Doxil
Doxorubicin hydrochloride · Injection, Suspension, Liposomal · Intravenous, Intravitreal
• DOXIL liposomal infusion can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m 2 to 550 mg/m 2 . Assess left ventricular cardiac function prior to initiation of DOXIL liposomal infusion and during and after treatment [see Warnings and Precautions (5.1) ] .
• Serious, life-threatening, and fatal infusion-related reactions can occur with DOXIL liposomal infusion Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold DOXIL liposomal infusion for infusion-related reactions and resume at a reduced rate. Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions [see Warnings and Precautions (5.2) ] . WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS…
Uses
1 INDICATIONS AND USAGE DOXIL liposomal infusion 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 DOXIL liposomal infusion is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. 1.2 AIDS-Related Kaposi’s Sarcoma 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. 1.3 Multiple Myeloma DOXIL liposomal infusion, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.
Dosage and administration
Administer DOXIL liposomal infusion 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 DOXIL liposomal infusion for other doxorubicin hydrochloride products. Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2) ] . 2.2 Ovarian Cancer The recommended dose of DOXIL liposomal infusion is 50 mg/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 DOXIL liposomal infusion 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 DOXIL liposomal infusion 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 DOXIL liposomal infusion after bortezomib on day 4 of each cycle [see Clinical Studies (14.3) ] . 2.5 Dose Modifications for Adverse Reactions Do not increase DOXIL liposomal infusion 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 DOXIL liposomal infusion 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 DOXIL liposomal infusion if no resolution after 2 weeks. Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization
• Delay dosing up to 2 weeks or until resolved to Grade 0–1, then decrease dose by 25%.
• Discontinue DOXIL liposomal infusion if no resolution after 2 weeks. Stomatitis Grade 1: Painless ulcers, erythema, or mild soreness
• If no previous Grade 3 or 4 toxicity: no dose adjustment.
• If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%. Grade 2: Painful erythema, edema, or ulcers, but can eat
• Delay dosing up to 2 weeks or until resolved to Grade 0–1.
• Discontinue DOXIL liposomal infusion if there is no resolution after 2 weeks.
• If resolved to Grade 0–1 within 2 weeks: o And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%. Grade 3: Painful erythema, edema, or ulcers, and cannot eat
• Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval.
• If after 2 weeks there is no resolution, discontinue DOXIL liposomal infusion. Grade 4: Requires parenteral or enteral support
• Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval.
• If after 2 weeks there is no resolution, discontinue DOXIL liposomal infusion. Neutropenia or Thrombocytopenia Grade 1 No dose reduction Grade 2 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 3 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose Grade 4 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor Table 2: Recommended Dose Modifications of DOXIL Liposomal Infusion for Toxicity When Administered in Combination With Bortezomib Toxicity DOXIL Liposomal Infusion Fever ≥38°C and ANC <1,000/mm 3
• Withhold dose for this cycle if before Day 4;
• Decrease dose by 25%, if after Day 4 of previous cycle. On any day of drug administration after Day 1 of each cycle:
• Platelet count <25,000/mm 3
• Hemoglobin <8 g/dL
• ANC <500/mm 3
• Withhold dose for this cycle if before Day 4;
• Decrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity. Grade 3 or 4 non-hematologic drug related toxicity Do not dose until recovered to Grade <2, then reduce dose by 25%. For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for DOXIL liposomal infusion. Refer to bortezomib manufacturer’s prescribing information. 2.6 Preparation and Administration 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.
Dosage forms and strengths
(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. Doxorubicin hydrochloride liposomal injection: 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) in single dose vials ( 3 )
Contraindications
4 CONTRAINDICATIONS 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) ].
• Hypersensitivity reactions to doxorubicin hydrochloride or the components of DOXIL liposomal infusion ( 4 , 5.2 )
Warnings and precautions
• Hand-Foot Syndrome may occur. Dose modification or discontinuation may be required ( 5.3 )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus. Use effective contraception ( 5.5 , 8.1 , 8.3 ) 5.1 Cardiomyopathy Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Include prior use of other anthracyclines or anthracenediones in calculations of cumulative dose. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation. In 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/m 2 to 550 mg/m 2 . 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. 5.2 Infusion-Related Reactions Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with DOXIL liposomal infusion: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Of 239 patients with ovarian cancer treated with DOXIL liposomal infusion in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle 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. 5.3 Hand-Foot Syndrome (HFS) In Trial 4, the incidence of HFS was 51% of patients in the DOXIL liposomal infusion arm and 0.9% of patients in the topotecan arm, including 24% Grade 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. 5.4 Secondary Oral Neoplasms Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to DOXIL liposomal infusion. These malignancies were diagnosed both during treatment with DOXIL liposomal infusion and up to 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. 5.5 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, DOXIL liposomal infusion can cause fetal harm when administered to a pregnant woman; avoid the use of DOXIL liposomal infusion during the 1 st 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 2 nd and 3 rd 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 )] .
Side effects
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 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/m 2 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. Table 3: Hematologic Adverse Reactions in Trial 4 DOXIL Liposomal Infusion Patients (n=239) Topotecan Patients (n=235) Neutropenia 500 – <1000/mm 3 8% 14% <500/mm 3 4.2% 62% Anemia 6.5 – <8 g/dL 5% 25% < 6.5 g/dL 0.4% 4.3% Thrombocytopenia 10,000 – <50,000/mm 3 1.3% 17% <10,000/mm 3 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 DOXIL Liposomal Infusion (%) 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 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/m 2 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/m 2 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/m 2 (range 3.3 to 798.6 mg/m 2 ); 3% received cumulative doses of greater than 450 mg/m 2 . 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/mm 3 (51% less than 50 cells/mm 3 ); mean absolute neutrophil count at study entry approximately 3,000 cells/mm 3 . 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.
Drug interactions
No formal drug interaction studies have been conducted with DOXIL liposomal infusion.
Use in specific populations
• Lactation: Discontinue breastfeeding ( 8.2 ). 8.1 Pregnancy 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 1 st 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 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 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/m 2 human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes. 8.2 Lactation 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. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating DOXIL liposomal infusion. Contraception 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) ] . 8.4 Pediatric Use The safety and effectiveness of DOXIL liposomal infusion in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of DOXIL liposomal infusion conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related 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. 8.6 Hepatic Impairment The pharmacokinetics of DOXIL liposomal infusion has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce DOXIL liposomal infusion for serum bilirubin of 1.2 mg/dL or higher.
Pregnancy
8.1 Pregnancy 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 1 st 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 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 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/m 2 human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of DOXIL liposomal infusion in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use 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.
Overdosage
Acute overdosage with doxorubicin hydrochloride causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.
Description
The active ingredient in DOXIL liposomal infusion is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in STEALTH liposomes for intravenous use. The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6‑trideoxy-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: 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: HSPC has the following structural formula: Representation of a STEALTH liposome: image-01-doxil-structural-formula image-02-mpge-dspe-structural-formula image-03-hspc-structural-formula image-04-stealth-liposome
Mechanism of action
12.1 Mechanism of Action The active ingredient of DOXIL liposomal infusion is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.
How supplied
(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 0338-9667-01 50 mg/25 mL (2 mg/mL) 30-mL 0338-9665-01 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
Storage
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
Patient information
Cardiomyopathy Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1) ] . Infusion-Related Reactions Advise patients about the symptoms of infusion related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2) ] . Myelosuppression Advise patients to contact their healthcare provider for 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.
Label text from the FDA structured product label by Baxter Healthcare Corporation (revised Mar 10, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Doxorubicin Hydrochloride in 4 products
Doxil NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0338-0063 | Doxorubicin Hydrochloride 2 mg/mL Injection, Suspension, Liposomal | Baxter Healthcare Company | NDA |
| 0338-0067 | Doxorubicin Hydrochloride 2 mg/mL Injection, Suspension, Liposomal | Baxter Healthcare Company | NDA |
| 0338-9665 | Doxorubicin Hydrochloride 2 mg/mL Injection, Suspension, Liposomal | Baxter Healthcare Corporation | NDA |
| 0338-9667 | Doxorubicin Hydrochloride 2 mg/mL Injection, Suspension, Liposomal | Baxter Healthcare Corporation | NDA |
Doxil recalls
- D-0048-2024 Oct 25, 2023 · Class II · Terminated
CGMP Deviations: Product was exposed to temperatures exceeding the labeled storage conditions during transportation were released by mistake.
Frequently asked questions
What is Doxil used for?
1 INDICATIONS AND USAGE DOXIL liposomal infusion 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…
What are the side effects of Doxil?
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,… See the full label for the complete list.
Who makes Doxil?
Doxil is listed by 2 labelers in the FDA NDC directory, including Baxter Healthcare Company, Baxter Healthcare Corporation.
Has Doxil been recalled?
The FDA enforcement database lists 1 recall for Doxil, most recently D-0048-2024 (class ii): CGMP Deviations: Product was exposed to temperatures exceeding the labeled storage conditions during transportation were released by mistake.