DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Doxorubicin hydrochloride liposome injection: 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) in single-dose vials. The drug product appears as translucent, red liposomal dispersion. Doxorubicin hydrochloride liposome injection: 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) in single-dose vials (3).

DRUG INTERACTIONS SECTION.

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

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of doxorubicin hydrochloride liposome injection conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposis 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.

ADVERSE REACTIONS SECTION.

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)] 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 NorthStar RxLLC at 1-844-375-6847 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 Kaposis 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 Kaposis 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/m2 once every weeks for minimum of four courses in randomized, multicenter, open-label study. In this trial, patients received doxorubicin hydrochloride liposome injection for median number of 3.2 months (range 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 presents the hematologic adverse reactions from Trial 4.Table 3: Hematologic Adverse Reactions in Trial Doxorubicin Hydrochloride Liposome Injection Patients(n=239)Topotecan Patients (n=235)Neutropenia 500 -<1000/mm3 8% 14%<500/mm3 4.2%62%Anemia 6.5 -<8 g/dL 5% 25%< 6.5 g/dL 0.4%4.3%Thrombocytopenia10,000 -<50,000/mm3 1.3% 17%<10,000/mm3 0%17%Table presents the non-hematologic adverse reactions from Trial 4. Table 4: Non-Hematologic Adverse Reactions in Trial 4Non-Hematologic Adverse Reaction 10% or GreaterDoxorubicin Hydrochloride Liposome Injection (%) treated (n=239)Topotecan (%) treated (n=235)All gradesGrades 3-4All gradesGrades 3-4Body as WholeAsthenia407528Fever210.8316Mucous Membrane Disorder143.83.40Back Pain121.7100.9Infection122.160.9Headache110.8150DigestiveNausea465638Stomatitis418150.4Vomiting3384410Diarrhea212.5354.2Anorexia202.5221.3Dyspepsia120.8140NervousDizziness4.20100RespiratoryPharyngitis160180.4Dyspnea154.1234.3Cough increased100120Skin and AppendagesHand-foot syndrome51240.90Rash294.2120.4Alopecia19N/A52N/AThe 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 Kaposis Sarcoma The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposis sarcoma (KS) enrolled in four open-label, uncontrolled trials of doxorubicin hydrochloride liposome injection administered at doses ranging from 10 to 40 mg/m2 every to 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/m2 of doxorubicin hydrochloride liposome injection every to weeks with median exposure of 4.2 months (range day to 26.6 months). The median cumulative dose was 120 mg/m2 (range 3.3 to 798.6 mg/m2); 3% received cumulative doses of greater than 450 mg/m2. 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/mm3 (51% less than 50 cells/mm3); mean absolute neutrophil count at study entry approximately 3,000 cells/mm3 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 Kaposis sarcoma and included myelosuppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of non-KS tumor, allergy to penicillin, and unspecified reasons. Tables and summarize adverse reactions reported in patients treated with doxorubicin hydrochloride liposome injection for AIDS-related Kaposis sarcoma in pooled analysis of the four trials. Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposis SarcomaPatients With Refractory or Intolerant AIDS-Related Kaposis Sarcoma (n=74)Total Patients With AIDS-Related Kaposis Sarcoma (n=720 )This includes subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least cycles of regimen containing at least of 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 pooled trials. Neutropenia< 1000/mm346%49%< 500/mm311%13%Anemia< 10 g/dL58%55%< g/dL16%18%Thrombocytopenia< 150,000/mm361%61%< 25,000/mm31.4%4.2%Table 6: Non-Hematologic Adverse Reactions Reported in >= 5% of Patients With AIDS-Related Kaposis SarcomaAdverse ReactionsPatients With Refractory or Intolerant AIDS-Related Kaposis Sarcoma(n=77)Total Patients With AIDS-Related Kaposis 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 subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least cycles of regimen containing at least of 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 pooled trials. The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposis sarcoma. Incidence 1% to 5% Body as 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 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/m2) administered on day following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, and 11) every weeks, in randomized, open-label, multicenter study (Trial 6). In this trial, patients in the doxorubicin hydrochloride liposome injection bortezomib combination group were treated for 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 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 ReactionDoxorubicin Hydrochloride Liposome Injection bortezomib(n=318) Bortezomib(n=318) Any (%)Grade 3-4Any (%)Grade 3-4Blood and lymphatic system disorders Neutropenia 36322216Thrombocytopenia 33242817Anemia 259219General disorders and administration site conditions Fatigue 367283Pyrexia 311221Asthenia 226184Gastrointestinal disorders Nausea 483401Diarrhea 467395Vomiting 324221Constipation 311311Mucositis/Stomatitis 2025<1Abdominal pain 11181Infections and infestations Herpes zoster 11292Herpes simplex 10061Investigations Weight decreased 12040Metabolism and Nutritional disorders Anorexia 19214<1Nervous system disorders Peripheral Neuropathy1 4274511Neuralgia 173204Paresthesia/dysesthesia 13<1100Respiratory, thoracic and mediastinal disorders Cough 180120Skin and subcutaneous tissue disorders Rash2 221181Hand-foot syndrome 196<101 Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. 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 postapproval use of doxorubicin hydrochloride liposome injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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)].

BOXED WARNING SECTION.

WARNING:CARDIOMYOPATHY and INFUSION-RELATED REACTIONS. Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m . Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment [see Warnings and Precautions (5.1)]. Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions [see Warnings and Precautions (5.2)]. Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m . Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment [see Warnings and Precautions (5.1)]. Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at reduced rate. Discontinue doxorubicin hydrochloride liposome injection 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.Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride, 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 doxorubicin hydrochloride for infusion-related reactions and resume at reduced rate. Discontinue doxorubicin hydrochloride infusion for serious or life-threatening infusion-related reactions 5.2). Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride, 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 doxorubicin hydrochloride for infusion-related reactions and resume at reduced rate. Discontinue doxorubicin hydrochloride infusion for serious or life-threatening infusion-related reactions 5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis,and Impairment of Fertility. Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, 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. Doxorubicin hydrochloride liposome injection resulted in mild to moderate ovarian and testicular atrophy in mice after administration of single dose of 36 mg/kg (about times the 50 mg/m2 human dose on mg/m2 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/m2 human dose on mg/m2 basis), and diffuse degeneration of the seminiferous tubules and marked decrease in spermatogenesis were observed in dogs after repeat doses of mg/kg/day (about 0.4 times the 50 mg/m2 human dose on mg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. 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. 12.3 Pharmacokinetics. The pharmacokinetic parameters for total doxorubicin following 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 Kaposis Sarcoma DoseParameter (units)10 mg/m220 mg/m2 Peak Plasma Concentration (mcg/mL)4.12 +- 0.2158.34 +- 0.49Plasma Clearance (L/h/m2)0.056 +- 0.010.041 +- 0.004Steady State Volume of Distribution (L/m2)2.83 +- 0.1452.72 +- 0.120AUC (mcg/mLoh) 277 +- 32.9590 +- 58.7First Phase (1) Half-Life (h) 4.7 +- 1.15.2 +- 1.4Second Phase (1) Half-Life (h) 52.3 +- 5.655.0 +- 4.8N=23 Mean +- Standard Error Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Relative to doxorubicin hydrochloride liposome injection doses at or below 20 mg/m2, the pharmacokinetics of total doxorubicin following 50 mg/m2 doxorubicin hydrochloride liposome injection dose are nonlinear. At this dose, the elimination half-life of doxorubicin hydrochloride liposome injection is longer and the clearance lower compared to 20 mg/m2 dose. Distribution: Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than to 10% free doxorubicin) remains liposome-encapsulated during circulation. In contrast to doxorubicin, which displays large volume of distribution (range 700 to 1100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection 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/m2 doxorubicin hydrochloride liposome injection.Elimination: The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0.041 L/h/m2 at dose of 20 mg/m2. Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Ovarian Cancer. 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 months of completing treatment. Patients received doxorubicin hydrochloride liposome injection at 50 mg/m2 every or weeks for to 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 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 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 below. Table 9: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials Trial (U.S.) N=27Trial (U.S.) N=82Trial (non-U.S.) N=36Response Rate 22.2%17.1%0%95% Confidence Interval 8.6% -42.3%9.7% -27%0% -9.7%In pooled analysis of Trials to 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, 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/m2 every weeks (n=239) or topotecan 1.5 mg/m2 daily for consecutive days every weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and progression-free interval of greater than months off treatment) and the presence of bulky disease (tumor mass greater than 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 Analyses1 Protocol Defined ITT Population Doxorubicin Hydrochloride Liposome Injection(n=239) Topotecan(n=235)TTP (Protocol Specified Primary Endpoint) Median (Months)2 p-value3 Hazard Ratio4 4.10.62 0.964.295% CI for Hazard Ratio (0.76, 1.20) Overall Survival Median (Months)2 p-value5 Hazard Ratio4 14.40.05 0.8213.795% CI for Hazard Ratio (0.68, 1.00) Response Rate Overall Response (%) 47 (19.7) 40 (17.0)Complete Response (%)9 (3.8) 11 (4.7)Partial Response (%) 38 (15.9) 29 (12.3)Median Duration of Response (Months)2 6.9 5.91 Analysis based on investigators strata for protocol defined ITT population. Kaplan-Meier estimates. p-value is based on the stratified log-rank test. 4Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. hazard ratio less than indicates an advantage for doxorubicin hydrochloride liposome injection. p-value not adjusted for multiple comparisons. 14.2 AIDS-Related Kaposis Sarcoma. Doxorubicin hydrochloride liposome injection was studied in an open-label, single-arm, multicenter study at dose of 20 mg/m2 every weeks, until disease progression or unacceptable toxicity (Trial 5). Data is described for cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of 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 day to 15 months). The median cumulative dose of doxorubicin hydrochloride liposome injection was 154 mg/m2 (range 20 to 620 mg/m2). 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/mm3; 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 Refractory1 AIDS-Related Kaposis Sarcoma Investigator AssessmentAll Evaluable Patients (n=34)Evaluable Patients Who Received Prior Doxorubicin (n=20)Response+ Partial (PR)27%30%Stable29%40%Progression44%30%Duration of PR (Days)Median7389Range42+ to 210+42+ to 210+Time to PR (Days)Median4353Range15 to 13315 to 109Indicator Lesion AssessmentAll Evaluable Patients (n=42)Evaluable Patients Who Received Prior Doxorubicin (n=23)Response+ Partial (PR)48%52%Stable26%30%Progression26%17%Duration of PR (Days)Median7179Range22+ to 210+35 to 210+Time to PR (Days)Median2248Range15 to 10915 to 1091 Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy. There were no complete responses in this population. 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 response was demonstrated. In one trial, of 17 (40%) patients had durable response (median duration not reached but was longer than 11.6 months). In the second trial, of 11 patients (40%) on stable antiretroviral therapy demonstrated durable responses. 14.3 Multiple Myeloma The efficacy of doxorubicin hydrochloride liposome injection in combination with bortezomib was evaluated in Trial 6, 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/m2) administered IV on day following bortezomib (1.3 mg/m2 IV on days 1, 4, and 11) or bortezomib alone every weeks for up to cycles or until disease progression or unacceptable toxicity. Patients who maintained response were allowed to receive further treatment. The median number of cycles in each treatment arm was (range to 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 CharacteristicsPatient CharacteristicsDoxorubicin Hydrochloride Liposome Injection+bortezomibn=324bortezomibN=322Median age in years (range) 61 (28, 85)62 (34, 88)% Male/female 58 4254 46% Caucasian/Black/other 90 6/ 494 4 2Disease Characteristics with IgG/IgA/Light chain 57 27 1262 24 /11% -microglobulin group <=2.5 mg/L 1414>2.5 mg/L and <=5.5 mg/L 5655>5.5 mg/L 3031Serum M-protein (g/dL): Median (Range) 2.5 (0 to10)2.7 (0 to 10)Urine M-protein (mg/24 hours): Median (Range) 107 (0 to 24883)66 (0 to 39657)Median Months Since Diagnosis 35.237.5% Prior Therapy One 3434More than one 6666Prior Systemic Therapies for Multiple Myeloma Corticosteroid (%) 99>99Anthracyclines 6867Alkylating agent (%) 9290Thalidomide/lenalidomide (%) 4043Stem cell transplantation (%) 5754The 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. Table 13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma Endpoint Doxorubicin Hydrochloride Liposome Injection bortezomibn=324 Bortezomibn=322Time to Progression1 Progression or death due to progression (n) 99 150 Censored (n) 225 172Median in days (months)282 (9.3) 197 (6.5)95% CI250;338 170;217Hazard ratio2 (95% CI) p-value3 0.55(0.43, 0.71)<0.001 Response (n)4303 310% Complete Response (CR) 3% Partial Response (PR)43 40% CR PR 48 43p-value5 0.25 Median Duration of Response (months) (95% CI) 10.2(10.2;12.9) 7.0(5.9;8.3)1 Kaplan Meier estimate. Hazard ratio based on stratified Cox proportional hazards regression. hazard ratio 1 indicates an advantage for doxorubicin hydrochloride liposome injection+bortezomib. Stratified log-rank test. RR as per EBMT criteria. Cochran-Mantel-Haenszel test adjusted for the stratification factors.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 median follow up of 8.6 years. 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 0.80, 1.14)]. 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Doxorubicin hydrochloride liposome injection is contraindicated in patients who have history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions (5.2)]. Hypersensitivity reactions to doxorubicin hydrocholoride or the components of doxorubicin hydrochloride liposome injection (4, 5.2).

DESCRIPTION SECTION.

11 DESCRIPTION. 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--L-lyxohexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C27 H29 NO11oHCl; its molecular weight is 579.99. The structure formula is:Doxorubicin hydrochloride liposome injection is 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 concentration of mg/mL (equivalent to 1.87 mg/mL of doxorubicin) and 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 as buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. Greater than 90% of the drug is encapsulated in the PEGYLATED liposomes.MPEG-DSPE has the following structural formula:n=ca. 45HSPC has the following structural formula:m,n=14 or 16Representation of PEGYLATED liposome:.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer doxorubicin hydrochloride liposome injection at an initial rate of mg/min to minimize the risk of infusion reactions. If no infusion related reactions occur, increase rate of infusion to complete administration over hour. Do not administer as bolus injection or undiluted solution (2). Ovarian cancer: 50 mg/m2 IV every weeks (2.2) AIDS-related Kaposis Sarcoma: 20 mg/m2 IV every weeks (2.3) Multiple Myeloma: 30 mg/m2 IV on day following bortezomib (2.4). Ovarian cancer: 50 mg/m2 IV every weeks (2.2) AIDS-related Kaposis Sarcoma: 20 mg/m2 IV every weeks (2.3) Multiple Myeloma: 30 mg/m2 IV on day following bortezomib (2.4). 2.1 Important Use Information Do not substitute doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity. 2.3 AIDS-Related Kaposis Sarcoma The recommended dose of doxorubicin hydrochloride liposome injection is 20 mg/m2 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/m2 intravenously over 60 minutes on day of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer doxorubicin hydrochloride liposome injection after bortezomib on day of each cycle [see Clinical Studies (14.3)]. 2.5 Dose Modifications for Adverse Reactions Do not increase doxorubicin hydrochloride liposome injection after 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 or HFS: no dose adjustment. If previous Grade or HFS: delay dose up to 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 cm in diameter Delay dosing up to weeks or until resolved to Grade 0-1. Discontinue doxorubicin hydrochloride liposome injection if no resolution after weeks. If resolved to Grade 0-1 within weeks: And no previous Grade or HFS: continue treatment at previous dose. And previous Grade or toxicity: decrease dose by 25%. Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothingo Delay dosing up to weeks or until resolved to Grade 0-1, then decrease dose by 25%.oDiscontinue doxorubicin hydrochloride liposome injection if no resolution after weeks.Grade 4: Diffuse or local process causing infectious complications, or bed ridden state or hospitalization Delay dosing up to weeks or until resolved to Grade 0-1, then decrease dose by 25%. oDiscontinue doxorubicin hydrochloride liposome injection if no resolution after weeks. Stomatitis Grade 1: Painless ulcers, erythema, or mild soreness If no previous Grade or toxicity: no dose adjustment. If previous Grade or toxicity: delay up to weeks then decrease dose by 25%. Grade 2: Painful erythema, edema, or ulcers, but can eat Delay dosing up to weeks or until resolved to Grade 0-1. Discontinue doxorubicin hydrochloride liposome injection if there is no resolution after weeks.o If resolved to Grade 0-1 within weeks: And no previous Grade or stomatitis: resume treatment at previous dose. And previous Grade or toxicity: decrease dose by 25%. Grade 3: Painful erythema, edema, or ulcers, and cannot eat Delay dosing up to weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection. Grade 4: Requires parenteral or enteral support Delay dosing up to weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection. Neutropenia or Thrombocytopenia Grade No dose reduction Grade Delay until ANC >= 1,500 and platelets >= 75,000; resume treatment at previous dose Grade Delay until ANC >= 1,500 and platelets >= 75,000; resume treatment at previous dose Grade 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 BortezomibToxicity Doxorubicin Hydrochloride Liposome Injection Fever >=38C and ANC <1,000/mm3 Withhold dose for this cycle if before Day 4; Decrease dose by 25%, if after Day of previous cycle. On any day of drug administration after Day of each cycle: Platelet count <25,000/mm3 Hemoglobin <8 g/dL ANC <500/mm3 Withhold dose for this cycle if before Day 4; Decrease dose by 25%, if after Day of previous cycle AND if bortezomib is reduced for hematologic toxicity. Grade or 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 manufacturers 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 2C to 8C (36F to 46F) 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 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 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:o 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 times day for days If the extravasation is in an extremity, elevate the extremity 2.7 Procedure for Proper Handling and Disposal Doxorubicin hydrochloride liposome injection is 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Doxorubicin hydrochloride liposome injection is sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single-dose vials. Each 10-mL vial contains 20 mg doxorubicin hydrochloride, USP at concentration of mg/mL. Each 30-mL vial contains 50 mg doxorubicin hydrochloride, USP at concentration of mg/mL. The following individually cartoned vials are available:Table 14 mg in vialfill volumevial sizeNDC s20 mg vial10-mL10-mL16714-742-0150 mg vial25-mL30-mL16714-856-01 Refrigerate unopened vials of doxorubicin hydrochloride liposome injection at 2C-8C (36F-46F). Do not freeze. Discard unused portion.Doxorubicin hydrochloride liposome injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Doxorubicin hydrochloride liposome injection is an anthracycline topoisomerase II inhibitor indicated for: Ovarian cancer After failure of platinum-based chemotherapy. (1.1) AIDS-related Kaposis 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.Doxorubicin hydrochloride is an anthracycline topoisomerase inhibitor indicated for: (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 Kaposis Sarcoma. Doxorubicin hydrochloride liposome injection is indicated for the treatment of AIDS-related Kaposis 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.

INFORMATION FOR PATIENTS SECTION.

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 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). Embryofetal Toxicity Advise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider with 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 months following treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.3)]. Lactation Advise females not to breastfeed during treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.2)]. Infertility Advise females and males of reproductive potential that doxorubicin hydrochloride liposome injection may cause temporary or permanent infertility [see Use in Specific Populations (8.3)]. Discoloration of Urine and Body Fluids Inform patients that following doxorubicin hydrochloride liposome injection administration, 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. Mfd. for: Northstar RxLLCMemphis, TN 38141Mfd. by: Natco Pharma LtdKothur 509 228 INDIARevised: 1219.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NON-CLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis,and Impairment of Fertility. Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, 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. Doxorubicin hydrochloride liposome injection resulted in mild to moderate ovarian and testicular atrophy in mice after administration of single dose of 36 mg/kg (about times the 50 mg/m2 human dose on mg/m2 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/m2 human dose on mg/m2 basis), and diffuse degeneration of the seminiferous tubules and marked decrease in spermatogenesis were observed in dogs after repeat doses of mg/kg/day (about 0.4 times the 50 mg/m2 human dose on mg/m2 basis).

NURSING MOTHERS SECTION.

8.3 Females and Males of Reproductive Potential 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 pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for months after treatment with doxorubicin hydrochloride liposome injection. 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 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)].

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL SECTION. Doxorubicin Injection 20 mg/10 mL Vial label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic parameters for total doxorubicin following 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 Kaposis Sarcoma DoseParameter (units)10 mg/m220 mg/m2 Peak Plasma Concentration (mcg/mL)4.12 +- 0.2158.34 +- 0.49Plasma Clearance (L/h/m2)0.056 +- 0.010.041 +- 0.004Steady State Volume of Distribution (L/m2)2.83 +- 0.1452.72 +- 0.120AUC (mcg/mLoh) 277 +- 32.9590 +- 58.7First Phase (1) Half-Life (h) 4.7 +- 1.15.2 +- 1.4Second Phase (1) Half-Life (h) 52.3 +- 5.655.0 +- 4.8N=23 Mean +- Standard Error Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Relative to doxorubicin hydrochloride liposome injection doses at or below 20 mg/m2, the pharmacokinetics of total doxorubicin following 50 mg/m2 doxorubicin hydrochloride liposome injection dose are nonlinear. At this dose, the elimination half-life of doxorubicin hydrochloride liposome injection is longer and the clearance lower compared to 20 mg/m2 dose. Distribution: Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than to 10% free doxorubicin) remains liposome-encapsulated during circulation. In contrast to doxorubicin, which displays large volume of distribution (range 700 to 1100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection 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/m2 doxorubicin hydrochloride liposome injection.Elimination: The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0.041 L/h/m2 at dose of 20 mg/m2. Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m2.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. In animal reproduction studies, doxorubicin hydrochloride liposome injection 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 2nd and 3rd trimesters. Advise pregnant women of the potential risk to 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

REFERENCES SECTION.

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

SPL UNCLASSIFIED SECTION.

50mgvial. 20mgcarton. 50mgcarton. graph. HSPC. MPEG. structure. PEGLYATED. 20mgvial.

USE IN SPECIFIC POPULATIONS SECTION.

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, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. In animal reproduction studies, doxorubicin hydrochloride liposome injection 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 2nd and 3rd trimesters. Advise pregnant women of the potential risk to 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. 8.2 Lactation 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.. 8.3 Females and Males of Reproductive Potential 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 pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for months after treatment with doxorubicin hydrochloride liposome injection. 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 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)]. 8.4 Pediatric Use. The safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established. 8.5 Geriatric Use. Clinical studies of doxorubicin hydrochloride liposome injection conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposis 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. 8.6 Hepatic Impairment. 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hand-Foot Syndrome may occur. Dose modification or discontinuation may be required (5.3)Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus. Use effective contraception (5.5, 8.1, 8.3). Hand-Foot Syndrome may occur. Dose modification or discontinuation may be required (5.3). Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus. Use effective contraception (5.5, 8.1, 8.3). 5.1 Cardiomyopathy Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Include prior use of other anthracyclines or anthracenediones in calculations of cumulative dose. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation. In clinical study in 250 patients with advanced cancer who were treated with doxorubicin hydrochloride liposome injection, the risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Cardiomyopathy was defined as >20% decrease in resting left ventricular ejection fraction (LVEF) from baseline where LVEF remained in the normal range or >10% decrease in LVEF from baseline where LVEF was less than the institutional lower limit of normal. Two percent of patients developed signs and symptoms of congestive heart failure without documented evidence of cardiomyopathy. Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. Administer doxorubicin hydrochloride liposome injection to patients with history of cardiovascular disease only when the potential benefit of treatment outweighs the risk. 5.2 Infusion-Related Reactions. Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Of 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle and none during subsequent cycles. Across multiple studies of doxorubicin hydrochloride liposome injection monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions. The majority of infusion-related events occurred during the first infusion. Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of doxorubicin hydrochloride liposome injection. Initiate doxorubicin hydrochloride liposome injection infusions at rate of mg/min and increase rate as tolerated [see Dosage and Administration (2.6)]. Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or infusion-related reactions and resume at reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection infusion for serious or life-threatening infusion-related reactions. 5.3 Hand-Foot Syndrome (HFS) In Trial 4, the incidence of HFS was 51% of patients in the doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade or cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade or cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of doxorubicin hydrochloride liposome injection in 4.2% of patients. HFS was generally observed after or cycles of treatment but may occur earlier. Delay doxorubicin hydrochloride liposome injection for the first episode of Grade or greater HFS [see Dosage and Administration (2.5)]. Discontinue doxorubicin hydrochloride liposome injection if HFS is severe and debilitating. 5.4 Secondary Oral Neoplasms Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to doxorubicin hydrochloride liposome injection. These malignancies were diagnosed both during treatment with doxorubicin hydrochloride liposome injection and up to years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer. The altered pharmacokinetics and preferential tissue distribution of liposomal doxorubicin that contributes to enhanced skin toxicity and mucositis compared to free doxorubicin may play role in the development of oral secondary malignancies with long-term use.. 5.5 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. 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 2nd and 3rd trimesters. At doses approximately 0.12 times the recommended clinical dose, doxorubicin hydrochloride liposome injection was embryotoxic and abortifacient in rabbits. Advise pregnant women of the potential risk to fetus. Advise females and males of reproductive potential to use effective contraception during and for months after treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.1) and (8.3)].