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Epirubicin (Systemic)



USAN:
Epirubicin hydrochloride

INN:

epirubicin

BAN:
epirubicin

VA CLASSIFICATION
Primary: AN200

Commonly used brand name(s): Ellence; Pharmorubicin PFS.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic adjunct —

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, breast (treatment )—Epirubicin is indicated as an adjuvant therapy in patients with axillary-node tumor involvement following resection1, in primary breast cancer{01}{02}.
—Epirubicin is also indicated, as a single agent and in combination therapy with other agents, for the treatment of [metastatic breast carcinoma ].{02}

[Carcinoma, esophageal (treatment adjunct)]1—Epirubicin is indicated, in combination with other agents (e.g., cisplatin and fluorouracil [ECF regimen]), for the treatment of esophageal and esophagogastric junction carcinomas and adenocarcinomas.{40}{41}{42}{43}{44}{45}{46}{47}{48}{49}{50}{51}{52}{53}{54}{55}{56}{57}{58}{59}{60}{61}{62}{63}{64}{65}{66}{67}{68}{69}

[Carcinoma, gastric (treatment)]—Epirubicin is indicated, as a single agent and in combination therapy with other agents, for the treatment of locally unresectable and metastatic gastric carcinoma.{02}

[Carcinoma, lung, non-small cell (treatment) ] or
[Carcinoma, lung, small cell (treatment)]—Epirubicin is indicated, as a single agent and in combination therapy with other agents, for the treatment of advanced non–small cell lung carcinoma and limited and extensive small cell lung carcinoma.{02}

[Carcinoma, ovarian (treatment)]—Epirubicin is indicated, as a single agent and in combination therapy with other agents, for the treatment of Stage III and IV (FIGO) ovarian carcinoma.{02}

[Lymphomas, Hodgkin's (treatment)] or
[Lymphomas, non-Hodgkin's (treatment)]—Epirubicin is indicated, in combination therapy with other agents, for the treatment of Hodgkin's lymphomas. {02} Epirubicin is also indicated, as a single agent and in combination therapy with other agents, for the treatment of non-Hodgkin's lymphomas.{02}

[Sarcoma, soft tissue (treatment) ]1—Epirubicin is indicated, alone or in combination with other agents (e.g., ifosfamide, cisplatin) and/or surgery, for the treatment of soft tissue sarcomas, in place of doxorubicin.{03}{04}{05}{06}{07}{08}{09}{10}{11}{12}{13}{14}{15}{16}{17}{18}{19}{20}{21}{22}

Acceptance not established
Use of epirubicin for the treatment of pancreatic carcinomas has not been established.{23}{24}{25}{26}{27}{28}{29}{30}{31}{32}{33}{34}{35}{36}{37}{38}{39}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Anthracycline
Molecular weight—
    579.95{01}

Mechanism of action/Effect:

Epirubicin (4'-epidoxorubicin) is the 4'-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin{01}. The exact mechanism of antineoplastic activity is unknown but epirubicin may produce a cytotoxic effect through intercalation with DNA, eventually inducing DNA cleavage by topoisomerase II. Epirubicin also inhibits DNA helicase activity, eventually interfering with DNA replication and transcription. Free radical production results in further cytotoxic activity{01}.

Distribution:

Volume of distribution (Vol D)—Steady state: 21 to 27 L per kg, indicating extensive uptake into the tissues{01}.

Epirubicin concentrates in red blood cells, resulting in a whole blood concentration of epirubicin that is two times greater than the plasma concentration{01}.

Other anthracyclines are known to distribute into human breast milk but it is unknown if epirubicin does.

Protein binding:

High (77%); predominantly to albumin{01}.

Biotransformation:

Hepatic, primarily, rapid; producing an active metabolite, epirubicinol, with one-tenth the activity of epirubicin{01}. Enzymatic reduction, glucuronidation and hydrolysis produce 3 metabolites with no inherent activity{01}.


Half-life:


Elimination:

Triphasic manner with mean half-lives of alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively{01}.


Elimination:


Biliary—
        35% as drug or metabolite over 4 days{01}.



Renal—
        20% as drug or metabolite over 4 days{01}.

{01}

Precautions to Consider

Carcinogenicity

Secondary acute myelogenous leukemia has been reported in patients treated with anthracycline cytotoxic agents. Risk of secondary leukemia increases with increasing doses of anthracyclines, when anthracyclines are used in combination with other DNA damaging agents or when other cytotoxic agents are given prior to anthracycline use. The cumulative risk for developing secondary leukemia is estimated to be 0.2% at three years, increasing to 0.8% at 5 years. Epirubicin is mutagenic and carcinogenic in animals and may be in humans as well{01}.

Pregnancy/Reproduction
Fertility—
Uterine and testicular atrophy have occurred in study animals. When epirubicin 0.3 milligrams per kilogram (mg/kg) (0.015 times the maximum recommended human dose on a body surface area basis) was administered daily to male and female rats during the mating cycle, no pregnancies resulted. Epirubicin may be genotoxic to human sperm, therefore males being treated with epirubicin should use contraception. Epirubicin may induce irreversible amenorrhea in premenopausal women{01}.

Pregnancy—
No adequate and well-controlled studies have been done in pregnant women. Due to the potential hazard to the fetus, women of child-bearing potential should be advised against becoming pregnant.

Epirubicin crosses the placenta and has been shown to cause fetal harm in animals, including fetal growth retardation, internal and external physical malformations, and fetal death. Risk-benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective.

Intravenous epirubicin doses of 0.8 mg/kg per day (0.04 times the maximum single human dose on a body surface area basis) were embryotoxic in rats. Doses of 2 mg/kg per day (0.1 times the maximum single human dose on a body surface area basis) were embryotoxic and produced malformations in surviving fetal rats. Intravenous doses of up to 0.2 mg/kg per day (0.02 times the maximum recommended human dose on a body surface area basis) of epirubicin given to rats and rabbits late in pregnancy did not adversely affect the offspring{01}.

FDA Pregnancy Category D

Breast-feeding

It is unknown if epirubicin is distributed into human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential harm to nursing infants, nursing should be discontinued prior to epirubicin administration{01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of epirubicin have not been performed in the pediatric population. Safety and efficacy have not been established. Pediatric patients may be at a higher risk for anthracycline induced acute manifestations of cardiotoxicity and for chronic heart failure{01}.


Geriatrics


Care should be taken in monitoring for toxicity in elderly women, who have a predicted 35% decrease in the plasma clearance of epirubicin.{01}


Dental

The bone marrow depressant effects of epirubicin may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal, and patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks{01}.

Epirubicin causes oral stomatitis, which can be severe and lead to painful mucosal ulcerations.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Blood dyscrasia-causing medications (see Appendix II)    (leukopenic and/thrombocytopenic effects of epirubicin may be increased with concurrent or recurrent therapy if these medications cause the same effects; dosage of epirubicin should be based on blood counts in these cases)


» Bone marrow depressants (seeAppendix II) or
» Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


» Cardioactive compounds    (medications that could cause heart failure (i.e., calcium channel blockers) may contribute to or precipitate cardiomyopathy; additional monitoring of cardiac function may be indicated{01})


» Cimetidine    (concomitant use of cimetidine increases the body concentration of epirubicin by reducing plasma clearance by as much as 30%; concurrent use of cimetidine and epirubicin is not recommended{01})


» Daunorubicin or
» Doxorubicin or
» Idarubicin or
» Mitoxantrone    (use of epirubicin in patients previously treated with maximum cumulative doses of anthracyclines may increase the risk of cardiotoxicity, gastrointestinal, hematological, and hepatic effects{01})


» Hepatotoxic medications (see Appendix II)    (concomitant use may increase the risk of toxicity; for example, high dose methotrexate may impair liver function and increase toxicity of subsequently administered epirubicin.)


» Radiation therapy to the pericardial or mediastinal region     (simultaneous use may result in increased cardiotoxicity)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by epirubicin therapy, the patient's antibody response to the vaccine may be decreased; the interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by epirubicin therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the epirubicin therapy; the interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year; in addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Electrocardiogram (ECG) changes, transient, including:
Arrythmias
Non-specific ST-T wave changes
Tachyarrhythmias
Atrioventricular block
Bundle-branch block    (withdrawal of epirubicin is not usually required)

{01}
Uric acid    (concentrations in blood and urine may increase secondary to increased purine catabolism)

{01}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergic reaction to epirubicin, other anthracyclines or anthracenediones
» Baseline neutrophil count <1,500 cells per mL
» Myocardial infarction, recent or severe cardiac insufficiency
» Prior treatment to maximum cumulative doses with anthracycline chemotherapeutic agents
» Severe hepatic function impairment    (contributes to toxicity by decreasing metabolism and clearance of epirubicin by up to 30%)


Risk–benefit should be considered when the following medical problems exist
» Bone marrow depression    (lower starting doses of 75 to 90 milligrams per square meter of body surface area are recommended for patients with pre-existing bone marrow depression{01})


» Infection, bacterial, viral, or fungal    (risk of severe generalized disease especially in the presence of recent or existing chickenpox and herpes zoster viruses)


» Heart disease    (cardiotoxicity may occur at lower doses)


» Hepatic function impairment    (elimination may be decreased; reduction in dosage is recommended{01}; one half of the normal starting dose is recommended in patients with serum bilirubin concentrations of 1.2 to 3 milligrams per 100 mL or aspartate aminotransferase (AST [SGOT]) levels of 2 to 4 times the upper limit of normal{01}; one quarter of the normal starting dose is recommended in patients with serum bilirubin concentrations of greater than 3 milligrams per 100 mL or AST [SGOT] levels of greater than 4 times the upper limit of normal)


» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.
Renal function impairment    (lower doses are recommended for patients with serum creatinine levels greater than 5 milligrams per 100 mL{01})


» Tumor cell infiltration of the bone marrow
» Caution should be used in patients with decreased bone marrow reserves secondary to prior chemotherapy or radiation therapy.

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Alanine aminotransferase (ALT [SGPT]) values and
» Aspartate aminotransferase (AST [SGOT]) values and
» Total bilirubin concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during treatment; frequency varies according to clinical state, agent, dose, and other agents being used concurrently{01})


» Creatinine, serum    (recommended prior to initiation of therapy and at periodic intervals during treatment{01})


Chest radiograph and
» Echocardiography (ECHO) or
» Multi–gated radionuclide angiography (MUGA) and
Electrocardiogram (ECG) studies    (recommended prior to initiation of therapy and at periodic intervals during treatment to evaluate left ventricular ejection fraction and cardiac function; frequency should increase if patient has preexisting cardiac disease or shows signs of cardiotoxicity{01})


Absolute neutrophil counts and
Leukocyte counts and
Platelet counts and
Red blood cell counts    (recommended prior to initiation of therapy and at periodic intervals during treatment; frequency varies according to clinical state, agent, dose, and other agents being used concurrently{01})


Calcium phosphate concentration, serum and
Potassium concentration, serum and
Uric acid concentration, serum    (recommended immediately following initial chemotherapy administration{01})




Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
Excessively rapid intravenous administration may produce facial flushing {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (>50%)
    
Anemia, leukopenia, neutropenia, or infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination )—usually asymptomatic
    
mucositis ( mainly oral) stomatitis, less often esophagitis (pain or burning in mouth or throat; bleeding, redness, or ulcers in mouth or throat; sores in mouth and on lips)

Note: With leukopenia, the nadir of leukocyte count occurs 10 to 14 days after a dose. Recovery usually occurs within 21 days after a dose. {01} Stomatitis or esophagitis progresses over a few days after administration. It may be severe and lead to ulceration and the potential for severe infections{01}. Most patients recover 3 weeks after dosing.


Incidence less frequent (5–50%)
    
conjunctivitis (redness or discharge of the eye, eyelid, or lining of the eyelid)
    
local reaction (red streaks along injected vein)
    
thrombocytopenia (unusual bleeding or bruising ; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Note: Extravasation may also occur without accompanying stinging or burning and even if blood returns well on aspiration of the infusion needle{01}.
A local reaction may indicate excessively rapid intravenous administration.
Phlebitis or thrombophlebitis occurs especially when small veins are used or a single vein is used repeatedly{01}.
Recall postradiation erythema occurs if the patient has previously received radiation therapy; severe dermatitis and/or mucositis in the irradiated area may occur with concurrent use{01}.


Incidence rare (<5%)
    
Allergic reaction ( skin rash or itching; fever; chills)
    
anaphylaxis (wheezing or difficulty breathing )
    
cardiotoxicity, usually in the form of congestive heart failure (shortness of breath; swelling of abdomen, feet, and lower legs; fast or irregular heartbeat)
    
extravasation, cellulitis, or tissue necrosis (pain at place of injection)
    
hyperuricemia or uric acid nephropathy (joint pain; lower back or side pain)
    
phlebitis or thrombophlebitis (pain , redness, or warmth at injection site)
    
postirradiation erythema, recall ( darkening or redness of skin at place of irradiation)
    
secondary leukemia (bleeding; enlarged liver, lymph nodes, and spleen; infection )
    
severe myelosuppression (fever; general tiredness or weakness; infection)

Note: Incidence of cardiotoxicity is greater in patients receiving total dosages of over 900 milligrams per square meter of body surface area, in patients with a history of cardiac disease or mediastinal/pericardial radiation, in patients taking other cardioactive drugs, and may be more frequent in children up to 2 years of age and in the elderly{01}.
Cardiotoxicity usually appears toward the end of treatment or within 2 to 3 months after completion of treatment. Early onset is manifested by a fast, slow, or irregular heartbeat. Delayed onset is usually in the form of congestive heart failure and is dependent on dose accumulation. Cardiomyopathy has been reported to be associated with persistent voltage reduction in the QRS complex, systolic interval prolongation, and reduction of ejection fraction. It may develop suddenly and may not be detected by routine ECG. It may be irreversible and fatal but responds to treatment if detected early.
Acute life-threatening arrhythmias have been reported during or within a few hours after administration.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (>50%)
    
Amenorrhea (lack of menstrual periods)
    
Nausea and vomiting —may be severe, causing dehydration and may require antiemetic prophylaxis

Incidence less frequent (5–50%)
    
diarrhea —may lead to dehydration
    
hot flashes

Incidence rare (< 5%)
    
Anorexia (loss of appetite; weight loss )
    
darkening of soles, palms, or nails



Those not indicating need for medical attention
Incidence more frequent
    
Loss of hair
    
reddish-colored urine

Note: Loss of hair is complete and reversible. It occurs in most cases and resolves 2 to 3 months after last dose{01}.
Reddish-colored urine clears within 48 hours{01}.




Those indicating the need for medical attention if they occur after medication is discontinued
    
Cardiotoxicity (fast or irregular heartbeat; shortness of breath; swelling of abdomen, feet, and lower legs)




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Bone marrow suppression

delayed congestive heart failure —manifested by ascites, gallop rhythm, hepatomegaly, pleural effusion, pulmonary edema, and tachycardia and affected by cumulative doses of epirubicin

Gastritis or gastrointestinal bleeding

grade 4 mucositis

Hematologic abnormalities —symptoms of overdose are qualitatively similar to the known toxicities of epirubicin

hyperthermia

multiple organ failure (respiratory and renal) — manifested by anuria, an increase in lactate dehydrogenase, and lactic acidosis

Treatment of overdose
Supportive care—(antibiotic therapy, blood transfusions, colony-stimulating factors, intensive care and platelet transfusions as necessary).

Monitor for congestive heart failure over time.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Epirubicin (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to epirubicin or other anthracyclines



Carcinogenicity—
Risk of secondary leukemia with increasing doses of anthracyclines, when anthracyclines are used in combination chemotherapy, or when cytotoxic agents are given prior to anthracycline use

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects





Use in children—Cardiotoxicity more frequent in children up to 2 years of age






Use in the elderly—Cardiotoxicity may be more frequent in patients 70 years of age and over, especially in women.
Other medications, especially blood dyscrasia–causing medications, cardioactive compounds, cimetidine, daunorubicin, doxorubicin, hepatotoxic medications, idarubicin, mitoxantrone, other bone marrow depressants, previous cytotoxic drug or radiation therapy
Other medical problems, especially baseline neutrophil count < 1500 per mL, previous allergic reaction to epirubicin, other anthracyclines, or anthracenediones, prior treatment to maximum cumulative doses with anthracycline agents, recent myocardial infarction or severe cardiac insufficiency, bone marrow depression, bacterial, fungal, or viral infections, heart disease, hepatic function impairment, or tumor cell infiltration of bone marrow

Proper use of this medication
» Caution in taking combination therapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician, especially blood counts, cardiac monitoring, and liver function tests

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine, or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling doctor or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
Signs of potential side effects, especially anemia, leukopenia, neutropenia, infection, mucositis, conjunctivitis, local reaction, thrombocytopenia, allergic reaction, anaphylaxis, cardiotoxicity, extravasation, cellulitis, tissue necrosis, hyperuricemia, uric acid nephropathy, phlebitis, thrombophlebitis, recall of postirradiation erythema, secondary leukemia , and severe myelosuppression

Physician or nurse can help in dealing with side effects

Reddish urine for 1 to 2 days after administration may be alarming to patient although medically insignificant

Possibility of hair loss; normal hair growth should resume after treatment has ended


General Dosing Information
Patients receiving epirubicin should be under supervision of a physician experienced in cancer chemotherapy. It is recommended that the patient be hospitalized at least during initial treatment{01}.

Epirubicin should not be used in patients who have previously received the maximum acceptable cumulative doses of any anthracycline cytotoxic agents{01}.

A variety of dosage schedules of epirubicin, in combination with other antitumor agents, are used. The prescriber should consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response and appearance or severity of toxicity{01}.

It is recommended that epirubicin be administered slowly into the tubing of a freely running intravenous infusion of 0.9% sodium chloride injection or 5% dextrose injection (over not less than 3 to 5 minutes). If possible, injection of epirubicin into small veins, veins over joints or in extremities with compromised venous or lymphatic drainage, or repeated injection into the same vein should be avoided. Epirubicin should not be administered as a direct push injection{01}.

Care must be taken to avoid extravasation during intravenous administration because of the risk of severe ulceration and necrosis. Facial flushing indicates too-rapid injection{01}.

If extravasation of epirubicin occurs during intravenous administration, as indicated by local swelling, burning or stinging (may also be painless), or erythematous streaking along the vein, the infusion should be stopped immediately and resumed, completing the dose, in another vein{01}.

Because it will cause local tissue necrosis, epirubicin must not be administered intramuscularly or subcutaneously{01}.

Development of hyperuricemia due to lysis of neoplastic cells (tumor lysis syndrome) may be prevented by adequate oral hydration and, in some cases, administration of allopurinol. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated{01}. Monitor serum uric acid, potassium, calcium phosphate, and creatinine beginning after first dose of epirubicin.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of epirubicin. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in the use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests. For patients at the maximum starting dose of epirubicin, prophylaxis with sulfamethoxazole-trimethoprim or a fluoroquinolone is recommended.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves , goggles, gowns, and masks.
   • Pregnant personnel should not come in contact with antineoplastic medication containers or mixing supplies.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampules, and unused medication.
   • Use of proper technique in handling spills, including the use of dilute sodium hypochlorite solution (1% active chlorine) and water, and proper disposal of waste.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Combination chemotherapy
Epirubicin may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages may be used.


Parenteral Dosage Forms

EPIRUBICIN HYDROCHLORIDE INJECTION

Usual adult dose
Carcinoma, breast
When used in combination with other chemotherapy agents, for primary breast carcinoma: Intravenous, 100 to 120 milligrams per square meter of body surface area, given on Day 1 of cycle or divided into 2 doses and given on Day 1 and Day 8, repeated every twenty-one to twenty-eight days for six cycles.{01}

Note: For primary breast carcinoma, the Canadian manufacturer states that epirubicin should be administered in combination with cyclophosphamide and fluorouracil (CEF-120 regimen): Intravenous, 60 mg/m 2 on Days 1 and 8, repeated every four weeks, for 6 cycles.


Note: For metastatic breast carcinoma, the Canadian manufacturer states epirubicin may be administered in combination with cyclophosphamide and fluorouracil (FEC regimen): Intravenous, 50 mg/m2.{02} As single-agent therapy: Intravenous, 75 to 90 mg/m 2, every three weeks. The dosage may be divided over 2 successive days. An alternative weekly dosage schedule of 12.5 to 25 mg/m 2 has been used, producing less clinical toxicity.{02}


Note: In patients with severe hepatic impairment, reduction in dosage is recommended{01}; one half of the normal starting dose is recommended in patients with serum bilirubin concentrations of 1.2 to 3 milligrams per 100 mL{02} or aspartate aminotransferase (AST [SGOT]) levels of 2 to 4 times the upper limit of normal{01}; one quarter of the normal starting dose is recommended in patients with serum bilirubin concentrations of greater than 3 milligrams per 100 mL{02} or AST [SGOT] levels of greater than 4 times the upper limit of normal.
In patients with severe renal impairment, reduction in the starting dose is recommended if serum creatinine level is greater than 5 milligrams per 100 mL{01}.
In patients with bone marrow depression or neoplastic bone marrow infiltration, a reduction in the starting dose to 75 to 90 milligrams per square meter of body surface area is recommended{01}.


Note: If at anytime during therapy the following occurs: Platelets < 50,000 per mL, absolute neutrophil count (ANC) < 250 per mL, neutropenic fever, or grade 3/4 non-hematologic toxicity, it is recommended that the Day 1 dose of subsequent treatment cycles be reduced to 75%. Subsequent cycles of treatment should be postponed until platelets ³ 100,000 per mL, ANC ³ 1500 per mL, and non-hematologic toxicity £ Grade 1{01}.
If at anytime during divided dose therapy the following occurs: Platelets 75,000 to 100,000 per mL or ANC 1000 to 1499 per mL, it is recommended that the Day 8 dose be reduced to 75% of the Day 1 dose. If on Day 8 platelets < 75,000 per mL, ANC < 1000 per mL, or Grade 3/4 non-hematologic toxicity occurs, omit the Day 8 dose{01}.


[Carcinoma, esophageal]1
As part of an ECF regimen, patients have benefited from intravenous doses of epirubicin 50 mg/m2, on day 1 of a 21–day treatment cycle, in conjunction with cisplatin (day 1) and a continuous infusion of fluorouracil, for up to 8 cycles. Patients have also benefited from intravenous doses of epirubicin 50 to 60 mg/m2, on day 1, or 20 mg/m2, on days 1 to 3 of a 28–day treatment cycle, in conjunction with cisplatin and fluorouracil, for up to 6 cycles.{40}

[Carcinoma, gastric]
Combination Therapy— Intravenous, doses of 80 mg/m2can be used in combination with fluorouracil.
{02}Single Agent— Intravenous, doses range from 75 to 100 mg/m2
{02}
[Carcinoma, lung, small cell ]
Combination Therapy—Intravenous, doses range from 50 to 90 mg/m 2, in combination with cisplatin or ifosfamide, cyclophosphamide and vincristine (CEV regimen), cyclophosphamide and etoposide (CEVP-16 regimen), or cisplatin and etoposide.
{02}Single Agent—Intravenous, 90 to 120 mg/m 2administered every three weeks.
{02}
[Carcinoma, lung, non-small cell]
Combination Therapy—Intravenous, doses range from 90 to 120 mg/m2 administered day 1, every three to four weeks, in combination with etoposide, cisplatin, mitomycin, vindesine, and vinblastine.
{02}Single agent—Intravenous, 120 to 150 mg/m 2 administered day 1, every three to four weeks.
{02}
[Carcinoma, ovarian]
Combination Therapy—Intravenous, doses range from 50 to 90 mg/m2, repeated at three to four week intervals, as second-line therapy, and in combination with cisplatin and cyclophosphamide when using as first-line therapy.
{02}Single Agent— Intravenous, doses range from 50 to 90 mg/m 2, at three to four week intervals, as second-line therapy.{02}

[Lymphomas, Hodgkin's]
Combination Therapy—Intravenous, 35 mg/m 2 every two weeks or 70 mg/m2 every three to four weeks (replacing doxorubicin in the ABVD regimen).
{02}
[Lymphomas, non-Hodgkin's ]
Combination Therapy—Intravenous, doses range from 60 to 75 mg/m2 (replacing doxorubicin in the CHOP, CHOP-bleo, or BACAP regimens).
{02}Single Agent—Intravenous, 75 to 90 mg/m 2, every three weeks.
{02}
[Sarcoma, soft tissue]1
Patients have benefited from intravenous doses of 45 to 60 mg/m 2/day, for 2 to 3 days of a twenty-one to twenty-eight day treatment cycle. Doses of 150 to 180 mg/m2, every twenty-one days, for up to 8 treatment cycles, has not been established as being more efficacious, but is more toxic. G-CSF support should be considered.{03}


Usual adult prescribing limits
The risk of developing congestive heart failure is estimated to be 0.9% at a total cumulative dosage of 550 mg per square meter of body surface area, 1.6% at a total cumulative dosage of 700 mg per square meter of body surface area, and 3.3.% at a total cumulative dosage of 900 mg per square meter of body surface area. This toxicity may develop at lower cumulative dosages in patients who have previously received chest irradiation, patients who have received medications increasing cardiotoxicity, or patients with pre-existing heart disease {01}.

Usual pediatric dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—


2 mg per mL (25– and 100–mL single–use vials) (Rx) [Ellence (sodium chloride USP) (water for injection USP)]

Canada—


2 mg per mL (5– and 25–mL vials) (Rx) [Pharmorubicin PFS ( sodium chloride USP) (water for injection USP) (lactose-free)]{02}


2 mg per mL (100–mL Pharmacy Bulk vial) (Rx) [Pharmorubicin PFS (sodium chloride USP) (water for injection USP) (lactose-free)]{02}

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Do not freeze. Protect from light{01}{02}.

Preparation of dosage form:
Epirubicin is provided as a preservative-free, ready to use solution{01}{02}.

Dispensing from the Pharmacy Bulk Vial should be completed within 8 hours of initial entry, due to risk of bacterial contamination. Use of the Pharmacy Bulk Vial is restricted to hospitals with a recognized intravenous admixture program and is intended for single puncture, multiple dispensing, and for intravenous use only.{02}

Stability:
Epirubicin should be used within 24 hours of the first penetration of the rubber stopper and any unused solution should be discarded{01}.

Avoid alkaline pH: causes hydrolysis of epirubicin.

Canadian manufacturer states that prepared syringes filled from the Pharmacy Bulk Vials are stable for 24 hours at room temperature or 48 hours under refrigeration. Any unused solution should be discarded.{02}

Incompatibilities:
Epirubicin should not be mixed with heparin or fluorouracil or other medications since a precipitate may form.

Canadian manufacturer states that epirubicin should not be mixed with any other drugs unless specific compatibility data is available.{02}

Auxiliary labeling:
   • Refrigerate. Do not freeze.
   • Protect from light.{01}{02}



Developed: 11/02/1999
Revised: 9/07/2001



References
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  1. Product Information: Pharmorubicin® PFS®, epirubicin hydrochloride. Pharmacia & Upjohn, Mississauga, Ontario, Canada. (PI Revised 12/2000) PI Reviewed 3/2001.
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