ADVERSE REACTIONS
Overall Adverse Reactions Profile
The following adverse reactions are discussed in more detail in other sections of the labeling.
- Cardiac Toxicity [ see Warnings and Precautions ]
- Infusion reactions [ see Warnings and Precautions ]
- Myelosuppression [ see Warnings and Precautions ]
- Hand-Foot syndrome [ see Warnings and Precautions ]
The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.
The most common serious adverse reactions observed with DOXIL are described in Section 6.2.
The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma and 318 patients with multiple myeloma [ see Adverse Reactions in Clinical Trials ].
Adverse Reactions in Clinical Trials
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.
The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer and AIDS-Related Kaposi's sarcoma.
Patients With Ovarian Cancer
The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other.
Table 6 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.
Table 6: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer | DOXIL Patients
(n = 239) | Topotecan Patients
(n = 235) |
|---|
| Neutropenia | | |
| 500 - <1000/mm3 | 19 (7.9%) | 33 (14.0%) |
| <500/mm3 | 10 (4.2%) | 146 (62.1%) |
| Anemia | | |
| 6.5 - <8 g/dL | 13 (5.4%) | 59 (25.1%) |
| < 6.5 g/dL | 1 (0.4%) | 10 (4.3%) |
| Thrombocytopenia | | |
| 10,000 - <50,000/mm3 | 3 (1.3%) | 40 (17.0%) |
| <10,000/mm3 | 0 (0.0%) | 40 (17.0%) |
Table 7 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.
Table 7: Ovarian Cancer Randomized Study | Non-Hematologic Adverse Reaction 10% or Greater | DOXIL (%) treated
(n = 239) | Topotecan (%) treated
(n =235) |
|---|
| All grades | Grades 3-4 | All grades | Grades 3-4 |
|---|
| Body as a Whole | | | | |
| Asthenia | 40.2 | 7.1 | 51.5 | 8.1 |
| Fever | 21.3 | 0.8 | 30.6 | 5.5 |
| Mucous Membrane Disorder | 14.2 | 3.8 | 3.4 | 0 |
| Back Pain | 11.7 | 1.7 | 10.2 | 0.9 |
| Infection | 11.7 | 2.1 | 6.4 | 0.9 |
| Headache | 10.5 | 0.8 | 14.9 | 0 |
| Digestive | | | | |
| Nausea | 46.0 | 5.4 | 63.0 | 8.1 |
| Stomatitis | 41.4 | 8.3 | 15.3 | 0.4 |
| Vomiting | 32.6 | 7.9 | 43.8 | 9.8 |
| Diarrhea | 20.9 | 2.5 | 34.9 | 4.2 |
| Anorexia | 20.1 | 2.5 | 21.7 | 1.3 |
| Dyspepsia | 12.1 | 0.8 | 14.0 | 0 |
| Nervous | | | | |
| Dizziness | 4.2 | 0 | 10.2 | 0 |
| Respiratory | | | | |
| Pharyngitis | 15.9 | 0 | 17.9 | 0.4 |
| Dyspnea | 15.1 | 4.1 | 23.4 | 4.3 |
| Cough increased | 9.6 | 0 | 11.5 | 0 |
| Skin and Appendages | | | | |
| Hand-foot syndrome | 50.6 | 23.8 | 0.9 | 0 |
| Rash | 28.5 | 4.2 | 12.3 | 0.4 |
| Alopecia | 19.2 | N/A | 52.3 | N/A |
The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.
Incidence 1% to 10%
Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest.
Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.
Hemic and Lymphatic: ecchymosis.
Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia.
Nervous: somnolence, dizziness, depression.
Respiratory: rhinitis, pneumonia, sinusitis, epistaxis.
Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne.
Special Senses: conjunctivitis, taste perversion, dry eyes.
Urinary: urinary tract infection, hematuria, vaginal moniliasis.
Patients With AIDS-Related Kaposi's Sarcoma
The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi's sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2.
Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients' median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3.
Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment.
Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi's sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.
Table 8: Hematology Data Reported in Patients With AIDS-Related Kaposi's Sarcoma | Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma
(n = 74) | Total Patients With AIDS-Related Kaposi's Sarcoma
(n = 720) |
|---|
| Neutropenia | | | | |
| < 1000/mm3 | 34 | (45.9%) | 352 | (48.9%) |
| < 500/mm3 | 8 | (10.8%) | 96 | (13.3%) |
| Anemia | | | | |
| < 10 g/dL | 43 | (58.1%) | 399 | (55.4%) |
| < 8 g/dL | 12 | (16.2%) | 131 | (18.2%) |
| Thrombocytopenia | | | | |
| < 150,000/mm3 | 45 | (60.8%) | 439 | (60.9%) |
| < 25,000/mm3 | 1 | (1.4%) | 30 | (4.2%) |
Table 9: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi's Sarcoma | Adverse Reactions | Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma
(n = 77) | Total Patients With AIDS-Related Kaposi's Sarcoma
(n = 705) |
|---|
| Nausea | 14 | (18.2%) | 119 | (16.9%) |
| Asthenia | 5 | (6.5%) | 70 | (9.9%) |
| Fever | 6 | (7.8%) | 64 | (9.1%) |
| Alopecia | 7 | (9.1%) | 63 | (8.9%) |
| Alkaline Phosphatase Increase | 1 | (1.3%) | 55 | (7.8%) |
| Vomiting | 6 | (7.8%) | 55 | (7.8%) |
| Diarrhea | 4 | (5.2%) | 55 | (7.8%) |
| Stomatitis | 4 | (5.2%) | 48 | (6.8%) |
| Oral Moniliasis | 1 | (1.3%) | 39 | (5.5%) |
The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi's sarcoma
Incidence 1% to 5%
Body as a Whole: headache, back pain, infection, allergic reaction, chills.
Cardiovascular: chest pain, hypotension, tachycardia.
Cutaneous: herpes simplex, rash, itching.
Digestive: mouth ulceration, anorexia, dysphagia.
Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.
Other: dyspnea, pneumonia, dizziness, somnolence.
Incidence Less Than 1%
Body As A Whole: sepsis, moniliasis, cryptococcosis.
Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia.
Digestive: hepatitis.
Metabolic and Nutritional Disorders: dehydration
Respiratory: cough increase, pharyngitis.
Skin and Appendages: maculopapular rash, herpes zoster.
Special Senses: taste perversion, conjunctivitis.
Patients With Multiple Myeloma
The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 10 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.
Table 10. Frequency of treatment emergent adverse reactions reported in ≥10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. | Adverse Reaction | DOXIL + bortezomib
(n=318) | Bortezomib
(n=318) |
|---|
| Any (%) | Grade 3 | Grade 4 | Any (%) | Grade 3 | Grade 4 |
|---|
| Blood and lymphatic system disorders | | | | | | |
| Neutropenia | 36 | 22 | 10 | 22 | 11 | 5 |
| Thrombocytopenia | 33 | 11 | 13 | 28 | 9 | 8 |
| Anemia | 25 | 7 | 2 | 21 | 8 | 2 |
| General disorders and administration site conditions | | | | | | |
| Fatigue | 36 | 6 | 1 | 28 | 3 | 0 |
| Pyrexia | 31 | 1 | 0 | 22 | 1 | 0 |
| Asthenia | 22 | 6 | 0 | 18 | 4 | 0 |
| Gastrointestinal disorders | | | | | | |
| Nausea | 48 | 3 | 0 | 40 | 1 | 0 |
| Diarrhea | 46 | 7 | 0 | 39 | 5 | 0 |
| Vomiting | 32 | 4 | 0 | 22 | 1 | 0 |
| Constipation | 31 | 1 | 0 | 31 | 1 | 0 |
| Mucositis/Stomatitis | 20 | 2 | 0 | 5 | <1 | 0 |
| Abdominal pain | 11 | 1 | 0 | 8 | 1 | 0 |
| Infections and infestations | | | | | | |
| Herpes zoster | 11 | 2 | 0 | 9 | 2 | 0 |
| Herpes simplex | 10 | 0 | 0 | 6 | 1 | 0 |
| Investigations | | | | | | |
| Weight decreased | 12 | 0 | 0 | 4 | 0 | 0 |
| Metabolism and Nutritional disorders | | | | | | |
| Anorexia | 19 | 2 | 0 | 14 | <1 | 0 |
| Nervous system disorders | | | | | | |
| Peripheral NeuropathyPeripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. | 42 | 7 | <1 | 45 | 10 | 1 |
| Neuralgia | 17 | 3 | 0 | 20 | 4 | 1 |
| Paraesthesia/dysesthesia | 13 | <1 | 0 | 10 | 0 | 0 |
| Respiratory, thoracic and mediastinal disorders | | | | | | |
| Cough | 18 | 0 | 0 | 12 | 0 | 0 |
| Skin and subcutaneous tissue disorders | | | | | | |
| RashRash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. | 22 | 1 | 0 | 18 | 1 | 0 |
| Hand-foot syndrome | 19 | 6 | 0 | <1 | 0 | 0 |
Post Marketing Experience
The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms.
Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal).
Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL.
Skin and subcutaneous tissue disorders: very rare cases of erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis have been reported.
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