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Clinical Trial 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.
Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) [see Clinical Studies] evaluating ELLENCE-containing combination regimens in patients with early breast cancer. 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 acute adverse events are summarized in Table 1.
Table 1: Clinically Relevant Acute Adverse Events in
Patients with Early Breast Cancer
|Event||% of Patients|
|Grades 1-4||Grades 3/4||Grades 1-4||Grades 3/4||Grades 1-4||Grades 3/4|
|Body as a Whole|
|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.|
Table 2 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.
Table 2: Long-Term Adverse Events in Patients with
Early Breast Cancer
|Event||% of Patients|
|Asymptomatic drops in LVEF||2.1*||1.4||0. 8 *|
|*In study MA-5, cardiac
function was not monitored after 5 years.
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.
Overview Of Acute And Delayed Toxicities
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].
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 WARNINGS AND 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 ELLENCE; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.
In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of ELLENCE (Figure 1). The estimated risk of ELLENCE-treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m², 1.6% at 700 mg/m², and 3.3% at 900 mg/m² . The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an ELLENCE cumulative dose of 900 mg/m² [see WARNINGS AND PRECAUTIONS].
Figure 1 : Risk of CHF in 9144 Patients Treated with
In another retrospective survey of 469 ELLENCE-treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients [see WARNINGS AND PRECAUTIONS].
Other 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.
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
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
|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
|ELLENCE Cumulative Dose > 720 mg/m²
|ELLENCE Cumulative Dose ≤ 720 mg/m²
|ELLENCE Cumulative Dose > 720 mg/m²
Injection-Site Reactions [see WARNINGS AND PRECAUTIONS].
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.
Immune system disorders: anaphylaxis
Metabolism and nutrition disorders: dehydration, hyperuricemia
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)
Read the Ellence (epirubicin hydrochloride) Side Effects Center for a complete guide to possible side effects
Do not administer epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Concomitant use of ELLENCE with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment.
Cimetidine increases the exposure to epirubicin [see CLINICAL PHARMACOLOGY]. Stop Cimetidine during treatment with ELLENCE.
Other Cytotoxic Drugs
ELLENCE used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects.
The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone [see CLINICAL PHARMACOLOGY].
The administration of epirubicin immediately prior to or after docetaxel did not have an effect on the systemic exposure of epirubicin, but increased the systemic exposure of epirubicinol and 7-deoxydoxorubicin aglycone [ see CLINICAL PHARMACOLOGY].
There are few data regarding the coadministration of radiation therapy and ELLENCE. In adjuvant trials of ELLENCE-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received ELLENCE-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of ELLENCE with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.
Concomitant Therapies-Hepatic Function
Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity.
Drug/Laboratory Test Interactions
There are no known interactions between ELLENCE and laboratory tests.
Read the Ellence Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/28/2016
Additional Ellence Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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