Epirubicin - Ellence®

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Usual Diluents

NS, D5W

Dilution Data

ELLENCE is provided as a preservative-free, ready-to-use solution. Also available as a lyophilized powder for solution that must be reconstituted.

ELLENCE should be administered 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 epirubicin infused over 15–20 minutes. For patients who require lower epirubicin starting doses due to organ dysfunction or who require modification of epirubicin doses during therapy, the epirubicin 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 PACKAGE INSERT FOR PRECAUTIONS). ELLENCE should be used within 24 hours of first penetration of the rubber stopper. Discard any unused solution.

Dilution summary:
Slow IVPush - administered into the tubing of a freely flowing intravenous infusion (NS or D5W)
[Doses < 100mg/m2 ] [10 - 15 minutes (≥3 minutes for LOW doses)]
[Doses 100-120mg/m2 ] [15 - 20 minutes]

IVPB:
[Doses ≤100 mg] [ 50 ml] [10 - 20 minutes]
[Doses >100 mg] [ 100 ml ] [15 - 20 minutes]

Stability / Miscellaneous

WARNINGS	CLINICAL PHARMACOLOGY	INDICATIONS
CONTRAINDICATIONS	DOSAGE AND ADMINISTRATION	RECONSTITUTION / DILUTION
	HOW SUPPLIED
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WARNINGS
Severe local tissue necrosis will occur if there is extravasation during administration (See PRECAUTIONS). Epirubicin must not be given by the intramuscular or subcutaneous route. Myocardial toxicity, manifested in its most severe form by potentially fatal congestive heart failure (CHF), may occur either during therapy with epirubicin or months to years after termination of therapy. The probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with ELLENCE may occur at lower cumulative doses whether or not cardiac risk factors are present. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. The occurrence of refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7110 patients with breast cancer who received adjuvant treatment with epirubicin-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years and 0.55% at 8 years. Dosage should be reduced in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION). Severe myelosuppression may occur. Epirubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

DESCRIPTION
ELLENCE Injection (epirubicin hydrochloride injection) is an anthracycline cytotoxic agent, intended for intravenous administration. ELLENCE is supplied as a sterile, clear, red solution and is available in polypropylene vials containing 50 and 200 mg of epirubicin hydrochloride as a preservative-free, ready-to-use solution. Each milliliter of solution contains 2 mg of epirubicin hydrochloride. Inactive ingredients include sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid, NF.

Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin.

CLINICAL PHARMACOLOGY
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 antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms.

Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors.

INDICATIONS AND USAGE
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.

CONTRAINDICATIONS
Patients should not be treated with ELLENCE Injection if they have any of the following conditions: baseline neutrophil count < 1500 cells/mm3; severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose; hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; or severe hepatic dysfunction (see WARNINGS and DOSAGE AND ADMINISTRATION).

DOSAGE AND ADMINISTRATION
ELLENCE Injection is administered to patients by intravenous infusion. ELLENCE is given 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. The recommended dosages of ELLENCE are as follows:

Starting Doses
The recommended starting dose of ELLENCE is 100 to 120 mg/m2. The following regimens were used in the trials supporting use of ELLENCE as a component of adjuvant therapy in patients with axillary-node positive breast cancer:

CEF-120:	Cyclophosphamide ELLENCE 5-Fluorouracil Repeated every 28 days for 6 cycles	75 mg/m2 PO D 1–14 60 mg/m2 IV D 1, 8 500 mg/m2 IV D 1, 8
FEC-100:	5-Fluorouracil ELLENCE Cyclophosphamide	500 mg/m2 100 mg/m2 500 mg/m2
	All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles

Patients administered the 120-mg/m2 regimen of ELLENCE also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra®, Bactrim®) or a fluoroquinolone.

Bone Marrow Dysfunction
Consideration should be given to administration of lower starting doses (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 PACKAGE INSERT FOR WARNINGS and PRECAUTIONS).

Hepatic Dysfunction
Definitive recommendations regarding use of ELLENCE in patients with hepatic dysfunction are not available because patients with hepatic abnormalities were excluded from participation in adjuvant trials of FEC-100/CEF-120 therapy. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions were recommended in clinical trials, although few patients experienced hepatic impairment: 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 Information regarding experience in patients with hepatic dysfunction is provided in PACKAGE INSERT: CLINICAL PHARMACOLOGY, Pharmacokinetics In Special Populations.

Renal Dysfunction
While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, lower doses should be considered in patients with severe renal impairment (serum creatinine > 5 mg/dL).

Dose Modifications
Dosage adjustments after the first treatment cycle should be made based on hematologic and nonhematologic toxicities. Patients experiencing during treatment cycle nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity should have the Day 1 dose in subsequent cycles reduced to 75% of the Day 1 dose given in the current cycle. Day 1 chemotherapy in subsequent courses of treatment should be delayed until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1.

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 Grade 3/4 nonhematologic toxicity has occurred, the Day 8 dose should be omitted

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Preparation & Administration Precautions
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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures normally used for proper handling and disposal of anticancer drugs should be considered for use with ELLENCE. Several guidelines on this subject have been published.1–8

Protective measures
The following protective measures should be taken when handling ELLENCE: Personnel should be trained in appropriate techniques for reconstitution and handling. Pregnant staff should be excluded from working with this drug. Personnel handling ELLENCE should wear protective clothing: goggles, gowns and disposable gloves and masks. A designated area should be defined for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. All items used for reconstitution, administration or cleaning (including gloves) should be placed in high-risk, waste-disposal bags for high temperature incineration. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All contaminated and cleaning materials should be placed in high-risk, waste-disposal bags for incineration. Accidental contact with the skin or eyes should be treated immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Medical attention should be sought. Always wash hands after removing gloves. Incompatibilities
Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. ELLENCE should not be mixed with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.

ELLENCE can be used in combination with other antitumor agents, but it is not recommended that it be mixed with other drugs in the same syringe.

Preparation of Infusion Solution
ELLENCE is provided as a preservative-free, ready-to-use solution.

ELLENCE should be administered 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 epirubicin infused over 15–20 minutes. For patients who require lower epirubicin starting doses due to organ dysfunction or who require modification of epirubicin doses during therapy, the epirubicin 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 PACKAGE INSERT FOR PRECAUTIONS). ELLENCE should be used within 24 hours of first penetration of the rubber stopper. Discard any unused solution.

EPIRUBICIN HYDROCHLORIDE injection, powder, lyophilized, for solution :
Reconstitution:
Prior to use, Epirubicin Hydrochloride for Injection 50 mg and 200 mg vials must be reconstituted with 25 mL and 100 mL, respectively, of Sterile Water for Injection, USP, resulting in a solution concentration of 2 mg/mL with a pH of 4.7 to 5.0. Shake vigorously. It may take up to 4 minutes for epirubicin hydrochloride to completely dissolve. Reconstituted solutions are stable for 24 hours when stored at 2 to 8°C (36 to 46°F) and protected from light, or 25°C (77°F) in normal lighting conditions.

Epirubicin Hydrochloride for Injection can be further diluted with Sterile Water for Injection, USP.

HOW SUPPLIED
ELLENCE Injection is available in polypropylene single-use CYTOSAFE™ vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths:

50 mg/25 mL single-use vial NDC 0009-5091-01
200 mg/100 mL single-use vial NDC 0009-5093-01

Store refrigerated between 2°C and 8°C (36°F and 46°F). Do not freeze. Protect from light.
Discard unused portion.

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).
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EPIRUBICIN HYDROCHLORIDE injection, powder, lyophilized, for solution:
Epirubicin Hydrochloride for Injection is available in single-use vials containing 50 mg and 200 mg epirubicin hydrochloride.

50 mg/vialNDC 61703-347-35

200 mg/vialNDC 61703-348-59

Store unopened vials at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light. Discard unused portion. Store Upright.

Reference(s)

PRIMARY:
1) [PACKAGE INSERT DATA] : ELLENCE (epirubicin hydrochloride) injection, solution. [Pharmacia and Upjohn Company] Division of Pfizer Inc, NY, NY 10017. Revised: 08/2009.

Proper handling and disposal: ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999: 32–41. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992 US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621. AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253(11):1590–1592. National Study Commision on Cytotoxic Exposure – Recommendations for Handling of Cytotoxic Agents. 1987. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. Clinical Oncology Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426–428. Jones RB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer J for Clin 1983; 33:258–263. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. AM J Hosp Pharm 1990; 47:1033–1049. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm1996; 53:1669–1685