DOXORUBICIN HYDROCHLORIDE- doxorubicin hydrochloride_injection, suspension, liposomal

The active ingredient of doxorubicin hydrochloride liposome injection 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. The pharmacokinetic parameters for total doxorubicin following a single dose of doxorubicin hydrochloride liposome injection infused over 30 minutes are presented in Table 8. Table 8: Pharmacokinetic Parameters of Total Doxorubicin from Doxorubicin Hydrochloride Liposome Injection in Patients With AIDS- Related Kaposi's Sarcoma Dose Parameter (units) 10 mg/m 2 20 mg/m 2 Peak Plasma Concentration (µg/mL) 4. 49 Plasma Clearance (L/h/m 2 0. 004 Steady State Volume of Distribution (L/m 2 2. 120 AUC (µg/mL∙h) 277 +/- 32. 9 590 +/- 58. 7 First Phase (λ 1 4. 4 Second Phase (λ 1 52. 8 N=23 Mean +/- Standard Error Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m 2 2 2 2 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 Metabolism Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0. 2 ng/mL in the plasma of patients who received 10 or 20 mg/m 2 Elimination The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0. 041 L/h/m 2 2 2.

Doxorubicin hydrochloride liposome injection is an anthracycline topoisomerase inhibitor indicated for: Ovarian cancer: 1. 1 AIDS-related Kaposi's Sarcoma: 1. 2 Multiple Myeloma: 1. 3 Doxorubicin hydrochloride liposome injection is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. 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. 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: 2 2. 2 AIDS-related Kaposi's Sarcoma: 2 2. 3 Multiple Myeloma: 2 2. 4 Do not substitute Do not administer [see Warnings and Precautions ( 5. 2 The recommended dose of doxorubicin hydrochloride liposome injection is 50 mg/m 2 The recommended dose of doxorubicin hydrochloride liposome injection is 20 mg/m 2 The recommended dose of doxorubicin hydrochloride liposome injection is 30 mg/m 2 [see Clinical Studies ( 14. 3 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. 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. And And 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, 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, Stomatitis Grade 1: Painless ulcers, erythema, or mild soreness If no previous Grade 3 or 4 toxicity: no dose adjustment. Grade 2: Painful erythema, edema, or ulcers, but can eat Delay dosing up to 2 weeks or until resolved to Grade 0-1. And And Grade 3: Painful erythema, edema, or ulcers, and cannot eat Delay dosing up to 2 weeks or until resolved to Grade 0-1. Grade 4: Requires parenteral or enteral support Delay dosing up to 2 weeks or until resolved to Grade 0-1. 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 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. 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%. 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. For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for doxorubicin hydrochloride liposome injection. Refer to bortezomib manufacturer's prescribing information. 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. Discard unused portion. 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 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 minutes 4 times a day for 3 days If the extravasation is in an extremity, elevate the extremity Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.

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 NorthStar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 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. 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 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 en dash <1000/mm 3 8% 14% <500/mm 3 4. 2% 62% Anemia 6. 5 en dash <8 g/dL 5% 25% < 6. 3% Thrombocytopenia 10,000 en dash <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 Doxorubicin Hydrochloride Liposome Injection (%) treated (n=239) Topotecan (%) treated (n=235) All grades Grades 3en dash4 All grades Grades 3en dash4 Body as a Whole Asthenia 40 7 52 8 Fever 21 0. 8 31 6 Mucous Membrane Disorder 14 3. 4 0 Back Pain 12 1. 9 Infection 12 2. 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. 2 Anorexia 20 2. 3 Dyspepsia 12 0. 8 14 0 Nervous Dizziness 4. 2 0 10 0 Respiratory Pharyngitis 16 0 18 0. 4 Dyspnea 15 4. 3 Cough increased 10 0 12 0 Skin and Appendages Hand-foot syndrome 51 24 0. 9 0 Rash 29 4. 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: Digestive: Hematologic and Lymphatic: Metabolic and Nutritional: Nervous: Respiratory: Skin and Appendages: Special Senses: Urinary: 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 2 2 2 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 3 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 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**) 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. 2% * 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. 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. The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi's sarcoma. Incidence 1% to 5% Body as a Whole: Cardiovascular: Cutaneous: Digestive: Metabolic and Nutritional: Other: Incidence Less Than 1% Body As A Whole: Cardiovascular: Digestive: Metabolic and Nutritional Disorders: Respiratory: Skin and Appendages: Special Senses: Patients With Multiple Myeloma The safety data described are from 318 patients treated with doxorubicin hydrochloride liposome injection (30 mg/m 2 2 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 3en dash4 Any (%) Grade 3en dash4 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 The following additional adverse reactions have been identified during postapproval 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: Respiratory, Thoracic and Mediastinal Disorders: Hematologic Disorders Skin and Subcutaneous Tissue Disorders: Secondary Oral Neoplasms: [see Warnings and Precautions ( 5.

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.

Lactation: 8. 2 Risk Summary Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1 st (see Data) nd rd The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Doxorubicin hydrochloride liposome injection 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 2 Risk Summary It is not known whether doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating doxorubicin hydrochloride liposome injection. Contraception Females Doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8. 1 Males Doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection [see Non-clinical Toxicology ( 13. 1 Infertility Females In females of reproductive potential, doxorubicin hydrochloride liposome injection 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 Doxorubicin hydrochloride liposome injection 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 The safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established. Clinical studies of doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection 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. The pharmacokinetics of doxorubicin hydrochloride liposome injection has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce doxorubicin hydrochloride liposome injection for serum bilirubin of 1. 2 mg/dL or higher.

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

OVERDOSAGE
Acute overdosage with doxorubicin hydrochloride causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.
NON-CLINICAL TOXICOLOGY
Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, however doxorubicin was shown to be mutagenic in the in vitro in vitro in vivo 2 2 2 2 2 2
CLINICAL STUDIES
Doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection at 50 mg/m 2 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. ) N=27 Trial 2 (U. ) N=82 Trial 3 (non-U. ) N=36 Response Rate 22. 1% 0% 95% Confidence Interval 8. 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. 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. 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 doxorubicin hydrochloride liposome injection 50 mg/m 2 2 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 Doxorubicin Hydrochloride Liposome Injection (n=239) Topotecan (n=235) TTP Median (Months) Kaplan-Meier estimates. 2 p-value p-value is based on the stratified log-rank test. 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 doxorubicin hydrochloride liposome injection. 96 95% CI for Hazard Ratio (0. 20) Overall Survival Median (Months) 14. 7 p-value p-value not adjusted for multiple comparisons. 05 Hazard Ratio 0. 82 95% CI for Hazard Ratio (0. 00) Response Rate Overall Response n (%) 47 (19. 0) Complete Response n (%) 9 (3. 7) Partial Response n (%) 38 (15. 3) Median Duration of Response (Months) 6. 9 Doxorubicin hydrochloride liposome injection was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m 2 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 doxorubicin hydrochloride liposome injection was 154 mg/m 2 2 3 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. 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+ to 210+ 42+ to 210+ Time to PR (Days) Median 43 53 Range 15 to 133 15 to 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+ to 210+ 35 to 210+ Time to PR (Days) Median 22 48 Range 15 to 109 15 to 109 Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent doxorubicin hydrochloride liposome injection 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. In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses. The efficacy of doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection (30 mg/m 2 2 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 Doxorubicin Hydrochloride Liposome Injection + 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 % beta 2 <=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. 0) Urine M-protein (mg/24 hours): Median (Range) 107 (0 to 24883) 66 (0 to 39657) Median Months Since Diagnosis 35. 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 doxorubicin hydrochloride liposome injection + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1. Table13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma Endpoint Doxorubicin Hydrochloride Liposome Injection + 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. 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 doxorubicin hydrochloride liposome injection+bortezomib. 55 (95% CI) (0. 71) p-value Stratified log-rank test. 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. 25 Median Duration of Response (months) 10. 0 (95% CI) (10. 3) Figure 1: Time to Progression Kaplan-Meier Curve At the final analysis of survival, 78% of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8. The median survival was 33 months in the doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection + bortezomib vs. bortezomib = 0. 96 (95% CI 0. Seventy-eight percent of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy.
REFERENCES
1. "Hazardous Drugs", OSHA,

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DOXORUBICIN HYDROCHLORIDE- doxorubicin hydrochloride_injection, suspension, liposomal Product manual source documgent