Epirubicin Hydrochloride

ELLENCE Injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer [see Clinical Studies].

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

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

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].

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 ELLENCE

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 with ELLENCE

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

Injection-Site Reactions [see WARNINGS AND PRECAUTIONS].

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, haemorrhage, 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)

Inform patients of the expected adverse effects of ELLENCE, including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis), alopecia and potential neutropenic complications.

Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with ELLENCE, as well as a risk of treatment-related leukemia.

Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of CHF, or injection-site pain occurs following therapy with ELLENCE.

Advise patients that their urine may appear red for 1 to 2 days after administration of ELLENCE and that they should not be alarmed.

Because ELLENCE may induce chromosomal damage in sperm, advise men undergoing treatment with ELLENCE to use effective contraceptive methods. Women treated with ELLENCE may develop irreversible amenorrhea, or premature menopause.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

Epirubicin is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Epirubicin is used to treat breast cancer.

Epirubicin may also be used for purposes not listed in this medication guide.

• Pharmacologic actions similar to those of daunorubicin and doxorubicin.1 2 3 4

• Intercalates between base pairs causing template disordering and steric obstruction; thereby inhibits DNA synthesis, DNA-dependent RNA synthesis, and protein synthesis 1 2 4 and triggers DNA cleavage by topoisomerase II.1 2 3 4 Also inhibits DNA helicase and generates cytotoxic free radicals.1 2 3 4

• Compared with doxorubicin, is more lipophilic, may have improved therapeutic index, 3 4 and is less toxic;2 3 similar spectrum of activity against a wide variety of solid tumors and hematologic malignancies, and complete cross-resistance.2 3 4

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.