Components:
Method of action:
Treatment option:
Medically reviewed by Oliinyk Elizabeth Ivanovna, PharmD. Last updated on 26.06.2023
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Dosage Forms And Strengths
DOXIL: doxorubicin HCl liposomal injection: single use vials contain 20 mg/10 mL and 50 mg/25 mL doxorubicin HCl as a translucent, red liposomal dispersion.
Storage And Handling
DOXIL is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials.
Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.
Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.
The following individually cartoned vials are available:
Table 14
| mg in vial | fill volume | vial size | NDC #s |
| 20 mg vial | 10-mL | 10-mL | 59676-960-01 |
| 50 mg vial | 25-mL | 30-mL | 59676-960-02 |
Refrigerate unopened vials of DOXIL at 2°- 8°C (36°- 46°F). Do not freeze.
DOXIL is a cytotoxic drug. Follow applicable special handling and disposal procedures.
REFERENCES
1. “Hazardous Drugs”, OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html
Manufactured by: TTY Biopharm Company Limited, Taoyuan City, 32069, Taiwan or GlaxoSmithKline Manufacturing S.p.A., Parma, Italy. Manufactured for: Janssen Products, LP, Horsham, PA 19044
Ovarian Cancer
DOXIL is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.
AIDS-Related Kaposi's Sarcoma
DOXIL is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.
Multiple Myeloma
DOXIL, 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.
Important Use Information
Do not substitute DOXIL for doxorubicin HCl injection.
Do not administer as an undiluted suspension or as an intravenous bolus.
Ovarian Cancer
The recommended dose of DOXIL is 50 mg/m² intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.
AIDS-Related Kaposi's Sarcoma
The recommended dose of DOXIL is 20 mg/m² intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.
Multiple Myeloma
The recommended dose of DOXIL 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 after bortezomib on day 4 of each cycle.
Dose Modifications For Adverse Reactions
Do not increase DOXIL 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 des quamati on not interfering with daily activities |
|
| Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter |
|
| Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing |
|
| Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization |
|
| Stomatitis | |
| Grade 1: Painless ulcers, erythema, or mild soreness |
|
| Grade 2: Painful erythema, edema, or |
|
| Grade 3: Painful erythema, edema, or ulcers, and cannot eat |
|
| Grade 4: Requires parenteral or enteral support |
|
| 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 for
Toxicity When Administered in Combination With Bortezomib
| Toxicity | DOXIL |
| Fever ≥ 38°C and ANC < 1,000/mm³ |
|
On any day of drug administration after Day 1 of each cycle:
|
|
| 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. Refer to bortezomib manufacturer's prescribing information.
Preparation And Administration
Preparation
Dilute DOXIL 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 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 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. Do not rapidly flush the infusion line.
Do not mix DOXIL with other drugs.
Management of Suspected Extravasation
Discontinue DOXIL for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:
- Do not remove the needle until attempts are made to aspirate extravasated fluid
- Do not flush the line
- Avoid applying pressure to the site
- Apply ice to the site intermittently for 15 min 4 times a day for 3 days
- If the extravasation is in an extremity, elevate the extremity
Procedure For Proper Handling And Disposal
DOXIL is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If DOXIL comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.
DOXIL is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin HCl .
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Cardiomyopathy
Doxorubicin HCl can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin HCl is generally proportional to the cumulative exposure. The relationship between cumulative DOXIL dose and the risk of cardiac toxicity has not been determined.
In a clinical study in 250 patients with advanced cancer who were treated with DOXIL, the risk of cardiotoxicity was 11% when the cumulative anthracycline dose was between 450-550 mg/m². Cardiotoxicity 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 cardiotoxicity.
Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of DOXIL, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Administer DOXIL to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.
Infusion-Related Reactions
Serious and sometimes life-threatening infusion-related reactions characterized by one or more of the following symptoms can occur with DOXIL: 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. The majority of infusion-related events occurred during the first infusion. Of 239 patients with ovarian cancer treated with DOXIL 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 monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions.
Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of DOXIL. Initiate DOXIL infusions at a rate of 1 mg/min and increase rate as tolerated. In the event of an infusionrelated reaction, temporarily stop the drug until resolution then resume at a reduced infusion rate. Discontinue DOXIL infusion for serious or life-threatening infusion-related reactions.
Hand-Foot Syndrome (HFS)
In Trial 4, the incidence of HFS was 51% of patients in the DOXIL arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in DOXIL-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of DOXIL in 4.2% of patients.
HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. Delay DOXIL for the first episode of Grade 2 or greater HFS. Discontinue DOXIL if HFS is severe and debilitating.
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. These malignancies were diagnosed both during treatment with DOXIL 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.
Embryofetal Toxicity
Based on animal data, DOXIL can cause fetal harm when administered to a pregnant woman. At doses approximately 0.12 times the recommended clinical dose, DOXIL 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.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
Mutagenicity or carcinogenicity studies have not been conducted with DOXIL, 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 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/m basis).
Use In Specific Populations
Pregnancy
Risk Summary
Based on findings in animals, DOXIL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, DOXIL was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose. There are no available human data informing the drug-associated risk. 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 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.
Lactation
Risk Summary
It is not known whether DOXIL 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 nursing infants from DOXIL, discontinue breastfeeding during treatment with DOXIL.
Females And Males Of Reproductive Potential
Contraception
Females
DOXIL can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL.
Males
DOXIL 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.
Infertility
Females
In females of reproductive potential, DOXIL may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin HCl. Recovery of menses and ovulation is related to age at treatment.
Males
DOXIL 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 .
Pediatric Use
The safety and effectiveness of DOXIL in pediatric patients have not been established.
Geriatric Use
Clinical studies of DOXIL 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 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.
Hepatic Impairment
The pharmacokinetics of DOXIL has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce DOXIL for serum bilirubin of 1.2 mg/dL or higher.
SIDE EFFECTS
The following adverse reactions are discussed in more detail in other sections of the labeling.
- Cardiomyopathy
- Infusion-Related Reactions
- Hand-Foot Syndrome
- Secondary Oral Neoplasms
The most common adverse reactions ( > 20%) observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.
Adverse Reactions In Clinical Trials
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.
The safety data reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma, and 318 patients with multiple myeloma.
The following tables present adverse reactions from clinical trials of single-agent DOXIL 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 50 mg/m once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received DOXIL 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 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 |
DOXIL (%) treated (n=239) |
Topotecan (%) treated (n=235) |
||
| All grades | Grades 3-4 | All grades | Grades 3-4 | All grades |
| 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 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 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/mm (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 DOXIL for AIDS-related Kaposi's sarcoma in a pooled analysis of the four trials.
Table 5: Hematologic Adverse Reactions Reported in
Patients With AIDS-Related Kaposi's Sarcoma
| Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n=74*) |
Total Patients With AIDS-Related Kaposi's Sarcoma (n=720†) |
|
| Neutropenia | ||
| < 1000/mm³ | 46% | 49% |
| < 500/mm³ | 11% | 13% |
| Anemia | ||
| < 10 g/dL | 58% | 55% |
| < 8 g/dL | 16% | 18% |
| Thrombocytopenia | ||
| < 150,000/mm³ | 61% | 61% |
| < 25,000/mm³ | 1.4% | 4.2% |
| *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. †This includes only subjects with AIDS-KS who had available data from the 4 pooled trials. |
||
Table 6: Non-Hematologic Adverse Reactions Reported in
≥ 5% of Patients With AIDS-Related Kaposi's Sarcoma
| Adverse Reactions | Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n=77*) |
T otal Patients With AIDS-Related Kaposi's Sarcoma (n=705†) |
| Nausea | 18% | 17% |
| Asthenia | 7% | 10% |
| Fever | 8% | 9% |
| Alopecia | 9% | 9% |
| Alkaline Phosphatase Increase | 1.3% | 8% |
| Vomiting | 8% | 8% |
| Diarrhea | 5% | 8% |
| Stomatitis | 5% | 7% |
| Oral Moniliasis | 1.3% | 6% |
| *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. †This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials. |
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 (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 + 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 in combination with bortezomib for multiple myeloma.
Table 7: Frequency of Treatment-Emergent Adverse
Reactions Reported in ≥ 10% Patients Treated for Multiple Myeloma With
DOXIL in Combination With Bortezomib
| Adverse Reaction | DOXIL + bortezomib (n=318) |
Bortezomib (n=318) |
||
| Any (%) | Grade 3-4 | Any (%) | Grade 3-4 | |
| Blood and lymphatic system disorders | ||||
| Neutropenia | 36 | 32 | 22 | 16 |
| Thrombocytopenia | 33 | 24 | 28 | 17 |
| Anemia | 25 | 9 | 21 | 9 |
| General disorders and administration site conditions | ||||
| Fatigue | 36 | 7 | 28 | 3 |
| Pyrexia | 31 | 1 | 22 | 1 |
| Asthenia | 22 | 6 | 18 | 4 |
| Gastrointestinal disorders | ||||
| Nausea | 48 | 3 | 40 | 1 |
| Diarrhea | 46 | 7 | 39 | 5 |
| Vomiting | 32 | 4 | 22 | 1 |
| Constipation | 31 | 1 | 31 | 1 |
| Mucositis/Stomatitis | 20 | 2 | 5 | < 1 |
| Abdominal pain | 11 | 1 | 8 | 1 |
| Infections and infestations | ||||
| Herpes zoster | 11 | 2 | 9 | 2 |
| Herpes simplex | 10 | 0 | 6 | 1 |
| Investigations Weight decreased | 12 | 0 | 4 | 0 |
| Metabolism and Nutritional disorders | ||||
| Anorexia | 19 | 2 | 14 | < 1 |
| Nervous system disorders | ||||
| Peripheral Neuropathy* | 42 | 7 | 45 | 11 |
| Neuralgia | 17 | 3 | 20 | 4 |
| Paresthesia/dysesthesia | 13 | < 1 | 10 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 18 | 0 | 12 | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rash† | 22 | 1 | 18 | 1 |
| Hand-foot syndrome | 19 | 6 | < 1 | 0 |
| *Peripheral neuropathy includes the following adverse
reactions: peripheral sensory neuropathy, neuropathy peripheral,
polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. †Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. |
||||
Postmarketing Experience
The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Musculoskeletal and Connective Tissue Disorders: 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
Secondary oral neoplasms:.
DRUG INTERACTIONS
No formal drug interaction studies have been conducted with DOXIL.
Risk Summary
Based on findings in animals, DOXIL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, DOXIL was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose. There are no available human data informing the drug-associated risk. 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 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.
The following adverse reactions are discussed in more detail in other sections of the labeling.
- Cardiomyopathy
- Infusion-Related Reactions
- Hand-Foot Syndrome
- Secondary Oral Neoplasms
The most common adverse reactions ( > 20%) observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.
Adverse Reactions In Clinical Trials
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.
The safety data reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma, and 318 patients with multiple myeloma.
The following tables present adverse reactions from clinical trials of single-agent DOXIL 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 50 mg/m once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received DOXIL 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 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 |
DOXIL (%) treated (n=239) |
Topotecan (%) treated (n=235) |
||
| All grades | Grades 3-4 | All grades | Grades 3-4 | All grades |
| 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 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 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/mm (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 DOXIL for AIDS-related Kaposi's sarcoma in a pooled analysis of the four trials.
Table 5: Hematologic Adverse Reactions Reported in
Patients With AIDS-Related Kaposi's Sarcoma
| Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n=74*) |
Total Patients With AIDS-Related Kaposi's Sarcoma (n=720†) |
|
| Neutropenia | ||
| < 1000/mm³ | 46% | 49% |
| < 500/mm³ | 11% | 13% |
| Anemia | ||
| < 10 g/dL | 58% | 55% |
| < 8 g/dL | 16% | 18% |
| Thrombocytopenia | ||
| < 150,000/mm³ | 61% | 61% |
| < 25,000/mm³ | 1.4% | 4.2% |
| *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. †This includes only subjects with AIDS-KS who had available data from the 4 pooled trials. |
||
Table 6: Non-Hematologic Adverse Reactions Reported in
≥ 5% of Patients With AIDS-Related Kaposi's Sarcoma
| Adverse Reactions | Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n=77*) |
T otal Patients With AIDS-Related Kaposi's Sarcoma (n=705†) |
| Nausea | 18% | 17% |
| Asthenia | 7% | 10% |
| Fever | 8% | 9% |
| Alopecia | 9% | 9% |
| Alkaline Phosphatase Increase | 1.3% | 8% |
| Vomiting | 8% | 8% |
| Diarrhea | 5% | 8% |
| Stomatitis | 5% | 7% |
| Oral Moniliasis | 1.3% | 6% |
| *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. †This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials. |
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 (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 + 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 in combination with bortezomib for multiple myeloma.
Table 7: Frequency of Treatment-Emergent Adverse
Reactions Reported in ≥ 10% Patients Treated for Multiple Myeloma With
DOXIL in Combination With Bortezomib
| Adverse Reaction | DOXIL + bortezomib (n=318) |
Bortezomib (n=318) |
||
| Any (%) | Grade 3-4 | Any (%) | Grade 3-4 | |
| Blood and lymphatic system disorders | ||||
| Neutropenia | 36 | 32 | 22 | 16 |
| Thrombocytopenia | 33 | 24 | 28 | 17 |
| Anemia | 25 | 9 | 21 | 9 |
| General disorders and administration site conditions | ||||
| Fatigue | 36 | 7 | 28 | 3 |
| Pyrexia | 31 | 1 | 22 | 1 |
| Asthenia | 22 | 6 | 18 | 4 |
| Gastrointestinal disorders | ||||
| Nausea | 48 | 3 | 40 | 1 |
| Diarrhea | 46 | 7 | 39 | 5 |
| Vomiting | 32 | 4 | 22 | 1 |
| Constipation | 31 | 1 | 31 | 1 |
| Mucositis/Stomatitis | 20 | 2 | 5 | < 1 |
| Abdominal pain | 11 | 1 | 8 | 1 |
| Infections and infestations | ||||
| Herpes zoster | 11 | 2 | 9 | 2 |
| Herpes simplex | 10 | 0 | 6 | 1 |
| Investigations Weight decreased | 12 | 0 | 4 | 0 |
| Metabolism and Nutritional disorders | ||||
| Anorexia | 19 | 2 | 14 | < 1 |
| Nervous system disorders | ||||
| Peripheral Neuropathy* | 42 | 7 | 45 | 11 |
| Neuralgia | 17 | 3 | 20 | 4 |
| Paresthesia/dysesthesia | 13 | < 1 | 10 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 18 | 0 | 12 | 0 |
| Skin and subcutaneous tissue disorders | ||||
| Rash† | 22 | 1 | 18 | 1 |
| Hand-foot syndrome | 19 | 6 | < 1 | 0 |
| *Peripheral neuropathy includes the following adverse
reactions: peripheral sensory neuropathy, neuropathy peripheral,
polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. †Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. |
||||
Postmarketing Experience
The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Musculoskeletal and Connective Tissue Disorders: 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
Secondary oral neoplasms:.
Acute overdosage with doxorubicin HCl causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.
- R52.1 – Chronic intractable pain
- R52.2 – Other chronic pain
- R52.9 – Unspecified pain
The pharmacokinetic parameters for total doxorubicin following a single dose of DOXIL infused over 30 minutes are presented in Table 8.
Table 8: Pharmacokinetic Parameters of Total
Doxorubicin from DOXIL in Patients With AIDS-Related Kaposi's Sarcoma
| Parameter (units) | Dose | |
| 10 mg/m² | 20 mg/m² | |
| Peak Plasma Concentration (μg/mL) | 4.12 ± 0.215 | 8.34 ± 0.49 |
| Plasma Clearance (L/h/m²) | 0.056 ± 0.01 | 0.041 ± 0.004 |
| Steady State Volume of Distribution (L/m²) | 2.83 ± 0.145 | 2.72 ± 0.120 |
| AUC (μg/mL•h) | 277 ± 32.9 | 590 ± 58.7 |
| First Phase (λ1) Half-Life (h) | 4.7 ± 1.1 | 5.2 ± 1.4 |
| Second Phase (λ1) Half-Life (h) | 52.3 ± 5.6 | 55.0 ± 4.8 |
| N=23 Mean ± Standard Error |
DOXIL displayed linear pharmacokinetics over the range of 10 to 20 mg/m². Relative to DOXIL doses at or below 20 mg/m², the pharmacokinetics of total doxorubicin following a 50 mg/m² DOXIL dose are nonlinear. At this dose, the elimination half-life of DOXIL 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 is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of DOXIL 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.
Elimination
The plasma clearance of total doxorubicin from DOXIL was 0.041 L/h/m² at a dose of 20 mg/m². Following administration of doxorubicin HCl, the plasma clearance of doxorubicin is 24 to 35 L/h/m².
- R52.1 – Chronic intractable pain
- R52.2 – Other chronic pain
- R52.9 – Unspecified pain
- R52.1 – Chronic intractable pain
- R52.2 – Other chronic pain
- R52.9 – Unspecified pain
