Epirubicin

ELLENCE is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer. ELLENCE is an anthracycline topoisomerase inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.

Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of epirubicin's cytotoxic and/or antiproliferative properties have not been completely elucidated. Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis. Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals.

• The recommended starting dose of ELLENCE is 100 to 120 mg/m 2. Dosage reductions are possible when given in certain combinations. • Administer intravenously in repeated 3- to 4-week cycles, either total dose on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. • Consider use of antiemetics when given in conjunction with other emetigenic drugs. • Patients administered the 120 mg/m 2 regimen of ELLENCE should receive prophylactic antibiotic therapy. • Adjust dosage after the first treatment cycle based on hematologic and nonhematologic toxicities. • Reduce dose in patients with hepatic impairment. • Consider lower doses in patients with severe renal impairment.

ELLENCE is contraindicated in patients with: • Severe myocardial insufficiency • Recent myocardial infarction or severe arrhythmias, or previous treatment with maximum cumulative dose of anthracyclines • Severe persistent drug-induced myelosuppression • Severe hepatic impairment (defined as Child-Pugh Class C or serum bilirubin level greater than 5 mg/dL) • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones • Severe myocardial insufficiency. • Recent myocardial infarction. • Severe persistent drug-induced myelosuppression. • Severe hepatic impairment. • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones.

Boxed warning (cardiac toxicity, secondary malignancies, extravasation and tissue necrosis, and severe myelosuppression •): Cardiac Toxicity: Myocardial damage, including acute left ventricular failure, can occur with ELLENCE. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 0.9% at a cumulative dose of 550 mg/m 2, 1.6% at 700 mg/m 2, and 3.3% at 900 mg/m 2. • Use in Patients with Hepatic Impairment: Monitor serum total bilirubin and AST levels before and during treatment with ELLENCE. In patients with elevated serum AST or serum total bilirubin, dosage reductions or discontinuation may be required. • Tumor Lysis Syndrome: Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Cardiac Toxicity • Secondary Malignancies • Extravasation and Tissue Necrosis • Severe Myelosuppression • Tumor-Lysis Syndrome • Thrombophlebitis and Thromboembolic Events • Potentiation of Radiation Toxicity and Radiation Recall The most common adverse reactions (≥10%) are leukopenia, neutropenia, anemia, thrombocytopenia, amenorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local skin toxicity, and rash/itch.

• Avoid using cardiotoxic agents in combination with ELLENCE. • Discontinue cimetidine during treatment with ELLENCE. Cardiotoxic Agents Closely monitor cardiac function when ELLENCE is used in combination with other cardiotoxic agents. Patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may be at an increased risk of developing cardiotoxicity. Trastuzumab may persist in the circulation for up to 7 months. Therefore, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. Monitor the patient's cardiac function closely if anthracyclines are used before this time. 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.

Store refrigerated between 2°C and 8°C (36°F and 46°F). Do not freeze. Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15–25°C). Solution for injection should be used within 24 hours after removal from refrigeration. Protect from light.