FDA label fab6acd0-8a42-4002-8f1a-707d27ff29d6

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m 2 . In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m 2 every 4 weeks. At all cumulative anthracycline doses between 450–500 mg/m 2 or between 500–550 mg/m 2 , the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [ see Warnings and Precautions (5.1) ]. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXILshould be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [ see Warnings and Precautions (5.2) ]. Severe myelosuppression may occur [ see Warnings and Precautions (5.3) ]. Dosage should be reduced in patients with impaired hepatic function [ see Dosage and Administration (2.6) and Use in Specific Populations (8.6) ]. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [ see Dosage and Administration (2.1) ]. WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, SUBSTITUTION See full prescribing information for complete boxed warning. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m 2 . Cardiac toxicity may also occur at lower cumulative doses with mediastinal irradiation or concurrent cardiotoxic agents ( 5.1 ). Acute infusion-related reactions, sometimes reversible upon terminating or slowing infusion, occurred in up to 10% of patients. Serious and sometimes fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications/emergency equipment to treat such reactions should be available for immediate use ( 5.2 ). Severe myelosuppression may occur ( 5.3 ) Reduce dosage in patients with impaired hepatic function ( 2.6 ). Accidental substitution of DOXIL resulted in severe side effects. Do not substitute on mg per mg basis with doxorubicin HCl ( 2.1 ).

5 WARNINGS AND PRECAUTIONS Hand-Foot Syndrome may occur. Dose modification or discontinuation may be required ( 5.4 ) Radiation recall reaction may occur ( 5.5 ) 5.1 Cardiac Toxicity Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m 2 . Lower (400 mg/m 2 ) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m 2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m 2 , or between 500–550 mg/m 2 , the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below. Table 5: Number of Patients With Advanced Breast Cancer DOXIL (n=250) Patients who Developed Cardiotoxicity (LVEF Defined) 10 Cardiotoxicity (With Signs & Symptoms of CHF) 0 Cardiotoxicity (no Signs & Symptoms of CHF) 10 Patients With Signs and Symptoms of CHF Only 2 In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of ≥15% over baseline or a ≥5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL + bortezomib arm (13%) experienced a reduction in LVEF. 5.2 Infusion Reactions Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: 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. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi's sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [ see Dosage and Administration (2) ]. 5.3 Myelosuppression Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC< 4,000 mm 3 ; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm 3 ; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [ see Adverse Reactions (6.2) ]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [ see Dosage and Administrations (2.5) ]. For patients with AIDS-related Kaposi's sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m 2 [ see Adverse Reactions (6.2) ]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [ see Adverse Reactions (6.2) ]. 5.4 Hand-Foot Syndrome (HFS) In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m 2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described above [ see definitions of HFS grades in Dosage and Administration (2.5) ]. Among 705 patients with AIDS-related Kaposi's sarcoma treated with DOXIL at 20 mg/m 2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m 2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [ see Dosage and Administration (2.5) ]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment. 5.5 Radiation Recall Reaction Recall reaction has occurred with DOXIL administration after radiotherapy. 5.6 Fetal Mortality Pregnancy Category D DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [ see Use in Specific Populations (8.1) ]. 5.7 Toxicity Potentiation The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. 5.8 Monitoring: Laboratory Tests Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [ see Warnings and Precautions (5.3) ].

<table width="70%"> <caption>Table 5: Number of Patients With Advanced Breast Cancer</caption> <col align="center" valign="top" width="60%"/> <col align="left" valign="top" width="40%"/> <thead> <tr> <th/> <th>DOXIL (n=250)</th> </tr> </thead> <tbody> <tr> <td>Patients who Developed Cardiotoxicity (LVEF Defined)</td> <td>10</td> </tr> <tr> <td>Cardiotoxicity (With Signs &amp; Symptoms of CHF)</td> <td>0</td> </tr> <tr> <td>Cardiotoxicity (no Signs &amp; Symptoms of CHF)</td> <td>10</td> </tr> <tr> <td>Patients With Signs and Symptoms of CHF Only</td> <td>2</td> </tr> </tbody> </table>

6 ADVERSE REACTIONS Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia and anemia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Ortho Biotech Products, LP at 1-888-227-5624 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Overall Adverse Reactions Profile The following adverse reactions are discussed in more detail in other sections of the labeling. Cardiac Toxicity [ see Warnings and Precautions (5.1) ] Infusion reactions [ see Warnings and Precautions (5.2) ] Myelosuppression [ see Warnings and Precautions (5.3) ] Hand-Foot syndrome [ see Warnings and Precautions (5.4) ] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section 6.2. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma and 318 patients with multiple myeloma [ see Adverse Reactions in Clinical Trials (6.2) ]. 6.2 Adverse Reactions in Clinical Trials 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 following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer and AIDS-Related Kaposi's sarcoma. Patients With Ovarian Cancer The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m 2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 6 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 6: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Patients (n = 239) Topotecan Patients (n = 235) Neutropenia 500 - <1000/mm 3 19 (7.9%) 33 (14.0%) <500/mm 3 10 (4.2%) 146 (62.1%) Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) < 6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 10,000 - <50,000/mm 3 3 (1.3%) 40 (17.0%) <10,000/mm 3 0 (0.0%) 40 (17.0%) Table 7 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 7: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater DOXIL (%) treated (n = 239) Topotecan (%) treated (n =235) All grades Grades 3-4 All grades Grades 3-4 Body as a Whole Asthenia 40.2 7.1 51.5 8.1 Fever 21.3 0.8 30.6 5.5 Mucous Membrane Disorder 14.2 3.8 3.4 0 Back Pain 11.7 1.7 10.2 0.9 Infection 11.7 2.1 6.4 0.9 Headache 10.5 0.8 14.9 0 Digestive Nausea 46.0 5.4 63.0 8.1 Stomatitis 41.4 8.3 15.3 0.4 Vomiting 32.6 7.9 43.8 9.8 Diarrhea 20.9 2.5 34.9 4.2 Anorexia 20.1 2.5 21.7 1.3 Dyspepsia 12.1 0.8 14.0 0 Nervous Dizziness 4.2 0 10.2 0 Respiratory Pharyngitis 15.9 0 17.9 0.4 Dyspnea 15.1 4.1 23.4 4.3 Cough increased 9.6 0 11.5 0 Skin and Appendages Hand-foot syndrome 50.6 23.8 0.9 0 Rash 28.5 4.2 12.3 0.4 Alopecia 19.2 N/A 52.3 N/A The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10% Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi's Sarcoma The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi's sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m 2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m 2 . Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m 2 . Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients' median CD4 count was 21.0 cells/mm 3 , with 50.8% of patients having less than 50 cells/mm 3 . The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm 3 . Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi's sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 8: Hematology Data Reported in Patients With AIDS-Related Kaposi's Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n = 74) Total Patients With AIDS-Related Kaposi's Sarcoma (n = 720) Neutropenia < 1000/mm 3 34 (45.9%) 352 (48.9%) < 500/mm 3 8 (10.8%) 96 (13.3%) Anemia < 10 g/dL 43 (58.1%) 399 (55.4%) < 8 g/dL 12 (16.2%) 131 (18.2%) Thrombocytopenia < 150,000/mm 3 45 (60.8%) 439 (60.9%) < 25,000/mm 3 1 (1.4%) 30 (4.2%) Table 9: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi's Sarcoma Adverse Reactions Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n = 77) Total Patients With AIDS-Related Kaposi's Sarcoma (n = 705) Nausea 14 (18.2%) 119 (16.9%) Asthenia 5 (6.5%) 70 (9.9%) Fever 6 (7.8%) 64 (9.1%) Alopecia 7 (9.1%) 63 (8.9%) Alkaline Phosphatase Increase 1 (1.3%) 55 (7.8%) Vomiting 6 (7.8%) 55 (7.8%) Diarrhea 4 (5.2%) 55 (7.8%) Stomatitis 4 (5.2%) 48 (6.8%) Oral Moniliasis 1 (1.3%) 39 (5.5%) The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi's sarcoma Incidence 1% to 5% Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1% Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma The safety data below are from 318 patients treated with DOXIL (30 mg/m 2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m 2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 10 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 10. Frequency of treatment emergent adverse reactions reported in ≥10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse Reaction DOXIL + bortezomib (n=318) Bortezomib (n=318) Any (%) Grade 3 Grade 4 Any (%) Grade 3 Grade 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0 Infections and infestations Herpes zoster 11 2 0 9 2 0 Herpes simplex 10 0 0 6 1 0 Investigations Weight decreased 12 0 0 4 0 0 Metabolism and Nutritional disorders Anorexia 19 2 0 14 <1 0 Nervous system disorders Peripheral Neuropathy Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. 42 7 <1 45 10 1 Neuralgia 17 3 0 20 4 1 Paraesthesia/dysesthesia 13 <1 0 10 0 0 Respiratory, thoracic and mediastinal disorders Cough 18 0 0 12 0 0 Skin and subcutaneous tissue disorders Rash Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. 22 1 0 18 1 0 Hand-foot syndrome 19 6 0 <1 0 0 6.3 Post Marketing Experience The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: very rare cases of erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis have been reported.

<table ID="Table-6" width="75%"> <caption>Table 6: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer</caption> <col align="left" valign="top" width="34%"/> <col align="center" valign="top" width="33%"/> <col align="center" valign="top" width="33%"/> <thead> <tr> <th/> <th>DOXIL Patients (n = 239)</th> <th>Topotecan Patients (n = 235)</th> </tr> </thead> <tbody> <tr> <td>Neutropenia</td> <td/> <td/> </tr> <tr> <td> 500 - &lt;1000/mm³ </td> <td>19 (7.9%)</td> <td>33 (14.0%)</td> </tr> <tr> <td> &lt;500/mm³ </td> <td>10 (4.2%)</td> <td>146 (62.1%)</td> </tr> <tr> <td>Anemia</td> <td/> <td/> </tr> <tr> <td> 6.5 - &lt;8 g/dL</td> <td>13 (5.4%)</td> <td>59 (25.1%)</td> </tr> <tr> <td> &lt; 6.5 g/dL</td> <td>1 (0.4%)</td> <td>10 (4.3%)</td> </tr> <tr> <td>Thrombocytopenia</td> <td/> <td/> </tr> <tr> <td> 10,000 - &lt;50,000/mm³ </td> <td>3 (1.3%)</td> <td>40 (17.0%)</td> </tr> <tr> <td> &lt;10,000/mm³ </td> <td>0 (0.0%)</td> <td>40 (17.0%)</td> </tr> </tbody> </table>

<table ID="Table-7" width="75%"> <caption>Table 7: Ovarian Cancer Randomized Study</caption> <col align="left" valign="top" width="25%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="19%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="19%"/> <thead> <tr styleCode="Botrule"> <th>Non-Hematologic Adverse Reaction 10% or Greater</th> <th colspan="2">DOXIL (%) treated (n = 239)</th> <th colspan="2">Topotecan (%) treated (n =235)</th> </tr> <tr> <th/> <th>All grades</th> <th>Grades 3-4</th> <th>All grades</th> <th>Grades 3-4</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold italics">Body as a Whole</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Asthenia</td> <td>40.2</td> <td>7.1</td> <td>51.5</td> <td>8.1</td> </tr> <tr> <td> Fever</td> <td>21.3</td> <td>0.8</td> <td>30.6</td> <td>5.5</td> </tr> <tr> <td> Mucous Membrane Disorder</td> <td>14.2</td> <td>3.8</td> <td>3.4</td> <td>0</td> </tr> <tr> <td> Back Pain</td> <td>11.7</td> <td>1.7</td> <td>10.2</td> <td>0.9</td> </tr> <tr> <td> Infection</td> <td>11.7</td> <td>2.1</td> <td>6.4</td> <td>0.9</td> </tr> <tr> <td> Headache</td> <td>10.5</td> <td>0.8</td> <td>14.9</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold italics">Digestive</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Nausea</td> <td>46.0</td> <td>5.4</td> <td>63.0</td> <td>8.1</td> </tr> <tr> <td> Stomatitis</td> <td>41.4</td> <td>8.3</td> <td>15.3</td> <td>0.4</td> </tr> <tr> <td> Vomiting</td> <td>32.6</td> <td>7.9</td> <td>43.8</td> <td>9.8</td> </tr> <tr> <td> Diarrhea</td> <td>20.9</td> <td>2.5</td> <td>34.9</td> <td>4.2</td> </tr> <tr> <td> Anorexia</td> <td>20.1</td> <td>2.5</td> <td>21.7</td> <td>1.3</td> </tr> <tr> <td> Dyspepsia</td> <td>12.1</td> <td>0.8</td> <td>14.0</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold italics">Nervous</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Dizziness</td> <td>4.2</td> <td>0</td> <td>10.2</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold italics">Respiratory</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Pharyngitis</td> <td>15.9</td> <td>0</td> <td>17.9</td> <td>0.4</td> </tr> <tr> <td> Dyspnea</td> <td>15.1</td> <td>4.1</td> <td>23.4</td> <td>4.3</td> </tr> <tr> <td> Cough increased</td> <td>9.6</td> <td>0</td> <td>11.5</td> <td>0</td> </tr> <tr> <td> <content styleCode="bold italics">Skin and Appendages</content> </td> <td/> <td/> <td/> <td/> </tr> <tr> <td> Hand-foot syndrome</td> <td>50.6</td> <td>23.8</td> <td>0.9</td> <td>0</td> </tr> <tr> <td> Rash</td> <td>28.5</td> <td>4.2</td> <td>12.3</td> <td>0.4</td> </tr> <tr> <td> Alopecia</td> <td>19.2</td> <td>N/A</td> <td>52.3</td> <td>N/A</td> </tr> </tbody> </table>

<table width="75%"> <caption>Table 8: Hematology Data Reported in Patients With AIDS-Related Kaposi&apos;s Sarcoma</caption> <col align="left" width="25%"/> <col align="center" width="19%"/> <col align="center" width="19%"/> <col align="center" width="18%"/> <col align="center" width="19%"/> <thead> <tr> <th/> <th colspan="2">Patients With Refractory or Intolerant AIDS-Related Kaposi&apos;s Sarcoma (n = 74)</th> <th colspan="2" valign="top">Total Patients With AIDS-Related Kaposi&apos;s Sarcoma (n = 720)</th> </tr> </thead> <tbody> <tr> <td>Neutropenia</td> <td/> <td/> <td/> <td/> </tr> <tr> <td> &lt; 1000/mm³ </td> <td>34</td> <td>(45.9%)</td> <td>352</td> <td>(48.9%)</td> </tr> <tr> <td> &lt; 500/mm³ </td> <td>8</td> <td>(10.8%)</td> <td>96</td> <td>(13.3%)</td> </tr> <tr> <td>Anemia</td> <td/> <td/> <td/> <td/> </tr> <tr> <td> &lt; 10 g/dL</td> <td>43</td> <td>(58.1%)</td> <td>399</td> <td>(55.4%)</td> </tr> <tr> <td> &lt; 8 g/dL</td> <td>12</td> <td>(16.2%)</td> <td>131</td> <td>(18.2%)</td> </tr> <tr> <td>Thrombocytopenia</td> <td/> <td/> <td/> <td/> </tr> <tr> <td> &lt; 150,000/mm³ </td> <td>45</td> <td>(60.8%)</td> <td>439</td> <td>(60.9%)</td> </tr> <tr> <td> &lt; 25,000/mm³ </td> <td>1</td> <td>(1.4%)</td> <td>30</td> <td>(4.2%)</td> </tr> </tbody> </table>