EPIRUBICIN HYDROCHLORIDE injection solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
epirubicin hydrochloride (UNII: 22966TX7J5) (epirubicin - UNII:3Z8479ZZ5X)
Available from:
Greenstone, LLC
INN (International Name):
epirubicin hydrochloride
Composition:
epirubicin hydrochloride 2 mg in 1 mL
Prescription type:
PRESCRIPTION DRUG
Authorization status:
New Drug Application Authorized Generic

EPIRUBICIN HYDROCHLORIDE- epirubicin hydrochloride injection, solution

Greenstone, LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Epirubicin HCl safely and effectively. See

full prescribing information for Epirubicin HCl.

Epirubicin HCl (epirubicin hydrochloride injection)

Initial U.S. Approval: 1999

WARNING: SEVERE OR LIFE-THREATENING HEMATOLOGICAL AND OTHER ADVERSE REACTIONS

See full prescribing information for complete boxed warning.

Severe local tissue necrosis associated with extravasation during administration (5.9)

Myocardial toxicity, manifested in its most severe form by potentially fatal congestive heart failure (CHF) (5.3)

Secondary acute myelogenous leukemia (AML) (5.4)

Reduce dosage in patients with impaired hepatic function (5.5)

Severe myelosuppression (5.2)

Administer only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic

agents (5)

RECENT MAJOR CHANGES

Boxed Warning

09/2011

Dosage and Administration, Preparation and Administration (2.3)

09/2011

Warnings and Precautions, Injection-Related Reactions, Hematologic, Cardiac,

Secondary Leukemia, Coadministration with Cimetidine, Pregnancy, Male Fertility

and Reproductive Outcomes, laboratory Testing, Inflammation following

Irradiation (5.1, 5.2, 5.3, 5.4, 5.11, 5.12, 5.13, 5.14, 5.15)

09/2011

Warnings and Precautions, Male Fertility and Reproductive Outcomes (5.13)

11/2011

Drug Interactions, Cadioactive Compounds, cimetidine, other Cytotoxic Drugs,

Radiation Therapy, Concomitant Therapies-Hepatic Function (7.1, 7.2, 7.3, 7.4, 7.5)

09/2011

INDICATIONS AND USAGE

Epirubicin HCl Injection is an anthracycline topoisomerase II inhibitor indicated as a component of adjuvant therapy in

patients with evidence of axillary node tumor involvement following resection of primary breast cancer (1.1).

DOSAGE AND ADMINISTRATION

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).

The recommended starting dose of Epirubicin HCl is 100 to 120 mg/m Dosage reductions are possible when given in

certain combinations (2.1).

Dosage adjustments after the first treatment cycle should be made based on hematologic and nonhematologic toxicities

(2.2).

Reduce dose in patients with hepatic impairment (2.2, 8.6, 12.3).

Consider lower doses in patients with severe renal impairment (2.2, 8.7,12.3).

DOSAGE FORMS AND STRENGTHS

Single use vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution (50

mg/25 mL and 200 mg/100 mL) (3)

CONTRAINDICATIONS

Patients should not be treated with Epirubicin HCl Injection if they have any of the following conditions: baseline neutrophil

count < 1500 cells/mm 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 (4).

WARNINGS AND PRECAUTIONS

A dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity

associated with Epirubicin HCl and represents the most common acute dose-limiting toxicity (5.2).

Cardiotoxicity is a known risk of anthracycline treatment and may be manifested by early (or acute) or late (delayed)

events (5.3).

The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in

patients treated with anthracyclines (5.4).

Serum total bilirubin and AST levels should be evaluated before and during treatment with Epirubicin HCl. 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 (5.5).

Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with

serum creatinine >5 mg/dL. Patients undergoing dialysis have not been studied (5.6).

Epirubicin HCl 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) (5.7).

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents

including Epirubicin HCl, may result in serious or fatal infections (5.8).

Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein.

Extravasation of Epirubicin HCl during the infusion may cause local pain, severe tissue lesions (vesication, severe

cellulitis), and necrosis. 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. Patients administered the 120-

mg/m regimen of Epirubicin HCl as a component of combination chemotherapy should also receive prophylactic

antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra®, Bactrim®) or a fluoroquinolone (5.9).

Epirubicin HCl is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be

considered before administration of Epirubicin HCl, particularly when given in conjunction with other emetigenic drugs

(5.10).

Administration of Epirubicin HCl after previous radiation therapy may induce an inflammatory recall reaction at the site

of the irradiation (5.11)

Thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been

coincidentally reported with the use of Epirubicin HCl (5.12).

Epirubicin HCl can cause fetal harm when administered to a pregnant woman. Advise women of potential risk to the

fetus (5.12).

ADVERSE REACTIONS

In early breast cancer, acute adverse events occurring in ≥10% of patients are leucopenia, neutropenia, anemia,

thrombocytopenia, amenhorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis,

alopecia, local toxicity and rash/itch (6).

Long term adverse events occurring at a frequency of 1–2% are asymptomatic drops in LVEF and CHF and secondary

leukemia (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.

DRUG INTERACTIONS

Do not administer Epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely

monitored (7.1).

Stop Cimetidine during treatment with Epirubicin HCl (7.2).

USE IN SPECIFIC POPULATIONS

Nursing Mothers: Discontinue nursing prior to taking Epirubicin HCl (8.3).

Pediatric Use: Safety and effectiveness of Epirubicin HCl in pediatric patients have not been established. Pediatric

patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF

(8.4).

Geriatric Use: Care should be taken in monitoring toxicity when Epirubicin HCl is administered to female patients ≥ 70

years of age. (8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 11/2011

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE

MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION

MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Modifications

2.3 Preparation and Administration Precautions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Injection-Related Reactions

5.2 Hematologic

5.3 Cardiac

5.4 Secondary Leukemia

5.5 Hepatic

5.6 Renal

5.7 Tumor-Lysis Syndrome

5.8 Immunosuppressant Effects/Increased Susceptibility to Infections

5.9 Gastrointestinal

5.10 Thrombophlebitis and Thromboembolic Phenomena

5.11 Coadministration with Cimetidine

5.12 Pregnancy

5.13 Male Fertility and Reproductive Outcomes

5.14 Laboratory Testing

5.15 Inflammation following Irradiation

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Overview of Acute and Delayed Toxicities

7 DRUG INTERACTIONS

7.1 Cardioactive Compounds

7.2 Cimetidine

7.3 Other Cytotoxic Drugs

7.4 Radiation Therapy

7.5 Concomitant Therapies-Hepatic Function

7.6 Drug/Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Breast Cancer

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY

ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION

RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE

MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION

2. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during

therapy with Epirubicin HCl 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/m , 1.6% at 700 mg/m , and 3.3% at 900 mg/m . In the adjuvant treatment of breast

cancer, the maximum cumulative dose used in clinical trials was 720 mg/m . The risk of

developing CHF increases rapidly with increasing total cumulative doses of Epirubicin HCl

in excess of 900 mg/m ; 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 Epirubicin HCl may occur at lower cumulative doses whether or not

cardiac risk factors are present [see Warnings and Precautions (5.3)].

3. 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 HCl-containing regimens, was

estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years [see Warnings and

Precautions (5.4)].

4. Severe myelosuppression may occur [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

Epirubicin HCl Injection 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

When possible, to reduce the risk of developing cardiotoxicity in patients receiving Epirubicin HCl

after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as

trastuzumab, Epirubicin HCl-based therapy should be delayed until the other agents have cleared from

the circulation [see Warnings and Precautions (5.3)].

Administer Epirubicin HCl Injection by intravenous infusion. Give Epirubicin HCl in repeated 3- to 4-

week cycles. The total dose of Epirubicin HCl may be given on Day 1 of each cycle or divided equally

Severe local tissue necrosis will occur if there is extravasation during administration.

Epirubicin HCl must not be given by the intramuscular or subcutaneous route [see Warnings

and Precautions (5.9)].

and given on Days 1 and 8 of each cycle. The recommended dosages of Epirubicin HCl are as follows:

2.1 Recommended Dose

The recommended dose of Epirubicin HCl is 100 to 120 mg/m . The following regimens are

recommended:

CEF-120:

Cyclophosphamide

75 mg/m PO D 1–14

Epirubicin HCl

60 mg/m IV D 1, 8

5-Fluorouracil

500 mg/m IV D 1, 8

Repeated every 28 days for 6 cycles

FEC-100:

5-Fluorouracil

500 mg/m

Epirubicin HCl

100 mg/m

Cyclophosphamide

500 mg/m

All drugs administered intravenously on Day 1 and repeated every 21 days

for 6 cycles

Patients administered the 120-mg/m regimen of Epirubicin HCl should receive prophylactic antibiotic

therapy.

2.2 Dose Modifications

Epirubicin HCl dosage adjustments for hematologic and non-hematologic toxicities within a cycle of

treatment, is based on nadir platelet counts <50,000/mm , absolute neutrophil counts (ANC) <250/mm ,

neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirubicin HCl 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 , ANC ≥1500/mm , and

nonhematologic toxicities have recovered to ≤ Grade 1.

Bone Marrow Dysfunction

Consider administering a lower starting dose (75–90 mg/m ) 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)]. For patients receiving a divided dose of Epirubicin HCl (Day 1 and

Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000–100,000/mm and ANC is

1000 to 1499/mm . If Day 8 platelet counts are <75,000/mm , ANC <1000/mm , or Grades 3/4

nonhematologic toxicity has occurred, omit the Day 8 dose.

Hepatic Impairment

Recommendations regarding use of Epirubicin HCl in patients with hepatic impairment are not available

because patients with hepatic abnormalities were not included in the adjuvant trials [see Warnings and

Precautions (5.5) and Clinical Pharmacology (12.3)]. In patients with elevated serum AST or serum total

bilirubin concentrations, the following dose reductions are recommended:

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

While no specific dose recommendation can be made based on the limited available data in patients with

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)].

2.3 Preparation and Administration Precautions

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

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 (15–25ºC).

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration,

whenever solution and container permit. Procedures for proper handling and disposal of anticancer

drugs should be used when handling and preparing Epirubicin HCl. Several guidelines on this subject

have been published.

[see References (15)].

Protective Measures

Take the following protective measures when handling Epirubicin HCl:

Train personnel in appropriate techniques for reconstitution and handling.

Exclude pregnant staff from working with this drug.

Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling

Epirubicin HCl.

Define a designated area for syringe preparation (preferably under a laminar flow system), with the

work surface protected by disposable, plastic-backed, absorbent paper.

Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk,

waste-disposal bags for high temperature incineration.

Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution,

preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk,

waste-disposal bags for incineration. Treat accidental contact with the skin or eyes 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. Seek medical attention. Always wash hands after removing

gloves.

Incompatibilities

Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug.

Do not mix Epirubicin HCl with heparin or fluorouracil due to chemical incompatibility that may lead to

precipitation.

Epirubicin HCl can be used in combination with other antitumor agents, but do not mix with other drugs

in the same syringe.

Preparation of Infusion Solution

Administer Epirubicin HCl 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/m should generally have Epirubicin HCl infused over 15–20 minutes. For patients who

require lower Epirubicin HCl starting doses due to organ dysfunction or who require modification of

Epirubicin HCl doses during therapy, the Epirubicin HCl 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

(5.9)]. Use Epirubicin HCl within 24 hours of first penetration of the rubber stopper. Discard any

unused solution.

3 DOSAGE FORMS AND STRENGTHS

Epirubicin HCl is provided 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

sizes: 50 mg/25 mL and 200 mg/100 mL.

4 CONTRAINDICATIONS

1–4

Patients should not be treated with Epirubicin HCl Injection if they have any of the following

conditions:

Severe myocardial insufficiency, recent myocardial infarction or severe arrhythmias [see Warnings and

Precautions (5.3)]

Previous treatment with maximum cumulative dose of anthracyclines [see Warnings and Precautions (5)].

Hypersensitivity to Epirubicin HCl, other anthracyclines, or anthracenediones [see Adverse Reactions

(6.2)].

5 WARNINGS AND PRECAUTIONS

Administer Epirubicin HCl Injection only under the supervision of qualified physicians experienced in

the use of cytotoxic therapy. Before beginning treatment with Epirubicin HCl, patients should recover

from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of

prior cytotoxic treatment. Also, precede initial treatment with Epirubicin HCl 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 Epirubicin HCl.

5.1 Injection-Related Reactions

Epirubicin HCl 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 Epirubicin

HCl during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis), and

necrosis. Administer Epirubicin HCl slowly into the tubing of a freely running intravenous infusion.

Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m should generally

have Epirubicin HCl infused over 15–20 minutes. For patients who require lower Epirubicin HCl

starting doses due to organ dysfunction or who require modification of Epirubicin HCl doses during

therapy, the Epirubicin HCl 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/m regimen of Epirubicin HCl as a

component of combination chemotherapy [see Clinical Studies (14.1) and Dosage and Administration

2.1)].

5.2 Hematologic

Epirubicin HCl 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 [see Dosage and Administration (2.2, 2.3)].

5.3 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 Epirubicin HCl 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 Epirubicin HCl

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 Epirubicin HCl and represents the cumulative dose-

limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of

therapy with Epirubicin HCl 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/m Epirubicin HCl 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

Epirubicin HCl cardiotoxicity [see Drug Interaction (7.4) and Dosage and Administration (2)]. Although

not formally tested, it is probable that the toxicity of Epirubicin HCl and other anthracyclines or

anthracenediones is additive. Cardiac toxicity with Epirubicin HCl 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 Epirubicin HCl 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 Epirubicin HCl in patients with impaired cardiac function

must be carefully evaluated.

Do not administer Epirubicin HCl in combination with other cardiotoxic agents unless the patient's

cardiac function is closely monitored. Patients receiving Epirubicin HCl 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. Avoid Epirubicin HCl-based therapy for up to 24 weeks

after stopping trastuzumab when possible. If Epirubicin HCl is used before this time, monitor cardiac

function carefully [see Dosage and Administration (2)].

5.4 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.

Epirubicin HCl is mutagenic, clastogenic, and carcinogenic in animals [see Nonclinical Toxicology

(13.1)].

5.5 Hepatic

The major route of elimination of epirubicin is the hepatobiliary system [see Clinical Pharmacology

(12.3)]. Evaluate serum total bilirubin and AST levels before and during treatment with Epirubicin HCl.

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 [see Dosage and Administration (2.2)].

Patients with severe hepatic impairment have not been evaluated; therefore, do not use Epirubicin HCl in

this patient population.

5.6 Renal

Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with

serum creatinine >5 mg/dL [see Dosage and Administration (2.2)]. Patients undergoing dialysis have not

been studied.

5.7 Tumor-Lysis Syndrome

As with other cytotoxic agents, Epirubicin HCl 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.

5.8 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 Epirubicin HCl. Killed or inactivated vaccines may be administered;

however, the response to such vaccines may be diminished.

5.9 Gastrointestinal

Epirubicin HCl is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of

antiemetics should be considered before administration of Epirubicin HCl, particularly when given in

conjunction with other emetigenic drugs [see Adverse Reactions (6.X)].

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 Epirubicin HCl.

5.11 Coadministration with Cimetidine

Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with

Epirubicin HCl.

[see Clinical Pharmacology (12.3)]

5.12 Pregnancy

Epirubicin HCl 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

Epirubicin HCl 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. [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 Epirubicin HCl therapy. Epirubicin HCl 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 Epirubicin HCl. 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 Epirubicin HCl after previous radiation therapy may

induce an inflammatory recall reaction at the site of the irradiation.

6 ADVERSE REACTIONS

6.1 Clinical Trial 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.

Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) [see Clinical Studies

(14.1)] evaluating Epirubicin HCl-containing combination regimens in patients with early breast cancer.

Of the 1260 patients treated in these studies, 620 patients received the higher-dose Epirubicin HCl

regimen (FEC-100/CEF-120), 280 patients received the lower-dose Epirubicin HCl regimen (FEC-50),

and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors

were not used in these trials. Clinically relevant acute adverse events are summarized in Table 2.

Table 2. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer

Event

% of Patients

FEC-100/CEF-120

FEC-50

CMF

(N=620)

(N=280)

(N=360)

Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4 Grades 1–4 Grades 3/4

Hematologic

Leukopenia

80.3

58.6

49.6

98.1

60.3

Neutropenia

80.3

67.2

53.9

10.5

95.8

78.1

Anemia

72.2

12.9

70.9

Thrombocytopenia

48.8

51.4

Endocrine

71.8

69.3

67.7

Amenorrhea

38.9

69.1

Hot flashes

Body as a Whole

Lethargy

45.8

72.7

Fever

Gas trointes tinal

Nausea/vomiting

92.4

25.0

83.2

22.1

85.0

Mucositis

58.5

52.9

Diarrhea

24.8

50.7

Anorexia

FEC & CEF = cyclophosphamide + Epirubicin HCl + 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.

Infection

Infection

21.5

15.0

25.9

Febrile neutropenia

Ocular

Conjunctivitis/keratitis

14.8

38.4

Skin

Alopecia

95.5

56.6

69.6

19.3

84.4

Local toxicity

19.5

Rash/itch

14.2

Skin changes

Delayed Events

Table 3 describes the incidence of delayed adverse events in patients participating in the MA-5 and

GFEA-05 trials.

Table 3. Long-Term Adverse Events in Patients with Early Breast Cancer

% of Patients

Event

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

Epirubicin HCl. However, an association between anthracyclines such as Epirubicin HCl and

ALL has not been clearly established.

Cardiac events

Asymptomatic drops in LVEF

Leukemia

6.2 Overview of Acute and Delayed Toxicities

Hematologic

Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of

hematologic toxicity associated with Epirubicin HCl 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 after drug administration. As with other cytotoxic

agents, Epirubicin HCl at the recommended dose in combination with cyclophosphamide and

fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may

also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia,

septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive

complications occur, use appropriate supportive measures (e.g., intravenous antibiotics, colony-

stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and

differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy

with Epirubicin HCl [see Warnings and Precautions (5.2)].

In study MA-5, cardiac function was not monitored after 5 years.

Gastrointestinal

A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated

with Epirubicin HCl. Clinical manifestations of mucositis may include a pain or burning sensation,

erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug

administration and, if severe, may progress over a few days to mucosal ulcerations; most patients

recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa

may also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe

vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; consider

prophylactic use of antiemetics before therapy [see Warnings and Precautions (5.10)].

Cutaneous and Hypersensitivity Reactions

Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3

months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and

hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and

anaphylaxis have been reported in patients treated with Epirubicin HCl; signs and symptoms of these

reactions may vary from skin rash and pruritus to fever, chills, and shock.

Cardiovascular

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 Epirubicin HCl (Figure

1). The estimated risk of Epirubicin HCl-treated patients developing clinically evident CHF was 0.9%

at a cumulative dose of 550 mg/m , 1.6% at 700 mg/m , and 3.3% at 900 mg/m . The risk of developing

CHF in the absence of other cardiac risk factors increased steeply after an Epirubicin HCl cumulative

dose of 900 mg/m [see Warnings and Precautions (5.4)].

Figure 1. Risk of CHF in 9144 Patients Treated with Epirubicin HCl

In another retrospective survey of 469 Epirubicin HCl-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 [see Warnings and Precautions (5.3)].

Secondary Leukemia

An analysis of 7110 patients who received adjuvant treatment with Epirubicin HCl in controlled clinical

trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk

of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27%

(approximate 95% CI, 0.14–0.40) at 3 years, 0.46% (approximate 95% CI, 0.28–0.65) at 5 years, and

0.55% (approximate 95% CI, 0.33–0.78) at 8 years. The risk of developing AML/MDS increased with

increasing Epirubicin HCl cumulative doses as shown in Figure 2.

Figure 2. Risk of AML/MDS in 7110 Patients Treated with Epirubicin HCl

The cumulative probability of developing AML/MDS was found to be particularly increased in patients

who received more than the maximum recommended cumulative dose of Epirubicin HCl (720 mg/m ) or

cyclophosphamide (6,300 mg/m ), as shown in Table 1.

Table 1. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of Epirubicin HCl

and Cyclophosphamide

Years from

Treatment

Start

Cumulative Probability of Developing AML/MDS

% (95% CI)

Cyclophosphamide Cumulative Dose

≤6,300 mg/m

Cyclophosphamide Cumulative Dose

>6,300 mg/m

Epirubicin HCl

Cumulative Dose

≤720 mg/m

N=4760

Epirubicin HCl

Cumulative Dose

>720 mg/m

N=111

Epirubicin HCl

Cumulative Dose

≤720 mg/m

N=890

Epirubicin HCl

Cumulative Dose

>720 mg/m

N=261

0.12 (0.01–0.22)

0.00 (0.00–0.00)

0.12 (0.00–0.37)

4.37 (1.69–7.05)

0.25 (0.08–0.42)

2.38 (0.00–6.99)

0.31 (0.00–0.75)

4.97 (2.06–7.87)

0.37 (0.13–0.61)

2.38 (0.00–6.99)

0.31 (0.00–0.75)

4.97 (2.06–7.87)

Injection-Site Reactions [see Warnings and Precautions (5.9)].

7 DRUG INTERACTIONS

7.1 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. Avoid epirubicin-based therapy for up to 24 weeks after

2

2

2

2

2

2

stopping trastuzumab when possible. If epirubicin is used before this time, monitor cardiac function

carefully [see Dosage and Administration (2) and Warnings and Precautions (5.3)].

Concomitant use of Epirubicin HCl with other cardioactive compounds that could cause heart failure

(e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment.

7.2 Cimetidine

Cimetidiene increases the exposure to epirubicin [see Clinical Pharmacology (12.3)]. Stop Cimetidine

during treatment with Epirubicin HCl.

7.3 Other Cytotoxic Drugs

Epirubicin HCl 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)].

7.4 Radiation Therapy

There are few data regarding the coadministration of radiation therapy and Epirubicin HCl. In adjuvant

trials of Epirubicin HCl-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 Epirubicin HCl-based chemotherapy concomitantly with radiation therapy but had

chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of

Epirubicin HCl with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation.

Administration of Epirubicin HCl after previous radiation therapy may induce an inflammatory recall

reaction at the site of the irradiation.

7.5 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.

7.6 Drug/Laboratory Test Interactions

There are no known interactions between Epirubicin HCl and laboratory tests.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D. See 'Warnings and Precautions' section.

Epirubicin HCl can cause fetal harm when administered to a pregnant woman. Administration of 0.8

mg/kg/day intravenously of epirubicin to rats (about 0.04 times the maximum recommended single human

dose on a body surface area basis) during Days 5 to 15 of gestation was embryotoxic (increased

resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight), but

was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats

(about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 9

and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, and dead

fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused

decreased placental weight. This dose was also teratogenic, causing 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 embryotoxic or 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 embryofetal toxicity or 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.

There are no adequate and well-controlled studies of Epirubicin HCl in pregnant women. Two

pregnancies have been reported in women taking epirubicin. A 34-year-old woman, 28 weeks pregnant

at her diagnosis of breast cancer, was treated with cyclophosphamide and epirubicin every 3 weeks for

3 cycles. She received the last dose at 34 weeks of pregnancy and delivered a healthy baby at 35 weeks.

A second 34-year-old woman with breast cancer metastatic to the liver was randomized to FEC-50 but

was removed from study because of pregnancy. She experienced a spontaneous abortion. 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 the fetus. Women of childbearing potential should be advised to

avoid becoming pregnant [see Warnings and Precautions (5.12)].

8.3 Nursing Mothers

Epirubicin was excreted into the milk of rats treated with 0.50 mg/kg/day of epirubicin during peri- and

postnatal periods. It is not known whether this drug is excreted in human milk. Because many drugs,

including other anthracyclines, are excreted in human milk and because of the potential for serious

adverse reactions in nursing infants from Epirubicin HCl, a decision should be made whether to

discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the

mother.

8.4 Pediatric Use

Safety and effectiveness of Epirubicin HCl have not been established in pediatric patients. Pediatric

patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for

chronic CHF. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated.

8.5 Geriatric Use

Although a lower starting dose of Epirubicin HCl was not used in trials in elderly female patients,

particular care should be taken in monitoring toxicity when Epirubicin HCl is administered to female

patients ≥ 70 years of age [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in

patients with hepatic dysfunction.. Do not treat patients with severe hepatic impairment with Epirubicin

HCl. Reduce the starting dose for patients with less severe hepatic impairment [see Dosage and

Administration (2.2) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol,

have been observed in patients with serum creatinine < 5 mg/dL. Consider lower doses in patients with

severe renal impairment (serum creatinine > 5 mg/dL), as a reduction in plasma clearance was reported

in these patients [see, Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ]. Patients on

dialysis have not been studied.

10 OVERDOSAGE

There is no known antidote for overdoses of Epirubicin HCl. A 36-year-old man with non-Hodgkin's

lymphoma received a daily 95 mg/m dose of Epirubicin HCl Injection 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 dose of Epirubicin HCl. 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

Epirubicin HCl. Additional instances of administration of doses higher than recommended have been

reported at doses ranging from 150 to 250 mg/m . 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.

11 DESCRIPTION

Epirubicin HCl Injection (epirubicin hydrochloride injection) is an anthracycline cytotoxic agent,

intended for intravenous administration. Epirubicin HCl 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. 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

NO HCl and a molecular weight of 579.95. The structural formula is as

follows:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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.

12.3 Pharmacokinetics

Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m 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 Epirubicin HCl at doses of

60 to 150 mg/m 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

with Solid Tumors

Receiving Intravenous Epirubicin HCl 60 to 150 mg/m

Dose

(mg/m )

C

(µg/mL)

AUC

(µgh/mL)

t

(hours )

CL

(L/hour)

Vs s

(L/kg)

5.7 ± 1.6

1.6 ± 0.2

35.3 ± 9

65 ± 8

21 ± 2

5.3 ± 1.5

1.7 ± 0.3

32.1 ± 5

83 ± 14

27 ± 11

9.0 ± 3.5

3.4 ± 0.7

33.7 ± 4

65 ± 13

23 ± 7

9.3 ± 2.9

4.2 ± 0.8

31.1 ± 6

69 ± 13

21 ± 7

*

2

2

max

§

1/2

#

Þ

Advanced solid tumor cancers, primarily of the lung

N=6 patients per dose level

Plasma concentration at the end of 6 to 10 minute infusion

Area under the plasma concentration curve

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 patient found about 60% of the total radioactive dose in

feces (34%) and urine (27%). These data are consistent with those from 3 patients with extrahepatic

obstruction and percutaneous drainage, in whom approximately 35% and 20% of the administered dose

were recovered as epirubicin or its major metabolites in bile and urine, respectively, in the 4 days after

treatment.

Effect of Age

A population analysis of plasma data from 36 cancer patients (13 males and 23 females, 20 to 73 years)

showed that age affects plasma clearance of epirubicin in female patients. The predicted plasma

clearance for a female patient of 70 years of age was about 35% lower than that for a female patient of

25 years of age. An insufficient number of males > 50 years of age were included in the study to draw

conclusions about age-related alterations in clearance in males. Although a lower Epirubicin HCl

starting dose does not appear necessary in elderly female patients, and was not used in clinical trials,

particular care should be taken in monitoring toxicity when Epirubicin HCl is administered to female

patients > 70 years of age [see Patient Counseling Information (17)].

Effect of Gender

In patients ≤ 50 years of age, mean clearance values in adult male and female patients were similar. The

clearance of epirubicin is decreased in elderly women.

Effect of Race

The influence of race on the pharmacokinetics of epirubicin has not been evaluated.

Effect of Hepatic Impairment\

Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in

patients with hepatic dysfunction. In a study of the effect of hepatic dysfunction, patients with solid

tumors were classified into 3 groups. Patients in Group 1 (n=22) had serum AST (SGOT) levels above

the upper limit of normal (median: 93 IU/L) and normal serum bilirubin levels (median: 0.5 mg/dL) and

Half-life of terminal phase

Plasma clearance

Steady state volume of distribution

were given Epirubicin HCl doses of 12.5 to 90 mg/m . Patients in Group 2 had alterations in both serum

AST (median: 175 IU/L) and bilirubin levels (median: 2.7 mg/dL) and were treated with an Epirubicin

HCl dose of 25 mg/m (n=8). Their pharmacokinetics were compared to those of patients with normal

serum AST and bilirubin values, who received Epirubicin HCl doses of 12.5 to 120 mg/m . The median

plasma clearance of epirubicin was decreased compared to patients with normal hepatic function by

about 30% in patients in Group 1 and by 50% in patients in Group 2. Patients with more severe hepatic

impairment have not been evaluated [see Dosage and Administration (2.2), and Warnings and Precautions

(5.5))].

Effect of Renal Impairment

No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol,

have been observed in patients with serum creatinine < 5 mg/dL. A 50% reduction in plasma clearance

was reported in four patients with serum creatinine ≥ 5 mg/dL [see Warnings and Precautions (5.6) and

Dosing and Administration (2.2)]. Patients on dialysis have not been studied.

Effect of Paclitaxel

The administration of paclitaxel (175–225 mg/m as a 3-hour infusion) immediately before or after

epirubicin (90 mg/m as bolus) caused variable increases in the systemic exposure (mean AUC) of

epirubicin ranging from 5% to 109%. At same doses of epirubicin and paclitaxel, the mean AUC of the

inactive metabolites of epirubicin (epirubicinol and 7-deoxy-aglycone) increased by 120% and 70%,

respectively, when paclitaxel was immediately administered after epirubicin. Epirubicin had no effect

on the exposure of paclitaxel whether it was administered before or after paclitaxel.

Effect of Docetaxel

The administration of docetaxel (70 mg/m as 1-hour infusion) immediately before or after epirubicin

(90 mg/m as bolus) had no effect on the systemic exposure (mean AUC) of epirubicin. However, the

mean AUC of epirubicinol and 7-deoxy-aglycone increased by 22.5% and 95%, respectively, when

docetaxel was immediately administered after epirubicin compared to epirubicin alone . Epirubicin had

no effect on the exposure of docetaxel whether it was administered before or after docetaxel.

Effect of Cimetidine

Coadministration of cimetidine (400 mg twice daily for 7 days starting 5 days before chemotherapy)

increased the mean AUC of epirubicin (100 mg/m ) by 50% and decreased its plasma clearance by 30%

.

Drugs metabolized by cytochrome P-450 enzymes.

No systematic in vitro or in vivo evaluation has been performed to examine the potential for inhibition

or induction by epirubicin of oxidative cytochrome P-450 isoenzymes.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been

conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats (about 0.2

times the maximum recommended human dose on a body surface area basis) approximately doubled the

incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5

mg/kg epirubicin intravenously to rats (about 0.025 times the maximum recommended human dose on a

body surface area basis) every 3 weeks for ten doses increased the incidence of subcutaneous fibromas

in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0

mg/kg/day (about 0.015 times the maximum recommended human dose on a body surface area basis) to

newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the

incidence of animals with tumors compared to controls during a 24-month observation period.

Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic

activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the

absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vitro

(chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic

activation and was also clastogenic in vivo (chromosome aberration in mouse bone marrow).

In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that

were given epirubicin daily for 2 weeks prior to mating and through Day 7 of gestation. When 0.3

mg/kg/day (about 0.015 times the maximum recommended human single dose on a body surface area

basis) was administered to both sexes, no pregnancies resulted. No effects on mating behavior or

fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and

reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence

of fetal growth retardation was observed in these studies at 0.03 mg/kg/day (about 0.0015 times the

maximum recommended human single dose on a body surface area basis). Multiple daily doses of

epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12

mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively (both

approximately 0.5 times the maximum recommended human dose on a body surface area basis). A single

dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats.

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Breast Cancer

Two randomized, open-label, multicenter studies evaluated the use of Epirubicin HCl Injection 100 to

120 mg/m in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients

with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III).

Study MA-5 evaluated 120 mg/m of Epirubicin HCl per course in combination with cyclophosphamide

and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women

with one or more positive lymph nodes to an Epirubicin HCl-containing CEF-120 regimen or to a CMF

regimen. Study GFEA-05 evaluated the use of 100 mg/m of Epirubicin HCl per course in combination

with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal

women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible

patients were either required to have ≥ 4 nodes involved with tumor or, if only 1 to 3 nodes were

positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3.

A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for

either study. Table 5 shows the treatment regimens that the patients received. Relapse-free survival was

defined as time to occurrence of a local, regional, or distant recurrence, or disease-related death.

Patients with contralateral breast cancer, second primary malignancy, or death from causes other than

breast cancer were censored at the time of the last visit prior to these events.

Table 5. Treatment Regimens Used in Phase 3 Studies of Patients with Early Breast Cancer

Treatment Groups

Agent

Regimen

MA-5

CEF-120 (total, 6 cycles) N=356

Cyclophosphamide

75 mg/m PO, d 1–14, q 28 days

N=716

Epirubicin HCl

60 mg/m IV, d 1 & 8, q 28 days

CMF (total, 6 cycles) N=360

Fluorouracil

500 mg/m IV, d 1 & 8, q 28 days

Cyclophosphamide

100 mg/m PO, d 1–14, q 28 days

Methotrexate

40 mg/m IV, d 1 & 8, q 28 days

Fluorouracil

600 mg/m IV, d 1 & 8, q 28 days

GFEA-

FEC-100 (total, 6 cycles)

Fluorouracil

500 mg/m IV, d 1, q 21 days

N=565

N=276

Epirubicin HCl

100 mg/m IV, d 1, q 21 days

Cyclophosphamide

500 mg/m IV, d 1, q 21 days

FEC-50 (total, 6 cycles)

Fluorouracil

500 mg/m IV, d 1, q 21 days

N=289

Epirubicin HCl

50 mg/m IV, d 1, q 21 days

Tamoxifen 30 mg daily ×

Cyclophosphamide

500 mg/m IV, d 1, q 21 days

3 years, postmenopausal

women, any receptor status

In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients

had 1 to 3 involved nodes and approximately 40% had ≥ 4 nodes involved with tumor. In the GFEA-05

study, the median age was 51 years and approximately half of the patients were postmenopausal. About

17% of the study population had 1 to 3 positive nodes and 80% of patients had ≥ 4 involved lymph

nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each

study.

Relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in

the intent-to-treat (ITT) patient populations in each study. Results were initially analyzed after up to 5

years of follow-up and these results are presented in the text below and in Table 3. Results after up to

10 years of follow-up are presented in Table 3. In Study MA-5, Epirubicin HCl-containing combination

therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus

53%, stratified logrank for the overall RFS p=0.013). The estimated reduction in the risk of relapse was

24% at 5 years. The OS was also greater for the Epirubicin HCl-containing CEF-120 regimen than for

the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p=0.043;

non-stratified logrank p=0.13). The estimated reduction in the risk of death was 29% at 5 years.

In Study GFEA-05, patients treated with the higher-dose Epirubicin HCl regimen (FEC-100) had a

significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p=0.007) and

OS (estimated 76% versus 65%, logrank for the overall survival p=0.007) than patients given the lower

dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated

reduction in the risk of death was 31% at 5 years. Results of follow-up up to 10 years (median follow-

up = 8.8 years and 8.3 years, respectively, for Study MA-5 and Study GFEA-05) are presented in Table

Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor

of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1–3 node positive and in those

with ≥4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were

observed in both pre- and postmenopausal women treated with FEC-100 compared to FEC-50.

Table 6. Efficacy Results from Phase 3 Studies of Patients with Early Breast Cancer

MA-5 Study

GFEA-05 Study

CEF-120

N=356

CMF

N=360

FEC-100

N=276

FEC-50

N=289

RFS at 5 yrs (%)

Hazard ratio

0.76

0.68

2-sided 95% CI

(0.60, 0.96)

(0.52, 0.89)

Logrank Test

stratified

(p = 0.013)

(p = 0.007)

OS at 5 yrs (%)

Hazard ratio

0.71

0.69

In women who underwent lumpectomy, breast irradiation was to be administered after completion of study

chemotherapy.

Patients also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluoroquinolone for

the duration of their chemotherapy.

All women were to receive breast irradiation after the completion of chemotherapy.

*

2-sided 95% CI

(0.52, 0.98)

(0.51, 0.92)

Logrank Test

stratified

(p = 0.043)

(unstratified p = 0.13)

(p = 0.007)

RFS at 10 yrs (%)

Hazard ratio

0.78

0.78

2-sided 95% CI

(0.63, 0.95)

(0.62, 0.99)

Logrank Test

stratified

(p = 0.017)

(unstratified p = 0.023)

(p = 0.040)

(unstratified p = 0.09)

OS at 10 yrs (%)

Hazard ratio

0.82

0.75

2-sided 95% CI

(0.65, 1.04)

(0.58, 0.96)

Logrank Test

stratified

(p = 0.100)

(unstratified p = 0.18)

(p = 0.023)

(unstratified p = 0.039)

The Kaplan-Meier curves for RFS and OS from Study MA-5 are shown in Figures 3 and 4 and those for

Study GFEA-05 are shown in Figures 5 and 6.

Figure 3. Relapse-Free Survival in Study MA-5

Based on Kaplan-Meier estimates

Hazard ratio: CMF:CEF-120 in MA-5, FEC-50:FEC-100 in GFEA-05

Patients in MA-5 were stratified by nodal status (1–3, 4 –10, and >10 positive nodes), type of initial surgery

(lumpectomy versus mastectomy), and by hormone receptor status (ER or PR positive (≥10 fmol), both negative

(<10 fmol), or unknown status). Patients in GFEA-05 were stratified by nodal status (1–3, 4 –10, and >10 positive

nodes).

Figure 4. Overall Survival in Study MA-5

Figure 5. Relapse-Free Survival in Study GFEA-05

Figure 6. Overall Survival in Study GFEA-05

See Table 6 for statistics on 5 and 10 year analyses.

15 REFERENCES

1.

2.

3.

4.

16 HOW SUPPLIED/STORAGE AND HANDLING

Epirubicin HCl 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

NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in

healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service,

Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health,

DHHS (NIOSH) Publication No. 2004-165.

OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational

Exposure to Hazardous Drugs. OSHA, 1999.

http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.

American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs.

Am J Health-Syst Pharm. 2006; 63:1172–1193.

Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy

guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing

Society.

strengths:

50 mg/25 mL single-use vial

NDC 59762-5091-01

200 mg/100 mL single-use vial

NDC 59762-5093-01

Store refrigerated between 2ºC and 8ºC (36ºF and 46ºF). 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 (15–25ºC). Solution for injection should be used

within 24 hours after removal from refrigeration.

17 PATIENT COUNSELING INFORMATION

Inform patients of the expected adverse effects of Epirubicin HCl, including gastrointestinal symptoms

(nausea, vomiting, diarrhea, and stomatitis), alopecia and potential neutropenic complications.

Patients should understand that there is a risk of irreversible myocardial damage associated with

treatment with Epirubicin HCl, as well as a risk of treatment-related leukemia.

Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms

of CHF, or injection-site pain occurs following therapy with Epirubicin HCl.

Advise patients that their urine may appear red for 1 to 2 days after administration of Epirubicin HCl and

that they should not be alarmed.

Because Epirubicin HCl may induce chromosomal damage in sperm, advise men undergoing treatment

with Epirubicin HCl to use effective contraceptive methods. Women treated with Epirubicin HCl may

develop irreversible amenorrhea, or premature menopause.

LAB-0339-5.0

November 2011

PRINCIPAL DISPLAY PANEL - 50 mg/25 mL Label

NDC 59762-5091-1

GREENSTONE BRAND

epirubicin hydrochloride

injection

50 mg/25 mL

(2 mg/mL)

Single Use 25 mL Vial

For Intravenous

Use Only

PRINCIPAL DISPLAY PANEL - 200 mg/100 mL Label

NDC 59762-5093-1

GREENSTONE BRAND

epirubicin hydrochloride

injection

200 mg/100 mL

(2 mg/mL)

Single Use 100 mL Vial

For Intravenous

Use Only

EPIRUBICIN HYDROCHLORIDE

epirubicin hydrochloride injection, solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:59 76 2-50 9 1

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

epirubicin hydro chlo ride (UNII: 229 6 6 TX7J5) (epirubicin - UNII:3Z8 479 ZZ5X)

epirubicin hydro chlo ride

2 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

so dium chlo ride (UNII: 451W47IQ8 X)

wa ter (UNII: 0 59 QF0 KO0 R)

hydro chlo ric a cid (UNII: QTT1758 2CB)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:59 76 2-50 9 1-1

25 mL in 1 VIAL, SINGLE-USE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA autho rized generic

NDA0 50 778

0 9 /15/19 9 9

EPIRUBICIN HYDROCHLORIDE

epirubicin hydrochloride injection, solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:59 76 2-50 9 3

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

epirubicin hydro chlo ride (UNII: 229 6 6 TX7J5) (epirubicin - UNII:3Z8 479 ZZ5X)

epirubicin hydro chlo ride

2 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

so dium chlo ride (UNII: 451W47IQ8 X)

Greenstone, LLC

wa ter (UNII: 0 59 QF0 KO0 R)

hydro chlo ric a cid (UNII: QTT1758 2CB)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:59 76 2-50 9 3-1

10 0 mL in 1 VIAL, SINGLE-USE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA autho rized generic

NDA0 50 778

0 9 /15/19 9 9

Labeler -

Greenstone, LLC (825560733)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Pfizer Ireland Pharmaceuticals

9 8 9 8 11526

MANUFACTURE

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Pfizer (Perth) Pty Limited

7578 6 8 9 6 3

MANUFACTURE

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Actavis Italy SPA A SOCIO UNICO

8 570 0 79 13

MANUFACTURE

Revised: 11/2011

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