Doxorubicin hydrochloride liposome injection is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

Doxorubicin hydrochloride liposome injection is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

Doxorubicin hydrochloride liposome injection, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

Do not substitute doxorubicin hydrochloride liposome injection for other doxorubicin hydrochloride products. Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2)].

The recommended dose of doxorubicin hydrochloride liposome injection is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.

The recommended dose of doxorubicin hydrochloride liposome injection is 20 mg/m2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.

The recommended dose of doxorubicin hydrochloride liposome injection is 30 mg/m2 intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer doxorubicin hydrochloride liposome injection after bortezomib on day 4 of each cycle [see Clinical Studies (14.3)].

Do not increase doxorubicin hydrochloride liposome injection after a dose reduction for toxicity.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="98%"> <caption> <span>Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse Reactions </span> </caption> <colgroup> <col width="38.14%"/> <col width="61.86%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Toxicity</span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Dose Adjustment</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Hand-Foot Syndrome (HFS) </span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities</td><td class="Rrule" valign="top"> <ul class="Disc"> <li>If no previous Grade 3 or 4 HFS: no dose adjustment.</li> <li>If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then decrease dose by 25%.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter</td><td class="Rrule" valign="top"> <ul class="Disc"> <li> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0-1.</span> </li> <li>Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks.</li> <li>If resolved to Grade 0-1 within 2 weeks:<ul class="Disc"> <li> <span class="Underline">And</span> no previous Grade 3 or 4 HFS: continue treatment at previous dose.</li> <li> <span class="Underline">And</span> previous Grade 3 or 4 toxicity: decrease dose by 25%.</li> </ul> </li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing</td><td class="Rrule" valign="top"> <ul class="Disc"> <li> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0-1, then </span>decrease dose by 25%.</li> <li>Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization</td><td class="Rrule" valign="top"> <ul class="Disc"> <li> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0-1, </span>then decrease dose by 25%.</li> <li>Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Stomatitis</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 1: Painless ulcers, erythema, or mild soreness</td><td class="Rrule" valign="top"> <ul class="Disc"> <li>If no previous Grade 3 or 4 toxicity: no dose adjustment.</li> <li>If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%.  </li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 2: Painful erythema, edema, or ulcers, but can eat</td><td class="Rrule" valign="top"> <ul class="Disc"> <li> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0-1.</span> </li> <li>Discontinue doxorubicin hydrochloride liposome injection if there is no resolution after 2 weeks.</li> <li>If resolved to Grade 0-1 within 2 weeks:<ul class="Disc"> <li>And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose.</li> <li>And previous Grade 3 or 4 toxicity: decrease dose by 25%.</li> </ul> </li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 3: Painful erythema, edema, or ulcers, and cannot eat</td><td align="justify" class="Rrule" valign="top"> <ul class="Disc"> <li> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0-1. </span> </li> </ul>Decrease dose by 25% and return to original dose interval.<br/> <ul class="Disc"> <li>If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 4: Requires parenteral or enteral support</td><td align="justify" class="Rrule" valign="top"> <ul class="Disc"> <li> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0-1. </span> </li> </ul>Decrease dose by 25% and return to original dose interval.<br/> <ul class="Disc"> <li>If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Neutropenia or Thrombocytopenia </span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 1</td><td align="justify" class="Rrule" valign="top">No dose reduction</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 2</td><td align="justify" class="Rrule" valign="top">Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Grade 3</td><td align="justify" class="Rrule" valign="top">Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Grade 4</td><td align="justify" class="Rrule" valign="top">Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="684.684"> <caption> <span>Table 2: Recommended Dose Modifications of Doxorubicin Hydrochloride Liposome Injection for Toxicity When Administered in Combination With Bortezomib </span> </caption> <colgroup> <col width="50%"/> <col width="50%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Toxicity </span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Doxorubicin Hydrochloride Liposome Injection</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Fever ≥38°C and <br/>ANC &lt;1,000/mm<span class="Sup">3</span></td><td class="Rrule" valign="top"> <ul class="Disc"> <li>Withhold dose for this cycle if before Day 4;</li> <li>Decrease dose by 25%, if after Day 4 of previous cycle.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">On any day of drug administration after Day 1 of each cycle:<br/> <ul class="Disc"> <li>Platelet count &lt;25,000/mm<span class="Sup">3</span> </li> <li>Hemoglobin &lt;8 g/dL</li> <li>ANC &lt;500/mm<span class="Sup">3 </span> </li> </ul> </td><td align="justify" class="Rrule" valign="top"> <ul class="Disc"> <li>Withhold dose for this cycle if before Day 4;</li> <li>Decrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity</li> </ul> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Grade 3 or 4 non-hematologic drug related toxicity</td><td align="justify" class="Rrule" valign="top">Do not dose until recovered to Grade &lt;2, then reduce dose by 25%.</td> </tr> </tbody> </table></div>

For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for doxorubicin hydrochloride liposome injection. Refer to bortezomib manufacturer’s prescribing information.

Preparation Dilute doxorubicin hydrochloride liposome injection doses up to 90 mg in 250 mL of 5% Dextrose Injection, USP prior to administration. Dilute doses exceeding 90 mg in 500 mL of 5% Dextrose Injection, USP prior to administration. Refrigerate diluted doxorubicin hydrochloride liposome injection at 2°C to 8°C (36°F to 46°F) and administer within 24 hours. Administration Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present. Do not use with in-line filters. Administer the first dose of doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour [see Warnings and Precautions (5.2)]. Do not rapidly flush the infusion line. Do not mix doxorubicin hydrochloride liposome injection with other drugs. Management of Suspected Extravasation Discontinue doxorubicin hydrochloride liposome injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If doxorubicin hydrochloride liposome injection comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

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

{ "type": "p", "children": [], "text": "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 a translucent, red liposomal dispersion." }

Doxorubicin hydrochloride liposome injection is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Doxorubicin hydrochloride liposome injection is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions (5.2)].\n" }

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 a clinical study in 250 patients with advanced cancer who were treated with doxorubicin hydrochloride liposome injection, the risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450  mg/m2 to 550 mg/m2. Cardiomyopathy was defined as >20% decrease in resting left ventricular ejection fraction (LVEF) from baseline where LVEF remained in the normal range or a >10% decrease in LVEF from baseline where LVEF was less than the institutional lower limit of normal. Two percent of patients developed signs and symptoms of congestive heart failure without documented evidence of cardiomyopathy.

Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. Administer doxorubicin hydrochloride liposome injection to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Of 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle 1 and none during subsequent cycles. Across multiple studies of doxorubicin hydrochloride liposome injection monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions. The majority of infusion-related events occurred during the first infusion.

Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of doxorubicin hydrochloride liposome injection. Initiate doxorubicin hydrochloride liposome injection infusions at a rate of 1 mg/min and increase rate as tolerated [see Dosage and Administration (2.6)]. Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions.

In Trial 4, the incidence of HFS was 51% of patients in the doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of doxorubicin hydrochloride liposome injection in 4.2% of patients. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. Delay doxorubicin hydrochloride liposome injection for the first episode of Grade 2 or greater HFS [see Dosage and Administration (2.5)]. Discontinue doxorubicin hydrochloride liposome injection if HFS is severe and debilitating.

Secondary oral cancers, primarily squamous cell carcinoma, have been reported from postmarketing experience in patients with long-term (more than one year) exposure to doxorubicin hydrochloride liposome injection. These malignancies were diagnosed both during treatment with doxorubicin hydrochloride liposome injection and up to 6 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 a role in the development of oral secondary malignancies with long-term use.

Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. At doses approximately 0.12 times the recommended clinical dose, doxorubicin hydrochloride liposome injection was embryotoxic and abortifacient in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.1, 8.3)].

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

The safety data reflect exposure to doxorubicin hydrochloride liposome injection in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma, and 318 patients with multiple myeloma. The most common adverse reactions (>20%) observed with doxorubicin hydrochloride liposome injection are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.

The following tables present adverse reactions from clinical trials of single-agent doxorubicin hydrochloride liposome injection in ovarian cancer and AIDS-Related Kaposi’s sarcoma.

Patients With Ovarian Cancer The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection 50 mg/m2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received doxorubicin hydrochloride liposome injection for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other. Table 3 presents the hematologic adverse reactions from Trial 4.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 3: Hematologic Adverse Reactions in Trial 4 </span> </caption> <tbody class="Headless"> <tr class="Botrule First First"> <td class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Doxorubicin Hydrochloride Liposome Injection Patients<br/>(n=239)</td><td align="center" class="Rrule" valign="top">Topotecan<br/> Patients<br/> <br/>(n=235)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Neutropenia<br/>500 - &lt;1,000/mm<span class="Sup">3</span> <br/>&lt;500/mm<span class="Sup">3</span></td><td align="center" class="Rrule" valign="top"> <br/>8 %<br/>4.2%</td><td align="center" class="Rrule" valign="top"> <br/>14%<br/>62%</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anemia<br/>6.5 - &lt;8 g/dL<br/>&lt; 6.5 g/dL</td><td align="center" class="Rrule" valign="top"> <br/>5 %<br/>0.4%</td><td align="center" class="Rrule" valign="top"> <br/>25%<br/>4.3%</td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Thrombocytopenia<br/>10,000 - &lt;50,000/mm<span class="Sup">3</span> <br/>&lt;10,000/mm<span class="Sup">3</span></td><td align="center" class="Rrule" valign="top"> <br/>1.3%<br/>0%</td><td align="center" class="Rrule" valign="top"> <br/>17%<br/>17%</td> </tr> </tbody> </table></div>

Table 4 presents the non-hematologic adverse reactions from Trial 4.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 4: Non-Hematologic Adverse Reactions in Trial 4 </span> </caption> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top">Non-Hematologic Adverse Reaction 10% or Greater</td><td align="center" class="Rrule" colspan="2" valign="top">Doxorubicin Hydrochloride Liposome Injection (%) treated (n=239)</td><td align="center" class="Rrule" colspan="2" valign="top">Topotecan (%) treated (n=235)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">All grades</td><td align="center" class="Rrule" valign="top">Grades 3-4</td><td align="center" class="Rrule" valign="top">All grades</td><td align="center" class="Rrule" valign="top">Grades 3-4</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">Body as a Whole</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Asthenia</td><td align="center" class="Rrule" valign="top">40</td><td align="center" class="Rrule" valign="top">7</td><td align="center" class="Rrule" valign="top">52</td><td align="center" class="Rrule" valign="top">8</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Fever</td><td align="center" class="Rrule" valign="top">21</td><td align="center" class="Rrule" valign="top">0.8</td><td align="center" class="Rrule" valign="top">31</td><td align="center" class="Rrule" valign="top">6</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mucous Membrane Disorder</td><td align="center" class="Rrule" valign="top">14</td><td align="center" class="Rrule" valign="top">3.8</td><td align="center" class="Rrule" valign="top">3.4</td><td align="center" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Back Pain</td><td align="center" class="Rrule" valign="top">12</td><td align="center" class="Rrule" valign="top">1.7</td><td align="center" class="Rrule" valign="top">10</td><td align="center" class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Infection</td><td align="center" class="Rrule" valign="top">12</td><td align="center" class="Rrule" valign="top">2.1</td><td align="center" class="Rrule" valign="top">6</td><td align="center" class="Rrule" valign="top">0.9</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Headache</td><td align="center" class="Rrule" valign="top">11</td><td align="center" class="Rrule" valign="top">0.8</td><td align="center" class="Rrule" valign="top">15</td><td align="center" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">Digestive</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Nausea</td><td align="center" class="Rrule" valign="top">46</td><td align="center" class="Rrule" valign="top">5</td><td align="center" class="Rrule" valign="top">63</td><td align="center" class="Rrule" valign="top">8</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Stomatitis</td><td align="center" class="Rrule" valign="top">41</td><td align="center" class="Rrule" valign="top">8</td><td align="center" class="Rrule" valign="top">15</td><td align="center" class="Rrule" valign="top">0.4</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Vomiting</td><td align="center" class="Rrule" valign="top">33</td><td align="center" class="Rrule" valign="top">8</td><td align="center" class="Rrule" valign="top">44</td><td align="center" class="Rrule" valign="top">10</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Diarrhea</td><td align="center" class="Rrule" valign="top">21</td><td align="center" class="Rrule" valign="top">2.5</td><td align="center" class="Rrule" valign="top">35</td><td align="center" class="Rrule" valign="top">4.2</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Anorexia</td><td align="center" class="Rrule" valign="top">20</td><td align="center" class="Rrule" valign="top">2.5</td><td align="center" class="Rrule" valign="top">22</td><td align="center" class="Rrule" valign="top">1.3</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dyspepsia</td><td align="center" class="Rrule" valign="top">12</td><td align="center" class="Rrule" valign="top">0.8</td><td align="center" class="Rrule" valign="top">14</td><td align="center" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">Nervous</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dizziness</td><td align="center" class="Rrule" valign="top">4.2</td><td align="center" class="Rrule" valign="top">0</td><td align="center" class="Rrule" valign="top">10</td><td align="center" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">Respiratory</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Pharyngitis</td><td align="center" class="Rrule" valign="top">16</td><td align="center" class="Rrule" valign="top">0</td><td align="center" class="Rrule" valign="top">18</td><td align="center" class="Rrule" valign="top">0.4</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Dyspnea</td><td align="center" class="Rrule" valign="top">15</td><td align="center" class="Rrule" valign="top">4.1</td><td align="center" class="Rrule" valign="top">23</td><td align="center" class="Rrule" valign="top">4.3</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Cough increased</td><td align="center" class="Rrule" valign="top">10</td><td align="center" class="Rrule" valign="top">0</td><td align="center" class="Rrule" valign="top">12</td><td align="center" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold"><span class="Italics">Skin and Appendages</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hand-foot syndrome</td><td align="center" class="Rrule" valign="top">51</td><td align="center" class="Rrule" valign="top">24</td><td align="center" class="Rrule" valign="top">0.9</td><td align="center" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Rash</td><td align="center" class="Rrule" valign="top">29</td><td align="center" class="Rrule" valign="top">4.2</td><td align="center" class="Rrule" valign="top">12</td><td align="center" class="Rrule" valign="top">0.4</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Alopecia</td><td align="center" class="Rrule" valign="top">19</td><td align="center" class="Rrule" valign="top">N/A</td><td align="center" class="Rrule" valign="top">52</td><td align="center" class="Rrule" valign="top">N/A</td> </tr> </tbody> </table></div>

The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4). Incidence 1% to 10% Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hematologic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi's Sarcoma The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma (KS) enrolled in four open-label, uncontrolled trials of doxorubicin hydrochloride liposome injection administered at doses ranging from 10 to 40 mg/m2 every 2 to 3 weeks. Demographics of the population were: median age 38.7 years (range 24 to 70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of doxorubicin hydrochloride liposome injection every 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/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 Kaposi's sarcoma and included myelosuppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Tables 5 and 6 summarize adverse reactions reported in patients treated with doxorubicin hydrochloride liposome injection for AIDS-related Kaposi's sarcoma in a pooled analysis of the four trials.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposi’s Sarcoma </span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>This includes only subjects with AIDS-KS who had available data from the 4 pooled trials.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top"></td><td class="Rrule" valign="top"><span class="Bold"> Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n=74<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a>)</span></td><td class="Rrule" valign="middle"><span class="Bold"> Total Patients With AIDS-Related Kaposi’s Sarcoma (n=720<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a>)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top">Neutropenia</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">&lt; 1,000/mm<span class="Sup">3</span></td><td align="center" class="Rrule" valign="top">46%</td><td align="center" class="Rrule" valign="top">49%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">&lt; 500/mm<span class="Sup">3</span></td><td align="center" class="Rrule" valign="top">11%</td><td align="center" class="Rrule" valign="top">13%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top">Anemia</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">&lt; 10 g/dL</td><td align="center" class="Rrule" valign="top">58%</td><td align="center" class="Rrule" valign="top">55%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">&lt; 8 g/dL</td><td align="center" class="Rrule" valign="top">16%</td><td align="center" class="Rrule" valign="top">18%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top">Thrombocytopenia</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">&lt; 150,000/mm<span class="Sup">3</span></td><td align="center" class="Rrule" valign="top">61%</td><td align="center" class="Rrule" valign="top">61%</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">&lt; 25,000/mm<span class="Sup">3</span></td><td align="center" class="Rrule" valign="top">1.4%</td><td align="center" class="Rrule" valign="top">4.2%</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 6: Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi’s Sarcoma </span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold"> Adverse Reactions </span></td><td class="Rrule" valign="top"><span class="Bold">Patients With Refractory or </span> <br/> <span class="Bold">Intolerant AIDS-Related Kaposi’s Sarcoma (n=77<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a>) </span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Total Patients With AIDS-Related Kaposi’s Sarcoma (n=705<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a>) </span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Nausea</td><td align="center" class="Rrule" valign="top">18%</td><td align="center" class="Rrule" valign="top">17%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Asthenia</td><td align="center" class="Rrule" valign="top">7%</td><td align="center" class="Rrule" valign="top">10%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Fever</td><td align="center" class="Rrule" valign="top">8%</td><td align="center" class="Rrule" valign="top">9%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Alopecia</td><td align="center" class="Rrule" valign="top">9%</td><td align="center" class="Rrule" valign="top">9%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Alkaline Phosphatase Increase</td><td align="center" class="Rrule" valign="top">1.3%</td><td align="center" class="Rrule" valign="top">8%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Vomiting</td><td align="center" class="Rrule" valign="top">8%</td><td align="center" class="Rrule" valign="top">8%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Diarrhea</td><td align="center" class="Rrule" valign="top">5%</td><td align="center" class="Rrule" valign="top">8%</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Stomatitis</td><td align="center" class="Rrule" valign="top">5%</td><td align="center" class="Rrule" valign="top">7%</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Oral Moniliasis</td><td align="center" class="Rrule" valign="top">1.3%</td><td align="center" class="Rrule" valign="top">6%</td> </tr> </tbody> </table></div>

The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi's sarcoma. Incidence 1% to 5% Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1% Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma The safety data described are from 318 patients treated with doxorubicin hydrochloride liposome injection (30 mg/m2) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the doxorubicin hydrochloride liposome injection + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in ≥10% Patients Treated for Multiple Myeloma With Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib </span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"><span class="Bold">Adverse Reaction</span></td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">D</span><span class="Bold">oxorubicin Hydrochloride Liposome Injection</span><span class="Bold"> + Bortezomib (n=318)</span></td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Bortezomib (n=318)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold"> Any (%)</span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Grade 3-4</span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Any (%)</span></td><td align="justify" class="Rrule" valign="top"><span class="Bold">Grade 3-4</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Blood and lymphatic system disorders </span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Neutropenia</td><td align="justify" class="Rrule" valign="top">36</td><td align="justify" class="Rrule" valign="top">32</td><td align="justify" class="Rrule" valign="top">22</td><td align="justify" class="Rrule" valign="top">16</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Thrombocytopenia</td><td align="justify" class="Rrule" valign="top">33</td><td align="justify" class="Rrule" valign="top">24</td><td align="justify" class="Rrule" valign="top">28</td><td align="justify" class="Rrule" valign="top">17</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Anemia</td><td align="justify" class="Rrule" valign="top">25</td><td align="justify" class="Rrule" valign="top">9</td><td align="justify" class="Rrule" valign="top">21</td><td align="justify" class="Rrule" valign="top">9</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">General disorders and administration site conditions </span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Fatigue</td><td align="justify" class="Rrule" valign="top">36</td><td align="justify" class="Rrule" valign="top">7</td><td align="justify" class="Rrule" valign="top">28</td><td align="justify" class="Rrule" valign="top">3</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Pyrexia</td><td align="justify" class="Rrule" valign="top">31</td><td align="justify" class="Rrule" valign="top">1</td><td align="justify" class="Rrule" valign="top">22</td><td align="justify" class="Rrule" valign="top">1</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Asthenia</td><td align="justify" class="Rrule" valign="top">22</td><td align="justify" class="Rrule" valign="top">6</td><td align="justify" class="Rrule" valign="top">18</td><td align="justify" class="Rrule" valign="top">4</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Gastrointestinal disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Nausea</td><td align="justify" class="Rrule" valign="top">48</td><td align="justify" class="Rrule" valign="top">3</td><td align="justify" class="Rrule" valign="top">40</td><td align="justify" class="Rrule" valign="top">1</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Diarrhea</td><td align="justify" class="Rrule" valign="top">46</td><td align="justify" class="Rrule" valign="top">7</td><td align="justify" class="Rrule" valign="top">39</td><td align="justify" class="Rrule" valign="top">5</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Vomiting</td><td align="justify" class="Rrule" valign="top">32</td><td align="justify" class="Rrule" valign="top">4</td><td align="justify" class="Rrule" valign="top">22</td><td align="justify" class="Rrule" valign="top">1</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Constipation</td><td align="justify" class="Rrule" valign="top">31</td><td align="justify" class="Rrule" valign="top">1</td><td align="justify" class="Rrule" valign="top">31</td><td align="justify" class="Rrule" valign="top">1</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Mucositis/Stomatitis</td><td align="justify" class="Rrule" valign="top">20</td><td align="justify" class="Rrule" valign="top">2</td><td align="justify" class="Rrule" valign="top">5</td><td align="justify" class="Rrule" valign="top">&lt;1</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Abdominal pain</td><td align="justify" class="Rrule" valign="top">11</td><td align="justify" class="Rrule" valign="top">1</td><td align="justify" class="Rrule" valign="top">8</td><td align="justify" class="Rrule" valign="top">1</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Infections and infestations</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Herpes zoster</td><td align="justify" class="Rrule" valign="top">11</td><td align="justify" class="Rrule" valign="top">2</td><td align="justify" class="Rrule" valign="top">9</td><td align="justify" class="Rrule" valign="top">2</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Herpes simplex</td><td align="justify" class="Rrule" valign="top">10</td><td align="justify" class="Rrule" valign="top">0</td><td align="justify" class="Rrule" valign="top">6</td><td align="justify" class="Rrule" valign="top">1</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Investigations</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Weight decreased</td><td align="justify" class="Rrule" valign="top">12</td><td align="justify" class="Rrule" valign="top">0</td><td align="justify" class="Rrule" valign="top">4</td><td align="justify" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Metabolism and Nutritional </span> <br/> <span class="Bold">disorders </span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anorexia</td><td align="justify" class="Rrule" valign="top">19</td><td align="justify" class="Rrule" valign="top">2</td><td align="justify" class="Rrule" valign="top">14</td><td align="justify" class="Rrule" valign="top">&lt;1</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Nervous system disorders </span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Peripheral Neuropathy<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></td><td align="justify" class="Rrule" valign="top">42</td><td align="justify" class="Rrule" valign="top">7</td><td align="justify" class="Rrule" valign="top">45</td><td align="justify" class="Rrule" valign="top">11</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Neuralgia</td><td align="justify" class="Rrule" valign="top">17</td><td align="justify" class="Rrule" valign="top">3</td><td align="justify" class="Rrule" valign="top">20</td><td align="justify" class="Rrule" valign="top">4</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Paresthesia/dysesthesia</td><td align="justify" class="Rrule" valign="top">13</td><td align="justify" class="Rrule" valign="top">&lt;1</td><td align="justify" class="Rrule" valign="top">10</td><td align="justify" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Respiratory, thoracic and</span> <br/> <span class="Bold"> mediastinal disorders</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Cough</td><td align="justify" class="Rrule" valign="top">18</td><td align="justify" class="Rrule" valign="top">0</td><td align="justify" class="Rrule" valign="top">12</td><td align="justify" class="Rrule" valign="top">0</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="top"><span class="Bold">Skin and subcutaneous </span> <br/> <span class="Bold">tissue disorders </span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Rash<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></td><td align="justify" class="Rrule" valign="top">22</td><td align="justify" class="Rrule" valign="top">1</td><td align="justify" class="Rrule" valign="top">18</td><td align="justify" class="Rrule" valign="top">1</td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Hand-foot syndrome</td><td align="justify" class="Rrule" valign="top">19</td><td align="justify" class="Rrule" valign="top">6</td><td align="justify" class="Rrule" valign="top">&lt;1</td><td align="justify" class="Rrule" valign="top">0</td> </tr> </tbody> </table></div>

The following additional adverse reactions have been identified during post approval use of doxorubicin hydrochloride liposome injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: muscle spasms Respiratory, Thoracic and Mediastinal Disorders: pulmonary embolism (in some cases fatal) Hematologic Disorders: Secondary acute myelogenous leukemia Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichenoid keratosis Secondary Oral Neoplasms: [see Warnings and Precautions (5.4)]

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

{ "type": "p", "children": [], "text": " No formal drug interaction studies have been conducted with doxorubicin hydrochloride liposome injection." }

Risk Summary

Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. In animal reproduction studies, doxorubicin hydrochloride liposome injection was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data). Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Advise pregnant women of the potential risk to a 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Doxorubicin hydrochloride liposome injection was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m2 human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

Risk Summary It is not known whether doxorubicin hydrochloride is present in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating doxorubicin hydrochloride liposome injection.

Contraception Females Doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection. Males Doxorubicin hydrochloride liposome injection may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection [see Non-clinical Toxicology (13.1)]. Infertility Females In females of reproductive potential, doxorubicin hydrochloride liposome injection may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin hydrochloride. Recovery of menses and ovulation is related to age at treatment. Males Doxorubicin hydrochloride liposome injection may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Non-clinical Toxicology (13.1)].

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

Clinical studies of doxorubicin hydrochloride liposome injection conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi’s sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.

In Trial 6, of 318 patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

The pharmacokinetics of doxorubicin hydrochloride liposome injection has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce doxorubicin hydrochloride liposome injection for serum bilirubin of 1.2 mg/dL or higher.

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

{ "type": "p", "children": [], "text": "Acute overdosage with doxorubicin hydrochloride causes increased risk of severe mucositis, leukopenia, and thrombocytopenia." }

The active ingredient in doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in pegylated liposomes for intravenous use. The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-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 C27H29NO11• HCl; its molecular weight is 579.99. The structural formula is:

{ "type": "p", "children": [], "text": "The active ingredient in doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in pegylated liposomes for intravenous use. The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-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 C27H29NO11• HCl; its molecular weight is 579.99. \n The structural formula is:" }

Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion. Each single-dose vial contains 20 mg or 50 mg doxorubicin hydrochloride, USP at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin) and a pH of 6.5. The pegylated liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine, 1.50 mg as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose, 100 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the pegylated liposomes.

{ "type": "p", "children": [], "text": "Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion. Each single-dose vial contains 20 mg or 50 mg doxorubicin hydrochloride, USP at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin) and a pH of 6.5. The pegylated liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine, 1.50 mg as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose, 100 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the pegylated liposomes." }

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

The pharmacokinetic parameters for total doxorubicin following a single dose of doxorubicin hydrochloride liposome injection infused over 30 minutes are presented in Table 8.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 8: Pharmacokinetic Parameters of Total Doxorubicin from Doxorubicin Hydrochloride Liposome Injection in Patients With AIDS-Related Kaposi’s Sarcoma </span> </caption> <tbody class="Headless"> <tr class="Botrule First First"> <td class="Lrule Rrule" rowspan="2" valign="top">Parameter (units)</td><td align="center" class="Rrule" colspan="2" valign="top">Dose</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">10 mg/m<span class="Sup">2</span></td><td align="center" class="Rrule" valign="top">20 mg/m<span class="Sup">2</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Peak Plasma Concentration (mcg/mL) </td><td align="center" class="Rrule" valign="top">4.12 ± 0.215</td><td align="center" class="Rrule" valign="top">8.34 ± 0.49</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Plasma Clearance (L/h/m<span class="Sup">2</span>) </td><td align="center" class="Rrule" valign="top">0.056 ± 0.01</td><td align="center" class="Rrule" valign="top">0.041 ± 0.004</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Steady State Volume of Distribution (L/m<span class="Sup">2</span>) </td><td align="center" class="Rrule" valign="top">2.83 ± 0.145</td><td align="center" class="Rrule" valign="top">2.72 ± 0.12</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">AUC (mcg/mL•h) </td><td align="center" class="Rrule" valign="top">277 ± 32.9</td><td align="center" class="Rrule" valign="top">590 ± 58.7</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">First Phase (λ<span class="Sub">1</span>) Half-Life (h) </td><td align="center" class="Rrule" valign="top">4.7 ± 1.1</td><td align="center" class="Rrule" valign="top">5.2 ± 1.4</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Second Phase (λ<span class="Sub">1</span>) Half-Life (h) </td><td align="center" class="Rrule" valign="top">52.3 ± 5.6</td><td align="center" class="Rrule" valign="top">55 ± 4.8</td> </tr> </tbody> </table></div>

N=23

Mean ± Standard Error

Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Relative to doxorubicin hydrochloride liposome injection doses at or below 20 mg/m2, the pharmacokinetics of total doxorubicin following a 50 mg/m2 doxorubicin hydrochloride liposome injection dose are nonlinear. At this dose, the elimination half-life of doxorubicin hydrochloride liposome injection is longer and the clearance lower compared to a 20 mg/m2 dose.

Distribution

Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5 to 10% free doxorubicin) remains liposome-encapsulated during circulation.

In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1,100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

Metabolism

Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m2 doxorubicin hydrochloride liposome injection.

Elimination

The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0.041 L/h/m2 at a dose of 20 mg/m2. Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m2.

Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. Doxorubicin hydrochloride liposome injection resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m2 human dose on a 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 a mg/m2 basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m2 human dose on a mg/m2 basis).

Doxorubicin hydrochloride liposome injection was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within 6 months of completing treatment. Patients received doxorubicin hydrochloride liposome injection at 50 mg/m2 every 3 or 4 weeks for 3 to 6+ cycles in the absence of dose-limiting toxicity or disease progression. The median age at diagnosis ranged from 52 to 64 years in the 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%). The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel- and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression. The response rates for the individual single arm trials are given in Table 9 below.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 9: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials </span> </caption> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Trial 1 (U.S.) <br/>N=27</td><td align="center" class="Rrule" valign="top"> <br/>Trial 2 (U.S.)<br/>N=82</td><td align="center" class="Rrule" valign="top"> <br/>Trial 3 (non-U.S.)<br/>N=36</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Response Rate</td><td align="justify" class="Rrule" valign="top">22.2%</td><td align="justify" class="Rrule" valign="top">17.1%</td><td align="justify" class="Rrule" valign="top">0%</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">95% Confidence Interval</td><td align="justify" class="Rrule" valign="top">8.6% to 42.3%</td><td align="justify" class="Rrule" valign="top">9.7% to 27%</td><td align="justify" class="Rrule" valign="top">0% to 9.7%</td> </tr> </tbody> </table></div>

In a pooled analysis of Trials 1-3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% 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, a randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either doxorubicin hydrochloride liposome injection 50 mg/m2 every 4 weeks (n=239) or topotecan 1.5 mg/m2 daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 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.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 10: Results of Efficacy Analyses<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Analysis based on investigators’ strata for protocol defined ITT population.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">†</a> </dt> <dd>Kaplan-Meier estimates.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">‡</a> </dt> <dd>p-value is based on the stratified log-rank test.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">§</a> </dt> <dd>Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for doxorubicin hydrochloride liposome injection.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">¶</a> </dt> <dd>p-value not adjusted for multiple comparisons.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"></td><td align="center" class="Rrule" colspan="3" valign="top">Protocol Defined ITT Population</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top">Doxorubicin Hydrochloride Liposome Injection<br/>(n=239)</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">Topotecan<br/>(n=235)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">TTP </span>(Protocol Specified Primary Endpoint)</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median (Months)<a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a></td><td align="center" class="Rrule" valign="top">4.1</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">4.2</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">p-value<a class="Sup" href="#footnote-9" name="footnote-reference-9">‡</a></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">0.62</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hazard Ratio<a class="Sup" href="#footnote-10" name="footnote-reference-10">§</a></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">0.96</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">95% CI for Hazard Ratio</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">(0.76, 1.2)</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Overall Survival </span></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median (Months)<a class="Sup" href="#footnote-7">*</a></td><td align="center" class="Rrule" valign="top">14.4</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">13.7</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">p-value<a class="Sup" href="#footnote-11" name="footnote-reference-11">¶</a></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">0.05</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hazard Ratio<a class="Sup" href="#footnote-10">§</a></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">0.82</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">95% CI for Hazard Ratio</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">(0.68, 1)</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Response Rate </span></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Overall Response n (%)</td><td align="center" class="Rrule" valign="top">47 (19.7)</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">40 (17)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Complete Response n (%)</td><td align="center" class="Rrule" valign="top">9 (3.8)</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">11 (4.7)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Partial Response n (%)</td><td align="center" class="Rrule" valign="top">38 (15.9)</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">29 (12.3)</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Median Duration of Response (Months)<a class="Sup" href="#footnote-7">*</a></td><td align="center" class="Rrule" valign="top">6.9</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">5.9</td> </tr> </tbody> </table></div>

Doxorubicin hydrochloride liposome injection was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m2 every 3 weeks, until disease progression or unacceptable toxicity (Trial 5).

Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride.

The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of doxorubicin hydrochloride liposome injection was 154 mg/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.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="711.8825"> <caption> <span>Table 11: Response in Patients with Refractory<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> AIDS-Related Kaposi’s Sarcoma </span> </caption> <colgroup> <col width="33.3302195235871%"/> <col width="33.3302195235871%"/> <col width="33.3395609528258%"/> </colgroup> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>There were no complete responses in this population.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="center" class="Lrule Rrule" valign="middle">Investigator Assessment</td><td align="center" class="Rrule" valign="middle">All Evaluable Patients (n=34)</td><td align="center" class="Rrule" valign="middle">Evaluable Patients Who Received Prior Doxorubicin (n=20)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Response<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Partial (PR)</td><td align="center" class="Rrule" valign="top">27 %</td><td align="center" class="Rrule" valign="top">30 %</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Stable</td><td align="center" class="Rrule" valign="top">29 %</td><td align="center" class="Rrule" valign="top">40 %</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Progression</td><td align="center" class="Rrule" valign="top">44 %</td><td align="center" class="Rrule" valign="top">30 %</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Duration of PR (Days)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median</td><td align="center" class="Rrule" valign="top">73</td><td align="center" class="Rrule" valign="top">89</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Range</td><td align="center" class="Rrule" valign="top">42+ to 210+</td><td align="center" class="Rrule" valign="top">42+ to 210+</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Time to PR (Days)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median</td><td align="center" class="Rrule" valign="top">43</td><td align="center" class="Rrule" valign="top">53</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Range</td><td align="center" class="Rrule" valign="top">15 to 133</td><td align="center" class="Rrule" valign="top">15 to 109</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Indicator Lesion Assessment</td><td align="center" class="Rrule" valign="middle">All Evaluable Patients (n=42)</td><td align="center" class="Rrule" valign="middle">Evaluable Patients Who Received Prior Doxorubicin (n=23)</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Response<a class="Sup" href="#footnote-13">†</a></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Partial (PR)</td><td align="center" class="Rrule" valign="top">48 %</td><td align="center" class="Rrule" valign="top">52 %</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Stable</td><td align="center" class="Rrule" valign="top">26 %</td><td align="center" class="Rrule" valign="top">30 %</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Progression</td><td align="center" class="Rrule" valign="top">26 %</td><td align="center" class="Rrule" valign="top">17 %</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Duration of PR (Days)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median</td><td align="center" class="Rrule" valign="top">71</td><td align="center" class="Rrule" valign="top">79</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Range</td><td align="center" class="Rrule" valign="top">22+ to 210+</td><td align="center" class="Rrule" valign="top">35+ to 210+</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="top">Time to PR (Days)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median</td><td align="center" class="Rrule" valign="top">22</td><td align="center" class="Rrule" valign="top">48</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Range</td><td align="center" class="Rrule" valign="top">15 to 109</td><td align="center" class="Rrule" valign="top">15 to 109</td> </tr> </tbody> </table></div>

Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent doxorubicin hydrochloride liposome injection and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses.

The efficacy of doxorubicin hydrochloride liposome injection in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either doxorubicin hydrochloride liposome injection (30 mg/m2) administered IV on day 4 following bortezomib (1.3 mg/m2 IV on days 1, 4, 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1 to 18). The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12).

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 12: Summary of Baseline Patient and Disease Characteristics </span> </caption> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Patient Characteristics</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">D</span><span class="Bold">oxorubicin Hydrochloride Liposome Injection + Bortezomib</span> <br/> <span class="Bold">n=324</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Bortezomib</span> <br/> <span class="Bold">n=322</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median age in years (range)</td><td align="center" class="Rrule" valign="top">61 (28, 85)</td><td align="center" class="Rrule" valign="top">62 (34, 88)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">% Male/female</td><td align="center" class="Rrule" valign="top">58 / 42</td><td align="center" class="Rrule" valign="top">54 / 46</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">% Caucasian/Black/other</td><td align="center" class="Rrule" valign="top">90 / 6/ 4</td><td align="center" class="Rrule" valign="top">94 / 4 / 2</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Disease Characteristics </span></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">% with IgG/IgA/Light chain</td><td align="center" class="Rrule" valign="top">57 / 27 / 12</td><td align="center" class="Rrule" valign="top">62 / 24 /11</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">% β<span class="Sub">2</span> -microglobulin group</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">≤2.5 mg/L</td><td align="center" class="Rrule" valign="top">14</td><td align="center" class="Rrule" valign="top">14</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">&gt;2.5 mg/L and ≤5.5 mg/L</td><td align="center" class="Rrule" valign="top">56</td><td align="center" class="Rrule" valign="top">55</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="top">&gt;5.5 mg/L</td><td align="center" class="Rrule" valign="top">30</td><td align="center" class="Rrule" valign="top">31</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Serum M-protein (g/dL): Median (Range) </span></td><td align="center" class="Rrule" valign="top">2.5 (0 to 10)</td><td align="center" class="Rrule" valign="top">2.7 (0 to 10)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Urine M-protein (mg/24 hours): Median (Range) </span></td><td align="center" class="Rrule" valign="top">107 (0 to 24,883)</td><td align="center" class="Rrule" valign="top">66 (0 to 39,657)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Median Months Since Diagnosis </span></td><td align="center" class="Rrule" valign="top">35.2</td><td align="center" class="Rrule" valign="top">37.5</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">% Prior Therapy </span></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">One</td><td align="center" class="Rrule" valign="top">34</td><td align="center" class="Rrule" valign="top">34</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">More than one</td><td align="center" class="Rrule" valign="top">66</td><td align="center" class="Rrule" valign="top">66</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Prior Systemic Therapies for Multiple Myeloma</span></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Corticosteroid (%)</td><td align="center" class="Rrule" valign="top">99</td><td align="center" class="Rrule" valign="top">&gt;99</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Anthracyclines</td><td align="center" class="Rrule" valign="top">68</td><td align="center" class="Rrule" valign="top">67</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Alkylating agent (%)</td><td align="center" class="Rrule" valign="top">92</td><td align="center" class="Rrule" valign="top">90</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Thalidomide/lenalidomide (%)</td><td align="center" class="Rrule" valign="top">40</td><td align="center" class="Rrule" valign="top">43</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">Stem cell transplantation (%)</td><td align="center" class="Rrule" valign="top">57</td><td align="center" class="Rrule" valign="top">54</td> </tr> </tbody> </table></div>

The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the doxorubicin hydrochloride liposome injection + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1.

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma </span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>Kaplan  Meier estimate.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio &lt; 1 indicates an advantage for doxorubicin hydrochloride liposome injection+bortezomib.</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">‡</a> </dt> <dd>Stratified log-rank test.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">§</a> </dt> <dd>RR as per EBMT criteria.</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">¶</a> </dt> <dd>Cochran-Mantel-Haenszel test adjusted for the stratification factors.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Endpoint</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">D</span><span class="Bold">oxorubicin Hydrochloride Liposome Injection + Bortezomib</span> <br/> <span class="Bold">n=324</span></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"><span class="Bold">Bortezomib</span> <br/> <span class="Bold">n=322</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Time to Progression<a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a></span></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Progression or death due to progression (n)</td><td align="center" class="Rrule" valign="top"> 99</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top"> 150</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Censored (n)</td><td align="center" class="Rrule" valign="top">225</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">172</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Median in days (months)</td><td align="center" class="Rrule" valign="top">282 (9.3)</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">197 (6.5)</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">95% CI</td><td align="center" class="Rrule" valign="top">250;338</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">170;217</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hazard ratio<a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">0.55</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">95% CI</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">(0.43, 0.71)</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">p-value<a class="Sup" href="#footnote-16" name="footnote-reference-16">‡</a></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">&lt;0.001</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold">Response (n)<a class="Sup" href="#footnote-17" name="footnote-reference-17">§</a></span></td><td align="center" class="Rrule" valign="top">303</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">310</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">% Complete Response (CR)</td><td align="center" class="Rrule" valign="top">5</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">3</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">% Partial Response (PR)</td><td align="center" class="Rrule" valign="top">43</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">40</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">% CR + PR</td><td align="center" class="Rrule" valign="top">48</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">43</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">p-value<a class="Sup" href="#footnote-18" name="footnote-reference-18">¶</a></td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">0.25</td><td align="center" class="Rrule" valign="top"></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"><span class="Bold"> Median Duration of Response (months)</span></td><td align="center" class="Rrule" valign="top">10.2</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">7</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">95% CI</td><td align="center" class="Rrule" valign="top">(10.2;12.9)</td><td align="center" class="Rrule" valign="top"></td><td align="center" class="Rrule" valign="top">(5.9;8.3)</td> </tr> </tbody> </table></div>

Figure 1-Time to Progression Kaplan-Meier Curve At the final analysis of survival, 78% of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for doxorubicin hydrochloride liposome injection + bortezomib vs. bortezomib= 0.96 (95% CI 0.8, 1.14)]. Seventy-eight percent of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy.

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

{ "type": "p", "children": [], "text": "1. “Hazardous Drugs”, OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html" }

Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion in 10 mL or 25 mL glass, single-dose vials. The following individually cartoned vials are available:

{ "type": "p", "children": [], "text": "Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion in 10 mL or 25 mL glass, single-dose vials.\n The following individually cartoned vials are available:" }

<div class="scrollingtable"><table cellpadding="0" cellspacing="0"> <caption> <span>Table 14 </span> </caption> <tbody class="Headless"> <tr class="Botrule First First"> <td align="justify" class="Lrule Rrule" valign="top">mg in vial</td><td align="justify" class="Rrule" valign="top">fill volume</td><td align="justify" class="Rrule" valign="top">vial size</td><td align="justify" class="Rrule" valign="top">NDC #s</td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">20 mg vial</td><td align="justify" class="Rrule" valign="top">10 mL</td><td align="justify" class="Rrule" valign="top">10 mL</td><td align="justify" class="Rrule" valign="top">72603-103-01</td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top">50 mg vial</td><td align="justify" class="Rrule" valign="top">25 mL</td><td align="justify" class="Rrule" valign="top">30 mL</td><td align="justify" class="Rrule" valign="top">72603-200-01</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0\" cellspacing=\"0\">\n<caption>\n<span>Table 14 </span>\n</caption>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First First\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">mg in vial</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">fill volume</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">vial size</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">NDC #s</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">20 mg vial</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">10 mL</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">10 mL</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">72603-103-01</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"justify\" class=\"Lrule Rrule\" valign=\"top\">50 mg vial</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">25 mL</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">30 mL</td><td align=\"justify\" class=\"Rrule\" valign=\"top\">72603-200-01</td>\n</tr>\n</tbody>\n</table></div>" }

Refrigerate unopened vials of doxorubicin hydrochloride liposome injection at 2° to 8°C (36° to 46°F). Do not freeze. Discard unused portion. Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures1.

{ "type": "p", "children": [], "text": "Refrigerate unopened vials of doxorubicin hydrochloride liposome injection at 2° to 8°C (36° to 46°F). Do not freeze. Discard unused portion. Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures1." }

Cardiomyopathy

{ "type": "p", "children": [], "text": "Cardiomyopathy" }

Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1)].\n" }

Infusion-Related Reactions

{ "type": "p", "children": [], "text": "Infusion-Related Reactions" }

Advise patients about the symptoms of infusion related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients about the symptoms of infusion related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2)].\n" }

Myelosuppression

{ "type": "p", "children": [], "text": "Myelosuppression" }

Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection.

{ "type": "p", "children": [], "text": "Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection." }

Hand-Foot Syndrome  

{ "type": "p", "children": [], "text": "Hand-Foot Syndrome  " }

Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions (5.3)].\n" }

Stomatitis

{ "type": "p", "children": [], "text": "Stomatitis" }

Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis).

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis)." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "Embryo-Fetal Toxicity" }

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].\n" }

Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection[see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection[see Use in Specific Populations (8.3)].\n" }

Lactation

{ "type": "p", "children": [], "text": "Lactation" }

Advise females not to breastfeed during treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise females not to breastfeed during treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.2)].\n" }

Infertility

{ "type": "p", "children": [], "text": "Infertility" }

Advise females and males of reproductive potential that doxorubicin hydrochloride liposome injection may cause temporary or permanent infertility [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females and males of reproductive potential that doxorubicin hydrochloride liposome injection may cause temporary or permanent infertility [see Use in Specific Populations (8.3)].\n" }

Discoloration of Urine and Body Fluids

{ "type": "p", "children": [], "text": "Discoloration of Urine and Body Fluids" }

Inform patients that following doxorubicin hydrochloride liposome injection administration, a 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.

{ "type": "p", "children": [], "text": "Inform patients that following doxorubicin hydrochloride liposome injection administration, a 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." }

Manufactured for:

{ "type": "p", "children": [], "text": "\nManufactured for:" }

Northstar Rx LLC

{ "type": "p", "children": [], "text": "Northstar Rx LLC" }

Memphis, TN 38141.

{ "type": "p", "children": [], "text": "Memphis, TN 38141." }

Manufactured by: Sun Pharmaceutical Industries Ltd.

{ "type": "p", "children": [], "text": "Manufactured by: Sun Pharmaceutical Industries Ltd." }

Halol-Baroda Highway,

{ "type": "p", "children": [], "text": "Halol-Baroda Highway," }

Halol-389 350, Gujarat, India.

{ "type": "p", "children": [], "text": "Halol-389 350, Gujarat, India." }

ISS. 09/2024

{ "type": "p", "children": [], "text": "ISS. 09/2024" }

5254979

{ "type": "p", "children": [], "text": "5254979" }

NDC 72603-103-01 Rx only DOXOrubicin Hydrochloride Liposome Injection 20 mg/10 mL (2 mg/mL) Cytotoxic Agent Must be diluted LIPOSOMAL FORMULATION DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE FOR INTRAVENOUS INFUSION ONLY AFTER DILUTION

{ "type": "p", "children": [], "text": "NDC 72603-103-01\n Rx only\n\nDOXOrubicin Hydrochloride Liposome Injection\n\n20 mg/10 mL (2 mg/mL)\n\nCytotoxic Agent\n\nMust be diluted\n\nLIPOSOMAL FORMULATION DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE\n\nFOR INTRAVENOUS INFUSION ONLY AFTER DILUTION\n" }

Sterile 10 mL Single-Dose Vial Aisling

{ "type": "p", "children": [], "text": "\nSterile\n\n10 mL Single-Dose Vial\n\n Aisling\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

NDC 72603-103-01 DOXOrubicin Hydrochloride Liposome Injection 20 mg/10 mL (2 mg/mL) Sterile Cytotoxic Agent MUST BE DILUTED PRIOR TO ADMINISTRATION LIPOSOMAL FORMULATION, DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE

{ "type": "p", "children": [], "text": "\n NDC 72603-103-01\nDOXOrubicin Hydrochloride Liposome Injection\n\n20 mg/10 mL (2 mg/mL)\n\nSterile\n\nCytotoxic Agent\n\nMUST BE DILUTED PRIOR TO ADMINISTRATION\n\nLIPOSOMAL FORMULATION, DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE\n" }

FOR INTRAVENOUS INFUSION ONLY AFTER DILUTION

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS INFUSION ONLY AFTER DILUTION\n" }

Store in a refrigerator, 2°C to 8°C (36°F to 46°F). Do Not Freeze.

{ "type": "p", "children": [], "text": "\nStore in a refrigerator, 2°C to 8°C (36°F to 46°F). Do Not Freeze.\n" }

10 mL Single-Dose Vial Aisling

{ "type": "p", "children": [], "text": "\n10 mL Single-Dose Vial Aisling\n" }

NDC 72603-200-01 Rx only DOXOrubicin Hydrochloride Liposome Injection 50 mg/25 mL (2 mg/mL)

{ "type": "p", "children": [], "text": "NDC 72603-200-01\n Rx only\n\nDOXOrubicin Hydrochloride Liposome Injection\n\n50 mg/25 mL (2 mg/mL)\n" }

Cytotoxic Agent Must be diluted LIPOSOMAL FORMULATION, DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE FOR INTRAVENOUS INFUSION ONLY AFTER DILUTION

{ "type": "p", "children": [], "text": "\nCytotoxic Agent\n\nMust be diluted\n\nLIPOSOMAL FORMULATION, DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE\n\nFOR INTRAVENOUS INFUSION ONLY AFTER DILUTION\n" }

Sterile

{ "type": "p", "children": [], "text": "\nSterile\n" }

25 mL Single-Dose Vial Aisling

{ "type": "p", "children": [], "text": "\n25 mL Single-Dose Vial\n\nAisling\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

NDC 72603-200-01 DOXOrubicin Hydrochloride Liposome Injection 50 mg/25 mL (2 mg/mL) Sterile Cytotoxic Agent MUST BE DILUTED PRIOR TO ADMINISTRATION LIPOSOMAL FORMULATION, DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE

{ "type": "p", "children": [], "text": "\n NDC 72603-200-01\nDOXOrubicin Hydrochloride Liposome Injection\n\n50 mg/25 mL (2 mg/mL)\n\nSterile\n\nCytotoxic Agent\n\nMUST BE DILUTED PRIOR TO ADMINISTRATION\n\nLIPOSOMAL FORMULATION, DO NOT SUBSTITUTE FOR DOXORUBICIN HYDROCHLORIDE\n" }

FOR INTRAVENOUS INFUSION ONLY AFTER DILUTION

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS INFUSION ONLY AFTER DILUTION\n" }

Store in a refrigerator, 2°C to 8°C (36°F to 46°F). Do Not Freeze.

{ "type": "p", "children": [], "text": "\nStore in a refrigerator, 2°C to 8°C (36°F to 46°F). Do Not Freeze.\n" }

25 mL Single-Dose Vial

{ "type": "p", "children": [], "text": "\n25 mL Single-Dose Vial\n" }

Aisling

{ "type": "p", "children": [], "text": "\nAisling\n" }

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

DOXIL liposomal infusion is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

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.

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)].

The recommended dose of DOXIL liposomal infusion is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.

The recommended dose of DOXIL liposomal infusion is 20 mg/m2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.

The recommended dose of DOXIL liposomal infusion is 30 mg/m2 intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer DOXIL liposomal infusion after bortezomib on day 4 of each cycle [see Clinical Studies (14.3)].

Do not increase DOXIL liposomal infusion after a dose reduction for toxicity.

<div class="scrollingtable"><table width="98.04%"> <caption> <span>Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse Reactions</span> </caption> <col width="46%"/> <col width="54%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Toxicity</span></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Dose Adjustment</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Hand-Foot Syndrome (HFS)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities</p> </td><td class="Botrule Rrule Toprule" valign="top"> <dl> <dt>•</dt> <dd>If no previous Grade 3 or 4 HFS: no dose adjustment.</dd> <dt>•</dt> <dd>If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then decrease dose by 25%.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter</p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0–1.</span> </dd> <dt>•</dt> <dd>Discontinue DOXIL liposomal infusion if no resolution after 2 weeks.</dd> <dt>•</dt> <dd>If resolved to Grade 0–1 within 2 weeks: <dl> <dt>•</dt> <dd> <span class="Underline">And</span> no previous Grade 3 or 4 HFS: continue treatment at previous dose.</dd> <dt>•</dt> <dd> <span class="Underline">And</span> previous Grade 3 or 4 toxicity: decrease dose by 25%.</dd> </dl> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing</p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0–1,</span> then decrease dose by 25%.</dd> <dt>•</dt> <dd>Discontinue DOXIL liposomal infusion if no resolution after 2 weeks.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization</p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0–1,</span> then decrease dose by 25%.</dd> <dt>•</dt> <dd>Discontinue DOXIL liposomal infusion if no resolution after 2 weeks.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Stomatitis</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 1: Painless ulcers, erythema, or mild soreness</p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>If no previous Grade 3 or 4 toxicity: no dose adjustment.</dd> <dt>•</dt> <dd>If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2: Painful erythema, edema, or ulcers, but can eat</p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0–1.</span> </dd> <dt>•</dt> <dd>Discontinue DOXIL liposomal infusion if there is no resolution after 2 weeks.</dd> <dt>•</dt> <dd>If resolved to Grade 0–1 within 2 weeks: <dl> <dt>•</dt> <dd> <span class="Underline">And</span> no previous Grade 3 or 4 stomatitis: resume treatment at previous dose.</dd> <dt>•</dt> <dd> <span class="Underline">And</span> previous Grade 3 or 4 toxicity: decrease dose by 25%.</dd> </dl> </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3: Painful erythema, edema, or ulcers, and cannot eat</p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0–1. </span> Decrease dose by 25% and return to original dose interval.</dd> <dt>•</dt> <dd>If after 2 weeks there is no resolution, discontinue DOXIL liposomal infusion.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4: Requires parenteral or enteral support</p> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Delay dosing up to 2 weeks or until resolved to Grade 0–1. </span> Decrease dose by 25% and return to original dose interval.</dd> <dt>•</dt> <dd>If after 2 weeks there is no resolution, discontinue DOXIL liposomal infusion.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Neutropenia or Thrombocytopenia</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 1</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">No dose reduction</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="98.04%"> <caption> <span>Table 2: Recommended Dose Modifications of DOXIL Liposomal Infusion for Toxicity When Administered in Combination With Bortezomib</span> </caption> <col width="41%"/> <col width="59%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Toxicity</span></th><th align="left" class="Botrule Rrule Toprule" valign="top"><span class="Bold">DOXIL Liposomal Infusion</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Fever ≥38°C and ANC &lt;1,000/mm<span class="Sup">3</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <dl> <dt>•</dt> <dd>Withhold dose for this cycle if before Day 4;</dd> <dt>•</dt> <dd>Decrease dose by 25%, if after Day 4 of previous cycle.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">On any day of drug administration after Day 1 of each cycle:</p> <dl> <dt>•</dt> <dd>Platelet count &lt;25,000/mm<span class="Sup">3</span> </dd> <dt>•</dt> <dd>Hemoglobin &lt;8 g/dL</dd> <dt>•</dt> <dd>ANC &lt;500/mm<span class="Sup">3</span> </dd> </dl> </td><td class="Botrule Rrule" valign="top"> <dl> <dt>•</dt> <dd>Withhold dose for this cycle if before Day 4;</dd> <dt>•</dt> <dd>Decrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity.</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Grade 3 or 4 non-hematologic drug related toxicity</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Do not dose until recovered to Grade &lt;2, then reduce dose by 25%.</p> </td> </tr> </tbody> </table></div>

For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for DOXIL liposomal infusion. Refer to bortezomib manufacturer’s prescribing information.

Preparation

Dilute 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 2°C to 8°C (36°F to 46°F) and administer within 24 hours.

Administration

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.

Do not use with in-line filters.

Administer the first dose of DOXIL liposomal infusion at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour [see Warnings and Precautions (5.2)]. Do not rapidly flush the infusion line.

Do not mix DOXIL liposomal infusion with other drugs.

Management of Suspected Extravasation

Discontinue DOXIL liposomal infusion for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

DOXIL liposomal infusion is a 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.

DOXIL (doxorubicin hydrochloride liposome injection): 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) translucent, red liposomal dispersion in single dose vials.

{ "type": "p", "children": [], "text": "DOXIL (doxorubicin hydrochloride liposome injection): 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) translucent, red liposomal dispersion in single dose vials. " }

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

{ "type": "p", "children": [], "text": "DOXIL liposomal infusion is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions (5.2)].\n" }

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 a 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 a >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 a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

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 1 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 a rate of 1 mg/min and increase rate as tolerated [see Dosage and Administration (2.6)]. Withhold DOXIL liposomal infusion for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions.

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 3 or 4 cases of HFS in DOXIL liposomal infusion-treated patients and no Grade 3 or 4 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 2 or 3 cycles of treatment but may occur earlier. Delay DOXIL liposomal infusion for the first episode of Grade 2 or greater HFS [see Dosage and Administration (2.5)]. Discontinue DOXIL liposomal infusion if HFS is severe and debilitating.

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 6 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 a role in the development of oral secondary malignancies with long-term use.

Based on findings in animals and its mechanism of action, DOXIL liposomal infusion can cause fetal harm when administered to a 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 a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL liposomal infusion [see Use in Specific Populations (8.1, 8.3)].

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 Kaposi’s 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 Kaposi’s sarcoma.

Patients With Ovarian Cancer

The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with DOXIL liposomal infusion 50 mg/m2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received DOXIL liposomal infusion for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other.

Table 3 presents the hematologic adverse reactions from Trial 4.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3: Hematologic Adverse Reactions in Trial 4</span> </caption> <col width="24%"/> <col width="30%"/> <col width="13%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="top"></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">DOXIL Liposomal Infusion <br/>Patients <br/>(n=239)</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Topotecan <br/>Patients<br/>(n=235)</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Neutropenia</p> </td><td class="Toprule" valign="middle"></td><td class="Toprule" valign="middle"></td> </tr> <tr> <td valign="top"> <p class="First">  500 – &lt;1000/mm<span class="Sup">3</span> </p> </td><td align="center" valign="middle"> <p class="First">8%</p> </td><td align="center" valign="middle"> <p class="First">14%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  &lt;500/mm<span class="Sup">3</span> </p> </td><td align="center" valign="middle"> <p class="First">4.2%</p> </td><td align="center" valign="middle"> <p class="First">62%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Anemia</p> </td><td valign="middle"></td><td valign="middle"></td> </tr> <tr> <td valign="top"> <p class="First">  6.5 – &lt;8 g/dL</p> </td><td align="center" valign="middle"> <p class="First">5%</p> </td><td align="center" valign="middle"> <p class="First">25%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  &lt; 6.5 g/dL</p> </td><td align="center" valign="middle"> <p class="First">0.4%</p> </td><td align="center" valign="middle"> <p class="First">4.3%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Thrombocytopenia</p> </td><td valign="middle"></td><td valign="middle"></td> </tr> <tr> <td valign="top"> <p class="First">  10,000 – &lt;50,000/mm<span class="Sup">3</span> </p> </td><td align="center" valign="middle"> <p class="First">1.3%</p> </td><td align="center" valign="middle"> <p class="First">17%</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  &lt;10,000/mm<span class="Sup">3</span> </p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">0.0%</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">17%</p> </td> </tr> </tbody> </table></div>

Table 4 presents the non-hematologic adverse reactions from Trial 4.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4: Non-Hematologic Adverse Reactions in Trial 4</span> </caption> <col width="30%"/> <col width="20%"/> <col width="22%"/> <col width="12%"/> <col width="13%"/> <thead> <tr class="First"> <th align="left" class="Botrule Toprule" valign="top"><span class="Bold">Non-Hematologic <br/>Adverse Reaction <br/>10% or Greater</span></th><th align="center" class="Botrule Toprule" colspan="2" valign="middle"><span class="Bold">DOXIL Liposomal Infusion (%) treated</span> <br/> <span class="Bold">(n=239)</span></th><th align="center" class="Botrule Toprule" colspan="2" valign="middle"><span class="Bold">Topotecan (%) <br/>treated</span> <br/> <span class="Bold">(n=235)</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule" valign="top"></th><th align="center" class="Botrule" valign="middle"><span class="Bold">All grades</span></th><th align="center" class="Botrule" valign="middle"><span class="Bold">Grades 3–4</span></th><th align="center" class="Botrule" valign="middle"><span class="Bold">All grades</span></th><th align="center" class="Botrule" valign="middle"><span class="Bold">Grades 3–4</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">  Body as a Whole</span></span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">    Asthenia</p> </td><td align="center" valign="middle"> <p class="First">40</p> </td><td align="center" valign="middle"> <p class="First">7</p> </td><td align="center" valign="middle"> <p class="First">52</p> </td><td align="center" valign="middle"> <p class="First">8</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Fever</p> </td><td align="center" valign="middle"> <p class="First">21</p> </td><td align="center" valign="middle"> <p class="First">0.8</p> </td><td align="center" valign="middle"> <p class="First">31</p> </td><td align="center" valign="middle"> <p class="First">6</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Mucous Membrane Disorder</p> </td><td align="center" valign="middle"> <p class="First">14</p> </td><td align="center" valign="middle"> <p class="First">3.8</p> </td><td align="center" valign="middle"> <p class="First">3.4</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Back Pain</p> </td><td align="center" valign="middle"> <p class="First">12</p> </td><td align="center" valign="middle"> <p class="First">1.7</p> </td><td align="center" valign="middle"> <p class="First">10</p> </td><td align="center" valign="middle"> <p class="First">0.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Infection</p> </td><td align="center" valign="middle"> <p class="First">12</p> </td><td align="center" valign="middle"> <p class="First">2.1</p> </td><td align="center" valign="middle"> <p class="First">6</p> </td><td align="center" valign="middle"> <p class="First">0.9</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Headache</p> </td><td align="center" valign="middle"> <p class="First">11</p> </td><td align="center" valign="middle"> <p class="First">0.8</p> </td><td align="center" valign="middle"> <p class="First">15</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">  Digestive</span></span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">    Nausea</p> </td><td align="center" valign="middle"> <p class="First">46</p> </td><td align="center" valign="middle"> <p class="First">5</p> </td><td align="center" valign="middle"> <p class="First">63</p> </td><td align="center" valign="middle"> <p class="First">8</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Stomatitis</p> </td><td align="center" valign="middle"> <p class="First">41</p> </td><td align="center" valign="middle"> <p class="First">8</p> </td><td align="center" valign="middle"> <p class="First">15</p> </td><td align="center" valign="middle"> <p class="First">0.4</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Vomiting</p> </td><td align="center" valign="middle"> <p class="First">33</p> </td><td align="center" valign="middle"> <p class="First">8</p> </td><td align="center" valign="middle"> <p class="First">44</p> </td><td align="center" valign="middle"> <p class="First">10</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Diarrhea</p> </td><td align="center" valign="middle"> <p class="First">21</p> </td><td align="center" valign="middle"> <p class="First">2.5</p> </td><td align="center" valign="middle"> <p class="First">35</p> </td><td align="center" valign="middle"> <p class="First">4.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Anorexia</p> </td><td align="center" valign="middle"> <p class="First">20</p> </td><td align="center" valign="middle"> <p class="First">2.5</p> </td><td align="center" valign="middle"> <p class="First">22</p> </td><td align="center" valign="middle"> <p class="First">1.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Dyspepsia</p> </td><td align="center" valign="middle"> <p class="First">12</p> </td><td align="center" valign="middle"> <p class="First">0.8</p> </td><td align="center" valign="middle"> <p class="First">14</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">  Nervous</span></span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">    Dizziness</p> </td><td align="center" valign="middle"> <p class="First">4.2</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td><td align="center" valign="middle"> <p class="First">10</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">  Respiratory</span></span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">    Pharyngitis</p> </td><td align="center" valign="middle"> <p class="First">16</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td><td align="center" valign="middle"> <p class="First">18</p> </td><td align="center" valign="middle"> <p class="First">0.4</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Dyspnea</p> </td><td align="center" valign="middle"> <p class="First">15</p> </td><td align="center" valign="middle"> <p class="First">4.1</p> </td><td align="center" valign="middle"> <p class="First">23</p> </td><td align="center" valign="middle"> <p class="First">4.3</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Cough increased</p> </td><td align="center" valign="middle"> <p class="First">10</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td><td align="center" valign="middle"> <p class="First">12</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">  Skin and Appendages</span></span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">    Hand-foot syndrome</p> </td><td align="center" valign="middle"> <p class="First">51</p> </td><td align="center" valign="middle"> <p class="First">24</p> </td><td align="center" valign="middle"> <p class="First">0.9</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First">    Rash</p> </td><td align="center" valign="middle"> <p class="First">29</p> </td><td align="center" valign="middle"> <p class="First">4.2</p> </td><td align="center" valign="middle"> <p class="First">12</p> </td><td align="center" valign="middle"> <p class="First">0.4</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">    Alopecia</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">19</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">N/A</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">52</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">N/A</p> </td> </tr> </tbody> </table></div>

The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4).

Incidence 1% to 10%

Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest.

Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.

Hematologic and Lymphatic: ecchymosis.

Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia.

Nervous: somnolence, dizziness, depression.

Respiratory: rhinitis, pneumonia, sinusitis, epistaxis.

Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne.

Special Senses: conjunctivitis, taste perversion, dry eyes.

Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma

The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma (KS) enrolled in four open-label, uncontrolled trials of DOXIL liposomal infusion administered at doses ranging from 10 to 40 mg/m2 every 2 to 3 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 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/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 Kaposi’s sarcoma and included myelosuppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 5 and Table 6 summarize adverse reactions reported in patients treated with DOXIL liposomal infusion for AIDS-related Kaposi’s sarcoma in a pooled analysis of the four trials.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposi’s Sarcoma</span> </caption> <col width="17%"/> <col width="36%"/> <col width="36%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="top"></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Patients With Refractory or<br/>Intolerant AIDS-Related Kaposi’s <br/>Sarcoma<br/>(n=74</span><a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a><span class="Bold">)</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Total Patients With AIDS-Related<br/>Kaposi’s Sarcoma<br/>(n=720</span><a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a><span class="Bold">)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>This includes only subjects with AIDS-KS who had available data from the 4 pooled trials.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" colspan="3" valign="top"> <p class="First">Neutropenia</p> </td> </tr> <tr> <td valign="top"> <p class="First">  &lt; 1000/mm<span class="Sup">3</span> </p> </td><td align="center" valign="middle"> <p class="First">46%</p> </td><td align="center" valign="middle"> <p class="First">49%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  &lt; 500/mm<span class="Sup">3</span> </p> </td><td align="center" valign="middle"> <p class="First">11%</p> </td><td align="center" valign="middle"> <p class="First">13%</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Anemia</p> </td> </tr> <tr> <td valign="top"> <p class="First">  &lt; 10 g/dL</p> </td><td align="center" valign="middle"> <p class="First">58%</p> </td><td align="center" valign="middle"> <p class="First">55%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  &lt; 8 g/dL</p> </td><td align="center" valign="middle"> <p class="First">16%</p> </td><td align="center" valign="middle"> <p class="First">18%</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Thrombocytopenia</p> </td> </tr> <tr> <td valign="top"> <p class="First">  &lt; 150,000/mm<span class="Sup">3</span> </p> </td><td align="center" valign="middle"> <p class="First">61%</p> </td><td align="center" valign="middle"> <p class="First">61%</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  &lt; 25,000/mm<span class="Sup">3</span> </p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">1.4%</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">4.2%</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6: Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi’s Sarcoma</span> </caption> <col width="29%"/> <col width="35%"/> <col width="36%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="top"><span class="Bold">Adverse Reactions</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Patients With Refractory or <br/>Intolerant AIDS-Related Kaposi’s <br/>Sarcoma <br/>(n=77</span><a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a><span class="Bold">)</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Total Patients With AIDS-Related <br/>Kaposi’s Sarcoma <br/>(n=705</span><a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a><span class="Bold">)</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">18%</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">17%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Asthenia</p> </td><td align="center" valign="middle"> <p class="First">7%</p> </td><td align="center" valign="middle"> <p class="First">10%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Fever</p> </td><td align="center" valign="middle"> <p class="First">8%</p> </td><td align="center" valign="middle"> <p class="First">9%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Alopecia</p> </td><td align="center" valign="middle"> <p class="First">9%</p> </td><td align="center" valign="middle"> <p class="First">9%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Alkaline Phosphatase Increase</p> </td><td align="center" valign="middle"> <p class="First">1.3%</p> </td><td align="center" valign="middle"> <p class="First">8%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Vomiting</p> </td><td align="center" valign="middle"> <p class="First">8%</p> </td><td align="center" valign="middle"> <p class="First">8%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Diarrhea</p> </td><td align="center" valign="middle"> <p class="First">5%</p> </td><td align="center" valign="middle"> <p class="First">8%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Stomatitis</p> </td><td align="center" valign="middle"> <p class="First">5%</p> </td><td align="center" valign="middle"> <p class="First">7%</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Oral Moniliasis</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">1.3%</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">6%</p> </td> </tr> </tbody> </table></div>

The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi’s sarcoma.

Incidence 1% to 5%

Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia.

Cutaneous: herpes simplex, rash, itching.

Digestive: mouth ulceration, anorexia, dysphagia.

Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence.

Incidence Less Than 1%

Body As A Whole: sepsis, moniliasis, cryptococcosis.

Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia.

Digestive: hepatitis.

Metabolic and Nutritional Disorders: dehydration.

Respiratory: cough increase, pharyngitis.

Skin and Appendages: maculopapular rash, herpes zoster.

Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma

The safety data described are from 318 patients treated with DOXIL liposomal infusion (30 mg/m2) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the DOXIL liposomal infusion + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with DOXIL liposomal infusion in combination with bortezomib for multiple myeloma.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in ≥10% Patients Treated for Multiple Myeloma With DOXIL Liposomal Infusion in Combination With Bortezomib</span> </caption> <col width="49%"/> <col width="13%"/> <col width="16%"/> <col width="10%"/> <col width="12%"/> <thead> <tr class="First"> <th align="left" class="Toprule" valign="top"><span class="Bold">Adverse Reaction</span></th><th align="center" class="Toprule" colspan="2" valign="middle"><span class="Bold">DOXIL Liposomal Infusion + <br/>bortezomib <br/>(n=318)</span></th><th align="center" class="Toprule" colspan="2" valign="middle"><span class="Bold">Bortezomib <br/>(n=318)</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule" valign="top"></th><th align="center" class="Botrule" valign="middle"><span class="Bold">Any (%)</span></th><th align="center" class="Botrule" valign="middle"><span class="Bold">Grade 3–4</span></th><th align="center" class="Botrule" valign="middle"><span class="Bold">Any (%)</span></th><th align="center" class="Botrule" valign="middle"><span class="Bold">Grade 3–4</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders</span> </p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Neutropenia</p> </td><td align="center" valign="middle"> <p class="First">36</p> </td><td align="center" valign="middle"> <p class="First">32</p> </td><td align="center" valign="middle"> <p class="First">22</p> </td><td align="center" valign="middle"> <p class="First">16</p> </td> </tr> <tr> <td valign="top"> <p class="First">Thrombocytopenia</p> </td><td align="center" valign="middle"> <p class="First">33</p> </td><td align="center" valign="middle"> <p class="First">24</p> </td><td align="center" valign="middle"> <p class="First">28</p> </td><td align="center" valign="middle"> <p class="First">17</p> </td> </tr> <tr> <td valign="top"> <p class="First">Anemia</p> </td><td align="center" valign="middle"> <p class="First">25</p> </td><td align="center" valign="middle"> <p class="First">9</p> </td><td align="center" valign="middle"> <p class="First">21</p> </td><td align="center" valign="middle"> <p class="First">9</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">General disorders and administration site conditions</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Fatigue</p> </td><td align="center" valign="middle"> <p class="First">36</p> </td><td align="center" valign="middle"> <p class="First">7</p> </td><td align="center" valign="middle"> <p class="First">28</p> </td><td align="center" valign="middle"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Pyrexia</p> </td><td align="center" valign="middle"> <p class="First">31</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td><td align="center" valign="middle"> <p class="First">22</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Asthenia</p> </td><td align="center" valign="middle"> <p class="First">22</p> </td><td align="center" valign="middle"> <p class="First">6</p> </td><td align="center" valign="middle"> <p class="First">18</p> </td><td align="center" valign="middle"> <p class="First">4</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Nausea</p> </td><td align="center" valign="middle"> <p class="First">48</p> </td><td align="center" valign="middle"> <p class="First">3</p> </td><td align="center" valign="middle"> <p class="First">40</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Diarrhea</p> </td><td align="center" valign="middle"> <p class="First">46</p> </td><td align="center" valign="middle"> <p class="First">7</p> </td><td align="center" valign="middle"> <p class="First">39</p> </td><td align="center" valign="middle"> <p class="First">5</p> </td> </tr> <tr> <td valign="top"> <p class="First">Vomiting</p> </td><td align="center" valign="middle"> <p class="First">32</p> </td><td align="center" valign="middle"> <p class="First">4</p> </td><td align="center" valign="middle"> <p class="First">22</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Constipation</p> </td><td align="center" valign="middle"> <p class="First">31</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td><td align="center" valign="middle"> <p class="First">31</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Mucositis/Stomatitis</p> </td><td align="center" valign="middle"> <p class="First">20</p> </td><td align="center" valign="middle"> <p class="First">2</p> </td><td align="center" valign="middle"> <p class="First">5</p> </td><td align="center" valign="middle"> <p class="First">&lt;1</p> </td> </tr> <tr> <td valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" valign="middle"> <p class="First">11</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td><td align="center" valign="middle"> <p class="First">8</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Herpes zoster</p> </td><td align="center" valign="middle"> <p class="First">11</p> </td><td align="center" valign="middle"> <p class="First">2</p> </td><td align="center" valign="middle"> <p class="First">9</p> </td><td align="center" valign="middle"> <p class="First">2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Herpes simplex</p> </td><td align="center" valign="middle"> <p class="First">10</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td><td align="center" valign="middle"> <p class="First">6</p> </td><td align="center" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Investigations</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Weight decreased</p> </td><td align="center" valign="middle"> <p class="First">12</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td><td align="center" valign="middle"> <p class="First">4</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Metabolism and Nutritional disorders</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Anorexia</p> </td><td align="center" valign="middle"> <p class="First">19</p> </td><td align="center" valign="middle"> <p class="First">2</p> </td><td align="center" valign="middle"> <p class="First">14</p> </td><td align="center" valign="middle"> <p class="First">&lt;1</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="middle"> <p class="First">Peripheral Neuropathy<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a> </p> </td><td align="center" valign="top"> <p class="First">42</p> </td><td align="center" valign="top"> <p class="First">7</p> </td><td align="center" valign="top"> <p class="First">45</p> </td><td align="center" valign="top"> <p class="First">11</p> </td> </tr> <tr> <td valign="top"> <p class="First">Neuralgia</p> </td><td align="center" valign="top"> <p class="First">17</p> </td><td align="center" valign="top"> <p class="First">3</p> </td><td align="center" valign="top"> <p class="First">20</p> </td><td align="center" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td valign="top"> <p class="First">Paresthesia/dysesthesia</p> </td><td align="center" valign="top"> <p class="First">13</p> </td><td align="center" valign="top"> <p class="First">&lt;1</p> </td><td align="center" valign="top"> <p class="First">10</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic and mediastinal disorders</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Cough</p> </td><td align="center" valign="middle"> <p class="First">18</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td><td align="center" valign="middle"> <p class="First">12</p> </td><td align="center" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td><td valign="top"></td><td valign="top"></td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="middle"> <p class="First">Rash<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a> </p> </td><td align="center" valign="top"> <p class="First">22</p> </td><td align="center" valign="top"> <p class="First">1</p> </td><td align="center" valign="top"> <p class="First">18</p> </td><td align="center" valign="top"> <p class="First">1</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Hand-foot syndrome</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">&lt;1</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

The following additional adverse reactions have been identified during postapproval use of DOXIL liposomal infusion. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: muscle spasms

Respiratory, Thoracic and Mediastinal Disorders: pulmonary embolism (in some cases fatal)

Hematologic Disorders: Secondary acute myelogenous leukemia

Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens‑Johnson syndrome, toxic epidermal necrolysis, lichenoid keratosis

Secondary Oral Neoplasms: [see Warnings and Precautions (5.4)].

No formal drug interaction studies have been conducted with DOXIL liposomal infusion.

{ "type": "p", "children": [], "text": "No formal drug interaction studies have been conducted with DOXIL liposomal infusion." }

Risk Summary

Based on findings in animals and its mechanism of action, DOXIL liposomal infusion can cause fetal harm when administered to a 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 a 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 Data

DOXIL liposomal infusion was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m2 human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

Risk Summary

It 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.

Verify the pregnancy status of females of reproductive potential prior to initiating DOXIL liposomal infusion.

Contraception

Females

DOXIL liposomal infusion can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL liposomal infusion.

Males

DOXIL 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 6 months after treatment with DOXIL liposomal infusion [see Non-clinical Toxicology (13.1)].

Infertility

Females

In 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.

Males

DOXIL 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)].

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

Clinical studies of DOXIL liposomal infusion conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi’s sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.

In Trial 6, of 318 patients treated with 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.

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.

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

{ "type": "p", "children": [], "text": "Acute overdosage with doxorubicin hydrochloride causes increased risk of severe mucositis, leukopenia, and thrombocytopenia." }

The active ingredient in DOXIL liposomal infusion is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in STEALTH liposomes for intravenous use.

{ "type": "p", "children": [], "text": "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-α-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 -NO11•HCl and the molecular weight is 579.99.

{ "type": "p", "children": [], "text": "The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6‑trideoxy-α-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 -NO11•HCl and the molecular weight is 579.99." }

The structural formula is:

{ "type": "p", "children": [], "text": "The structural formula is:" }

DOXIL liposomal infusion is a sterile, translucent, red liposomal dispersion. Each single- dose vial contains 20 mg or 50 mg doxorubicin hydrochloride at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin). 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, 1.55 mg as a buffer; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0); and sucrose, 94 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH liposomes.

{ "type": "p", "children": [], "text": "DOXIL liposomal infusion is a sterile, translucent, red liposomal dispersion. Each single- dose vial contains 20 mg or 50 mg doxorubicin hydrochloride at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin). 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, 1.55 mg as a buffer; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0); and sucrose, 94 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH liposomes. " }

MPEG-DSPE has the following structural formula:

{ "type": "p", "children": [], "text": "MPEG-DSPE has the following structural formula:" }

HSPC has the following structural formula:

{ "type": "p", "children": [], "text": "HSPC has the following structural formula:" }

Representation of a STEALTH liposome:

{ "type": "p", "children": [], "text": "Representation of a STEALTH liposome:" }

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.

The pharmacokinetic parameters for total doxorubicin following a single dose of DOXIL infused over 30 minutes are presented in Table 8.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 8: Pharmacokinetic Parameters of Total Doxorubicin from DOXIL Liposomal Infusion in Patients With AIDS-Related Kaposi’s Sarcoma</span> </caption> <col width="42%"/> <col width="14%"/> <col width="15%"/> <thead> <tr class="First"> <th align="left" class="Toprule" valign="top"></th><th align="center" class="Botrule Toprule" colspan="2" valign="top"><span class="Bold">Dose</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule" valign="top"><span class="Bold">Parameter (units)</span></th><th align="center" class="Botrule" valign="top"><span class="Bold">10 mg/m<span class="Sup">2</span></span></th><th align="center" class="Botrule" valign="top"><span class="Bold">20 mg/m<span class="Sup">2</span></span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">N=23<br/>Mean ± Standard Error</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Peak Plasma Concentration (µg/mL)</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">4.12 ± 0.215</p> </td><td align="center" class="Toprule" valign="top"> <p class="First">8.34 ± 0.49</p> </td> </tr> <tr> <td valign="top"> <p class="First">Plasma Clearance (L/h/m<span class="Sup">2</span>)</p> </td><td align="center" valign="top"> <p class="First">0.056 ± 0.01</p> </td><td align="center" valign="top"> <p class="First">0.041 ± 0.004</p> </td> </tr> <tr> <td valign="top"> <p class="First">Steady State Volume of Distribution (L/m<span class="Sup">2</span>)</p> </td><td align="center" valign="top"> <p class="First">2.83 ± 0.145</p> </td><td align="center" valign="top"> <p class="First">2.72 ± 0.120</p> </td> </tr> <tr> <td valign="top"> <p class="First">AUC (µg/mL∙h)</p> </td><td align="center" valign="top"> <p class="First">277 ± 32.9</p> </td><td align="center" valign="top"> <p class="First">590 ± 58.7</p> </td> </tr> <tr> <td valign="top"> <p class="First">First Phase (λ<span class="Sub">1</span>) Half-Life (h)</p> </td><td align="center" valign="top"> <p class="First">4.7 ± 1.1</p> </td><td align="center" valign="top"> <p class="First">5.2 ± 1.4</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Second Phase (λ<span class="Sub">1</span>) Half-Life (h)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">52.3 ± 5.6</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">55.0 ± 4.8</p> </td> </tr> </tbody> </table></div>

DOXIL 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 a 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 a 20 mg/m2 dose.

Distribution

Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5–10% free doxorubicin) remains liposome-encapsulated during circulation.

In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/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%.

Metabolism

Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m2 DOXIL liposomal infusion.

Elimination

The plasma clearance of total doxorubicin from DOXIL liposomal infusion was 0.041 L/h/m2 at a dose of 20 mg/m2. Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m2.

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 a single dose of 36 mg/kg (about 2 times the 50 mg/m2 human dose on a 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 a mg/m2 basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m2 human dose on a mg/m2 basis).

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 6 months of completing treatment. Patients received DOXIL liposomal infusion at 50 mg/m2 every 3 or 4 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 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%).

The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel- and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression.

The response rates for the individual single arm trials are given in Table 9 below.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 9: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials</span> </caption> <col width="24%"/> <col width="15%"/> <col width="15%"/> <col width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="top"></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Trial 1 (U.S.)</span> <br/> <span class="Bold">N=27</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Trial 2 (U.S.)</span> <br/> <span class="Bold">N=82</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Trial 3 (non-U.S.)</span> <br/> <span class="Bold">N=36</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Response Rate</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">22.2%</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">17.1%</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">0%</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">95% Confidence Interval</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">8.6% – 42.3%</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">9.7% – 27.0%</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">0.0% – 9.7%</p> </td> </tr> </tbody> </table></div>

In a pooled analysis of Trials 1–3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% 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, a 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 4 weeks (n=239) or topotecan 1.5 mg/m2 daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 10: Results of Efficacy Analyses<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></span> </caption> <col width="42%"/> <col width="20%"/> <col width="12%"/> <thead> <tr class="First"> <th align="left" class="Toprule" valign="top"></th><th align="center" class="Botrule Toprule" colspan="2" valign="middle">Protocol Defined ITT Population</th> </tr> <tr class="Last"> <th align="left" class="Botrule" valign="top"></th><th align="center" class="Botrule" valign="middle">DOXIL Liposomal<br/>Infusion<br/>(n=239)</th><th align="center" class="Botrule" valign="middle">Topotecan<br/>(n=235)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Analysis based on investigators' strata for protocol defined ITT population.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">†</a> </dt> <dd>Kaplan-Meier estimates.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">‡</a> </dt> <dd>p-value is based on the stratified log-rank test.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">§</a> </dt> <dd>Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for DOXIL liposomal infusion.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">¶</a> </dt> <dd>p-value not adjusted for multiple comparisons.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">TTP </span> (Protocol Specified Primary Endpoint)</p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="middle"> <p class="First">  Median (Months)<a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a> </p> </td><td align="center" valign="top"> <p class="First">4.1</p> </td><td align="center" valign="top"> <p class="First">4.2</p> </td> </tr> <tr> <td valign="top"> <p class="First">  p-value<a class="Sup" href="#footnote-9" name="footnote-reference-9">‡</a> </p> </td><td align="center" colspan="2" valign="top"> <p class="First">0.62</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Hazard Ratio<a class="Sup" href="#footnote-10" name="footnote-reference-10">§</a> </p> </td><td align="center" colspan="2" valign="top"> <p class="First">0.96</p> </td> </tr> <tr> <td valign="top"> <p class="First">  95% CI for Hazard Ratio</p> </td><td align="center" colspan="2" valign="top"> <p class="First">(0.76, 1.20)</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Overall Survival</span> </p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Median (Months) <a class="Sup" href="#footnote-8">†</a> </p> </td><td align="center" valign="top"> <p class="First">14.4</p> </td><td align="center" valign="top"> <p class="First">13.7</p> </td> </tr> <tr> <td valign="middle"> <p class="First">  p-value<a class="Sup" href="#footnote-11" name="footnote-reference-11">¶</a> </p> </td><td align="center" colspan="2" valign="top"> <p class="First">0.05</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Hazard Ratio<a class="Sup" href="#footnote-10">§</a> </p> </td><td align="center" colspan="2" valign="top"> <p class="First">0.82</p> </td> </tr> <tr> <td valign="top"> <p class="First">  95% CI for Hazard Ratio</p> </td><td align="center" colspan="2" valign="top"> <p class="First">(0.68, 1.00)</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Response Rate</span> </p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Overall Response n (%)</p> </td><td align="center" valign="top"> <p class="First">47 (19.7)</p> </td><td align="center" valign="top"> <p class="First">40 (17.0)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Complete Response n (%)</p> </td><td align="center" valign="top"> <p class="First">9 (3.8)</p> </td><td align="center" valign="top"> <p class="First">11 (4.7)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Partial Response n (%)</p> </td><td align="center" valign="top"> <p class="First">38 (15.9)</p> </td><td align="center" valign="top"> <p class="First">29 (12.3)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="middle"> <p class="First">  Median Duration of Response (Months) <a class="Sup" href="#footnote-8">†</a> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">6.9</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">5.9</p> </td> </tr> </tbody> </table></div>

DOXIL liposomal infusion was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m2 every 3 weeks, until disease progression or unacceptable toxicity (Trial 5).

Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride.

The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 11: Response in Patients with Refractory<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> AIDS-Related Kaposi’s Sarcoma</span> </caption> <col width="28%"/> <col width="15%"/> <col width="21%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>There were no complete responses in this population.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Investigator Assessment</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">All Evaluable <br/>Patients <br/>(n=34)</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">Evaluable Patients <br/>Who Received Prior <br/>Doxorubicin <br/>(n=20)</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Response<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a> </p> </td> </tr> <tr> <td valign="top"> <p class="First">  Partial (PR)</p> </td><td align="center" valign="middle"> <p class="First">27%</p> </td><td align="center" valign="middle"> <p class="First">30%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Stable</p> </td><td align="center" valign="middle"> <p class="First">29%</p> </td><td align="center" valign="middle"> <p class="First">40%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Progression</p> </td><td align="center" valign="middle"> <p class="First">44%</p> </td><td align="center" valign="middle"> <p class="First">30%</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Duration of PR (Days)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Median</p> </td><td align="center" valign="middle"> <p class="First">73</p> </td><td align="center" valign="middle"> <p class="First">89</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Range</p> </td><td align="center" valign="middle"> <p class="First">42+ – 210+</p> </td><td align="center" valign="middle"> <p class="First">42+ – 210+</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Time to PR (Days)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Median</p> </td><td align="center" valign="middle"> <p class="First">43</p> </td><td align="center" valign="middle"> <p class="First">53</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">  Range</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">15 – 133</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">15 – 109</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Indicator Lesion Assessment</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">All Evaluable <br/>Patients <br/>(n=42)</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">Evaluable Patients <br/>Who Received Prior <br/>Doxorubicin <br/>(n=23)</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Response<a class="Sup" href="#footnote-13">†</a> </p> </td> </tr> <tr> <td valign="top"> <p class="First">  Partial (PR)</p> </td><td align="center" valign="middle"> <p class="First">48%</p> </td><td align="center" valign="middle"> <p class="First">52%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Stable</p> </td><td align="center" valign="middle"> <p class="First">26%</p> </td><td align="center" valign="middle"> <p class="First">30%</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Progression</p> </td><td align="center" valign="middle"> <p class="First">26%</p> </td><td align="center" valign="middle"> <p class="First">17%</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Duration of PR (Days)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Median</p> </td><td align="center" valign="middle"> <p class="First">71</p> </td><td align="center" valign="middle"> <p class="First">79</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Range</p> </td><td align="center" valign="middle"> <p class="First">22+ – 210+</p> </td><td align="center" valign="middle"> <p class="First">35 – 210+</p> </td> </tr> <tr> <td colspan="3" valign="top"> <p class="First">Time to PR (Days)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Median</p> </td><td align="center" valign="middle"> <p class="First">22</p> </td><td align="center" valign="middle"> <p class="First">48</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Range</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">15 – 109</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">15 – 109</p> </td> </tr> </tbody> </table></div>

Retrospective 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 a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses.

The efficacy of DOXIL liposomal infusion in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either DOXIL liposomal infusion (30 mg/m2) administered IV on day 4 following bortezomib (1.3 mg/m2 IV on days 1, 4, 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1–18).

The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 12: Summary of Baseline Patient and Disease Characteristics</span> </caption> <col width="49%"/> <col width="24%"/> <col width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Patient Characteristics</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">DOXIL Liposomal<br/>Infusion + bortezomib</span> <br/> <span class="Bold">n=324</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">bortezomib</span> <br/> <span class="Bold">n=322</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">  Median age in years (range)</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">61 (28, 85)</p> </td><td align="center" class="Toprule" valign="middle"> <p class="First">62 (34, 88)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  % Male/female </p> </td><td align="center" valign="middle"> <p class="First">58 / 42</p> </td><td align="center" valign="middle"> <p class="First">54 / 46</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">  % Caucasian/Black/other </p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">90 / 6 / 4</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">94 / 4 / 2</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Disease Characteristics</span> </p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  % with IgG/IgA/Light chain </p> </td><td align="center" valign="middle"> <p class="First">57 / 27 / 12</p> </td><td align="center" valign="middle"> <p class="First">62 / 24 / 11</p> </td> </tr> <tr> <td valign="top"> <p class="First">  % β<span class="Sub">2</span>-microglobulin group</p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">    ≤2.5 mg/L</p> </td><td align="center" valign="middle"> <p class="First">14</p> </td><td align="center" valign="middle"> <p class="First">14</p> </td> </tr> <tr> <td valign="top"> <p class="First">    &gt;2.5 mg/L and ≤5.5 mg/L</p> </td><td align="center" valign="middle"> <p class="First">56</p> </td><td align="center" valign="middle"> <p class="First">55</p> </td> </tr> <tr> <td valign="top"> <p class="First">    &gt;5.5 mg/L</p> </td><td align="center" valign="middle"> <p class="First">30</p> </td><td align="center" valign="middle"> <p class="First">31</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Serum M-protein (g/dL): Median (Range)</span> </p> </td><td align="center" valign="middle"> <p class="First">2.5 (0–10.0)</p> </td><td align="center" valign="middle"> <p class="First">2.7 (0–10.0)</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Urine M-protein (mg/24 hours): Median (Range)</span> </p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">107 (0–24883)</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">66 (0–39657)</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Median Months Since Diagnosis</span> </p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">35.2</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">37.5</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">% Prior Therapy</span> </p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  One</p> </td><td align="center" valign="middle"> <p class="First">34</p> </td><td align="center" valign="middle"> <p class="First">34</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">  More than one</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">66</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">66</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Prior Systemic Therapies for Multiple Myeloma</span> </p> </td><td valign="top"></td><td valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">  Corticosteroid (%)</p> </td><td align="center" valign="middle"> <p class="First">99</p> </td><td align="center" valign="middle"> <p class="First">&gt;99</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Anthracyclines</p> </td><td align="center" valign="middle"> <p class="First">68</p> </td><td align="center" valign="middle"> <p class="First">67</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Alkylating agent (%)</p> </td><td align="center" valign="middle"> <p class="First">92</p> </td><td align="center" valign="middle"> <p class="First">90</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Thalidomide/lenalidomide (%)</p> </td><td align="center" valign="middle"> <p class="First">40</p> </td><td align="center" valign="middle"> <p class="First">43</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">  Stem cell transplantation (%)</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">57</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">54</p> </td> </tr> </tbody> </table></div>

The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the DOXIL liposomal infusion + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 13: Efficacy of DOXIL Liposomal Infusion in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma</span> </caption> <col width="41%"/> <col width="30%"/> <col width="14%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="top"><span class="Bold">Endpoint</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">DOXIL Liposomal Infusion <br/>+ bortezomib</span> <br/> <span class="Bold">n=324</span></th><th align="center" class="Botrule Toprule" valign="middle"><span class="Bold">Bortezomib <br/> <br/>n=322</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>Kaplan Meier estimate.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio &lt; 1 indicates an advantage for DOXIL liposomal infusion +bortezomib.</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">‡</a> </dt> <dd>Stratified log-rank test.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">§</a> </dt> <dd>RR as per EBMT criteria.</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">¶</a> </dt> <dd>Cochran-Mantel-Haenszel test adjusted for the stratification factors.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Time to Progression</span><a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a> </p> </td><td class="Toprule" valign="top"></td><td class="Toprule" valign="top"></td> </tr> <tr> <td valign="top"> <p class="First">Progression or death due to progression (n)</p> </td><td align="center" valign="middle"> <p class="First">99</p> </td><td align="center" valign="middle"> <p class="First">150</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Censored (n)</p> </td><td align="center" valign="middle"> <p class="First">225</p> </td><td align="center" valign="middle"> <p class="First">172</p> </td> </tr> <tr> <td valign="top"> <p class="First">  Median in days (months)</p> </td><td align="center" valign="middle"> <p class="First">282 (9.3)</p> </td><td align="center" valign="middle"> <p class="First">197 (6.5)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  95% CI</p> </td><td align="center" valign="middle"> <p class="First">250; 338</p> </td><td align="center" valign="middle"> <p class="First">170; 217</p> </td> </tr> <tr> <td valign="middle"> <p class="First">  Hazard ratio<a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a> </p> </td><td align="center" colspan="2" valign="top"> <p class="First">0.55</p> </td> </tr> <tr> <td valign="top"> <p class="First">  (95% CI)</p> </td><td align="center" colspan="2" valign="top"> <p class="First">(0.43, 0.71)</p> </td> </tr> <tr> <td valign="top"> <p class="First">  p-value<a class="Sup" href="#footnote-16" name="footnote-reference-16">‡</a> </p> </td><td align="center" colspan="2" valign="top"> <p class="First">&lt;0.001</p> </td> </tr> <tr> <td valign="middle"> <p class="First"> <span class="Bold">Response (n)</span><a class="Sup" href="#footnote-17" name="footnote-reference-17">§</a> </p> </td><td align="center" valign="top"> <p class="First">303</p> </td><td align="center" valign="top"> <p class="First">310</p> </td> </tr> <tr> <td valign="top"> <p class="First">  % Complete Response (CR) </p> </td><td align="center" valign="top"> <p class="First">5</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">  % Partial Response (PR) </p> </td><td align="center" valign="top"> <p class="First">43</p> </td><td align="center" valign="top"> <p class="First">40</p> </td> </tr> <tr> <td valign="top"> <p class="First">  % CR + PR</p> </td><td align="center" valign="top"> <p class="First">48</p> </td><td align="center" valign="top"> <p class="First">43</p> </td> </tr> <tr> <td valign="middle"> <p class="First">  p-value<a class="Sup" href="#footnote-18" name="footnote-reference-18">¶</a> </p> </td><td align="center" colspan="2" valign="top"> <p class="First">0.25</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Median Duration of Response (months)</span> </p> </td><td align="center" valign="middle"> <p class="First">10.2</p> </td><td align="center" valign="middle"> <p class="First">7.0</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">(95% CI)</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">(10.2; 12.9)</p> </td><td align="center" class="Botrule" valign="middle"> <p class="First">(5.9; 8.3)</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="top"></td> </tr> <tr class="Last"> <td align="center" class="Botrule" valign="top"><a name="fig1"></a><img alt="Figure 1" src="/dailymed/image.cfm?name=image-05.jpg&amp;setid=1c153e9e-4cf2-4ac7-9cf9-16f9b48d7dce"/><p class="MultiMediaCaptionNotCentered">Figure 1 - Time to Progression Kaplan-Meier Curve</p> </td> </tr> </tbody> </table></div>

At 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 a 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.

{ "type": "", "children": [], "text": "" }

Refrigerate unopened vials of DOXIL (doxorubicin hydrochloride liposome injection) at 2°C- 8°C (36°F- 46°F). Do not freeze. Discard unused portion.

DOXIL liposomal infusion is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Cardiomyopathy

Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

Advise patients about the symptoms of infusion related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2)].

Myelosuppression

Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection.

Hand-Foot Syndrome

Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions (5.3)].

Stomatitis

Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis).

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a 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 6 months following treatment with DOXIL liposomal infusion [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with DOXIL liposomal infusion [see Use in Specific Populations (8.2)].

Infertility

Advise 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 Fluids

Inform patients that following DOXIL liposomal infusion administration, a 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.

Manufactured for:Baxter Healthcare CorporationDeerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Manufactured for:Baxter Healthcare CorporationDeerfield, IL 60015 USA\n" }

Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc.

{ "type": "p", "children": [], "text": "Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc." }

HA-30-01-919

{ "type": "p", "children": [], "text": "HA-30-01-919" }

USA - 749706

{ "type": "p", "children": [], "text": "USA - 749706" }

NDC 0338-0063-01

{ "type": "p", "children": [], "text": "NDC 0338-0063-01" }

DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

20 mg in 10 mL(2 mg/mL)

{ "type": "p", "children": [], "text": "20 mg in 10 mL(2 mg/mL)" }

Single-Dose Vial. Discard unused portion.

{ "type": "p", "children": [], "text": "Single-Dose Vial. Discard unused portion." }

LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride" }

FOR INTRAVENOUS INFUSION ONLY

{ "type": "p", "children": [], "text": "FOR INTRAVENOUS INFUSION ONLY" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Cytotoxic

{ "type": "p", "children": [], "text": "Cytotoxic" }

HA-65-01-805

{ "type": "p", "children": [], "text": "HA-65-01-805" }

Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze.

{ "type": "p", "children": [], "text": "Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze." }

See package insert for dosage information.

{ "type": "p", "children": [], "text": "See package insert for dosage information." }

Baxter Healthcare CorporationDeerfield, IL 60015

{ "type": "p", "children": [], "text": "Baxter Healthcare CorporationDeerfield, IL 60015" }

Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries.

{ "type": "p", "children": [], "text": "Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries." }

Bar Code0100303380063017

{ "type": "p", "children": [], "text": "Bar Code0100303380063017" }

Bar Code696988

{ "type": "p", "children": [], "text": "Bar Code696988" }

LOT

{ "type": "p", "children": [], "text": "LOT" }

EXP

{ "type": "p", "children": [], "text": "EXP" }

{ "type": "", "children": [], "text": "" }

US

{ "type": "p", "children": [], "text": "US" }

749703882

{ "type": "p", "children": [], "text": "749703882" }

Barcode

{ "type": "p", "children": [], "text": "Barcode" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

20 mg in 10 mL(2 mg/mL)

{ "type": "p", "children": [], "text": "\n20 mg in 10 mL(2 mg/mL)\n" }

Single-Dose Vial. Discard unused portion.

{ "type": "p", "children": [], "text": "\nSingle-Dose Vial. Discard unused portion.\n" }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "\nLIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride\n" }

FOR INTRAVENOUS INFUSION ONLY AFTER DILUTION.

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUS INFUSION ONLY AFTER DILUTION.\n" }

Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic

{ "type": "p", "children": [], "text": "\nRefrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

Use 5% Dextrose Injection, USP when diluting DOXIL.

{ "type": "p", "children": [], "text": "Use 5% Dextrose Injection, USP when diluting DOXIL." }

Bar Code3 03380 06301 7

{ "type": "p", "children": [], "text": "Bar Code3 03380 06301 7" }

Note: Liposomal formulation.Recommended Dosage:see prescribing information.

{ "type": "p", "children": [], "text": "\nNote: Liposomal formulation.Recommended Dosage:see prescribing information.\n" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "\nLIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride\n" }

Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015Product of Italy

{ "type": "p", "children": [], "text": "Manufactured for:\nBaxter Healthcare Corporation\nDeerfield, IL 60015Product of Italy" }

Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.

{ "type": "p", "children": [], "text": "Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries." }

GTIN 003033800630172D Bar CodeS/NEXPLOT

{ "type": "p", "children": [], "text": "GTIN 003033800630172D Bar CodeS/NEXPLOT" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

Each mL containsdoxorubicin Hydrochloride, 2 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, 1.55 mg; hydrochloric acidand/or sodium hydroxide mayhave been added for pH adjustment (6.0 to 7.0)and sucrose, 94 mg.

{ "type": "p", "children": [], "text": "Each mL containsdoxorubicin Hydrochloride, 2 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, 1.55 mg; hydrochloric acidand/or sodium hydroxide mayhave been added for pH adjustment (6.0 to 7.0)and sucrose, 94 mg." }

HA-80-02-881

{ "type": "p", "children": [], "text": "\nHA-80-02-881\n" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

20 mg in 10 mL(2 mg/mL)

{ "type": "p", "children": [], "text": "20 mg in 10 mL(2 mg/mL)" }

Single-Dose Vial. Discard unused portion.

{ "type": "p", "children": [], "text": "Single-Dose Vial. Discard unused portion." }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride" }

FOR INTRAVENOUSINFUSION ONLY

{ "type": "p", "children": [], "text": "FOR INTRAVENOUSINFUSION ONLY" }

Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic

{ "type": "p", "children": [], "text": "Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Baxter Logo

{ "type": "p", "children": [], "text": "Baxter Logo" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

N3Bar Code0338-0063-01 7

{ "type": "p", "children": [], "text": "N3Bar Code0338-0063-01 7" }

Note: Liposomal formulation.See package insert for dosageinformation.

{ "type": "p", "children": [], "text": "Note: Liposomal formulation.See package insert for dosageinformation." }

USA6943440882

{ "type": "p", "children": [], "text": "USA6943440882" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride" }

Manufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product Taiwan

{ "type": "p", "children": [], "text": "Manufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product Taiwan" }

Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.

{ "type": "p", "children": [], "text": "Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries." }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

GTIN 00303380063017Bar CodeS/NEXPLOT

{ "type": "p", "children": [], "text": "GTIN 00303380063017Bar CodeS/NEXPLOT" }

NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0063-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

Each mL containsdoxorubicin Hydrochloride, 2 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.

{ "type": "p", "children": [], "text": "Each mL containsdoxorubicin Hydrochloride, 2 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-80-02-880

{ "type": "p", "children": [], "text": "HA-80-02-880" }

NDC 0338-0067-01

{ "type": "p", "children": [], "text": "NDC 0338-0067-01" }

DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

50 mg in 25 mL(2 mg/mL)

{ "type": "p", "children": [], "text": "50 mg in 25 mL(2 mg/mL)" }

Single-Dose Vial. Discard unused portion.

{ "type": "p", "children": [], "text": "Single-Dose Vial. Discard unused portion." }

LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "LIPOSOMAL FORMULATION - DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride" }

FOR INTRAVENOUSINFUSION ONLY

{ "type": "p", "children": [], "text": "FOR INTRAVENOUSINFUSION ONLY" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Cytotoxic

{ "type": "p", "children": [], "text": "Cytotoxic" }

HA-65-01-806

{ "type": "p", "children": [], "text": "HA-65-01-806" }

Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze.

{ "type": "p", "children": [], "text": "Refrigerate, 2°-8°C (36°-46°F). Do Not Freeze." }

See package insert for dosageinformation.

{ "type": "p", "children": [], "text": "See package insert for dosageinformation." }

Baxter Healthcare CorporationDeerfield, IL 60015

{ "type": "p", "children": [], "text": "Baxter Healthcare CorporationDeerfield, IL 60015" }

Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries.

{ "type": "p", "children": [], "text": "Baxter, Doxil, and Stealth are registered trademarks of Baxter International Inc., or its subsidiaries." }

Bar Code0100303380067015

{ "type": "p", "children": [], "text": "Bar Code0100303380067015" }

Bar Code696987

{ "type": "p", "children": [], "text": "Bar Code696987" }

LOT

{ "type": "p", "children": [], "text": "LOT" }

EXP

{ "type": "p", "children": [], "text": "EXP" }

{ "type": "", "children": [], "text": "" }

US749704882

{ "type": "p", "children": [], "text": "US749704882" }

Barcode

{ "type": "p", "children": [], "text": "Barcode" }

NDC 0338-0067-01

{ "type": "p", "children": [], "text": "NDC 0338-0067-01" }

DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nDOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

50 mg in 25 mL(2 mg/mL)

{ "type": "p", "children": [], "text": "\n50 mg in 25 mL(2 mg/mL)\n" }

Single-Dose Vial. Discard unused portion.

{ "type": "p", "children": [], "text": "\nSingle-Dose Vial. Discard unused portion.\n" }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "\nLIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride\n" }

FOR INTRAVENOUSINFUSION ONLYAFTER DILUTION.

{ "type": "p", "children": [], "text": "\nFOR INTRAVENOUSINFUSION ONLYAFTER DILUTION.\n" }

Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic

{ "type": "p", "children": [], "text": "\nRefrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Baxter Logo

{ "type": "p", "children": [], "text": "\nBaxter Logo\n" }

NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

Use 5% Dextrose Injection, USPwhen diluting DOXIL.

{ "type": "p", "children": [], "text": "Use 5% Dextrose Injection, USPwhen diluting DOXIL." }

Bar Code3 03380 06701 5

{ "type": "p", "children": [], "text": "Bar Code3 03380 06701 5" }

Note: Liposomal formulation.Recommended Dosage:see prescribing information.

{ "type": "p", "children": [], "text": "\nNote: Liposomal formulation.Recommended Dosage:see prescribing information.\n" }

NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "\nLIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride\n" }

Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015Product of Italy

{ "type": "p", "children": [], "text": "Manufactured for:\nBaxter Healthcare Corporation\nDeerfield, IL 60015Product of Italy" }

Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.

{ "type": "p", "children": [], "text": "Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries." }

GTIN 003033800670152D Bar CodeS/NEXPLOT

{ "type": "p", "children": [], "text": "GTIN 003033800670152D Bar CodeS/NEXPLOT" }

NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "\nNDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)\n" }

Each mL containsdoxorubicin Hydrochloride, 2 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, 1.55 mg;hydrochloric acid and/or sodium hydroxide may have been addedfor pH adjustment (6.0 to 7.0)and sucrose, 94 mg.

{ "type": "p", "children": [], "text": "Each mL containsdoxorubicin Hydrochloride, 2 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, 1.55 mg;hydrochloric acid and/or sodium hydroxide may have been addedfor pH adjustment (6.0 to 7.0)and sucrose, 94 mg." }

HA-80-02-883

{ "type": "p", "children": [], "text": "\nHA-80-02-883\n" }

NDC 0338-0067-01

{ "type": "p", "children": [], "text": "NDC 0338-0067-01" }

DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

50 mg in 25 mL(2 mg/mL)

{ "type": "p", "children": [], "text": "50 mg in 25 mL(2 mg/mL)" }

Single-Dose Vial. Discard unused portion.

{ "type": "p", "children": [], "text": "Single-Dose Vial. Discard unused portion." }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride" }

FOR INTRAVENOUSINFUSION ONLY

{ "type": "p", "children": [], "text": "FOR INTRAVENOUSINFUSION ONLY" }

Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic

{ "type": "p", "children": [], "text": "Refrigerate, 2°-8°C(36°-46°F). Do Not Freeze.Cytotoxic" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Baxter Logo

{ "type": "p", "children": [], "text": "Baxter Logo" }

NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

N3Bar Code0338-0067-01 5

{ "type": "p", "children": [], "text": "N3Bar Code0338-0067-01 5" }

Note: Liposomal formulation.See package insert for dosageinformation.

{ "type": "p", "children": [], "text": "Note: Liposomal formulation.See package insert for dosageinformation." }

USA693385882

{ "type": "p", "children": [], "text": "USA693385882" }

Bar Code

{ "type": "p", "children": [], "text": "Bar Code" }

NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride

{ "type": "p", "children": [], "text": "LIPOSOMAL FORMULATION -DO NOT SUBSTITUTEFOR DOXORUBICIN Hydrochloride" }

Manufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product of Taiwan

{ "type": "p", "children": [], "text": "Manufactured for:Baxter Healthcare CorporationDeerfield, IL 60015Product of Taiwan" }

Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries.

{ "type": "p", "children": [], "text": "Baxter, Doxil, and Stealthare registered trademarksof Baxter International Inc.,or its subsidiaries." }

NDC 0338-0067-01DOXIL(DOXOrubicinHydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0067-01DOXIL(DOXOrubicinHydrochlorideliposome injection)" }

GTIN 00303380067015Bar CodeS/NEXPLOT

{ "type": "p", "children": [], "text": "GTIN 00303380067015Bar CodeS/NEXPLOT" }

NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)

{ "type": "p", "children": [], "text": "NDC 0338-0067-01DOXIL(DOXOrubicin Hydrochlorideliposome injection)" }

Each mL containsdoxorubicin Hydrochloride, 2 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.

{ "type": "p", "children": [], "text": "Each mL containsdoxorubicin Hydrochloride, 2 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

{ "type": "p", "children": [], "text": "HA-80-02-882" }

Doxorubicin Hydrochloride Injection is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.

Doxorubicin Hydrochloride Injection is indicated for the treatment of

The recommended dosage of Doxorubicin Hydrochloride Injection is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles.

Cardiomyopathy

Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1)].

Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin greater than 5 mg/dL) [see Contraindications (4)].

Dosage modifications for Doxorubicin Hydrochloride Injection in patients with elevated serum total bilirubin concentrations [see Warnings and Precautions (5.5), Use in Specific Populations (8.6)] are provided in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1. Recommended Dosage Modification for Elevated Serum Total Bilirubin</span> </caption> <col width="50%"/> <col width="50%"/> <thead> <tr class="First Last"> <th align="center" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Serum Total Bilirubin Concentration</span></th><th align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Dosage Modification</span></th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.2–3 mg/dL</p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First">50%</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3.1–5 mg/dL</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">75%</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Greater than 5 mg/dL</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">Do not initiate Doxorubicin Hydrochloride Injection; <br/>discontinue Doxorubicin Hydrochloride Injection</p> </td> </tr> </tbody> </table></div>

Doxorubicin Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1

Preparation

Dilution of Doxorubicin Hydrochloride Injection

Administration

Administration by Intravenous Injection

Administration by Continuous Intravenous Infusion

Management of Suspected Extravasation

Immediately discontinue Doxorubicin Hydrochloride Injection for burning or stinging sensation or other evidence indicating peri-venous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

Management of Contact with Skin or Eyes

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.

Incompatibility with Other Drugs

Do not admix Doxorubicin Hydrochloride Injection with other drugs. If Doxorubicin Hydrochloride Injection is mixed with heparin or fluorouracil, a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride.

Doxorubicin Hydrochloride Injection:

{ "type": "p", "children": [], "text": "Doxorubicin Hydrochloride Injection: " }

20 mg/10 mL clear red solution in a single‑dose vial

{ "type": "p", "children": [], "text": "20 mg/10 mL clear red solution in a single‑dose vial" }

10 mg/5 mL clear red solution in a single‑dose vial

{ "type": "p", "children": [], "text": "10 mg/5 mL clear red solution in a single‑dose vial" }

Doxorubicin Hydrochloride Injection are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Doxorubicin Hydrochloride Injection are contraindicated in patients with:" }

{ "type": "", "children": [], "text": "" }

Cardiomyopathy

Doxorubicin hydrochloride can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy is generally proportional to the cumulative exposure. Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for doxorubicin hydrochloride. Cardiomyopathy may develop during treatment or up to several years after completion of treatment and can include decrease in LVEF and signs and symptoms of congestive heart failure (CHF). The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin hydrochloride, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2, and 6 to 20% at a dose of 500 mg/m2, when doxorubicin hydrochloride is administered every 3 weeks. There is an additive or potentially synergistic increase in the risk of cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents, such as cyclophosphamide and trastuzumab.

Pericarditis and myocarditis have also been reported during or following doxorubicin hydrochloride treatment.

Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of Doxorubicin Hydrochloride Injection, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as the cumulative dose exceeds 300 mg/m2. Use the same method of assessment of LVEF at all time points [see Use in Specific Populations (8.4)]. Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Dosage and Administration (2.3)].

Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin hydrochloride administration in patients who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m2 and who will continue to receive doxorubicin hydrochloride.

Arrhythmias

Doxorubicin hydrochloride can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin hydrochloride administration and at any time point during treatment. Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia, can occur. Electrocardiographic changes, including non-specific ST-T wave changes, atrioventricular and bundle-branch block can also occur. These electrocardiographic changes may be transient and self-limited and may not require a dosage modification of doxorubicin hydrochloride.

The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin hydrochloride. Cumulative incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate trials involving the adjuvant treatment of women with breast cancer. These leukemias generally occur within 1 to 3 years of treatment.

Extravasation of doxorubicin hydrochloride can cause severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. Extravasation should be considered if a patient experiences a burning or stinging sensation or shows other evidence indicating peri-venous infiltration or extravasation; however, extravasation may be present in patients who do not experience a stinging or burning sensation or when blood return is present on aspiration of the infusion needle.

When given via a peripheral venous line, infuse Doxorubicin Hydrochloride Injection over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation.

If extravasation is suspected, immediately discontinue the intravenous injection or continuous intravenous infusion [see Dosage and Administration (2.5)]. Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. In adults, if appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.

Doxorubicin hydrochloride can cause myelosuppression. In Study 1, the incidence of severe myelosuppression was: grade 4 leukopenia (0.3%), grade 3 leukopenia (3%), and grade 4 thrombocytopenia (0.1%). A dose-dependent, reversible neutropenia is the predominant manifestation of myelosuppression from doxorubicin hydrochloride. When doxorubicin hydrochloride is administered every 21 days, the neutrophil count reaches its nadir 10 to 14 days after administration with recovery usually occurring by day 21.

Obtain complete blood counts prior to each treatment and carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Delay next dose of Doxorubicin Hydrochloride Injection if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction.

The clearance of doxorubicin is decreased in patients with elevated serum bilirubin with an increased risk of toxicity [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Contraindications (4)]. Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum bilirubin levels of 1.2 to 5 mg/dL [see Dosage and Administration (2.4)]. Obtain liver tests including ALT, AST, alkaline phosphatase, and bilirubin prior to and during therapy.

Doxorubicin hydrochloride can induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.

Doxorubicin hydrochloride can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive doxorubicin hydrochloride after prior radiation therapy.

Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment. Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Breast Cancer

The safety data below were collected from 1492 women who received doxorubicin hydrochloride at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 2. No treatment-related deaths were reported in patients on either arm of the study.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 2. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes</span> </caption> <col width="35%"/> <col width="33%"/> <col width="32%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Adverse Reactions</span></th><th align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">AC</span><a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> <br/> <span class="Bold">N = 1492</span></th><th align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Conventional CMF</span> <br/> <span class="Bold">N = 739</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">%</span></th><th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">%</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">AC = doxorubicin hydrochloride, cyclophosphamide; CMF = cyclophosphamide, methotrexate, fluorouracil</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Includes pooled data from patients who received either AC for 4 cycles or AC for 4 cycles followed by CMF for 3 cycles</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Alopecia</p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First">92</p> </td><td align="center" class="Botrule Rrule Toprule" valign="middle"> <p class="First">71</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">Vomiting</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">     Vomiting ≤12 hours</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">34</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">25</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">     Vomiting &gt;12 hours</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">37</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Intractable</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">Leukopenia</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">     Grade 3 (1,000–1,999 /mm<span class="Sup">3</span>)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">3.4</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">9.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 4 (&lt;1000 /mm<span class="Sup">3</span>)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0.3</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Shock, sepsis</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Systemic infection</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">Cardiac dysfunction</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">     Asymptomatic</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.2</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.1</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">     Transient</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.1</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Symptomatic</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0.1</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">Thrombocytopenia</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">     Grade 3 (25,000–49,999 /mm<span class="Sup">3</span>)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.3</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 4 (&lt;25,000 /mm<span class="Sup">3</span>)</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0.1</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during postapproval use of Doxorubicin Hydrochloride Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac – Cardiogenic shock

Cutaneous – Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia

Gastrointestinal – Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa

Hypersensitivity – Anaphylaxis

Laboratory Abnormalities – Increased ALT, increased AST

Neurological – Peripheral sensory and motor neuropathy, seizures, coma

Ocular – Conjunctivitis, keratitis, lacrimation

Vascular – Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism

Other – Malaise/asthenia, fever, chills, weight gain

Inhibitors of CYP3A4, CYP2D6, and P-gp

Concomitant use of doxorubicin hydrochloride with inhibitors of CYP3A4, CYP2D6, or P-glycoprotein (P-gp), increased concentrations of doxorubicin, which may increase the incidence and severity of adverse reactions of doxorubicin hydrochloride. Avoid concomitant use of Doxorubicin Hydrochloride Injection with inhibitors of CYP3A4, CYP2D6, or P-gp.

Inducers of CYP3A4, CYP2D6, or P-gp

Concomitant use of doxorubicin hydrochloride with inducers of CYP3A4, CYP2D6, or P-gp may decrease the concentration of doxorubicin. Avoid concomitant use of Doxorubicin Hydrochloride Injection with inducers of CYP3A4, CYP2D6, or P-gp.

Paclitaxel

Paclitaxel, when given prior to doxorubicin hydrochloride, increases the plasma-concentrations of doxorubicin and its metabolites. Administer Doxorubicin Hydrochloride Injection prior to paclitaxel if used concomitantly.

Concomitant use of trastuzumab and doxorubicin hydrochloride results in an increased risk of cardiac dysfunction. Avoid concomitant administration of Doxorubicin Hydrochloride Injection and trastuzumab [see Warnings and Precautions (5.1)].

Patients receiving doxorubicin after stopping treatment with trastuzumab may also be at an increased risk of developing cardiotoxicity. Trastuzumab may persist in the circulation for up to 7 months. Therefore, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, carefully monitor cardiac function.

Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin hydrochloride-containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with doxorubicin hydrochloride-based chemotherapy resulted in a significantly lower tumor response rate (48% vs. 63%; p = 0.007) and shorter time to progression compared to doxorubicin hydrochloride-based chemotherapy alone.

Doxorubicin hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m2 intravenously daily for 5 days per cycle every 2–3 weeks) and doxorubicin hydrochloride (50 mg/m2 intravenous once per cycle every 2–3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by increased total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

Risk Summary

Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and embryotoxic in rabbits when administered during organogenesis at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m2 (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Doxorubicin hydrochloride was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) when administered during the period of organogenesis in rats. Teratogenicity and embryotoxicity were also seen using discrete periods of treatment. The most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies. Doxorubicin hydrochloride was embryotoxic (increase in embryo‑fetal deaths) and abortifacient at 0.4 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) in rabbits when administered during the period of organogenesis.

Risk Summary

Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m2 of doxorubicin hydrochloride given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours. There are no data on the effects of doxorubicin hydrochloride on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Doxorubicin Hydrochloride Injection and for 10 days after the final dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Doxorubicin Hydrochloride Injection.

Contraception

Females

Doxorubicin Hydrochloride Injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use highly effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment. [see Use in Specific Populations (8.1)].

Males

Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Due to the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment [see Nonclinical Toxicology (13.1)]. Males with pregnant partners should use condoms during treatment and for at least 10 days after the final dose [see Nonclinical Toxicology (13.1), Use in Specific Populations (8.1)].

Infertility

Females

In females of reproductive potential, Doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment [see Nonclinical Toxicology (13.1)].

Males

Doxorubicin hydrochloride 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 Nonclinical Toxicology (13.1)].

Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride. Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary.

There are no recommended dose adjustments based on age. Doxorubicin clearance was increased in patients aged 2 years to 20 years as compared to adults, while doxorubicin clearance was similar in infants less than 2 years as compared to adults [see Clinical Pharmacology (12.3)].

Clinical experience in patients who were 65 years of age and older who received doxorubicin hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients.

The clearance of doxorubicin was reduced in patients with elevated serum total bilirubin levels. Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5 mg/dL) [see Contraindications (4)]. Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum total bilirubin levels greater than 1.2 mg/dL [See Dosage and Administration (2.4), Warnings and Precautions (5.5)].

Few cases of overdose have been described.

{ "type": "p", "children": [], "text": "Few cases of overdose have been described." }

A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin hydrochloride (300 mg/m2) in one day. He was treated with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump inhibitor and antimicrobial prophylaxis. The patient suffered sinus tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis. The patient recovered completely 26 days after the overdose.

{ "type": "p", "children": [], "text": "A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin hydrochloride (300 mg/m2) in one day. He was treated with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump inhibitor and antimicrobial prophylaxis. The patient suffered sinus tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis. The patient recovered completely 26 days after the overdose. " }

A 17-year-old girl with osteogenic sarcoma received 150 mg of doxorubicin hydrochloride daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4–7 after the overdose and chills and pyrexia on day 7. The patient was treated with antibiotics and platelets and recovered 18 days after overdose.

{ "type": "p", "children": [], "text": "A 17-year-old girl with osteogenic sarcoma received 150 mg of doxorubicin hydrochloride daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4–7 after the overdose and chills and pyrexia on day 7. The patient was treated with antibiotics and platelets and recovered 18 days after overdose." }

Doxorubicin hydrochloride is an anthracycline topoisomerase inhibitor isolated from cultures of Streptomyces peucetius var. caesius. The chemical name of doxorubicin hydrochloride is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. The chemical structure of doxorubicin hydrochloride is:

{ "type": "p", "children": [], "text": "Doxorubicin hydrochloride is an anthracycline topoisomerase inhibitor isolated from cultures of Streptomyces peucetius var. caesius. The chemical name of doxorubicin hydrochloride is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. The chemical structure of doxorubicin hydrochloride is:" }

Doxorubicin Hydrochloride Injection, for intravenous use is a clear red, sterile, isotonic aqueous solution provided in vials containing 10 mg/5 mL doxorubicin hydrochloride (equivalent to 9.37 mg of doxorubicin free base), 20 mg/10 mL doxorubicin hydrochloride (equivalent to 18.74 mg of doxorubicin free base). The drug product has demonstrated inherent antimicrobial activity suitable for a multiple dose presentation. Each milliliter of solution contains 2 mg of doxorubicin hydrochloride and 9 mg of sodium chloride. The pH of the solution is adjusted to 3.0 with hydrochloric acid, USP.

{ "type": "p", "children": [], "text": "Doxorubicin Hydrochloride Injection, for intravenous use is a clear red, sterile, isotonic aqueous solution provided in vials containing 10 mg/5 mL doxorubicin hydrochloride (equivalent to 9.37 mg of doxorubicin free base), 20 mg/10 mL doxorubicin hydrochloride (equivalent to 18.74 mg of doxorubicin free base). The drug product has demonstrated inherent antimicrobial activity suitable for a multiple dose presentation. Each milliliter of solution contains 2 mg of doxorubicin hydrochloride and 9 mg of sodium chloride. The pH of the solution is adjusted to 3.0 with hydrochloric acid, USP." }

The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.

Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m2 to 70 mg/m2.

Distribution

The distribution half-life is approximately 5 minutes. Steady-state distribution volume ranges from 809 L/m2 to 1214 L/m2. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin up to 1.1 µg/mL.

Doxorubicin does not cross the blood brain barrier.

Elimination

Plasma clearance is ranges from 324 mL/min/m2 to 809 mL/min/m2. The terminal half-life is 20 hours to 48 hours.

Metabolism

Doxorubicin is a substrate of CYP3A4, CYP2D6, and P-gp.

Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin hydrochloride.

Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5.

Excretion

Plasma clearance is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5% to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days.

Specific Populations

Weight

Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

Pediatric Patients

Following administration of doses ranging from 10 mg/m2 to 75 mg/m2 of doxorubicin hydrochloride to 60 patients ranging from 2 months to 20 years, doxorubicin clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 patients ranging from 2 to 20 years (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older patients (ranging from 2 to 20 years) and approached the range of clearance values determined in adults [see Use in Specific Populations (8.4)].

Sex

A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours).

Patients with Hepatic Impairment

The clearance of doxorubicin and doxorubicinol was reduced in patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.4), Warnings and Precautions (5.5)].

Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2)]. Doxorubicin hydrochloride was 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.

Doxorubicin hydrochloride decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area).

A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

The efficacy of doxorubicin hydrochloride-containing regimens for the post-operative, adjuvant treatment of surgically resected breast cancer was evaluated in a meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG meta-analyses compared cyclophosphamide, methotrexate, and fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and doxorubicin hydrochloride-containing regimens with CMF as an active control (6 trials including 3510 patients). Data from the meta-analysis of trials comparing CMF to no therapy were used to establish the historical treatment effect size for CMF regimens. The major efficacy outcome measures were disease-free survival (DFS) and overall survival (OS).

Of the 3510 women (2157 received doxorubicin hydrochloride-containing regimens and 1353 received CMF treatment) with early breast cancer involving axillary lymph nodes included in the six trials from the meta-analyses, approximately 70% were premenopausal and 30% were postmenopausal.

At the time of the meta-analysis, 1745 first recurrences and 1348 deaths had occurred. The analyses demonstrated that doxorubicin hydrochloride-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS with a hazard ratio (HR) of 0.91 (95% CI: 0.82, 1.01) and on OS with a HR of 0.91 (95% CI: 0.81, 1.03). Efficacy results are provided in Table 3 and Figures 1 and 2.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 3. Summary of Randomized Trials Comparing Doxorubicin Hydrochloride-Containing Regimens Versus CMF in Meta-Analysis</span> </caption> <col width="19%"/> <col width="18%"/> <col width="17%"/> <col width="12%"/> <col width="18%"/> <col width="17%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Study </span> <br/> <span class="Bold">(starting year)</span></th><th align="center" class="Botrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Regimens</span></th><th align="center" class="Botrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">No. of Cycles</span></th><th align="center" class="Botrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">No. of Patients</span></th><th align="center" class="Botrule Rrule Toprule" colspan="2" valign="middle"><span class="Bold">Doxorubicin Hydrochloride-Containing Regimens vs. CMF</span> <br/> <span class="Bold">HR</span><a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a><span class="Bold"> (95% CI)</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">DFS</span></th><th align="center" class="Botrule Rrule" valign="middle"><span class="Bold">OS</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="6" valign="top"><span class="Bold">Abbreviations:</span> DFS = disease free survival; OS = overall survival; AC = doxorubicin hydrochloride, cyclophosphamide; AVbCMF = doxorubicin hydrochloride, vinblastine, cyclophosphamide, methotrexate, fluorouracil; CMF = cyclophosphamide, methotrexate, fluorouracil; CMFVA = cyclophosphamide, methotrexate, fluorouracil, vincristine, doxorubicin hydrochloride; FAC = fluorouracil, doxorubicin hydrochloride, cyclophosphamide; FACV = fluorouracil, doxorubicin hydrochloride, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval</td> </tr> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Hazard ratio of less than 1 indicates that the treatment with doxorubicin hydrochloride-containing regimens is associated with lower risk of disease recurrences or death compared to the treatment with CMF.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">‡</a> </dt> <dd>Patients received alternating cycles of AVb and CMF.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">NSABP B-15<br/>(1984)</p> </td><td align="center" class="Rrule Toprule" valign="middle"> <p class="First">AC</p> </td><td align="center" class="Rrule Toprule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Rrule Toprule" valign="middle"> <p class="First">1562<a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a> </p> </td><td align="center" class="Rrule Toprule" valign="middle"> <p class="First">0.93 (0.82, 1.06)</p> </td><td align="center" class="Rrule Toprule" valign="middle"> <p class="First">0.97 (0.83, 1.12)</p> </td> </tr> <tr> <td align="center" class="Rrule" valign="middle"> <p class="First">CMF</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">776</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" rowspan="2" valign="middle"> <p class="First">SECSG 2 <br/>(1976)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">FAC</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">260</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.86 (0.66, 1.13)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.93 (0.69, 1.26)</p> </td> </tr> <tr> <td align="center" class="Rrule" valign="middle"> <p class="First">CMF</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">268</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" rowspan="2" valign="middle"> <p class="First">ONCOFRANCE<br/>(1978)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">FACV</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">12</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">138</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.71 (0.49, 1.03)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.65 (0.44, 0.96)</p> </td> </tr> <tr> <td align="center" class="Rrule" valign="middle"> <p class="First">CMF</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">12</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">113</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" rowspan="2" valign="middle"> <p class="First">SE Sweden BCG A <br/>(1980)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">AC</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">21</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.59 (0.22, 1.61)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.53 (0.21, 1.37)</p> </td> </tr> <tr> <td align="center" class="Rrule" valign="middle"> <p class="First">CMF</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">22</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Lrule Rrule" rowspan="2" valign="middle"> <p class="First">NSABC Israel Br0283<br/> (1983)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">AVbCMF<a class="Sup" href="#footnote-4" name="footnote-reference-4">‡</a> </p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">4<br/>6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">55</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.91 (0.53, 1.57)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.88 (0.47, 1.63)</p> </td> </tr> <tr> <td align="center" class="Rrule" valign="middle"> <p class="First">CMF</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">50</p> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">Austrian BCSG 3 <br/>(1984)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">CMFVA</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">121</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">1.07 (0.73, 1.55)</p> </td><td align="center" class="Rrule" valign="middle"> <p class="First">0.93 (0.64, 1.35)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="middle"> <p class="First">CMF</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">124</p> </td><td class="Botrule Rrule" valign="middle"></td><td class="Botrule Rrule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Combined Studies</span> </p> </td><td class="Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First">Doxorubicin Hydrochloride-Containing Regimen</p> </td><td align="center" class="Lrule Rrule Toprule" valign="middle"> <p class="First">      <span class="Bold">2157</span> </p> </td><td align="center" class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">0.91 (0.82, 1.01)</span> </p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">0.91 (0.81, 1.03)</span> </p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule" valign="middle"> <p class="First">CMF</p> </td><td class="Botrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">      <span class="Bold">1353</span> </p> </td> </tr> </tbody> </table></div>

Figure 1. Meta-analysis of Disease-Free Survival

Figure 2. Meta-analysis of Overall Survival

{ "type": "", "children": [], "text": "" }

Doxorubicin Hydrochloride Injection

Doxorubicin Hydrochloride Injection is a sterile, isotonic solution, available in single-dose ONCO-TAIN® glass vials:

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Unit of Sale</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Total Strength/Total Volume</span> </p> <p> <span class="Bold">(Concentration)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">NDC 0069-4031-12</span> </p> <p>Carton of 1 Single-dose Vial</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20 mg/10 mL</p> <p>(2 mg/mL)</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NDC 0069-5629-05</span> </p> <p>Carton of 1 Single-dose Vial</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 mg/5 mL</p> <p>(2 mg/mL)</p> </td> </tr> </tbody> </table></div>

ONCO-TAIN® is the vial external protection system.

Retain in carton until contents are used. For single-dose ONCO-TAIN® glass vials, discard unused portion.

Storage

Store all vials at 2°C to 8°C (36°F to 46°F). Protect from light.

Storage of Doxorubicin Hydrochloride Injection under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15ºC to 30ºC (59ºF to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Handling and Disposal

Doxorubicin Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1

Cardiomyopathy

Advise patients that Doxorubicin Hydrochloride Injection can cause irreversible myocardial damage and to contact a healthcare provider for symptoms of heart failure during or after treatment [see Warnings and Precautions (5.1)].

Secondary Malignancy

Advise patients of the increased risk of treatment-related leukemia [see Warnings and Precautions (5.2)].

Myelosuppression

Advise patients that Doxorubicin Hydrochloride Injection can reduce the absolute neutrophil count resulting in an increased risk of infection and to contact a healthcare provider for new onset fever or symptoms of infection [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment [see Warnings and Precautions (5.8), Use in Specific Populations (8.3)].

Advise patients that Doxorubicin Hydrochloride Injection may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects. Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment [see Warnings and Precautions (5.8), Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with Doxorubicin Hydrochloride Injection and for 10 days after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of the potential loss of fertility from Doxorubicin Hydrochloride Injection [see Use in Specific Populations (8.3)].

Gastrointestinal and Dermatologic Adverse Reactions

Advise patients that Doxorubicin Hydrochloride Injection can cause nausea, vomiting, diarrhea, mouth/oral pain and sores and to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking [see Adverse Reactions (6)]. Advise patients that Doxorubicin Hydrochloride Injection can cause alopecia [see Adverse Reactions (6.1)].

Administration

Advise patients that Doxorubicin Hydrochloride Injection can cause their urine to appear red for 1 to 2 days after administration.

This product’s labeling may have been updated. For the most current prescribing information, please visit www.pfizer.com.

{ "type": "p", "children": [], "text": "This product’s labeling may have been updated. For the most current prescribing information, please visit www.pfizer.com. " }

Distributed by

{ "type": "p", "children": [], "text": "Distributed by" }

Pfizer Labs

{ "type": "p", "children": [], "text": "Pfizer Labs" }

Division of Pfizer Inc.

{ "type": "p", "children": [], "text": "Division of Pfizer Inc." }

New York, NY 10001

{ "type": "p", "children": [], "text": "New York, NY 10001" }

Novaplus is a registered trademark of Vizient, Inc.

{ "type": "p", "children": [], "text": "Novaplus is a registered trademark of Vizient, Inc." }

LAB-1602-1.0

{ "type": "p", "children": [], "text": "LAB-1602-1.0" }

<div class="scrollingtable"><table width="100%"> <col width="3%"/> <col width="34%"/> <col width="28%"/> <col width="34%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Patient Information</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">DOXORUBICIN</span> (dok-s<span class="Italics">uh</span>-<span class="Bold">roo</span>-b<span class="Italics">uh</span>-sin) <span class="Bold">HYDROCHLORIDE</span> <br/> <span class="Bold">injection, for intravenous use </span> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <a name="_Refwhatisthemostimportantinformation"></a><span class="Bold">What is the most important information I should know about Doxorubicin?</span> <br/> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Doxorubicin may cause serious side effects including:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Heart muscle problems.</span> Doxorubicin can cause heart muscle damage that may lead to heart failure. Heart failure means your heart does not pump blood well. Heart failure is irreversible in some cases and can lead to death. Heart failure can happen during your treatment with Doxorubicin or months to years after stopping treatment. Your risk of heart muscle damage increases with higher total amounts of Doxorubicin that you receive in your lifetime. Your risk of heart failure is higher if you: <br/> <dl> <dt>o</dt> <dd>have other heart problems</dd> <dt>o</dt> <dd>have had or are currently receiving radiation therapy to your chest </dd> <dt>o</dt> <dd>have had treatment with certain other anti-cancer medicines</dd> <dt>o</dt> <dd>take other medicines that can have severe side effects on your heart <br/> </dd> <dt> </dt> <dd>Tell your healthcare provider if you get any of these symptoms of heart failure during or after treatment with Doxorubicin:</dd> </dl> </dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"></td><td valign="top"> <dl> <dt>•</dt> <dd>extreme tiredness or weakness</dd> <dt>•</dt> <dd>shortness of breath</dd> </dl> </td><td valign="top"> <dl> <dt>•</dt> <dd>fast heartbeat</dd> <dt>•</dt> <dd>swelling of your feet and ankles</dd> </dl> </td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"></td><td class="Rrule" colspan="3" valign="top"> <p class="First">Your healthcare provider will do tests to check the strength of your heart muscle before, during, and after your treatment with Doxorubicin.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Heart rhythm problems.</span> Doxorubicin can cause serious heart rhythm problems that may lead to death. This can happen during your infusion, within a few hours after your infusion or anytime during treatment with Doxorubicin. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast, irregular or slow, or you feel lightheaded, dizzy, short of breath, chest discomfort or you faint. </dd> <dt>•</dt> <dd> <span class="Bold">Risk of new cancers.</span> You may have an increased risk of developing certain blood cancers called acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with Doxorubicin. Talk with your healthcare provider about your risk of developing new cancers if you receive Doxorubicin. </dd> <dt>•</dt> <dd> <span class="Bold">Skin damage at or near the vein where Doxorubicin is given.</span> Doxorubicin can damage the skin if it leaks out of the vein and might cause blisters, skin sores or severe tissue damage, which may require skin grafts. Tell your healthcare provider if you get burning or stinging during your infusion. </dd> <dt>•</dt> <dd> <span class="Bold">Decreased blood cell counts.</span> Doxorubicin can cause a decrease in neutrophils (a type of white blood cell important in fighting bacterial infections) and platelets (important for clotting and to control bleeding). This may lead to a serious infection, the need for blood transfusions, treatment in a hospital or death. Your healthcare provider will check your blood cell counts before each infusion and during treatment with Doxorubicin. Call your healthcare provider right away if you get a fever (temperature of 100.4°F or higher) or chills with shivering.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What is Doxorubicin?</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First">Doxorubicin is a prescription medicine used to treat certain types of cancers. Doxorubicin may be used alone or along with other anti-cancer medicines.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Do not receive Doxorubicin if:</span> <br/> </p> <dl> <dt>•</dt> <dd>you have had a recent heart attack (within the past 4 to 6 weeks) or have severe heart problems.</dd> <dt>•</dt> <dd>your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy.</dd> <dt>•</dt> <dd>you have severe liver problems.</dd> <dt>•</dt> <dd>you have had a severe allergic reaction to Doxorubicin.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Before you receive Doxorubicin, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>have heart problems including heart failure.</dd> <dt>•</dt> <dd>are currently receiving radiation therapy or plan to receive radiation to the chest.</dd> <dt>•</dt> <dd>have liver problems.</dd> <dt>•</dt> <dd>have had an allergic reaction to doxorubicin.</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. You should not become pregnant during treatment with Doxorubicin. Tell your healthcare provider right away if you become pregnant or think you may be pregnant.<br/> <span class="Bold">Females who are able to become pregnant</span>: <dl> <dt>o</dt> <dd>Your healthcare provider will check to see if you are pregnant before you start treatment with Doxorubicin.</dd> <dt>o</dt> <dd>You should use effective birth control (contraception) during treatment with Doxorubicin and for 6 months after treatment.</dd> </dl> </dd> <dt> </dt> <dd> <span class="Bold">Males</span>:<dl> <dt>o</dt> <dd>Doxorubicin can affect your sperm and could cause birth defects.</dd> <dt>o</dt> <dd>If you have a female partner who can become pregnant, you should use effective birth control during treatment with Doxorubicin and for 3 months after treatment.</dd> <dt>o</dt> <dd>If you have a pregnant partner, you should use condoms during treatment with Doxorubicin and for at least 10 days after the final dose.</dd> <dt>o</dt> <dd>Talk to your healthcare provider about birth control methods that may be right for you.</dd> </dl> </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. Doxorubicin can pass into your breast milk. Do not breastfeed during treatment with Doxorubicin and for 10 days after the final dose. Talk to your healthcare provider about the best way to feed your baby during this time. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">How will I receive Doxorubicin? </span> </p> <dl> <dt>•</dt> <dd>Doxorubicin will be given to you into your vein through an intravenous (IV) line.</dd> <dt>•</dt> <dd>Your healthcare provider will do blood tests to check for side effects during treatment with Doxorubicin.</dd> <dt>•</dt> <dd>Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Doxorubicin. </dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of Doxorubicin?</span> <br/> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Doxorubicin may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd>See <span class="Bold">“<a href="#_Refwhatisthemostimportantinformation">What is the most important information I should know about Doxorubicin?</a>”</span> </dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">The most common side effects of Doxorubicin include:</span> </p> <dl> <dt>•</dt> <dd>total hair loss (alopecia). Your hair may re-grow after your treatment.</dd> <dt>•</dt> <dd>nausea</dd> <dt>•</dt> <dd>vomiting</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Other side effects:</span> </p> <dl> <dt>•</dt> <dd>Red colored urine. You may have red colored urine for 1 to 2 days after your infusion of Doxorubicin. This is normal. Tell your healthcare provider if it does not stop in a few days, or if you see what looks like blood or blood clots in your urine. </dd> <dt>•</dt> <dd>Call your healthcare provider if you have severe symptoms that prevent you from eating or drinking, such as:<dl> <dt>o</dt> <dd>nausea</dd> <dt>o</dt> <dd>vomiting</dd> <dt>o</dt> <dd>diarrhea</dd> <dt>o</dt> <dd>mouth pain or sores</dd> </dl> </dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Doxorubicin may cause fertility problems in males.</span> This could affect your ability to father a child. Talk to your healthcare provider if this is a concern for you. <br/> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Doxorubicin may cause fertility problems in females.</span> Your periods (menstrual cycle) may completely stop when you receive Doxorubicin. Your periods may or may not return following treatment. Early menopause has also happened. Talk to your healthcare provider if this is a concern for you. </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First">These are not all of the possible side effects of Doxorubicin.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of Doxorubicin.</span> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First">You can ask your pharmacist or healthcare provider for information about Doxorubicin that is written for health professionals.</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in Doxorubicin?</span> <br/> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Active ingredient:</span> doxorubicin hydrochloride<br/> </p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Inactive ingredients for Doxorubicin Hydrochloride Injection:</span> sodium chloride, and hydrochloric acid, USP.</p> <p>Distributed by</p> <p>Pfizer Labs</p> <p>Division of Pfizer Inc.</p> <p>New York, NY 10001</p> </td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"><a name="id2469"></a><img alt="Logo" src="/dailymed/image.cfm?name=doxorubicin-04a.jpg&amp;setid=d31d7f58-66d0-4826-b6b5-5914c031965f"/></td> </tr> <tr> <td class="Lrule Rrule" colspan="4" valign="top"> <p class="First">Novaplus is a registered trademark of Vizient, Inc.</p> <p>LAB-1603-1.0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <br/>For more information, call 1-800-438-1985 or visit <a href="https://www.pfizer.com/">www.pfizer.com</a>.</p> </td> </tr> <tr class="Last"> <td class="Botrule" colspan="3" valign="top"> <p class="First">This Patient Information has been approved by the U.S. Food and Drug Administration.</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Revised: 7/2024</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"3%\"/>\n<col width=\"34%\"/>\n<col width=\"28%\"/>\n<col width=\"34%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Patient Information</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">DOXORUBICIN</span> (dok-s<span class=\"Italics\">uh</span>-<span class=\"Bold\">roo</span>-b<span class=\"Italics\">uh</span>-sin) <span class=\"Bold\">HYDROCHLORIDE</span>\n<br/>\n<span class=\"Bold\">injection, for intravenous use </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<a name=\"_Refwhatisthemostimportantinformation\"></a><span class=\"Bold\">What is the most important information I should know about Doxorubicin?</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Doxorubicin may cause serious side effects including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Heart muscle problems.</span> Doxorubicin can cause heart muscle damage that may lead to heart failure. Heart failure means your heart does not pump blood well. Heart failure is irreversible in some cases and can lead to death. Heart failure can happen during your treatment with Doxorubicin or months to years after stopping treatment. Your risk of heart muscle damage increases with higher total amounts of Doxorubicin that you receive in your lifetime. Your risk of heart failure is higher if you: <br/>\n<dl>\n<dt>o</dt>\n<dd>have other heart problems</dd>\n<dt>o</dt>\n<dd>have had or are currently receiving radiation therapy to your chest </dd>\n<dt>o</dt>\n<dd>have had treatment with certain other anti-cancer medicines</dd>\n<dt>o</dt>\n<dd>take other medicines that can have severe side effects on your heart <br/>\n</dd>\n<dt> </dt>\n<dd>Tell your healthcare provider if you get any of these symptoms of heart failure during or after treatment with Doxorubicin:</dd>\n</dl>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>extreme tiredness or weakness</dd>\n<dt>•</dt>\n<dd>shortness of breath</dd>\n</dl>\n</td><td valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>fast heartbeat</dd>\n<dt>•</dt>\n<dd>swelling of your feet and ankles</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td class=\"Rrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">Your healthcare provider will do tests to check the strength of your heart muscle before, during, and after your treatment with Doxorubicin.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Heart rhythm problems.</span> Doxorubicin can cause serious heart rhythm problems that may lead to death. This can happen during your infusion, within a few hours after your infusion or anytime during treatment with Doxorubicin. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast, irregular or slow, or you feel lightheaded, dizzy, short of breath, chest discomfort or you faint. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Risk of new cancers.</span> You may have an increased risk of developing certain blood cancers called acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with Doxorubicin. Talk with your healthcare provider about your risk of developing new cancers if you receive Doxorubicin. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Skin damage at or near the vein where Doxorubicin is given.</span> Doxorubicin can damage the skin if it leaks out of the vein and might cause blisters, skin sores or severe tissue damage, which may require skin grafts. Tell your healthcare provider if you get burning or stinging during your infusion. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Decreased blood cell counts.</span> Doxorubicin can cause a decrease in neutrophils (a type of white blood cell important in fighting bacterial infections) and platelets (important for clotting and to control bleeding). This may lead to a serious infection, the need for blood transfusions, treatment in a hospital or death. Your healthcare provider will check your blood cell counts before each infusion and during treatment with Doxorubicin. Call your healthcare provider right away if you get a fever (temperature of 100.4°F or higher) or chills with shivering.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is Doxorubicin?</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">Doxorubicin is a prescription medicine used to treat certain types of cancers. Doxorubicin may be used alone or along with other anti-cancer medicines.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Do not receive Doxorubicin if:</span>\n<br/>\n</p>\n<dl>\n<dt>•</dt>\n<dd>you have had a recent heart attack (within the past 4 to 6 weeks) or have severe heart problems.</dd>\n<dt>•</dt>\n<dd>your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy.</dd>\n<dt>•</dt>\n<dd>you have severe liver problems.</dd>\n<dt>•</dt>\n<dd>you have had a severe allergic reaction to Doxorubicin.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before you receive Doxorubicin, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have heart problems including heart failure.</dd>\n<dt>•</dt>\n<dd>are currently receiving radiation therapy or plan to receive radiation to the chest.</dd>\n<dt>•</dt>\n<dd>have liver problems.</dd>\n<dt>•</dt>\n<dd>have had an allergic reaction to doxorubicin.</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. You should not become pregnant during treatment with Doxorubicin. Tell your healthcare provider right away if you become pregnant or think you may be pregnant.<br/>\n<span class=\"Bold\">Females who are able to become pregnant</span>: <dl>\n<dt>o</dt>\n<dd>Your healthcare provider will check to see if you are pregnant before you start treatment with Doxorubicin.</dd>\n<dt>o</dt>\n<dd>You should use effective birth control (contraception) during treatment with Doxorubicin and for 6 months after treatment.</dd>\n</dl>\n</dd>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Males</span>:<dl>\n<dt>o</dt>\n<dd>Doxorubicin can affect your sperm and could cause birth defects.</dd>\n<dt>o</dt>\n<dd>If you have a female partner who can become pregnant, you should use effective birth control during treatment with Doxorubicin and for 3 months after treatment.</dd>\n<dt>o</dt>\n<dd>If you have a pregnant partner, you should use condoms during treatment with Doxorubicin and for at least 10 days after the final dose.</dd>\n<dt>o</dt>\n<dd>Talk to your healthcare provider about birth control methods that may be right for you.</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. Doxorubicin can pass into your breast milk. Do not breastfeed during treatment with Doxorubicin and for 10 days after the final dose. Talk to your healthcare provider about the best way to feed your baby during this time. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How will I receive Doxorubicin? </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Doxorubicin will be given to you into your vein through an intravenous (IV) line.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider will do blood tests to check for side effects during treatment with Doxorubicin.</dd>\n<dt>•</dt>\n<dd>Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Doxorubicin. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of Doxorubicin?</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Doxorubicin may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>See <span class=\"Bold\">“<a href=\"#_Refwhatisthemostimportantinformation\">What is the most important information I should know about Doxorubicin?</a>”</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of Doxorubicin include:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>total hair loss (alopecia). Your hair may re-grow after your treatment.</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n<dt>•</dt>\n<dd>vomiting</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Other side effects:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Red colored urine. You may have red colored urine for 1 to 2 days after your infusion of Doxorubicin. This is normal. Tell your healthcare provider if it does not stop in a few days, or if you see what looks like blood or blood clots in your urine. </dd>\n<dt>•</dt>\n<dd>Call your healthcare provider if you have severe symptoms that prevent you from eating or drinking, such as:<dl>\n<dt>o</dt>\n<dd>nausea</dd>\n<dt>o</dt>\n<dd>vomiting</dd>\n<dt>o</dt>\n<dd>diarrhea</dd>\n<dt>o</dt>\n<dd>mouth pain or sores</dd>\n</dl>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Doxorubicin may cause fertility problems in males.</span> This could affect your ability to father a child. Talk to your healthcare provider if this is a concern for you. <br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Doxorubicin may cause fertility problems in females.</span> Your periods (menstrual cycle) may completely stop when you receive Doxorubicin. Your periods may or may not return following treatment. Early menopause has also happened. Talk to your healthcare provider if this is a concern for you. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">These are not all of the possible side effects of Doxorubicin.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of Doxorubicin.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">You can ask your pharmacist or healthcare provider for information about Doxorubicin that is written for health professionals.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in Doxorubicin?</span>\n<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Active ingredient:</span> doxorubicin hydrochloride<br/>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Inactive ingredients for Doxorubicin Hydrochloride Injection:</span> sodium chloride, and hydrochloric acid, USP.</p>\n<p>Distributed by</p>\n<p>Pfizer Labs</p>\n<p>Division of Pfizer Inc.</p>\n<p>New York, NY 10001</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\"><a name=\"id2469\"></a><img alt=\"Logo\" src=\"/dailymed/image.cfm?name=doxorubicin-04a.jpg&amp;setid=d31d7f58-66d0-4826-b6b5-5914c031965f\"/></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">Novaplus is a registered trademark of Vizient, Inc.</p>\n<p>LAB-1603-1.0</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">\n<p class=\"First\">\n<br/>For more information, call 1-800-438-1985 or visit <a href=\"https://www.pfizer.com/\">www.pfizer.com</a>.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">This Patient Information has been approved by the U.S. Food and Drug Administration.</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">Revised: 7/2024</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 0069-5629-05

{ "type": "p", "children": [], "text": "NDC 0069-5629-05" }

Single-dose vialRx only

{ "type": "p", "children": [], "text": "Single-dose vialRx only" }

Discard unused portion

{ "type": "p", "children": [], "text": "Discard unused portion" }

DOXOrubicinHydrochloride Injection

{ "type": "p", "children": [], "text": "DOXOrubicinHydrochloride Injection" }

10 mg/5 mL (2 mg/mL)

{ "type": "p", "children": [], "text": "10 mg/5 mL (2 mg/mL)" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only" }

novaplusTM

{ "type": "p", "children": [], "text": "novaplusTM\n" }

NDC 0069-5629-05

{ "type": "p", "children": [], "text": "NDC 0069-5629-05" }

Single-dose vial. Discard unused portion

{ "type": "p", "children": [], "text": "Single-dose vial. Discard unused portion" }

DOXOrubicinHydrochloride Injection

{ "type": "p", "children": [], "text": "DOXOrubicinHydrochloride Injection" }

10 mg/5 mL (2 mg/mL)

{ "type": "p", "children": [], "text": "10 mg/5 mL (2 mg/mL)" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only" }

novaplusTM

{ "type": "p", "children": [], "text": "novaplusTM\n" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Warning: Hazardous Drug

{ "type": "p", "children": [], "text": "Warning: Hazardous Drug" }

Single-dose vialNDC 0069-4031-12Discard unused portionRx only

{ "type": "p", "children": [], "text": "Single-dose vialNDC 0069-4031-12Discard unused portionRx only" }

DOXOrubicinHydrochloride Injection

{ "type": "p", "children": [], "text": "DOXOrubicinHydrochloride Injection" }

20 mg/10 mL (2 mg/mL)

{ "type": "p", "children": [], "text": "20 mg/10 mL (2 mg/mL)" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only" }

Warning: Hazardous DrugnovaplusTM

{ "type": "p", "children": [], "text": "Warning: Hazardous DrugnovaplusTM\n" }

NDC 0069-4031-12

{ "type": "p", "children": [], "text": "NDC 0069-4031-12" }

Single-dose vial. Discard unused portion

{ "type": "p", "children": [], "text": "Single-dose vial. Discard unused portion" }

DOXOrubicinHydrochlorideInjection

{ "type": "p", "children": [], "text": "DOXOrubicinHydrochlorideInjection" }

20 mg/10 mL(2 mg/mL)

{ "type": "p", "children": [], "text": "20 mg/10 mL(2 mg/mL)" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

novaplusTM

{ "type": "p", "children": [], "text": "novaplusTM\n" }

Warning: Hazardous Drug

{ "type": "p", "children": [], "text": "Warning: Hazardous Drug" }