorubicin is approximately 70%. Metabolism Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m 2 DOXIL liposomal infusion. Elimination The plasma clearance of total doxorubicin from DOXIL liposomal infusion was 0.041 L/h/m 2 at a dose of 20 mg/m 2 . Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m 2 .

12.1 Mechanism of Action The active ingredient of DOXIL liposomal infusion is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

12.3 Pharmacokinetics The pharmacokinetic parameters for total doxorubicin following a single dose of DOXIL infused over 30 minutes are presented in Table 8 . Table 8: Pharmacokinetic Parameters of Total Doxorubicin from DOXIL Liposomal Infusion in Patients With AIDS-Related Kaposi’s Sarcoma Dose Parameter (units) 10 mg/m 2 20 mg/m 2 N=23 Mean ± Standard Error Peak Plasma Concentration (µg/mL) 4.12 ± 0.215 8.34 ± 0.49 Plasma Clearance (L/h/m 2 ) 0.056 ± 0.01 0.041 ± 0.004 Steady State Volume of Distribution (L/m 2 ) 2.83 ± 0.145 2.72 ± 0.120 AUC (µg/mL∙h) 277 ± 32.9 590 ± 58.7 First Phase (λ 1 ) Half-Life (h) 4.7 ± 1.1 5.2 ± 1.4 Second Phase (λ 1 ) Half-Life (h) 52.3 ± 5.6 55.0 ± 4.8 DOXIL liposomal infusion displayed linear pharmacokinetics over the range of 10 to 20 mg/m 2 . Relative to DOXIL liposomal infusion doses at or below 20 mg/m 2 , the pharmacokinetics of total doxorubicin following a 50 mg/m 2 DOXIL liposomal infusion dose are nonlinear. At this dose, the elimination half-life of DOXIL liposomal infusion is longer and the clearance lower compared to a 20 mg/m 2 dose. Distribution Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5–10% free doxorubicin) remains liposome-encapsulated during circulation. In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/m 2 ), the small steady state volume of distribution of liposomal doxorubicin suggests that DOXIL liposomal infusion is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of DOXIL liposomal infusion has not been determined; the plasma protein binding of doxorubicin is approximately 70%. Metabolism Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m 2 DOXIL liposomal infusion. Elimination The plasma clearance of total doxorubicin from DOXIL liposomal infusion was 0.041 L/h/m 2 at a dose of 20 mg/m 2 . Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m 2 .

20220531

9

3 DOSAGE FORMS AND STRENGTHS DOXIL (doxorubicin hydrochloride liposome injection): 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) translucent, red liposomal dispersion in single dose vials. Doxorubicin hydrochloride liposomal injection: 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) in single dose vials ( 3 )

DOXIL doxorubicin hydrochloride doxorubicin hydrochloride doxorubicin SODIUM N-(CARBONYL-METHOXYPOLYETHYLENE GLYCOL 2000)-1,2-DISTEAROYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE hydrogenated soybean lecithin cholesterol ammonium sulfate histidine hydrochloric acid sodium hydroxide sucrose DOXIL doxorubicin hydrochloride doxorubicin hydrochloride doxorubicin SODIUM N-(CARBONYL-METHOXYPOLYETHYLENE GLYCOL 2000)-1,2-DISTEAROYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE hydrogenated soybean lecithin cholesterol ammonium sulfate histidine hydrochloric acid sodium hydroxide sucrose

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Mutagenicity or carcinogenicity studies have not been conducted with DOXIL liposomal infusion, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. DOXIL liposomal infusion resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m 2 human dose on a mg/m 2 basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times the 50 mg/m 2 human dose on a mg/m 2 basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m 2 human dose on a mg/m 2 basis).

13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Mutagenicity or carcinogenicity studies have not been conducted with DOXIL liposomal infusion, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. DOXIL liposomal infusion resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m 2 human dose on a mg/m 2 basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times the 50 mg/m 2 human dose on a mg/m 2 basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m 2 human dose on a mg/m 2 basis).

NDA050718

DOXIL

doxorubicin hydrochloride

0338-0067

HUMAN PRESCRIPTION DRUG

INTRAVITREAL

PRINCIPAL DISPLAY PANEL - 20 mg Vial Carton NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) 20 mg in 10 mL (2 mg/mL) Single-Dose Vial. Discard unused portion. LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride FOR INTRAVENOUS INFUSION ONLY Rx only Cytotoxic HA-65-01-805 Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze. See package insert for dosage information. Baxter Healthcare Corporation Deerfield, IL 60015 Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries. Bar Code 0100303380063017 Bar Code 696988 LOT EXP Carton Label US 749703 882 Barcode NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) 20 mg in 10 mL (2 mg/mL) Single-Dose Vial. Discard unused portion. LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride FOR INTRAVENOUS INFUSION ONLY AFTER DILUTION. Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze. Cytotoxic Rx only Baxter Logo NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) Use 5% Dextrose Injection, USP when diluting DOXIL. Bar Code 3 03380 06301 7 Note: Liposomal formulation. Recommended Dosage: see prescribing information. NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 Product of Italy Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries. GTIN 00303380063017 2D Bar Code S/N EXP LOT NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) Each mL contains doxorubicin Hydrochloride, 2 mg. STEALTH liposome carriers are composed of cholesterol, 3.19 mg; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg; and N-(carbonyl- methoxypolyethylene glycol 2000)-1,2-distearoyl-sn- glycerol-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine, 1.55 mg; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0) and sucrose, 94 mg. HA-80-02-881 NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) 20 mg in 10 mL (2 mg/mL) Single-Dose Vial. Discard unused portion. LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride FOR INTRAVENOUS INFUSION ONLY Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze. Cytotoxic Rx only Baxter Logo NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) N 3 Bar Code 0338-0063-01 7 Note: Liposomal formulation. See package insert for dosage information. USA 6943440 882 Bar Code NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 Product Taiwan Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries. NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) GTIN 00303380063017 Bar Code S/N EXP LOT NDC 0338-0063-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) Each mL contains doxorubicin Hydrochloride, 2 mg. STEALTH liposome carriers are composed of cholesterol, 3.19 mg; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg; and N-(carbonyl- methoxypolyethylene glycol 2000)-1,2-distearoyl-sn- glycerol-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine; hydrochloric acid and/or sodium hydroxide; and sucrose. HA-80-02-880 NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) 50 mg in 25 mL (2 mg/mL) Single-Dose Vial. Discard unused portion. LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride FOR INTRAVENOUS INFUSION ONLY Rx only Cytotoxic HA-65-01-806 Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze. See package insert for dosage information. Baxter Healthcare Corporation Deerfield, IL 60015 Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries. Bar Code 0100303380067015 Bar Code 696987 LOT EXP Carton Label US 749704 882 Barcode NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) 50 mg in 25 mL (2 mg/mL) Single-Dose Vial. Discard unused portion. LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride FOR INTRAVENOUS INFUSION ONLY AFTER DILUTION. Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze. Cytotoxic Rx only Baxter Logo NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) Use 5% Dextrose Injection, USP when diluting DOXIL. Bar Code 3 03380 06701 5 Note: Liposomal formulation. Recommended Dosage: see prescribing information. NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 Product of Italy Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries. GTIN 00303380067015 2D Bar Code S/N EXP LOT NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) Each mL contains doxorubicin Hydrochloride, 2 mg. STEALTH liposome carriers are composed of cholesterol, 3.19 mg; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg; and N-(carbonyl- methoxypolyethylene glycol 2000)-1,2-distearoyl-sn- glycerol-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine, 1.55 mg; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0) and sucrose, 94 mg. HA-80-02-883 NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) 50 mg in 25 mL (2 mg/mL) Single-Dose Vial. Discard unused portion. LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride FOR INTRAVENOUS INFUSION ONLY Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze. Cytotoxic Rx only Baxter Logo NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) N 3 Bar Code 0338-0067-01 5 Note: Liposomal formulation. See package insert for dosage information. USA 693385 882 Bar Code NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 Product of Taiwan Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries. NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) GTIN 00303380067015 Bar Code S/N EXP LOT NDC 0338-0067-01 DOXIL (DOXOrubicin Hydrochloride liposome injection) Each mL contains doxorubicin Hydrochloride, 2 mg. STEALTH liposome carriers are composed of cholesterol, 3.19 mg; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg; and N-(carbonyl- methoxypolyethylene glycol 2000)-1,2-distearoyl-sn- glycerol-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine; hydrochloric acid and/or sodium hydroxide; and sucrose. HA-80-02-882 Representative 20 mg Container Label Representative Carton Label 0338-0063-01 Italy 1 of 2 Representative Carton Label 0338-0063-01 Italy 2 of 2 Representative Carton label 20 mg Taiwan Representative Container Label 50 mg Representative Carton Label 0338-0067-01 Italy 1 of 2 Representative Carton Label 0338-0067-01 Italy 2 of 2 Representative Carton Label 50 mg Taiwan

Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc. HA-30-01-919 USA - 749706

17 PATIENT COUNSELING INFORMATION Cardiomyopathy Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1) ] . Infusion-Related Reactions Advise patients about the symptoms of infusion related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2) ] . Myelosuppression Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection. Hand-Foot Syndrome Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions (5.3) ] . Stomatitis Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis). Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1) ]. Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with DOXIL liposomal infusion [see Use in Specific Populations (8.3) ] . Lactation Advise females not to breastfeed during treatment with DOXIL liposomal infusion [see Use in Specific Populations (8.2) ]. Infertility Advise females and males of reproductive potential that DOXIL liposomal infusion may cause temporary or permanent infertility [see Use in Specific Populations (8.3) ]. Discoloration of Urine and Body Fluids Inform patients that following DOXIL liposomal infusion administration, a reddish-orange color to the urine and other body fluids may be observed. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.

14 CLINICAL STUDIES 14.1 Ovarian Cancer DOXIL liposomal infusion was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within 6 months of completing treatment. Patients received DOXIL liposomal infusion at 50 mg/m 2 every 3 or 4 weeks for 3–6+ cycles in the absence of dose-limiting toxicity or disease progression. The median age at diagnosis ranged from 52 to 64 years in the 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%). The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel- and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression. The response rates for the individual single arm trials are given in Table 9 below. Table 9: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials Trial 1 (U.S.) N=27 Trial 2 (U.S.) N=82 Trial 3 (non-U.S.) N=36 Response Rate 22.2% 17.1% 0% 95% Confidence Interval 8.6% – 42.3% 9.7% – 27.0% 0.0% – 9.7% In a pooled analysis of Trials 1–3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks. In Trial 4, a randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either DOXIL liposomal infusion 50 mg/m 2 every 4 weeks (n=239) or topotecan 1.5 mg/m 2 daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 cm in size). The primary outcome measure was time to progression (TTP). Other endpoints included overall survival and objective response rate. Of the 474 patients, the median age at diagnosis was 60 years (range 25 to 87), 90% were FIGO stage III and IV; 46% were platinum sensitive; and 45% had bulky disease. There was no statistically significant difference in TTP between the two arms. Results are provided in Table 10 . Table 10: Results of Efficacy Analyses Analysis based on investigators' strata for protocol defined ITT population. Protocol Defined ITT Population DOXIL Liposomal Infusion (n=239) Topotecan (n=235) TTP (Protocol Specified Primary Endpoint) Median (Months) Kaplan-Meier estimates. 4.1 4.2 p-value p-value is based on the stratified log-rank test. 0.62 Hazard Ratio Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for DOXIL liposomal infusion. 0.96 95% CI for Hazard Ratio (0.76, 1.20) Overall Survival Median (Months) 14.4 13.7 p-value p-value not adjusted for multiple comparisons. 0.05 Hazard Ratio 0.82 95% CI for Hazard Ratio (0.68, 1.00) Response Rate Overall Response n (%) 47 (19.7) 40 (17.0) Complete Response n (%) 9 (3.8) 11 (4.7) Partial Response n (%) 38 (15.9) 29 (12.3) Median Duration of Response (Months) 6.9 5.9 14.2 AIDS-Related Kaposi’s Sarcoma DOXIL liposomal infusion was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m 2 every 3 weeks, until disease progression or unacceptable toxicity (Trial 5). Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride. The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of DOXIL liposomal infusion was 154 mg/m 2 (range 20 to 620 mg/m 2 ). Among the 77 patients, mean age was 38 years (range 24 to 54); 87% were Caucasian, 5% Hispanic, 4% Black, and 4% Asian/Other/Unknown; median CD4 count was 10 cells/mm 3 ; ACTG staging criteria were 78% poor risk for tumor burden, 96% poor risk for immune system, and 58% poor risk for systemic illness at baseline; and mean Karnofsky status score was 74%. All patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonary lesions, and 14% had lesions of the stomach/intestine. Two analyses of tumor response were used: one based on investigator assessment of changes in lesions based on modified ACTG criteria (partial response defined as no new lesions, sites of disease, or worsening edema; flattening of ≥50% of previously raised lesions or area of indicator lesions decreasing by ≥50%; and response lasting at least 21 days with no prior progression), and one based on changes in up to five prospectively indentified representative indicator lesions (partial response defined as flattening of ≥50% of previously raised indicator lesions, or >50% decrease in the area of indicator lesions and lasting at least 21 days with no prior progression). Of the 77 patients, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment; analyses of tumor responses are shown in Table 11 . Table 11: Response in Patients with Refractory Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy. AIDS-Related Kaposi’s Sarcoma Investigator Assessment All Evaluable Patients (n=34) Evaluable Patients Who Received Prior Doxorubicin (n=20) Response There were no complete responses in this population. Partial (PR) 27% 30% Stable 29% 40% Progression 44% 30% Duration of PR (Days) Median 73 89 Range 42+ – 210+ 42+ – 210+ Time to PR (Days) Median 43 53 Range 15 – 133 15 – 109 Indicator Lesion Assessment All Evaluable Patients (n=42) Evaluable Patients Who Received Prior Doxorubicin (n=23) Response Partial (PR) 48% 52% Stable 26% 30% Progression 26% 17% Duration of PR (Days) Median 71 79 Range 22+ – 210+ 35 – 210+ Time to PR (Days) Median 22 48 Range 15 – 109 15 – 109 Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent DOXIL liposomal infusion and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses. 14.3 Multiple Myeloma The efficacy of DOXIL liposomal infusion in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either DOXIL liposomal infusion (30 mg/m 2 ) administered IV on day 4 following bortezomib (1.3 mg/m 2 IV on days 1, 4, 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1–18). The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms ( Table 12 ). Table 12: Summary of Baseline Patient and Disease Characteristics Patient Characteristics DOXIL Liposomal Infusion + bortezomib n=324 bortezomib n=322 Median age in years (range) 61 (28, 85) 62 (34, 88) % Male/female 58 / 42 54 / 46 % Caucasian/Black/other 90 / 6 / 4 94 / 4 / 2 Disease Characteristics % with IgG/IgA/Light chain 57 / 27 / 12 62 / 24 / 11 % β 2 -microglobulin group ≤2.5 mg/L 14 14 >2.5 mg/L and ≤5.5 mg/L 56 55 >5.5 mg/L 30 31 Serum M-protein (g/dL): Median (Range) 2.5 (0–10.0) 2.7 (0–10.0) Urine M-protein (mg/24 hours): Median (Range) 107 (0–24883) 66 (0–39657) Median Months Since Diagnosis 35.2 37.5 % Prior Therapy One 34 34 More than one 66 66 Prior Systemic Therapies for Multiple Myeloma Corticosteroid (%) 99 >99 Anthracyclines 68 67 Alkylating agent (%) 92 90 Thalidomide/lenalidomide (%) 40 43 Stem cell transplantation (%) 57 54 The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the DOXIL liposomal infusion + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1 . Table 13: Efficacy of DOXIL Liposomal Infusion in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma Endpoint DOXIL Liposomal Infusion + bortezomib n=324 Bortezomib n=322 Time to Progression Kaplan Meier estimate. Progression or death due to progression (n) 99 150 Censored (n) 225 172 Median in days (months) 282 (9.3) 197 (6.5) 95% CI 250; 338 170; 217 Hazard ratio Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio < 1 indicates an advantage for DOXIL liposomal infusion +bortezomib. 0.55 (95% CI) (0.43, 0.71) p-value Stratified log-rank test. <0.001 Response (n) RR as per EBMT criteria. 303 310 % Complete Response (CR) 5 3 % Partial Response (PR) 43 40 % CR + PR 48 43 p-value Cochran-Mantel-Haenszel test adjusted for the stratification factors. 0.25 Median Duration of Response (months) 10.2 7.0 (95% CI) (10.2; 12.9) (5.9; 8.3) Figure 1- Time to Progression Kaplan-Meier Curve At the final analysis of survival, 78% of subjects in the DOXIL liposomal infusion and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the DOXIL liposomal infusion and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for DOXIL liposomal infusion + bortezomib vs. bortezomib = 0.96 (95% CI 0.80, 1.14)]. Seventy-eight percent of subjects in the DOXIL liposomal infusion and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy. Figure 1

15 REFERENCES 1. “Hazardous Drugs”, OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html

8.5 Geriatric Use Clinical studies of DOXIL liposomal infusion conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi’s sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. In Trial 6, of 318 patients treated with DOXIL liposomal infusion in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

8.4 Pediatric Use The safety and effectiveness of DOXIL liposomal infusion in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, DOXIL liposomal infusion can cause fetal harm when administered to a pregnant woman; avoid the use of DOXIL liposomal infusion during the 1 st trimester. In animal reproduction studies, DOXIL liposomal infusion was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data ) . Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2 nd and 3 rd trimesters. Advise pregnant women 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 DOXIL liposomal infusion was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m 2 human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

8 USE IN SPECIFIC POPULATIONS • Lactation: Discontinue breastfeeding ( 8.2 ). 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, DOXIL liposomal infusion can cause fetal harm when administered to a pregnant woman; avoid the use of DOXIL liposomal infusion during the 1 st trimester. In animal reproduction studies, DOXIL liposomal infusion was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data ) . Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2 nd and 3 rd trimesters. Advise pregnant women 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 DOXIL liposomal infusion was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m 2 human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes. 8.2 Lactation Risk Summary It is not known whether DOXIL liposomal infusion is present in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from DOXIL liposomal infusion, discontinue breastfeeding during treatment with DOXIL liposomal infusion. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating DOXIL liposomal infusion. Contraception Females DOXIL liposomal infusion can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL liposomal infusion. Males DOXIL liposomal infusion may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with DOXIL liposomal infusion [see Non-clinical Toxicology (13.1) ]. Infertility Females In females of reproductive potential, DOXIL liposomal infusion may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin hydrochloride. Recovery of menses and ovulation is related to age at treatment . Males DOXIL liposomal infusion may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Non-clinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of DOXIL liposomal infusion in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of DOXIL liposomal infusion conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi’s sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. In Trial 6, of 318 patients treated with DOXIL liposomal infusion in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. 8.6 Hepatic Impairment The pharmacokinetics of DOXIL liposomal infusion has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce DOXIL liposomal infusion for serum bilirubin of 1.2 mg/dL or higher.

16 HOW SUPPLIED/STORAGE AND HANDLING DOXIL (doxorubicin hydrochloride liposome injection) is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single-dose vials. The following individually cartoned vials are available: Table 14 vial concentration vial size NDC #s 20 mg/10 mL (2 mg/ mL) 10-mL 0338-0063-01 50 mg/25 mL (2 mg/mL) 30-mL 0338-0067-01 Refrigerate unopened vials of DOXIL (doxorubicin hydrochloride liposome injection) at 2°C- 8°C (36°F- 46°F). Do not freeze. Discard unused portion. DOXIL liposomal infusion is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

Refrigerate unopened vials of DOXIL (doxorubicin hydrochloride liposome injection) at 2°C- 8°C (36°F- 46°F). Do not freeze. Discard unused portion. DOXIL liposomal infusion is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS • DOXIL liposomal infusion can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Assess left ventricular cardiac function prior to initiation of DOXIL liposomal infusion and during and after treatment [see Warnings and Precautions (5.1) ] . • Serious, life-threatening, and fatal infusion-related reactions can occur with DOXIL liposomal infusion Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold DOXIL liposomal infusion for infusion-related reactions and resume at a reduced rate. Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions [see Warnings and Precautions (5.2) ] . WARNING: CARDIOMYOPATHY and INFUSION- RELATED REACTIONS See full prescribing information for complete boxed warning. • DOXIL liposomal infusion can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Assess left ventricular cardiac function prior to initiation of DOXIL liposomal infusion, during treatment, and after treatment ( 5.1 ). • Serious, life-threatening, and fatal infusion‑related reactions can occur. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold DOXIL liposomal infusion for infusion-related reactions and resume at a reduced rate. Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions ( 5.2 ).