DOXORUBICIN HYDROCHLORIDE

Doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride, USP an anthracycline topoisomerase inhibitor, that is encapsulated in PEGYLATED liposomes for intravenous use. The chemical name of doxorubicin hydrochloride, USP is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxohexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C 27 H 29 NO 11 •HCl; its molecular weight is 579.99. The structure formula is: Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single-dose vials. Each vial contains 20 mg or 50 mg doxorubicin hydrochloride, USP at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin) and a pH of 6.5. The PEGYLATED 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 for pH adjustment; and sucrose 94 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the PEGYLATED liposomes. MPEG-DSPE has the following structural formula: n=ca. 45 HSPC has the following structural formula: m,n=14 or 16 Representation of a PEGYLATED liposome:

Doxorubicin hydrochloride liposome injection 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 Doxorubicin hydrochloride liposome injection 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 Doxorubicin hydrochloride liposome injection 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 Doxorubicin hydrochloride liposome injection, 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.

Administer doxorubicin hydrochloride liposome injection 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 IV every 4 weeks ( 2.2 ) AIDS-related Kaposi’s Sarcoma: 20 mg/m 2 IV every 3 weeks ( 2.3 ) Multiple Myeloma: 30 mg/m 2 IV on day 4 following bortezomib ( 2.4 ) 2.1 Important Use Information Do not substitute doxorubicin hydrochloride liposome injection for 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection after bortezomib on day 4 of each cycle [see Clinical Studies ( 14.3 )]. 2.5 Dose Modifications for Adverse Reactions Do not increase doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection. 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 doxorubicin hydrochloride liposome injection. 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 Doxorubicin Hydrochloride Liposome Injection for Toxicity When Administered in Combination With Bortezomib Toxicity Doxorubicin Hydrochloride Liposome Injection 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 doxorubicin hydrochloride liposome injection. Refer to bortezomib manufacturer’s prescribing information. 2.6 Preparation and Administration Preparation Dilute doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection with other drugs. Management of Suspected Extravasation Discontinue doxorubicin hydrochloride liposome injection 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 min 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 Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 If doxorubicin hydrochloride liposome injection comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

Doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection ( 4 , 5.2 )

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 )] The most common adverse reactions (>20%) observed with doxorubicin hydrochloride liposome injection are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. 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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 doxorubicin hydrochloride liposome injection in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma, and 318 patients with multiple myeloma. The following tables present adverse reactions from clinical trials of single-agent doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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 Doxorubicin Hydrochloride Liposome Injection 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% Thrombocytopenia10,000 -<50,000/mm 3 1.3% 17% <10,000/mm 3 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 Doxorubicin Hydrochloride Liposome Injection (%) 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 doxorubicin hydrochloride liposome injection 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 to 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 doxorubicin hydrochloride liposome injection 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. Tables 5 and 6 summarize adverse reactions reported in patients treated with doxorubicin hydrochloride liposome injection 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 * ) Total Patients With AIDS-Related Kaposi's Sarcoma (n=720 * * ) *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. **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*) Total Patients With AIDS-Related Kaposi’s Sarcoma (n=705**) 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% *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. **This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials. 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 doxorubicin hydrochloride liposome injection (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 doxorubicin hydrochloride liposome injection + 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 doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma. Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in ≥ 10% Patients Treated for Multiple Myeloma With Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib Adverse Reaction Doxorubicin Hydrochloride Liposome Injection + 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 1 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 2 22 1 18 1 Hand-foot syndrome 19 6 <1 0 1 Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. 2 Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of doxorubicin hydrochloride liposome injection. 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 )].

No formal drug interaction studies have been conducted with doxorubicin hydrochloride liposome injection.