Epirubicin hydrochloride

Epirubicin hydrochloride
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

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Black Box Warning

WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION See full prescribing information for complete Boxed Warning. * Severe local tissue necrosis will occur if there is extravasation during administration. ELLENCE must not be given by the intramuscular or subcutaneous route. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with ELLENCE 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 ELLENCE 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 ELLENCE-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years. Severe myelosuppression may occur

Overview

Epirubicin hydrochloride is an anthracycline topoisomerase II inhibitor that is FDA approved for the treatment of primary breast cancer with evidence of axillary node tumor involvement. There is a Black Box Warning for this drug as shown here. Common adverse reactions include leukopenia, neutropenia, anemia, thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local toxicity and rash/itch.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Epirubicin hydrochloride is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.

• Dosage: 100 to 120 mg/m2 for 3 to 4 week cycles

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Epirubicin hydrochloride in adult patients.

Non–Guideline-Supported Use

• Carcinoma of bladder
• Carcinoma of esophagus
• Gastric cancer
• Hodgkin's disease
• Malignant tumor of nasopharynx
• Metastatic breast cancer
• Non-Hodgkin's lymphoma
• Non-small cell lung cancer
• Ovarian cancer
• Small cell carcinoma of lung
• Soft tissue sarcoma

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Safety and efficacy have not been established in pediatric patients

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Epirubicin hydrochloride in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Epirubicin hydrochloride in pediatric patients.

Contraindications

Patients should not be treated with ELLENCE Injection if they have any of the following conditions:

• Cardiomyopathy and/or heart failure, recent myocardial infarction or severe arrhythmias.
• Previous treatment with maximum cumulative dose of anthracyclines.
• Hypersensitivity to ELLENCE, other anthracyclines, or anthracenediones

Warnings

WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION See full prescribing information for complete Boxed Warning. * Severe local tissue necrosis will occur if there is extravasation during administration. ELLENCE must not be given by the intramuscular or subcutaneous route. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with ELLENCE 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 ELLENCE 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 ELLENCE-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years. Severe myelosuppression may occur

Administer ELLENCE Injection only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with ELLENCE, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, precede initial treatment with ELLENCE by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to ELLENCE.

Injection-Related Reactions

ELLENCE Injection is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of ELLENCE during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Administer ELLENCE slowly into the tubing of a freely running intravenous infusion. 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 [see DOSAGE AND ADMINISTRATION (2.3)]. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Immediately terminate infusion and restart in another vein if a burning or stinging sensation indicates perivenous infiltration. Perivenous infiltration may occur without causing pain. Facial flushing, as well as local erythematous streaking along the vein, may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis. Give prophylactic antibiotic therapy to patients administered the 120-mg/m2 regimen of ELLENCE as a component of combination chemotherapy.

Hematologic

Ellence can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anemia [see ADVERSE REACTIONS (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy.

Cardiac

Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of ELLENCE consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of ELLENCE treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of ELLENCE and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with ELLENCE or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported.

Given the risk of cardiomyopathy, exceed a cumulative dose of 900 mg/m2 ELLENCE only with extreme caution. Risk factors [active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs, especially those with long half-lives (e.g., trastuzumab)] may increase the risk of ELLENCE cardiotoxicity. 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.

Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of ELLENCE at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Perform repeated MUGA or ECHO determinations of LVEF, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with ELLENCE in patients with impaired cardiac function must be carefully evaluated.

Do not administer ELLENCE in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity.

Secondary Leukemia

The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. 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 the anthracyclines have been escalated. These leukemias can have a short 1- to 3-year latency period.

ELLENCE is mutagenic, clastogenic, and carcinogenic in animals.

Hepatic

The major route of elimination of epirubicin is the hepatobiliary system. Evaluate serum total bilirubin and AST levels before and during treatment with ELLENCE. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients. Patients with severe hepatic impairment have not been evaluated; therefore, do not use ELLENCE in this patient population.

Renal

Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL. Patients undergoing dialysis have not been studied.

Tumor-Lysis Syndrome

As with other cytotoxic agents, ELLENCE may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor-lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, consider the potential for tumor-lysis syndrome in potentially susceptible patients and consider monitoring serum uric acid, potassium, calcium, phosphate, and creatinine immediately after initial chemotherapy administration. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. Avoid vaccination with a live vaccine in patients receiving ELLENCE. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

5.9 Gastrointestinal ELLENCE is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of ELLENCE, particularly when given in conjunction with other emetigenic drugs [see ADVERSE REACTIONS (6.2)].

5.10 Thrombophlebitis and Thromboembolic Phenomena As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of ELLENCE.

5.11 Coadministration with Cimetidine Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with ELLENCE [see CLINICAL PHARMACOLOGY (12.3)].

5.12 Pregnancy ELLENCE can cause fetal harm when administered to a pregnant woman. Epirubicin was embryolethal and teratogenic in rats and rabbits. There are no adequate and well-controlled studies of ELLENCE in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods [see USE IN SPECIFIC POPULATIONS (8.1)].

5.13 Male Fertility and Reproductive Outcomes Males with female sexual partners of childbearing potential should use contraception during and after cessation of ELLENCE therapy. ELLENCE may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain [see NONCLINICAL TOXICOLOGY (13.1)].

5.14 Laboratory Testing Assess blood counts, including absolute neutrophil counts, and liver function before and during each cycle of therapy with ELLENCE. Perform repeated evaluations of LVEF during therapy [see WARNINGS AND PRECAUTIONS (5.5 and 5.6)].

5.15 Inflammation following Irradiation As with other anthracyclines, administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Epirubicin hydrochloride Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Epirubicin hydrochloride Postmarketing Experience in the drug label.

Drug Interactions

Cardioactive Compounds

Do not administer epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity.

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.

Cimetidine

Cimetidine increases the exposure to epirubicin. Stop Cimetidine during treatment with ELLENCE.

Other 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.

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.

Radiation 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.

Concomitant Therapies-Hepatic Function

Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity.

Drug/Laboratory Test Interactions

There are no known interactions between ELLENCE and laboratory tests.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Epirubicin hydrochloride in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Epirubicin hydrochloride in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Epirubicin hydrochloride during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Epirubicin hydrochloride in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Epirubicin hydrochloride in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Epirubicin hydrochloride in geriatric settings.

Gender

There is no FDA guidance on the use of Epirubicin hydrochloride with respect to specific gender populations.

Race

There is no FDA guidance on the use of Epirubicin hydrochloride with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Epirubicin hydrochloride in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Epirubicin hydrochloride in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Epirubicin hydrochloride in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Epirubicin hydrochloride in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Epirubicin hydrochloride Administration in the drug label.

Monitoring

There is limited information regarding Epirubicin hydrochloride Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Epirubicin hydrochloride and IV administrations.

Overdosage

There is limited information regarding Epirubicin hydrochloride overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Epirubicin hydrochloride Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Epirubicin hydrochloride Mechanism of Action in the drug label.

Structure

There is limited information regarding Epirubicin hydrochloride Structure in the drug label.

Pharmacodynamics

There is limited information regarding Epirubicin hydrochloride Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Epirubicin hydrochloride Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Epirubicin hydrochloride Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Epirubicin hydrochloride Clinical Studies in the drug label.

How Supplied

There is limited information regarding Epirubicin hydrochloride How Supplied in the drug label.

Storage

There is limited information regarding Epirubicin hydrochloride Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Epirubicin hydrochloride Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Epirubicin hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Epirubicin hydrochloride Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Epirubicin hydrochloride Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.