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Doxil

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Doxil

Side Effects
Interactions

SIDE EFFECTS

Overall Adverse Reactions Profile

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

The most common adverse reactions observed with DOXIL (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) are described in Section 6.2.

The safety data described below reflect exposure to DOXIL (doxorubicin hcl 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 [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 (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) compared to topotecan.

Table 7: Ovarian Cancer Randomized Study

Non-Hematologic
Adverse Reaction
10% or Greater
DOXIL (doxorubicin hcl liposome injection) (%)
treated
(n =239)
Topotecan (%)
treated
(n=235)
  All grades Grades 3-4 All grades Grades 3-4
Body as a Whole
  Asthenia 40.2 7.1 51.5 8.1
  Fever 21.3 0.8 30.6 5.5
  Mucous Membrane 14.2 3.8 3.4 0
Disorder
  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 AIDSrelated 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 (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) . 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
(n = 74)
Total Patients With
AIDS-Related
(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

Adverse Reactions Patients With Refractory
or IntolerantAIDS-Related
Kaposi's (n = 77)
Total Patients With
AIDS-Related
(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 (doxorubicin hcl liposome injection) (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 (doxorubicin hcl liposome injection) + 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 (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) 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 Neuropathy* 42 7 < 1 45 10 1
Neuralgia 17 3 0 20 4 1
Paresthesia/dysesthesia 13 < 1 0 10 0 0
Respiratory, thoracic and mediastinal disorders
Cough 18 0 0 12 0 0
Skin and subcutaneous tissue disorders
Rash** 22 1 0 18 1 0
Hand-foot syndrome 19 6 0 < 1 0 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.

Post Marketing Experience

The following additional adverse reactions have been identified during post approval use of DOXIL (doxorubicin hcl liposome injection) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: 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 (doxorubicin hcl liposome injection) .

Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis have been reported.

Read the Doxil (doxorubicin hcl liposome injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with DOXIL (doxorubicin hcl liposome injection) . DOXIL (doxorubicin hcl liposome injection) may interact with drugs known to interact with the conventional formulation of doxorubicin HCl.

Read the Doxil Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

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