BOXED WARNING SECTION.

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

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in more detail in other sections of the labeling.oCardiomyopathy [see Warnings and Precautions (5.1)]oInfusion-Related Reactions [see Warnings and Precautions (5.2)]oHand-Foot Syndrome [see Warnings and Precautions (5.3)]oSecondary Oral Neoplasms [see Warnings and Precautions (5.4)]. oCardiomyopathy [see Warnings and Precautions (5.1)]. oInfusion-Related Reactions [see Warnings and Precautions (5.2)]. oHand-Foot Syndrome [see Warnings and Precautions (5.3)]. oSecondary Oral Neoplasms [see Warnings and Precautions (5.4)]. Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia (6).To report SUSPECTED ADVERSE REACTIONS contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.The safety data reflect exposure to DOXIL liposomal infusion in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposis sarcoma, and 318 patients with multiple myeloma.The most common adverse reactions (>20%) observed with DOXIL liposomal infusion are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.The following tables present adverse reactions from clinical trials of single-agent DOXIL liposomal infusion in ovarian cancer and AIDS-Related Kaposis sarcoma.. Patients With Ovarian CancerThe safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with DOXIL liposomal infusion 50 mg/m2 once every weeks for minimum of four courses in randomized, multicenter, open-label study. In this trial, patients received DOXIL liposomal infusion 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 4DOXIL Liposomal Infusion Patients (n=239)Topotecan Patients (n=235)Neutropenia 500 <1000/mm3 8%14% <500/mm3 4.2%62%Anemia 6.5 <8 g/dL5%25% 6.5 g/dL0.4%4.3%Thrombocytopenia 10,000 <50,000/mm3 1.3%17% <10,000/mm3 0.0%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 GreaterDOXIL Liposomal Infusion (%) treated(n=239)Topotecan (%) treated(n=235)All gradesGrades 3-4All gradesGrades 3-4 Body as Whole Asthenia407528 Fever210.8316 Mucous Membrane Disorder143.83.40 Back Pain121.7100.9 Infection122.160.9 Headache110.8150 Digestive Nausea465638 Stomatitis418150.4 Vomiting3384410 Diarrhea212.5354.2 Anorexia202.5221.3 Dyspepsia120.8140 Nervous Dizziness4.20100 Respiratory Pharyngitis160180.4 Dyspnea154.1234.3 Cough increased100120 Skin and Appendages Hand-foot syndrome51240.90 Rash294.2120.4 Alopecia19N/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 SarcomaThe 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 DOXIL liposomal infusion administered at doses ranging from 10 to 40 mg/m2 every to weeks. Demographics of the population were: median age 38.7 years (range 24-70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL liposomal infusion 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. Table and Table summarize adverse reactions reported in patients treated with DOXIL liposomal infusion 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=74This 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.)Total Patients With AIDS-Related Kaposis Sarcoma(n=720This includes only subjects with AIDS-KS who had available data from the pooled trials.)Neutropenia 1000/mm3 46%49% 500/mm3 11%13%Anemia 10 g/dL58%55% 8 g/dL16%18%Thrombocytopenia 150,000/mm3 61%61% 25,000/mm3 1.4%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=77This 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.)Total Patients With AIDS-Related Kaposis Sarcoma(n=705This includes only subjects with AIDS-KS who had available adverse event data from the pooled trials.)Nausea18%17%Asthenia7%10%Fever8%9%Alopecia9%9%Alkaline Phosphatase Increase1.3%8%Vomiting8%8%Diarrhea5%8%Stomatitis5%7%Oral Moniliasis1.3%6%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 MyelomaThe safety data described are from 318 patients treated with DOXIL liposomal infusion (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 DOXIL liposomal infusion 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 DOXIL liposomal infusion in combination with bortezomib for multiple myeloma.Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in >=10% Patients Treated for Multiple Myeloma With DOXIL Liposomal Infusion in Combination With BortezomibAdverse ReactionDOXIL Liposomal Infusion bortezomib(n=318)Bortezomib(n=318)Any (%)Grade 3-4Any (%)Grade 3-4Blood and lymphatic system disordersNeutropenia36322216Thrombocytopenia33242817Anemia259219General disorders and administration site conditionsFatigue367283Pyrexia311221Asthenia226184Gastrointestinal disordersNausea483401Diarrhea467395Vomiting324221Constipation311311Mucositis/Stomatitis2025<1Abdominal pain11181Infections and infestationsHerpes zoster11292Herpes simplex10061InvestigationsWeight decreased12040Metabolism and Nutritional disordersAnorexia19214<1Nervous system disordersPeripheral NeuropathyPeripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. 4274511Neuralgia173204Paresthesia/dysesthesia13<1100Respiratory, thoracic and mediastinal disordersCough180120Skin and subcutaneous tissue disordersRashRash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. 221181Hand-foot syndrome196<10. 6.2 Postmarketing Experience. The following additional adverse reactions have been identified during post approval use of DOXIL liposomal infusion. 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 spasmsRespiratory, Thoracic and Mediastinal Disorders: pulmonary embolism (in some cases fatal)Hematologic Disorders: Secondary acute myelogenous leukemiaSkin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichenoid keratosisSecondary Oral Neoplasms: [see Warnings and Precautions (5.4)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility. Mutagenicity or carcinogenicity studies have not been conducted with DOXIL liposomal infusion, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. DOXIL liposomal infusion resulted in mild to moderate ovarian and testicular atrophy in mice after administration of 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 DOXIL liposomal infusion is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.. 12.3 Pharmacokinetics. The pharmacokinetic parameters for total doxorubicin following single dose of DOXIL infused over 30 minutes are presented in Table 8.Table 8: Pharmacokinetic Parameters of Total Doxorubicin from DOXIL Liposomal Infusion in Patients With AIDS-Related Kaposis SarcomaDoseParameter (units)10 mg/m2 20 mg/m2 N=23Mean +- Standard ErrorPeak Plasma Concentration (ug/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 (ug/mLh)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 +- 4.8DOXIL liposomal infusion displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Relative to DOXIL liposomal infusion doses at or below 20 mg/m2, the pharmacokinetics of total doxorubicin following 50 mg/m2 DOXIL liposomal infusion dose are nonlinear. At this dose, the elimination half-life of DOXIL liposomal infusion is longer and the clearance lower compared to 20 mg/m2 dose.. DistributionDirect 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 large volume of distribution (range 700 to 1100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that DOXIL liposomal infusion is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of DOXIL liposomal infusion has not been determined; the plasma protein binding of doxorubicin is approximately 70%.. MetabolismDoxorubicinol, 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 DOXIL liposomal infusion.. EliminationThe plasma clearance of total doxorubicin from DOXIL liposomal infusion 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. DOXIL liposomal infusion was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within months of completing treatment. Patients received DOXIL liposomal infusion at 50 mg/m2 every or weeks for 3-6+ cycles in the absence of dose-limiting toxicity or disease progression.The median age at diagnosis ranged from 52 to 64 years in the 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 TrialsTrial (U.S.)N=27Trial (U.S.)N=82Trial (non-U.S.)N=36Response Rate22.2%17.1%0%95% Confidence Interval8.6% 42.3%9.7% 27.0%0.0% 9.7%In pooled analysis of Trials 1-3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks.In Trial 4, randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either DOXIL liposomal infusion 50 mg/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 AnalysesAnalysis based on investigators strata for protocol defined ITT population. Protocol Defined ITT PopulationDOXIL LiposomalInfusion(n=239)Topotecan(n=235)TTP (Protocol Specified Primary Endpoint) Median (Months)Kaplan-Meier estimates. 4.14.2 p-valuep-value is based on the stratified log-rank test. 0.62 Hazard RatioHazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. hazard ratio less than indicates an advantage for DOXIL liposomal infusion. 0.96 95% CI for Hazard Ratio (0.76, 1.20)Overall Survival Median (Months) 14.413.7 p-valuep-value not adjusted for multiple comparisons. 0.05 Hazard Ratio 0.82 95% CI for Hazard Ratio (0.68, 1.00)Response Rate Overall Response (%)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) 6.95.9. 14.2 AIDS-Related Kaposis Sarcoma. DOXIL liposomal infusion 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 DOXIL liposomal infusion 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 RefractoryPatients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy. AIDS-Related Kaposis SarcomaInvestigator AssessmentAll Evaluable Patients(n=34)Evaluable Patients Who Received Prior Doxorubicin(n=20)ResponseThere were no complete responses in this population. Partial (PR)27%30% Stable29%40% Progression44%30%Duration of PR (Days) Median7389 Range42+ 210+42+ 210+Time to PR (Days) Median4353 Range15 13315 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) Median7179 Range22+ 210+35 210+Time to PR (Days) Median2248 Range15 10915 109Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent DOXIL liposomal infusion and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until 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 DOXIL liposomal infusion 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 DOXIL liposomal infusion (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 1-18).The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12).Table 12: Summary of Baseline Patient and Disease CharacteristicsPatient CharacteristicsDOXIL LiposomalInfusion bortezomibn=324bortezomibn=322 Median 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 2-microglobulin group <=2.5 mg/L1414 >2.5 mg/L and <=5.5 mg/L5655 >5.5 mg/L3031Serum M-protein (g/dL): Median (Range)2.5 (0-10.0)2.7 (0-10.0)Urine M-protein (mg/24 hours): Median (Range)107 (0-24883)66 (0-39657)Median Months Since Diagnosis35.237.5% Prior Therapy One3434 More than one6666Prior Systemic Therapies for Multiple Myeloma Corticosteroid (%)99>99 Anthracyclines6867 Alkylating agent (%)9290 Thalidomide/lenalidomide (%)4043 Stem 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 DOXIL liposomal infusion bortezomib combination. Efficacy results are as shown in Table 13 and Figure . Table 13: Efficacy of DOXIL Liposomal Infusion in Combination With Bortezomib in the Treatment of Patients With Multiple MyelomaEndpointDOXIL LiposomalInfusion bortezomibn=324Bortezomibn=322Time to ProgressionKaplan Meier estimate.Progression or death due to progression (n)99150 Censored (n)225172 Median in days (months)282 (9.3)197 (6.5) 95% CI250; 338170; 217 Hazard ratioHazard ratio based on stratified Cox proportional hazards regression. hazard ratio 1 indicates an advantage for DOXIL liposomal infusion +bortezomib. 0.55 (95% CI) (0.43, 0.71) p-valueStratified log-rank test. <0.001Response (n)RR as per EBMT criteria.303310 Complete Response (CR) 53 Partial Response (PR) 4340 CR PR4843 p-valueCochran-Mantel-Haenszel test adjusted for the stratification factors. 0.25Median Duration of Response (months)10.27.0(95% CI)(10.2; 12.9)(5.9; 8.3)Figure 1- Time to Progression Kaplan-Meier CurveAt the final analysis of survival, 78% of subjects in the DOXIL liposomal infusion and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after median follow up of 8.6 years. The median survival was 33 months in the DOXIL liposomal infusion and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for DOXIL liposomal infusion bortezomib vs. bortezomib 0.96 (95% CI 0.80, 1.14)]. Seventy-eight percent of subjects in the DOXIL liposomal infusion and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy.. Figure 1.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. The active ingredient in DOXIL liposomal infusion is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in STEALTH liposomes for intravenous use.The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6-trideoxy--L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C27-H29 -NO11oHCl and the molecular weight is 579.99.The structural formula is:DOXIL liposomal infusion is sterile, translucent, red liposomal dispersion. Each single-dose vial contains 20 mg or 50 mg doxorubicin hydrochloride at concentration of mg/mL (equivalent to 1.87 mg/mL of doxorubicin) and pH of 6.5. The STEALTH liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine 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 STEALTH liposomes.MPEG-DSPE has the following structural formula:HSPC has the following structural formula:Representation of STEALTH liposome:. Structural Formula. MPEG-DSPE Structural Formula. HSPC Structural Formula. Representation of STEALTH liposome.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer DOXIL liposomal infusion 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).oOvarian cancer: 50 mg/m2 IV every weeks (2.2)oAIDS-related Kaposis Sarcoma: 20 mg/m2 IV every weeks(2.3)oMultiple Myeloma: 30 mg/m2 IV on day following bortezomib (2.4). oOvarian cancer: 50 mg/m2 IV every weeks (2.2). oAIDS-related Kaposis Sarcoma: 20 mg/m2 IV every weeks(2.3). oMultiple Myeloma: 30 mg/m2 IV on day following bortezomib (2.4). 2.1 Important Use Information. Do not substitute DOXIL liposomal infusion for other doxorubicin hydrochloride products.Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2)].. 2.2 Ovarian Cancer. The recommended dose of DOXIL liposomal infusion is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.. 2.3 AIDS-Related Kaposis Sarcoma. The recommended dose of DOXIL liposomal infusion 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 DOXIL liposomal infusion 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 DOXIL liposomal infusion after bortezomib on day of each cycle [see Clinical Studies (14.3)].. 2.5 Dose Modifications for Adverse Reactions. Do not increase DOXIL liposomal infusion after dose reduction for toxicity.Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse ReactionsToxicityDose AdjustmentHand-Foot Syndrome (HFS)Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activitiesoIf no previous Grade or HFS: no dose adjustment.oIf 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 diameteroDelay dosing up to weeks or until resolved to Grade 0-1.oDiscontinue DOXIL liposomal infusion if no resolution after weeks.oIf resolved to Grade 0-1 within weeks: oAnd no previous Grade or HFS: continue treatment at previous dose.oAnd previous Grade or toxicity: decrease dose by 25%. Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothingoDelay dosing up to weeks or until resolved to Grade 0-1, then decrease dose by 25%.oDiscontinue DOXIL liposomal infusion if no resolution after weeks.Grade 4: Diffuse or local process causing infectious complications, or bed ridden state or hospitalizationoDelay dosing up to weeks or until resolved to Grade 0-1, then decrease dose by 25%.oDiscontinue DOXIL liposomal infusion if no resolution after weeks.StomatitisGrade 1: Painless ulcers, erythema, or mild sorenessoIf no previous Grade or toxicity: no dose adjustment.oIf previous Grade or toxicity: delay up to weeks then decrease dose by 25%.Grade 2: Painful erythema, edema, or ulcers, but can eatoDelay dosing up to weeks or until resolved to Grade 0-1.oDiscontinue DOXIL liposomal infusion if there is no resolution after weeks.oIf resolved to Grade 0-1 within weeks: oAnd no previous Grade or stomatitis: resume treatment at previous dose.oAnd previous Grade or toxicity: decrease dose by 25%. Grade 3: Painful erythema, edema, or ulcers, and cannot eatoDelay dosing up to weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval.oIf after weeks there is no resolution, discontinue DOXIL liposomal infusion.Grade 4: Requires parenteral or enteral supportoDelay dosing up to weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval.oIf after weeks there is no resolution, discontinue DOXIL liposomal infusion.Neutropenia or ThrombocytopeniaGrade 1No dose reductionGrade 2Delay until ANC >= 1,500 and platelets >= 75,000; resume treatment at previous doseGrade 3Delay until ANC >= 1,500 and platelets >= 75,000; resume treatment at previous doseGrade 4Delay until ANC >= 1,500 and platelets >= 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factorTable 2: Recommended Dose Modifications of DOXIL Liposomal Infusion for Toxicity When Administered in Combination With BortezomibToxicityDOXIL Liposomal InfusionFever >=38C and ANC <1,000/mm3 oWithhold dose for this cycle if before Day 4;oDecrease dose by 25%, if after Day of previous cycle.On any day of drug administration after Day of each cycle:oPlatelet count <25,000/mm3oHemoglobin <8 g/dLoANC <500/mm3oWithhold dose for this cycle if before Day 4;oDecrease dose by 25%, if after Day of previous cycle AND if bortezomib is reduced for hematologic toxicity. Grade or non-hematologic drug related toxicityDo not dose until recovered to Grade <2, then reduce dose by 25%.For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for DOXIL liposomal infusion. Refer to bortezomib manufacturers prescribing information.. oIf no previous Grade or HFS: no dose adjustment.. oIf previous Grade or HFS: delay dose up to weeks, then decrease dose by 25%.. oDelay dosing up to weeks or until resolved to Grade 0-1.. oDiscontinue DOXIL liposomal infusion if no resolution after weeks.. oIf resolved to Grade 0-1 within weeks: oAnd no previous Grade or HFS: continue treatment at previous dose.oAnd previous Grade or toxicity: decrease dose by 25%. oAnd no previous Grade or HFS: continue treatment at previous dose.. oAnd previous Grade or toxicity: decrease dose by 25%.. oDelay dosing up to weeks or until resolved to Grade 0-1, then decrease dose by 25%.. oDiscontinue DOXIL liposomal infusion if no resolution after weeks.. oDelay dosing up to weeks or until resolved to Grade 0-1, then decrease dose by 25%.. oDiscontinue DOXIL liposomal infusion if no resolution after weeks.. oIf no previous Grade or toxicity: no dose adjustment.. oIf previous Grade or toxicity: delay up to weeks then decrease dose by 25%.. oDelay dosing up to weeks or until resolved to Grade 0-1.. oDiscontinue DOXIL liposomal infusion if there is no resolution after weeks.. oIf resolved to Grade 0-1 within weeks: oAnd no previous Grade or stomatitis: resume treatment at previous dose.oAnd previous Grade or toxicity: decrease dose by 25%. oAnd no previous Grade or stomatitis: resume treatment at previous dose.. oAnd previous Grade or toxicity: decrease dose by 25%.. oDelay dosing up to weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval.. oIf after weeks there is no resolution, discontinue DOXIL liposomal infusion.. oDelay dosing up to weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval.. oIf after weeks there is no resolution, discontinue DOXIL liposomal infusion.. oWithhold dose for this cycle if before Day 4;. oDecrease dose by 25%, if after Day of previous cycle.. oPlatelet count <25,000/mm3. oHemoglobin <8 g/dL. oANC <500/mm3. oWithhold dose for this cycle if before Day 4;. oDecrease dose by 25%, if after Day of previous cycle AND if bortezomib is reduced for hematologic toxicity.. 2.6 Preparation and Administration. PreparationDilute DOXIL liposomal infusion doses up to 90 mg in 250 mL of 5% Dextrose Injection, USP prior to administration. Dilute doses exceeding 90 mg in 500 mL of 5% Dextrose Injection, USP prior to administration. Refrigerate diluted DOXIL liposomal infusion at 2C to 8C (36F to 46F) and administer within 24 hours.. AdministrationInspect 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 DOXIL liposomal infusion 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 DOXIL liposomal infusion with other drugs.. Management of Suspected ExtravasationDiscontinue DOXIL liposomal infusion for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:oDo not remove the needle until attempts are made to aspirate extravasated fluidoDo not flush the lineoAvoid applying pressure to the siteoApply ice to the site intermittently for 15 min times day for daysoIf the extravasation is in an extremity, elevate the extremity. oDo not remove the needle until attempts are made to aspirate extravasated fluid. oDo not flush the line. oAvoid applying pressure to the site. oApply ice to the site intermittently for 15 min times day for days. oIf the extravasation is in an extremity, elevate the extremity. 2.7 Procedure for Proper Handling and Disposal. DOXIL liposomal infusion is cytotoxic drug. Follow applicable special handling and disposal procedures.1 If DOXIL liposomal infusion comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. DOXILliposomal infusion: 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 liposomal 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 DOXIL liposomal infusion.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of DOXIL liposomal infusion 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 DOXIL liposomal infusion in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. DOXIL liposomal infusion is sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single-dose vials.The following individually cartoned vials are available:Table 14mg in vialfill volumevial sizeNDC s20 mg vial10-mL10-mL0338-0063-0150 mg vial25-mL30-mL0338-0067-01. Refrigerate unopened vials of DOXIL liposomal infusion at 2C- 8C (36F- 46F). Do not freeze. Discard unused portion.DOXIL liposomal infusion is cytotoxic drug. Follow applicable special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. CardiomyopathyAdvise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1)].. Infusion-Related ReactionsAdvise 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)].. MyelosuppressionAdvise patients to contact their healthcare provider for new onset fever or symptoms of infection.. Hand-Foot SyndromeAdvise 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)].. StomatitisAdvise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis).. Embryo-Fetal ToxicityAdvise 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 DOXIL liposomal infusion [see Use in Specific Populations (8.3)].. LactationAdvise females not to breastfeed during treatment with DOXIL liposomal infusion [see Use in Specific Populations (8.2)]. InfertilityAdvise females and males of reproductive potential that DOXIL liposomal infusion may cause temporary or permanent infertility [see Use in Specific Populations (8.3)]. Discoloration of Urine and Body FluidsInform patients that following DOXIL liposomal infusion 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.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NON-CLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility. Mutagenicity or carcinogenicity studies have not been conducted with DOXIL liposomal infusion, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. DOXIL liposomal infusion resulted in mild to moderate ovarian and testicular atrophy in mice after administration of 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).

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 20 mg Vial Carton. NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)20 mg in 10 mL(2 mg/mL)Single-Dose Vial. Discard unused portion.LIPOSOMAL FORMULATION DO NOT SUBSTITUTE FOR DOXORUBICIN HydrochlorideFOR INTRAVENOUS INFUSION ONLYRx onlyCytotoxicHA-65-01-805Refrigerate, 2-8C(36-46F). Do Not Freeze.See package insert for dosage information.Baxter Healthcare CorporationDeerfield, IL 60015Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries.Bar Code0100303380063017Bar Code696988LOTEXPNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)20 mg in 10 mL(2 mg/mL)Single-Dose Vial. Discard unused portion.LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideFOR INTRAVENOUSINFUSION ONLYRefrigerate, 2-8C(36-46F). Do Not Freeze.CytotoxicRx onlyBaxter LogoNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)N3Bar Code0338-0063-01 7Note: Liposomal formulation.See package insert for dosageinformation.USA6943440882Bar CodeNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideManufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product of ItalyBaxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)GTIN 00303380063017Bar CodeS/NEXPLOTNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)Each mL containsdoxorubicin Hydrochloride, mg.STEALTH liposome carriersare composed of cholesterol,3.19 mg; fully hydrogenated soyphosphatidylcholine (HSPC),9.58 mg; and N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycerol-3-phosphoethanolaminesodium salt (MPEG-DSPE),3.19 mg. Each mL also containsammonium sulfate,approximately 0.6 mg;histidine; hydrochloric acidand/or sodium hydroxide;and sucrose.HA-80-02-881NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)20 mg in 10 mL(2 mg/mL)Single-Dose Vial. Discard unused portion.LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideFOR INTRAVENOUSINFUSION ONLYRefrigerate, 2-8C(36-46F). Do Not Freeze.CytotoxicRx onlyBaxter LogoNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)N3Bar Code0338-0063-01 7Note: Liposomal formulation.See package insert for dosageinformation.USA6943440882Bar CodeNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideManufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product TaiwanBaxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)GTIN 00303380063017Bar CodeS/NEXPLOTNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)Each mL containsdoxorubicin Hydrochloride, mg.STEALTH liposome carriersare composed of cholesterol,3.19 mg; fully hydrogenated soyphosphatidylcholine (HSPC),9.58 mg; and N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycerol-3-phosphoethanolaminesodium salt (MPEG-DSPE),3.19 mg. Each mL also containsammonium sulfate,approximately 0.6 mg;histidine; hydrochloric acidand/or sodium hydroxide;and sucrose.HA-80-02-880NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)50 mg in 25 mL(2 mg/mL)Single-Dose Vial. Discard unused portion.LIPOSOMAL FORMULATION DO NOT SUBSTITUTE FOR DOXORUBICIN HydrochlorideFOR INTRAVENOUSINFUSION ONLYRx onlyCytotoxicHA-65-01-806Refrigerate, 2-8C (36-46F). Do Not Freeze.See package insert for dosageinformation.Baxter Healthcare CorporationDeerfield, IL 60015Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries.Bar Code0100303380067015Bar Code696987LOTEXPNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)50 mg in 25 mL(2 mg/mL)Single-Dose Vial. Discard unused portion.LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideFOR INTRAVENOUSINFUSION ONLYRefrigerate, 2-8C(36-46F). Do Not Freeze.CytotoxicRx onlyBaxter LogoNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)N3Bar Code0338-0067-01 5Note: Liposomal formulation.See package insert for dosageinformation.USA693385882Bar CodeNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideManufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product of ItalyBaxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)GTIN 00303380067015Bar CodeS/NEXPLOTNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)Each mL containsdoxorubicin Hydrochloride, mg.STEALTH liposome carriersare composed of cholesterol,3.19 mg; fully hydrogenated soyphosphatidylcholine (HSPC),9.58 mg; and N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycerol-3-phosphoethanolaminesodium salt (MPEG-DSPE),3.19 mg. Each mL also containsammonium sulfate,approximately 0.6 mg;histidine; hydrochloric acidand/or sodium hydroxide;and sucrose.HA-80-02-883NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)50 mg in 25 mL(2 mg/mL)Single-Dose Vial. Discard unused portion.LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideFOR INTRAVENOUSINFUSION ONLYRefrigerate, 2-8C(36-46F). Do Not Freeze.CytotoxicRx onlyBaxter LogoNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)N3Bar Code0338-0067-01 5Note: Liposomal formulation.See package insert for dosageinformation.USA693385882Bar CodeNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN HydrochlorideManufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product of TaiwanBaxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.NDC 0338-0067-01DOXIL(DOXOrubicinHydrochlorideliposome injection)GTIN 00303380067015Bar CodeS/NEXPLOTNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)Each mL containsdoxorubicin Hydrochloride, mg.STEALTH liposome carriersare composed of cholesterol,3.19 mg; fully hydrogenated soyphosphatidylcholine (HSPC),9.58 mg; and N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycerol-3-phosphoethanolaminesodium salt (MPEG-DSPE),3.19 mg. Each mL also containsammonium sulfate,approximately 0.6 mg;histidine; hydrochloric acidand/or sodium hydroxide;and sucrose.HA-80-02-882. Representative 20 mg Container Label. Representative Carton Label 0338-0063-01. Representative Carton label 20 mg Taiwan. Representative Container Label 50 mg. Representative Carton Label 0338-0067-01. Representative Carton Label 50 mg Taiwan.

PEDIATRIC USE SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic parameters for total doxorubicin following single dose of DOXIL infused over 30 minutes are presented in Table 8.Table 8: Pharmacokinetic Parameters of Total Doxorubicin from DOXIL Liposomal Infusion in Patients With AIDS-Related Kaposis SarcomaDoseParameter (units)10 mg/m2 20 mg/m2 N=23Mean +- Standard ErrorPeak Plasma Concentration (ug/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 (ug/mLh)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 +- 4.8DOXIL liposomal infusion displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Relative to DOXIL liposomal infusion doses at or below 20 mg/m2, the pharmacokinetics of total doxorubicin following 50 mg/m2 DOXIL liposomal infusion dose are nonlinear. At this dose, the elimination half-life of DOXIL liposomal infusion is longer and the clearance lower compared to 20 mg/m2 dose.. DistributionDirect 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 large volume of distribution (range 700 to 1100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that DOXIL liposomal infusion is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of DOXIL liposomal infusion has not been determined; the plasma protein binding of doxorubicin is approximately 70%.. MetabolismDoxorubicinol, 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 DOXIL liposomal infusion.. EliminationThe plasma clearance of total doxorubicin from DOXIL liposomal infusion 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 SummaryBased on findings in animals and its mechanism of action, DOXIL liposomal infusion can cause fetal harm when administered to pregnant woman; avoid the use of DOXIL liposomal infusion during the 1st trimester. In animal reproduction studies, DOXIL liposomal infusion was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data). Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 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 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.. Data. Animal DataDOXIL liposomal infusion was embryotoxic at doses of 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/m2 human dose on mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

REFERENCES SECTION.

15 REFERENCES. 3.Hazardous Drugs, OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html. 3.Hazardous Drugs, OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

1.1 Ovarian Cancer. DOXIL liposomal infusion is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Discontinue breastfeeding (8.2). oLactation: Discontinue breastfeeding (8.2). 8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action, DOXIL liposomal infusion can cause fetal harm when administered to pregnant woman; avoid the use of DOXIL liposomal infusion during the 1st trimester. In animal reproduction studies, DOXIL liposomal infusion was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data). Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 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 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.. Data. Animal DataDOXIL liposomal infusion was embryotoxic at doses of 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/m2 human dose on mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.. 8.2 Lactation. Risk SummaryIt is not known whether DOXIL liposomal infusion is present in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from DOXIL liposomal infusion, discontinue breastfeeding during treatment with DOXIL liposomal infusion.. 8.3 Females and Males of Reproductive Potential. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating DOXIL liposomal infusion.. Contraception. FemalesDOXIL liposomal infusion 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 DOXIL liposomal infusion.. MalesDOXIL liposomal infusion may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for months after treatment with DOXIL liposomal infusion [see Non-clinical Toxicology (13.1)]. Infertility. FemalesIn females of reproductive potential, DOXIL liposomal infusion may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin hydrochloride. Recovery of menses and ovulation is related to age at treatment. MalesDOXIL liposomal infusion may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Non-clinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of DOXIL liposomal infusion in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of DOXIL liposomal infusion conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related 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 DOXIL liposomal infusion in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.. 8.6 Hepatic Impairment. The pharmacokinetics of DOXIL liposomal infusion has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce DOXIL liposomal infusion for serum bilirubin of 1.2 mg/dL or higher.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHand-Foot Syndrome may occur. Dose modification or discontinuation may be required (5.3)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus. Use effective contraception (5.5, 8.1, 8.3). oHand-Foot Syndrome may occur. Dose modification or discontinuation may be required (5.3). oEmbryo-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 DOXIL liposomal infusion, 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 DOXIL liposomal infusion, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. Administer DOXIL liposomal infusion 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 DOXIL liposomal infusion: 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 DOXIL liposomal infusion 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 DOXIL liposomal infusion 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 DOXIL liposomal infusion. Initiate DOXIL liposomal infusions at rate of mg/min and increase rate as tolerated [see Dosage and Administration (2.6)]. Withhold DOXIL liposomal infusion for Grade 1, 2, or infusion-related reactions and resume at reduced infusion rate. Discontinue DOXIL liposomal 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 DOXIL liposomal infusion arm and 0.9% of patients in the topotecan arm, including 24% Grade or cases of HFS in DOXIL liposomal infusion-treated patients and no Grade or cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of DOXIL liposomal infusion in 4.2% of patients.HFS was generally observed after or cycles of treatment but may occur earlier. Delay DOXIL liposomal infusion for the first episode of Grade or greater HFS [see Dosage and Administration (2.5)]. Discontinue DOXIL liposomal infusion 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 DOXIL liposomal infusion. These malignancies were diagnosed both during treatment with DOXIL liposomal infusion 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, DOXIL liposomal infusion can cause fetal harm when administered to pregnant woman; avoid the use of DOXIL liposomal infusion 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, DOXIL liposomal infusion 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 DOXIL liposomal infusion [see Use in Specific Populations (8.1, 8.3)].