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Doxorubicin Hydrochloride Liposome

FDA Drug Information • Also known as: Doxorubicin Hydrochloride Liposome

Brand Names
Doxorubicin Hydrochloride Liposome
Route
INTRAVENOUS
Dosage Form
INJECTION, SUSPENSION, LIPOSOMAL
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS

  • Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment [see Warnings and Precautions (5.1) ] .
  • Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions [see Warnings and Precautions (5.2) ] . WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS See full prescribing information for complete boxed warning.
  • Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection, during treatment, and after treatment ( 5.1 ).
  • Serious, life-threatening, and fatal infusion‑related reactions can occur. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions ( 5.2 ).

    • Description

    11 DESCRIPTION The active ingredient in Doxorubicin hydrochloride liposome injection 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 C 27 H 29 NO 11

  • HCl and the molecular weight is 579.99. 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 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: HSPC has the following structural formula: Representation of a STEALTH liposome: Doxorubicin HCl Structural Formula MPEG-DSPE Structural Formula HSPC Structural Formula STEALTH liposome Representation

    • What Is Doxorubicin Hydrochloride Liposome Used For?

    1 INDICATIONS AND USAGE Doxorubicin hydrochloride liposome injection is an anthracycline topoisomerase inhibitor indicated for:

  • Ovarian cancer: After failure of platinum-based chemotherapy ( 1.1 )
  • AIDS-related Kaposi’s Sarcoma: After failure of prior systemic chemotherapy or intolerance to such therapy ( 1.2 )
  • Multiple Myeloma: In combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy ( 1.3 ) 1.1 Ovarian Cancer Doxorubicin hydrochloride liposome injection is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. 1.2 AIDS-Related Kaposi’s Sarcoma 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. 1.3 Multiple Myeloma Doxorubicin hydrochloride liposome injection, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION Administer doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related reactions occur, increase rate of infusion to complete administration over 1 hour. Do not administer as bolus injection or undiluted solution ( 2 ).

  • Ovarian cancer: 50 mg/m 2 intravenously every 4 weeks ( 2.2 )
  • AIDS-related Kaposi’s Sarcoma: 20 mg/m 2 intravenously every 3 weeks ( 2.3 )
  • Multiple Myeloma: 30 mg/m 2 intravenously on day 4 following bortezomib ( 2.4 ) 2.1 Important Use Information Do not substitute doxorubicin hydrochloride liposome injection for other doxorubicin hydrochloride products. Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2) ] . 2.2 Ovarian Cancer The recommended dose of doxorubicin hydrochloride liposome injection is 50 mg/m 2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity. 2.3 AIDS-Related Kaposi’s Sarcoma The recommended dose of doxorubicin hydrochloride liposome injection is 20 mg/m 2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity. 2.4 Multiple Myeloma The recommended dose of doxorubicin hydrochloride liposome injection is 30 mg/m 2 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) ] . 2.5 Dose Modifications for Adverse Reactions Do not increase doxorubicin hydrochloride liposome injection after a dose reduction for toxicity. Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse Reactions Toxicity Dose Adjustment Hand-Foot Syndrome (HFS) Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities
  • If no previous Grade 3 or 4 HFS: no dose adjustment.
  • If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then decrease dose by 25%. Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1.
  • Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks.
  • If resolved to Grade 0-1 within 2 weeks: o And no previous Grade 3 or 4 HFS: continue treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%.
  • Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks. Grade 4: Diffuse or local process causing infectious complications, or a bed ridden...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling.

  • Cardiomyopathy [see Warnings and Precautions (5.1) ]
  • Infusion-Related Reactions [see Warnings and Precautions (5.2) ]
  • Hand-Foot Syndrome [see Warnings and Precautions (5.3) ]
  • Secondary Oral Neoplasms [see Warnings and Precautions (5.4) ] Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The safety data reflect exposure to doxorubicin hydrochloride liposome injection in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma, and 318 patients with multiple myeloma. The most common adverse reactions (>20%) observed with doxorubicin hydrochloride liposome injection are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The following tables present adverse reactions from clinical trials of single-agent doxorubicin hydrochloride liposome injection in ovarian cancer and AIDS-Related Kaposi’s sarcoma. Patients With Ovarian Cancer The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection 50 mg/m 2 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. Table 3: Hematologic Adverse Reactions in Trial 4 Doxorubicin hydrochloride Liposome Injection Patients (n=239) Topotecan Patients (n=235) Neutropenia 500 - <1000/mm3 8% 14% <500/mm3 4.2% 62% Anemia 6.5 - <8 g/dL 5% 25% < 6.5 g/dL 0.4% 4.3% Thrombocytopenia 10,000 - <50,000/mm3 1.3% 17% <10,000/mm3 0.0% 17% Table 4 presents the non-hematologic adverse reactions from Trial 4. Table 4: Non-Hematologic Adverse Reactions in Trial 4 Non-Hematologic Adverse Reaction 10% or Greater Doxorubicin hydrochloride Liposome Injection (%) treated (n=239) Topotecan (%) treated (n=235) All grades Grades 3-4 All grades Grades 3-4 Body as a Whole Asthenia 40 7 52 8 Fever 21 0.8 31 6 Mucous Membrane Disorder 14 3.8 3.4 0 Back Pain 12 1.7 10 0.9 Infection 12 2.1 6 0.9 Headache 11 0.8 15 0 Digestive Nausea 46 5 63 8 Stomatitis 41 8 15 0.4 Vomiting 33 8 44 10 Diarrhea 21 2.5 35 4.2 Anorexia 20 2.5 22 1.3 Dyspepsia 12 0.8 14 0 Nervous Dizziness 4.2 0 10 0 Respiratory Pharyngitis 16 0 18 0.4 Dyspnea 15 4.1 23 4.3 Cough increased 10 0 12 0 Skin and Appendages Hand-foot syndrome 51 24 0.9 0 Rash 29 4.2 12 0.4 Alopecia 19 N/A 52 N/A The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4). Incidence 1% to 10% Cardiovascular: 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...

    • Drug Interactions

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

    Contraindications

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

  • Hypersensitivity reactions to doxorubicin hydrochloride or the components of doxorubicin hydrochloride liposome injection ( 4 , 5.2 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid use of doxorubicin hydrochloride liposome injection during the 1 st 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 2 nd and 3 rd 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 Doxorubicin hydrochloride liposome injection was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m 2 human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

    Overdosage

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

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single-dose vials. The following individually cartoned vials are available: Table 14 vial concentration vial size NDC #’s 20 mg/10 mL (2 mg/mL) 10-mL 0338-0080-01 50 mg/25 mL (2 mg/mL) 30 mL 0338-0086-01 Refrigerate unopened vials of doxorubicin hydrochloride liposome injection at 2°C- 8°C (36°F- 46°F). Do not freeze. Discard unused portion. Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.