Ellence

ELLENCE- epirubicin hydrochloride injection, solution
Pharmacia and Upjohn Company LLC

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/m2 , 1.6% at 700 mg/m2 , and 3.3% at 900 mg/m2. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with ELLENCE [see Warnings and Precautions (5.1)].
  • Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including ELLENCE [see Warnings and Precautions (5.2)].
  • Extravasation and Tissue Necrosis: Extravasation of ELLENCE can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area [see Warnings and Precautions (5.3)].
  • Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur [see Warnings and Precautions (5.4)].

1 INDICATIONS AND USAGE

ELLENCE 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 (14.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

When possible, to reduce the risk of developing cardiotoxicity in patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, delay ELLENCE-based therapy until the other agents have cleared from the circulation [see Warnings and Precautions (5.1)].

Antiemetics may reduce nausea and vomiting; consider use of antiemetics before administration of ELLENCE or when clinically indicated, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6.1)].

Patients administered the 120 mg/m2 regimen of ELLENCE should receive prophylactic antibiotic therapy.

2.2 Recommended Dose

The recommended dose of ELLENCE is 100 to 120 mg/m2 administered as an intravenous bolus [see Dosage and Administration (2.4)].

The following regimens are recommended:

CEF-120: Cyclophosphamide 75 mg/m2 oral on Days 1 to 14
ELLENCE 60 mg/m2 intravenously on Days 1 and 8
5-Fluorouracil 500 mg/m2 intravenously on Days 1 and 8
Repeat every 28 days for 6 cycles
FEC-100: 5-Fluorouracil 500 mg/m2 intravenously on Day 1
ELLENCE 100 mg/m2 intravenously on Day 1
Cyclophosphamide 500 mg/m2 intravenously on Day 1
Repeat every 21 days for 6 cycles

Administer ELLENCE in repeated 3- to 4-week cycles. The total dose of ELLENCE may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle.

2.3 Dose Modifications

ELLENCE dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3 , absolute neutrophil counts (ANC) <250/mm3 , neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce ELLENCE Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3 , ANC ≥1500/mm3 , and nonhematologic toxicities have recovered to ≤ Grade 1.

Cardiac Toxicity

Discontinue ELLENCE in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1)].

Bone Marrow Dysfunction

Consider administering a lower starting dose (75–90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration [see Warnings and Precautions (5.4)]. For patients receiving a divided dose of ELLENCE (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000–100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3 , ANC <1000/mm3 , or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose.

Hepatic Impairment

In patients with elevated serum AST or serum total bilirubin concentrations [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)], reduce dosage as follows:

  • Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose
  • Bilirubin >3 mg/dL or AST >4 times upper limit of normal 1/4 of recommended starting dose

Renal Impairment

Consider lower doses in patients with severe renal impairment (serum creatinine >5 mg/dL) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

2.4 Preparation and Administration Precautions

Preparation

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).

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ELLENCE is a cytotoxic drug. Follow applicable special handling and disposable procedures1 [see References (15)].

Incompatibilities

Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix ELLENCE with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.

ELLENCE can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.

Administration

Administer ELLENCE into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m2 should generally have ELLENCE infused over 15–20 minutes.

For patients who require lower ELLENCE starting doses due to organ dysfunction or who require modification of ELLENCE doses during therapy, the ELLENCE infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis.

A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein [see Warnings and Precautions (5.3)].

Storage

Use ELLENCE within 24 hours of first penetration of the rubber stopper. Discard any unused solution.

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