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ELLENCE® (epirubicin HCl) Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ELLENCE was evaluated in two studies (Studies MA-5 and GFEA-05) evaluating combination regimens in patients with early breast cancer [see Clinical Studies (14.1)]. Of the 1260 patients treated in these studies, 620 patients received the higher-dose ELLENCE regimen (FEC-100/CEF-120), 280 patients received the lower-dose ELLENCE regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant adverse reactions are summarized in Table 1.

Table 1. Adverse Reactions 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
FEC & CEF = cyclophosphamide + ELLENCE + 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.
Hematologic
  Leukopenia 80 59 50 1.5 98 60
  Neutropenia 80 67 54 11 96 78
  Anemia 72 6 13 0 71 0.9
  Thrombocytopenia 49 5 4.6 0 51 3.6
Endocrine
  Amenorrhea 72 0 69 0 68 0
  Hot flashes 39 4 5 0 69 6
Body as a Whole
  Lethargy 46 1.9 1.1 0 73 0.3
  Fever 5 0 1.4 0 4.5 0
Gastrointestinal
  Nausea/vomiting 92 25 83 22 85 6
  Mucositis 59 9 9 0 53 1.9
  Diarrhea 25 0.8 7 0 51 2.8
  Anorexia 2.9 0 1.8 0 6 0.3
Infection
  Infection 22 1.6 15 0 26 0.6
  Febrile neutropenia NA 6 0 0 NA 1.1
Ocular
  Conjunctivitis/keratitis 15 0 1.1 0 38 0
Skin
  Alopecia 96 57 70 19 84 7
  Local toxicity 20 0.3 2.5 0.4 8 0
  Rash/itch 9 0.3 1.4 0 14 0
  Skin changes 4.7 0 0.7 0 7 0

Delayed Events

Table 2 describes the incidence of delayed adverse reactions in patients participating in the MA-5 and GFEA-05 trials.

Table 2. Long-Term Adverse Reactions in Patients with Early Breast Cancer
Event % of Patients
FEC-100/CEF-120
(N=620)
FEC-50
(N=280)
CMF
(N=360)
*
In study MA-5, cardiac function was not monitored after 5 years.
Cardiac events
Asymptomatic drops in LVEF 2.1* 1.4 0.8*
CHF 1.5 0.4 0.3
Leukemia
AML 0.8 0 0.3

Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving ELLENCE. However, an association between anthracyclines such as ELLENCE and ALL has not been clearly established.

Hematologic

Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with ELLENCE and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21 after drug administration. As with other cytotoxic agents, ELLENCE at the recommended dose in combination with cyclophosphamide and fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive complications occur, use appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy with ELLENCE [see Warnings and Precautions (5.4)].

Gastrointestinal

A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with ELLENCE. 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; consider prophylactic use of antiemetics before therapy [see Dosage and Administration (2.1)].

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 ELLENCE; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.

Cardiovascular

Serious drug-related cardiovascular adverse events that occurred during clinical trials with ELLENCE, administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism.

Secondary Leukemia

An analysis of 7110 patients who received adjuvant treatment with ELLENCE in controlled clinical trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14–0.40) at 3 years, 0.46% (approximate 95% CI, 0.28–0.65) at 5 years, and 0.55% (approximate 95% CI, 0.33–0.78) at 8 years. The risk of developing AML/MDS increased with increasing ELLENCE cumulative doses as shown in Figure 2.

Figure 2. Risk of AML/MDS in 7110 Patients Treated with ELLENCE

Figure 2

The cumulative probability of developing AML/MDS was found to be particularly increased in patients who received more than the maximum recommended cumulative dose of ELLENCE (720 mg/m2) or cyclophosphamide (6,300 mg/m2), as shown in Table 3.

Table 3. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of ELLENCE and Cyclophosphamide
Years from Treatment Start Cumulative Probability of Developing AML/MDS
% (95% CI)
Cyclophosphamide Cumulative Dose
≤6,300 mg/m2
Cyclophosphamide Cumulative Dose
>6,300 mg/m2
ELLENCE Cumulative Dose
≤720 mg/m2
N=4760
ELLENCE Cumulative Dose
>720 mg/m2
N=111
ELLENCE Cumulative Dose
≤720 mg/m2
N=890
ELLENCE Cumulative Dose
>720 mg/m2
N=261
3 0.12 (0.01–0.22) 0.00 (0.00–0.00) 0.12 (0.00–0.37) 4.37 (1.69–7.05)
5 0.25 (0.08–0.42) 2.38 (0.00–6.99) 0.31 (0.00–0.75) 4.97 (2.06–7.87)
8 0.37 (0.13–0.61) 2.38 (0.00–6.99) 0.31 (0.00–0.75) 4.97 (2.06–7.87)

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ELLENCE. 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.

Infections and infestations: sepsis, pneumonia

Immune system disorders: anaphylaxis

Metabolism and nutrition disorders: dehydration, hyperuricemia

Vascular disorders: shock, hemorrhage, embolism arterial, thrombophlebitis, phlebitis

Respiratory, thoracic and mediastinal disorders: pulmonary embolism

Gastrointestinal disorders: erosions, ulcerations, pain or burning sensation, bleeding, hyperpigmentation of the oral mucosa

Skin and subcutaneous tissue disorders: erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction), urticaria

Renal and urinary disorders: red coloration of urine for 1 to 2 days after administration

General disorders and administration site conditions: fever, chills

Injury, poisoning and procedural complications: chemical cystitis (following intravesical administration)

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