ADVERSE REACTIONS
On-Study Events
Integrated safety data are available from two studies (Studies MA-5 and GFEA-05, see CLINICAL STUDIES) evaluating epirubicin-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose epirubicin regimen (FEC-100/CEF-120), 280 patients received the lower dose epirubicin regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 5.
Table 5. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer | Event | % of Patients |
|---|
FEC-100/CEF-120
(N=620) | FEC-50
(N=280) | CMF
(N=360) |
|---|
Grades
1–4 | Grades
3/4 | Grades
1–4 | Grades
3/4 | Grades
1–4 | Grades
3/4 |
|---|
| Hematologic | | | | | | |
| Leukopenia | 80.3 | 58.6 | 49.6 | 1.5 | 98.1 | 60.3 |
| Neutropenia | 80.3 | 67.2 | 53.9 | 10.5 | 95.8 | 78.1 |
| Anemia | 72.2 | 5.8 | 12.9 | 0 | 70.9 | 0.9 |
| Thrombocytopenia | 48.8 | 5.4 | 4.6 | 0 | 51.4 | 3.6 |
| Endocrine | | | | | | |
| Amenorrhea | 71.8 | 0 | 69.3 | 0 | 67.7 | 0 |
| Hot flashes | 38.9 | 4.0 | 5.4 | 0 | 69.1 | 6.4 |
| Body as a Whole | | | | | | |
| Lethargy | 45.8 | 1.9 | 1.1 | 0 | 72.7 | 0.3 |
| Fever | 5.2 | 0 | 1.4 | 0 | 4.5 | 0 |
| Gastrointestinal | | | | | | |
| Nausea/vomiting | 92.4 | 25.0 | 83.2 | 22.1 | 85.0 | 6.4 |
| Mucositis | 58.5 | 8.9 | 9.3 | 0 | 52.9 | 1.9 |
| Diarrhea | 24.8 | 0.8 | 7.1 | 0 | 50.7 | 2.8 |
| Anorexia | 2.9 | 0 | 1.8 | 0 | 5.8 | 0.3 |
| Infection | | | | | | |
| Infection | 21.5 | 1.6 | 15.0 | 0 | 25.9 | 0.6 |
| Febrile neutropenia | NA | 6.1 | 0 | 0 | NA | 1.1 |
| Ocular | | | | | | |
| Conjunctivitis/keratitis | 14.8 | 0 | 1.1 | 0 | 38.4 | 0 |
| Skin | | | | | | |
| Alopecia | 95.5 | 56.6 | 69.6 | 19.3 | 84.4 | 6.7 |
| Local toxicity | 19.5 | 0.3 | 2.5 | 0.4 | 8.1 | 0 |
| Rash/itch | 8.9 | 0.3 | 1.4 | 0 | 14.2 | 0 |
| Skin changes | 4.7 | 0 | 0.7 | 0 | 7.2 | 0 |
FEC & CEF = cyclophosphamide + epirubicin + fluorouracil; CMF = cyclophosphamide + methotrexate + fluorouracil NA = not available
Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF.
Delayed Events
Table 6 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.
Table 6. Long-Term Adverse Events in Patients with Early Breast Cancer | | % of Patients
|
|---|
| Event | FEC-100/CEF-120
(N=620) | FEC-50
(N=280) | CMF
(N=360) |
|---|
| Cardiac events | | | |
| Asymptomatic drops in LVEF | 2.1 | 1.40.4 | 0.8 |
| CHF | 1.5 | | 0.3 |
| Leukemia | | | |
| AML | 0.8 | 0 | 0.3 |
Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving epirubicin. However, an association between anthracyclines such as epirubicin and ALL has not been clearly established.
Overview of Acute and Delayed Toxicities
Hematologic - See WARNINGS.
Gastrointestinal. A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with epirubicin. Clinical manifestations of mucositis may include a pain or burning sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations; most patients recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur.
Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before therapy (see PRECAUTIONS).
Cutaneous and Hypersensitivity Reactions. Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3 months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and anaphylaxis have been reported in patients treated with epirubicin; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.
Cardiovascular - See WARNINGS.
Secondary Leukemia - See WARNINGS.
Injection-Site Reactions - See PRECAUTIONS.
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