The following adverse reactions are discussed in more detail in other sections of the labeling.
- Cardiomyopathy [see WARNINGS AND PRECAUTIONS]
- Infusion-Related Reactions [see WARNINGS AND PRECAUTIONS]
- Hand-Foot Syndrome [see WARNINGS AND PRECAUTIONS]
- Secondary Oral Neoplasms [see WARNINGS AND PRECAUTIONS]
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/m² 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 | |
| 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/mm³ (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*) |
Total 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
| 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 Neuropathy1 | 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 | ||||
| Rash2 | 22 | 1 | 18 | 1 |
| Hand-foot syndrome | 19 | 6 | < 1 | 0 |
| 1Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. 2Rash 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: [see WARNINGS AND PRECAUTIONS].