Ellence epirubicin hydrochloride 2 mg/mL Injection, Solution
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Anthracycline Topoisomerase Inhibitor class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Epirubicin is used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. Epirubicin is in a class of medications called anthracyclines. It works by slowing or stopping the growth of cancer cells in your body.
Read the full MedlinePlus article ↗- Ellence (epirubicin) is a chemotherapy drug used after breast cancer surgery when cancer cells have been found in the lymph nodes under your arm. The goal is to reduce the risk of...
- What exactly is Ellence used for, and why am I getting it with other chemo drugs?
- Very common ones include nausea, vomiting, hair loss, mouth sores, and fatigue from low blood counts — your team will give you anti-nausea medication to help. Hair loss is usually...
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🧪 Inactive Ingredients / Excipients
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UNII QTT17582CB
A strong acid used to adjust and maintain the proper pH level in liquid medicines, ensuring stability and preventing breakdown of active ingredients.
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UNII 451W47IQ8X
Sodium chloride is common table salt. It's used in medicines as a buffer to maintain proper pH, as a filler to add bulk, or to adjust the osmotic balance in liquid formulations.
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UNII 55X04QC32I
A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
4 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
| Medicare Part B allowsASP · J9178 | $1.994 / J9178 unit | — |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Ellence 2 mg/mLthis 00009-5093-01 | Pharmacia | 1 vial | — | AP | Discontinued | — |
| Ellence 2 mg/mL 00009-5091-01 | Pharmacia | 1 vial | — | AP | Discontinued | — |
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⏳ Availability & generic status
The FDA lists approved generic versions of this medicine, but that does not always mean a pharmacy can get one today. Patent rules, launch agreements, supply and pricing can affect when generics actually arrive.
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 00009-5093-01 You're viewing this | 1 VIAL, SINGLE-DOSE in 1 CARTON (0009-5093-01) / 100 mL in 1 VIAL, SINGLE-DOSE | 1999-09-15 | Discontinued by firm |
| 00009-5093-10 | 1 VIAL, SINGLE-DOSE in 1 CARTON (0009-5093-10) / 100 mL in 1 VIAL, SINGLE-DOSE | 2025-03-24 | Active |
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🧭 About this NDC listing & data coverage
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| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | ✓ Available |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
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📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
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 . 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) ] . WARNING: CARDIAC TOXICITY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION See full prescribing information for complete boxed warning . • 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 . 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 ( 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 ( 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 ( 5.3 ). • Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur ( 5.4 ).
🎯 Indications and Usage ▾
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) ] . 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 ( 1 ).
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION • The recommended starting dose of ELLENCE is 100 to 120 mg/m 2 . Dosage reductions are possible when given in certain combinations ( 2.2 ). • 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 ( 2.2 ). • Consider use of antiemetics when given in conjunction with other emetigenic drugs ( 2.1 ). • Patients administered the 120 mg/m 2 regimen of ELLENCE should receive prophylactic antibiotic therapy ( 2.1 ). • Adjust dosage after the first treatment cycle based on hematologic and nonhematologic toxicities ( 2.3 ). • Reduce dose in patients with hepatic impairment ( 2.3 , 8.6 ). • Consider lower doses in patients with severe renal impairment ( 2.3 , 8.7 ).
2.1Important 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/m 2 regimen of ELLENCE should receive prophylactic antibiotic therapy.
2.2Recommended Dose The recommended dose of ELLENCE is 100 to 120 mg/m 2 administered as an intravenous bolus [see Dosage and Administration (2.4) ] . The following regimens are recommended: CEF-120: Cyclophosphamide 75 mg/m 2 oral on Days 1 to 14 ELLENCE 60 mg/m 2 intravenously on Days 1 and 8 5-Fluorouracil 500 mg/m 2 intravenously on Days 1 and 8 Repeat every 28 days for 6 cycles FEC-100: 5-Fluorouracil 500 mg/m 2 intravenously on Day 1 ELLENCE 100 mg/m 2 intravenously on Day 1 Cyclophosphamide 500 mg/m 2 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.
2.3Dose Modifications ELLENCE dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm 3 , absolute neutrophil counts (ANC) <250/mm 3 , 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/mm 3 , ANC ≥1500/mm 3 , 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/m 2 ) 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/mm 3 and ANC is 1000 to 1499/mm 3 .
If Day 8 platelet counts are <75,000/mm 3 , ANC <1000/mm 3 , 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 (ser…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Injection: 50 mg/25 mL (2 mg/mL), 200 mg/100 mL (2 mg/mL) clear red solution in a single-dose vial. Injection: 50 mg/25 mL (2 mg/mL), 200 mg/100 mL (2 mg/mL) solution in single-dose vials ( 3 ).
⛔ Contraindications ▾
4 CONTRAINDICATIONS ELLENCE is contraindicated in patients with: • Severe myocardial insufficiency [see Warnings and Precautions (5.1) ] • Recent myocardial infarction or severe arrhythmias, or previous treatment with maximum cumulative dose of anthracyclines [see Warnings and Precautions (5.1) ] • Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4) ] • Severe hepatic impairment (defined as Child-Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5) ] • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones [see Adverse Reactions (6.1) ] • Severe myocardial insufficiency ( 4 ). • Recent myocardial infarction ( 4 ). • Severe persistent drug-induced myelosuppression ( 4 ). • Severe hepatic impairment ( 4 ). • Severe hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones ( 4 ).
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • 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 ( 2.3 , 5.5 ). • Tumor Lysis Syndrome: Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Consider hydration, urine alkalinization, and prophylaxis with allopurinol to minimize potential complications of hyperuricemia and tumor lysis syndrome ( 5.7 ). • Thrombophlebitis and Thromboembolic Events: Thrombophlebitis and thromboembolic events, including pulmonary embolism (in some cases fatal) have been reported with the use of ELLENCE.
Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein ( 5.9 ). • Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including ELLENCE, may result in serious or fatal infections ( 5.7 ). • Potentiation of Radiation Toxicity and Radiation Recall: Administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation ( 5.10 ). • Embryo-Fetal Toxicity: ELLENCE can cause fetal harm.
Advise patients of the potential risk to a fetus and to use effective contraception ( 5.11 , 8.1 , 8.3 ).
5.1Cardiac Toxicity ELLENCE and other anthracycline drugs can result in either early (or acute) or late (delayed) cardiac toxicity. The principal manifestations of early cardiac toxicity are sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. However, tachycardia (including premature ventricular contractions and ventricular tachycardia), bradycardia, as well as atrioventricular and bundle-branch block have been reported.
Early cardiac toxicity does not usually predict the subsequent occurrence of delayed cardiotoxicity and generally should not be considered a reason for suspending treatment with ELLENCE. Delayed cardiac toxicity is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF). If it occurs, late cardiotoxicity usually develops late during therapy with ELLENCE or within 2 to 3 months after completion of treatment, but there are reports of it occurring several months to years after treatment termination.
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). 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. Given the risk of cardiac toxicity, cumulative doses of 900 mg/m 2 ELLENCE should generally be avoided.
Figure 1. Risk of CHF in 9144 Patients Treated with ELLENCE Prior history of cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of other cardiotoxic drugs, increase the risk of developing late cardiac toxicity. Avoid administration of ELLENCE in combination with other cardiotoxic drugs.
Although not formally tested, it is probable that the toxicity of ELLENCE and other anthracyclines or anthracenediones is additive. Cardiac toxicity with ELLENCE may occur at lower cumulative doses whether or not cardiac risk factors are present. Patients receiving ELLENCE after stopping treatment with other cardiotoxic drugs, especially those with long half-lives such as trastuzumab, may be at increased risk of developing cardiotoxicity [see Dosage and Administration (2) and Drug Interaction (7.1) ] .
Perform a baseline ECG and evaluation of LVEF prior to initiating treatment with ELLENCE. Monitor…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Cardiac Toxicity [see Warnings and Precautions (5.1) ] • Secondary Malignancies [see Warnings and Precautions (5.2) ] • Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3) ] • Severe Myelosuppression [see Warnings and Precautions (5.4) ] • Tumor-Lysis Syndrome [see Warnings and Precautions (5.7) ] • Thrombophlebitis and Thromboembolic Events [see Warnings and Precautions (5.9) ] • Potentiation of Radiation Toxicity and Radiation Recall [see Warnings and Precautions (5.10) ] 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 ( 6 ).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials 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. The safety of ELLENCE was evaluated in two studies (Studies MA-5 and GFEA-05) evaluating combination regimens in patients with early breast cancer [see Clinical Studies (14.1) ] . 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 adverse reactions are summarized in Table 1. Table 1.
Adverse Reactions in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4 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. Hematologic Leukopenia 80 59 50 1.5 98 60 Neutropenia 80 67 54 11 96 78 Anemia 72 6 13 0 71
0.9Thrombocytopenia 49 5 4.6 0 51
3.6Endocrine Amenorrhea 72 0 69 0 68 0 Hot flashes 39 4 5 0 69 6 Body as a Whole Lethargy 46 1.9 1.1 0 73
0.3Fever 5 0 1.4 0 4.5 0 Gastrointestinal Nausea/vomiting 92 25 83 22 85 6 Mucositis 59 9 9 0 53
1.9Diarrhea 25 0.8 7 0 51
2.8Anorexia 2.9 0 1.8 0 6
0.3Infection Infection 22 1.6 15 0 26
0.6 Febrile neutropenia NA 6 0 0 NA
1.1Ocular Conjunctivitis/keratitis 15 0 1.1 0 38 0 Skin Alopecia 96 57 70 19 84 7 Local toxicity 20 0.3 2.5 0.4 8 0 Rash/itch 9 0.3 1.4 0 14 0 Skin changes 4.7 0 0.7 0 7 0 Delayed Events Table 2 describes the incidence of delayed adverse reactions in patients participating in the MA-5 and GFEA-05 trials. Table 2. Long-Term Adverse Reactions in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) 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. Cardiac events Asymptomatic drops in LVEF
2.1In study MA-5, cardiac function was not monitored after 5 years. 1.4
0.8CHF 1.5 0.4
0.3Leukemia AML 0.8 0
0.3Hematologic 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 af…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS • Avoid using cardiotoxic agents in combination with ELLENCE ( 7.1 ). • Discontinue cimetidine during treatment with ELLENCE ( 7.2 ).
7.1Cardiotoxic 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 [see Dosage and Administration (2) and Warnings and Precautions (5.1) ] . 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.
7.2Cimetidine Cimetidine increases the exposure to epirubicin [see Clinical Pharmacology (12.3) ]. Discontinue cimetidine during treatment with ELLENCE.
7.3Other Cytotoxic Drugs ELLENCE used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects. Paclitaxel: The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone [see Clinical Pharmacology (12.3) ]. Docetaxel: 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 (12.3) ].
7.4Radiation Therapy 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.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed ( 8.2 ). • Females and Males of Reproductive Potential: May impair fertility ( 8.3 ).
8.1Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, ELLENCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] ; avoid the use of ELLENCE during the 1 st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of epirubicin during the 2 nd and 3 rd trimesters. There are reports of fetal and/or neonatal cardiotoxicity following in utero exposure to epirubicin (see Clinical Considerations ).
In animal reproduction studies in pregnant rats, epirubicin was embryo-fetal lethal and caused structural abnormalities when administered during organogenesis at doses less than the maximum recommended human dose on a body surface area basis ( see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions There have been rare reports of fetal and/or neonatal transient ventricular hypokinesia, transient elevation of cardiac enzymes, and a case of fetal demise from suspected anthracycline-induced cardiotoxicity following in utero exposure to epirubicin in 2 nd and/or 3 rd trimesters. Cardiotoxicity is a known risk of anthracycline treatment in adults [see Warnings and Precautions (5.1) ].
Monitor the fetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care. Data Animal Data Intravenous administration of 0.8 mg/kg/day epirubicin (about 0.04 times the maximum recommended single human dose on a body surface area basis) to rats during Days 5 to 15 of gestation resulted in embryofetal lethality (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight). Intravenous administration of 2 mg/kg/day epirubicin (about 0.1 times the maximum recommended single human dose on a body surface area basis) to rats on Days 9 and 10 of gestation resulted in embryo-fetal lethality (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight and numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations.
Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of teratogenicity were observed.
When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring.
8.2Lactation Risk Summary There are no data on the presence of epirubicin in human milk, the effects on the breastfed child, or…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, ELLENCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] ; avoid the use of ELLENCE during the 1 st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of epirubicin during the 2 nd and 3 rd trimesters. There are reports of fetal and/or neonatal cardiotoxicity following in utero exposure to epirubicin (see Clinical Considerations ).
In animal reproduction studies in pregnant rats, epirubicin was embryo-fetal lethal and caused structural abnormalities when administered during organogenesis at doses less than the maximum recommended human dose on a body surface area basis ( see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions There have been rare reports of fetal and/or neonatal transient ventricular hypokinesia, transient elevation of cardiac enzymes, and a case of fetal demise from suspected anthracycline-induced cardiotoxicity following in utero exposure to epirubicin in 2 nd and/or 3 rd trimesters. Cardiotoxicity is a known risk of anthracycline treatment in adults [see Warnings and Precautions (5.1) ].
Monitor the fetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care. Data Animal Data Intravenous administration of 0.8 mg/kg/day epirubicin (about 0.04 times the maximum recommended single human dose on a body surface area basis) to rats during Days 5 to 15 of gestation resulted in embryofetal lethality (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight). Intravenous administration of 2 mg/kg/day epirubicin (about 0.1 times the maximum recommended single human dose on a body surface area basis) to rats on Days 9 and 10 of gestation resulted in embryo-fetal lethality (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight and numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations.
Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of teratogenicity were observed.
When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring.
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness of ELLENCE have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity or late cardiovascular dysfunction. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated.
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical experience in patients who were 65 years of age and older who received ELLENCE chemotherapy regimens for primary breast cancer showed no overall differences in safety and effectiveness compared with younger patients. In elderly female patients, closely monitor for increased toxicity due to the risk of decreased clearance of epirubicin [see Clinical Pharmacology (12.3) ].
🆘 Overdosage ▾
10 OVERDOSAGE There is no known antidote for overdoses of ELLENCE. A 36-year-old man with non-Hodgkin's lymphoma received a daily 95 mg/m 2 dose of ELLENCE for 5 consecutive days. Five days later, he developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding.
No signs of acute cardiac toxicity were observed. He was treated with antibiotics, colony-stimulating factors, and antifungal agents, and recovered completely. A 63-year-old woman with breast cancer and liver metastasis received a single 320 mg/m 2 dose of ELLENCE.
She was hospitalized with hyperthermia and developed multiple organ failure (respiratory and renal), with lactic acidosis, increased lactate dehydrogenase, and anuria. Death occurred within 24 hours after administration of ELLENCE. Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m 2 .
The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care. If an overdose occurs, provide supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) until the recovery of toxicities.
Delayed CHF has been observed months after anthracycline administration. Observe patients carefully over time for signs of CHF and provided with appropriate supportive therapy.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action 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.
12.3Pharmacokinetics Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m 2 and plasma clearance is not affected by the duration of infusion or administration schedule. Pharmacokinetic parameters for epirubicin following 6- to 10-minute, single-dose intravenous infusions of ELLENCE at doses of 60 to 150 mg/m 2 in patients with solid tumors are shown in Table 4. The plasma concentration declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.
Table 4. Summary of Mean (±SD) Pharmacokinetic Parameters in Patients Advanced solid tumor cancers, primarily of the lung with Solid Tumors Receiving Intravenous ELLENCE 60 to 150 mg/m 2 Dose N=6 patients per dose level (mg/m 2 ) C max Plasma concentration at the end of 6 to 10 minutes infusion (µg/mL) AUC Area under the plasma concentration curve (µg∙h/mL) t 1/2 Half-life of terminal phase (hours) CL Plasma clearance (L/hour) Vss Steady state volume of distribution (L/kg) 60 5.7 ± 1.6 1.6 ± 0.2 35.3 ± 9 65 ± 8 21 ± 2 75 5.3 ± 1.5 1.7 ± 0.3 32.1 ± 5 83 ± 14 27 ± 11 120 9.0 ± 3.5 3.4 ± 0.7 33.7 ± 4 65 ± 13 23 ± 7 150 9.3 ± 2.9 4.2 ± 0.8 31.1 ± 6 69 ± 13 21 ± 7 Distribution Following intravenous administration, epirubicin is rapidly and widely distributed into the tissues.
Binding of epirubicin to plasma proteins, predominantly albumin, is about 77% and is not affected by drug concentration. Epirubicin also appears to concentrate in red blood cells; whole blood concentrations are approximately twice those of plasma. Metabolism Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells.
Four main metabolic routes have been identified: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin.
As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites. Excretion Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion.
Mass-balance data from 1…
🧬 Mechanism of Action ▾
12.1Mechanism of Action 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.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING ELLENCE is available in polypropylene single-dose CYTOSAFE ® vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use, clear, red solution in the following strengths: Unit of Sale Strength NDC 0009-5091-01 Carton of 1 Single-dose Vial 50 mg/25 mL (2 mg/mL) NDC 0009-5093-01 Carton of 1 Single-dose Vial 200 mg/100 mL (2 mg/mL) Discard unused portion. ELLENCE is available in ONCO-TAIN ® glass vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use, clear, red solution in the following strengths: Unit of Sale Strength NDC 0009-5091-25 Carton of 1 Single-dose Vial 50 mg/25 mL (2 mg/mL) NDC 0009-5093-10 Carton of 1 Single-dose Vial 200 mg/100 mL (2 mg/mL) ONCO-TAIN ® is the vial external protection system.
Discard unused portion. Store refrigerated between 2°C and 8°C (36°F and 46°F). Do not freeze.
Protect from light. 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. ELLENCE is a hazardous drug. Follow applicable special handling and disposal procedures 1 [see References (15) ].
📦 Storage and Handling ▾
Store refrigerated between 2°C and 8°C (36°F and 46°F). Do not freeze. Protect from light.
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.
ELLENCE is a hazardous drug. Follow applicable special handling and disposal procedures 1 [see References (15) ].
📋 Description ▾
11 DESCRIPTION ELLENCE (epirubicin hydrochloride injection) is an anthracycline topoisomerase inhibitor 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 9 mg sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid and/or sodium hydroxide, NF. Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin.
The chemical name is (8S- cis )-10-[(3-amino-2,3,6-trideoxy-α-L- arabino -hexopyranosyl)oxy]-7,8,9,10-tetrahydro6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula C 27 H 29 NO 11 HCl and a molecular weight of 579.95. The structural formula is as follows: Chemical Structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Cardiac Toxicity Inform patients that there is a risk of irreversible myocardial damage associated with treatment with ELLENCE. Advise patients to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.1) ]. Secondary Malignancies Inform patients that there is an increased risk of treatment-related leukemia from ELLENCE [see Warnings and Precautions (5.2) ].
Extravasation and Tissue Necrosis Inform patients that ELLENCE can cause severe injection site reactions. Advise patients to contact a healthcare provider if injection site pain occurs after receiving ELLENCE [see Warnings and Precautions (5.3) ]. Severe Myelosuppression Inform patients that ELLENCE can cause leukopenia, thrombocytopenia, or anemia.
Advise patients to contact a healthcare provider for new onset fever or symptoms of infection [see Warnings and Precautions (5.4) ]. Nausea and Vomiting Inform patients that ELLENCE can cause nausea or vomiting. Advise patients to contact a healthcare provider should they develop any severe symptoms [see Adverse Reactions (6.1) ].
Common Adverse Reactions Inform patients of the expected adverse effects of ELLENCE, including diarrhea, stomatitis, and alopecia [see Adverse Reactions (6.1) ]. Red Coloration of Urine Advise patients that their urine may appear red for 1 to 2 days after administration of ELLENCE and that they should not be alarmed [see Adverse Reactions (6.2) ]. Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1) ] . • Advise female patients of reproductive potential to use effective contraception during treatment with ELLENCE and for 6 months after the last dose [see Warnings and Precautions (5.11) and Use in Specific Populations (8.3) ] . • Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ELLENCE.
Advise male patients with pregnant partners to use condoms during treatment and for at least 7 days after the last dose of ELLENCE [see Use in Specific Populations (8.3) ] . Lactation Advise female patients not to breastfeed during treatment with ELLENCE and for at least 7 days after the last dose [see Use in Specific Populations (8.2) ] . Infertility Women treated with ELLENCE may develop irreversible amenorrhea, or premature menopause.
Advise patients that ELLENCE may impair female and male fertility [see Use in Specific Populations (8.3) ] .