Epirubicin Hydrochloride

Pronunciation: EH-pih-ROO-bih-sin HIGH-droe-KLOR-ide
Class: Anthracycline

Trade Names

Ellence
- Solution for injection 2 mg/mL

Pharmorubicin PFS (Canada)

Pharmacology

Epirubicin is a cell cycle phase, nonspecific anthracycline. It 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.

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Pharmacokinetics

Absorption

C max is 5.3 to 9.3 mcg/mL. AUC is 1.6 to 4.2 mcg•h/mL (dose dependent).

Distribution

Rapidly and widely distributed into tissues. Approximately 77% is protein bound (predominantly albumin).

Metabolism

Extensively and rapidly metabolized by liver and also by other organs and cells, including RBC.

Elimination

Parent and metabolites eliminated through biliary, and to a lesser extent, urinary. Triphasic elimination with alpha t ½ is approximately 3 min, beta t ½ is 2.5 h, and gamma t ½ is approximately 33 h. Cl is 65 to 83 L/h.

Special Populations

Hepatic Function Impairment

Cl is reduced.

Indications and Usage

Breast cancer with axillary node involvement.

Unlabeled Uses

Small-cell lung cancer, nonsmall-cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma.

Contraindications

Baseline neutrophil count less than 1,500 cells/mm 3 ; severe myocardial insufficiency or recent MI; severe arrhythmias; previous treatment with anthracyclines up to the max cumulative dose; hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; severe hepatic dysfunction.

Dosage and Administration

Epirubicin is given in repeated 3- to 4-wk cycles. The total dose may be given on day 1 of each cycle or divided equally and given on days 1 and 8 of each cycle.

Breast Cancer, Combination Therapy
Adults

IV Recommended starting dose is 100 to 120 mg/m 2 . Make dosage adjustments after the first treatment cycle based on hematologic and nonhematologic toxicities. Patients experiencing nadir platelet counts less than 50,000/mm 3 , absolute neutrophil counts (ANC) less than 250/mm 3 , neutropenic fever, or grades 3/4 nonhematologic toxicity after the first treatment cycle should have the day 1 dose in subsequent cycles reduced 75% of the day 1 dose given in the current cycle. Delay day 1 chemotherapy in subsequent courses until platelet counts are at least 100,000/mm 3 , ANC at least 1,500/mm 3 , and nonhematologic toxicities have recovered to grade 1 or less. For patients receiving a divided dose (ie, day 1 and day 8), the day 8 dose should be 75% of day 1 if platelet counts are 75,000 to 100,000/mm 3 and ANC is 1,000 to 1,499 mm 3 . If day 8 platelet counts are less than 75,000/mm 3 , ANC less than 1,000/mm 3 , or grade 3/4 nonhematologic toxicity has occurred, omit the day 8 dose.

Bone Marrow Dysfunction
Adults

IV Consider a lower starting dose (75 to 90 mg/m 2 ) for heavily pretreated patients, patients with preexisting bone marrow depression, or in the presence of neoplastic bone marrow infiltration.

Hepatic Dysfunction

Definitive recommendations are not available because patients with hepatic abnormalities were excluded from adjuvant trials. If bilirubin is 1.2 to 3 mg/dL or AST is 2 to 4 ULN, give 1/ 2 of recommended starting dose. If bilirubin is greater than 3 mg/dL or AST is greater than 4 times the ULN, give 1/ 4 of recommended starting dose. Patients with severe hepatic impairment should not receive epirubicin.

Renal Dysfunction

Because of limited available data, no specific recommendations can be made; however, consider lower doses in patients with severe renal function impairment (serum creatinine greater than 5 mg/dL).

General Advice

  • For IV infusion only. Not for IV bolus, intradermal, subcutaneous, IM, or intra-arterial administration.
  • Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine), preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration.
  • Avoid exposure to direct contact of the skin, mucous membranes, and eyes. If accidental skin or mucus membrane contact occurs, wash thoroughly with soap and water or sodium bicarbonate solution. If accidental eye contact occurs, immediately institute vigorous irrigation.
  • Do not administer if particulate matter or cloudiness is noted. Solution has a red-orange color, which is normal and of no concern.
  • Administer prescribed dose slowly (over 3 to 20 minutes) into freely flowing IV infusion of sodium chloride 0.9% injection or D5W. Attach tubing to butterfly needle or other suitable device and insert into large vein. Take precautions to avoid extravasation. A burning or stinging sensation may be indicative of perivenous infiltration; immediately terminate infusion and restart in another vein.
  • Do not mix with any other medications. Flush infusion line with D5W or 0.9% sodium chloride injection prior to administration of any concomitant medication.

Storage/Stability

Store vials in refrigerator (36° to 46°F). Protect from light and freezing. Use within 24 h of first penetration of the rubber stopper. Discard any unused solution. Do not save unused portions for later use.

Drug Interactions

Cimetidine

Cimetidine increases the AUC of epirubicin 50%. Stop cimetidine treatment during treatment with epirubicin.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Adverse reactions listed occurred in patients receiving combination therapy with epirubicin, cyclophosphamide, and fluorouracil.

Cardiovascular

Delayed dose-related cardiomyopathy; acute arrhythmias. Previous therapy with other anthracyclines may increase risk of cardiotoxicity.

Dermatologic

Alopecia (96%); rash; contact dermatitis; urticaria; radiation recall; nail hyperpigmentation.

Endocrine

Hot flashes.

GI

Moderate to high potential for nausea and vomiting; mucositis within 5 to 10 days of administration; diarrhea.

Genitourinary

Amenorrhea.

Hematologic

Dose-limiting bone marrow suppression, leukocyte nadir at 10 to 14 days and recovery by day 21; thrombocytopenia and anemia also may occur with nadirs at 14 to 20 days and 7 to 14 days, respectively.

Special Senses

Conjunctivitis; keratitis.

Miscellaneous

Acute leukemia and malignant tumors observed.

Precautions

Warnings

IV route only. Do not administer via IM or subcutaneous route.

Hepatic function impairment

Reduce dose of epirubicin in patients with impaired hepatic function. Evaluate serum total bilirubin and AST levels before and during treatment with epirubicin. Lower doses are recommended in patients with elevated bilirubin or AST. Patients with severe hepatic impairment should not use epirubicin.

Extravasation

Local irritation or phlebitis may occur. Severe local tissue necrosis will occur in there is extravasation. Refer to your institution-specific protocol. Monitor IV infusion site for signs or symptoms of extravasation. If noted, immediately discontinue infusion and restart in another vein. Frequently examine extravasation site and immediately inform health care provider if pain, erythema, edema, or vesiculation is noted or if patient reports persistent pain.

Myocardial toxicity

May occur either during therapy with epirubicin or months to years after termination of therapy.

Secondary, acute, myelogenous leukemia (AML)

AML has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. 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 latency period.

Myelosuppression

Severe myelosuppression may occur.


Monitor

Total cumulative dose

Document total cumulative dose. Ensure that dosing beyond 900 mg/m 2 is only attempted after careful evaluation of the patient and clinical situation.


Pregnancy

Category D .

Lactation

Undetermined. Mothers should discontinue nursing prior to taking this drug.

Children

Safety and efficacy in pediatric patients not established.

Renal Function

Reduce dose of epirubicin in patients with renal function impairment. Dosage adjustment is necessary in patients with serum creatinine more than 5 mg/dL.

Hepatic Function

Evaluate serum total bilirubin and AST levels before and during treatment with epirubicin. Lower doses are recommended in patients with elevated bilirubin or AST. Patients with severe hepatic impairment should not use epirubicin. Specific guidelines are not available for dosage reduction in renal dysfunction.

Cardiac function

Discontinue therapy at the first sign of impaired cardiac function and resume therapy only after careful evaluation of the risk vs benefit of continued therapy.

Concurrent cytotoxic therapy

May show on-treatment additive toxicity, especially hematologic and GI effects.

Flushing/local streaking

Facial flushing or local erythematous streaking along the vein may be indicative of excessively rapid administration and may precede local phlebitis or thrombophlebitis.

Hematologic

A dose-dependent, reversible leukopenia and/or neutropenia. The WBC nadir is reached 10 to 14 days from drug administration. It is usually transient, returning to normal values by day 21 after drug administration. Severe thrombocytopenia and anemia also may occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. Monitor patient for signs or symptoms of infection or bleeding. Inform health care provider immediately if noted and be prepared to treat appropriately (eg, IV antibiotics, colony stimulating factors, transfusions).

Hyperuricemia

Evaluate risk of developing hyperuricemia before starting therapy and initiate hypouricemic therapy, including adequate fluid intake, and monitoring of uric acid, before starting treatment in patient determined to be at risk for developing hyperuricemia and urate precipitation.

Male contraception

Ensure that men undergoing epirubicin therapy use effective contraceptive methods.

Radiation therapy

Previous radiation therapy may induce an inflammatory recall reaction at the site of irradiation.

Secondary leukemia

The occurrence with or without preleukemic phase has been reported in patients treated with anthracyclines.

Thromboembolic phenomenon

Thrombophlebitis and thromboembolic phenomenon, including pulmonary embolism, have been reported.

Tumor lysis syndrome

Epirubicin may induce hyperuricemia.

Overdosage

Symptoms

Bone marrow aplasia, grade 4 mucositis, GI bleeding, hyperthermia, multiple organ failure (respiratory and renal), acute lactic acidosis, increased lactate dehydrogenase, anuria, death

Patient Information

  • Review the treatment regimen including dosing schedule, duration of treatment, and monitoring that will be required.
  • Review benefits of therapy and risks, including potential of developing secondary acute myelogenous leukemia, irreversible amenorrhea, or premature menopause.
  • Advise patient, family, or caregiver that medication will be prepared and administered by health care professionals in a health care setting.
  • Advise patient, family, or caregiver that medication will be used in combination with other agents to achieve maximum benefit possible.
  • Advise patient, family, or caregiver that medication may cause a red coloration of the urine but that this is not a problem and is expected.
  • Advise patient, family, or caregiver that medication may cause hair loss but that this is reversible when therapy is stopped.
  • Advise patient, family, or caregiver to immediately report any of the following to health care provider: rash; hives; difficulty breathing; chest pain; palpitations; swelling or rapid weight gain; fever, chills, or other signs of infection; sores in mouth; bleeding or unusual bruising; pain, redness, or swelling at injection site.
  • Advise patient, family, or caregiver to report any of the following to health care provider: persistent nausea, vomiting, or appetite loss; persistent or worsening general body weakness.
  • Caution men undergoing epirubicin therapy to use effective contraceptive methods during treatment.
  • Caution women of childbearing potential to avoid becoming pregnant during therapy.
  • Advise patient that following discharge from the hospital that frequent follow-up visits, electrocardiograms, heart function tests, and laboratory tests will be required to monitor therapy and to keep appointments.

Copyright © 2009 Wolters Kluwer Health.

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