Epirubicin Hydrochloride

Name: Epirubicin Hydrochloride

How supplied

Dosage Forms And Strengths

ELLENCE 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.

Storage And Handling

ELLENCE 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 strengths:

50 mg/25 mL single-use vial NDC 0009-5091-01
200 mg/100 mL single-use vial NDC 0009-5093-01

Store refrigerated between 2°C and 8°C (36°F and 46°F). Do not freeze. Protect from light.

Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15-25°C). Solution for injection should be used within 24 hours after removal from refrigeration.

REFERENCES

1. 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.

2. 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.

3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.

4. 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.

Distributed by: Pharmacia & Upjohn Co, Division of Pfizer Inc., New York, NY, NY 10017. Revised: December 2014

Warnings

Included as part of the PRECAUTIONS section.

Overdose

There is no known antidote for overdoses of ELLENCE. A 36-year-old man with non-Hodgkin's lymphoma received a daily 95 mg/m² dose of ELLENCE 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/m² dose of ELLENCE. She was hospitalized with hyperthermia and developed multiple organ failure (respiratory and renal), with lactic acidosis, increased lactate dehydrogenase, and anuria. Death occurred within 24 hours after administration of ELLENCE. Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m² . 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.

What happens if i miss a dose (ellence)?

Call your doctor for instructions if you miss an appointment for your epirubicin injection.

What should i avoid while receiving epirubicin (ellence)?

Do not receive a "live" vaccine while using epirubicin, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), Bacillus Calmette-Guérin (BCG), oral polio, rotavirus, yellow fever, varicella (chickenpox), zoster (shingles), oral typhoid vaccine, and nasal flu (influenza) vaccine.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Cautions for Epirubicin Hydrochloride

Contraindications

  • Known hypersensitivity to epirubicin, other anthracyclines, anthracenediones, or any ingredient in the formulation.1

  • Baseline neutrophil count <1500/mm3.1

  • Severe myocardial or hepatic impairment or recent myocardial infarction.1

  • Previous anthracycline therapy up to the maximum cumulative dose.1

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

Administer only under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.1

Patients must have recovered from acute toxicities (e.g., stomatitis, neutropenia, thrombocytopenia, generalized infections) of prior cytotoxic therapy before starting treatment with epirubicin.1

Prior to and during therapy, assess hematopoietic, hepatic, renal, and cardiac function; monitor for clinical complications associated with myelosuppression (e.g., granulocytopenia, infections) and potential cardiotoxicity (e.g., CHF), especially with increasing cumulative exposure to anthracyclines.1

Provide supportive care for the treatment of toxicity (e.g., severe neutropenia, severe infectious complications, cardiotoxicity).1

Carcinogenicity

Possible secondary AML; risk of refractory AML increases with concomitant DNA-damaging antineoplastics, extensive exposure to cytotoxic drugs, or escalation of anthracycline doses.1

The cumulative risk for adjuvant epirubicin therapy-related leukemia is estimated as 0.2 and 0.8% at 3 and 5 years, respectively.1

Fertility

Possible chromosomal damage in human spermatozoa; males should utilize effective contraceptive methods.1

Possible irreversible amenorrhea in premenopausal women.1

Local Effects

Local pain, severe tissue lesions, and severe local necrosis if extravasation occurs.1 Must not be given IM or sub-Q (see IV Administration under Dosage and Administration).1

Possible venous sclerosis if injected into a small vessel or injected repeatedly into the same vein.1

Tumor Lysis Syndrome

Tumor lysis syndrome may result from extensive purine catabolism accompanying rapid cellular destruction; monitor serum uric acid concentration.1

Minimize or prevent by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.1

Major Toxicities

Hematologic Effects

Possible dose-dependent, reversible leukopenia and/or granulocytopenia (most common acute dose-limiting toxicity).1

Leukocyte nadir at day 10–14, with return to baseline by day 21.1

Possible severe myelosuppression.1

Cardiac Effects

Early (acute) cardiotoxicity (e.g, sinus tachycardia, ECG abnormalities such as nonspecific ST-T wave changes, AV block, ventricular tachycardia) does not predict subsequent development of delayed cardiotoxicity, is rarely of clinical importance, and generally is not an indication for suspension of therapy.1

Delayed cardiotoxicity (cardiomyopathy), manifested by reduced left ventricular ejection fraction (LVEF) and CHF, may be life-threatening.1 Active or occult cardiovascular disease, prior or concomitant irradiation to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase risk.1

Monitor LVEF during therapy and discontinue epirubicin at the first sign of impaired cardiac function.1

Strictly monitor cardiac function in patients with risk factors for cardiotoxicity; evaluate risk versus benefit of continued therapy in those with impaired cardiac function.1

Cardiotoxicity is a cumulative dose-limiting toxicity of the drug.1 Probability of developing CHF estimated as 0.9, 1.6, and 3.3% at cumulative epirubicin hydrochloride dosages of 550, 700, and 900 mg/m2, respectively.1 Risk of CHF increases rapidly with total cumulative dose >900 mg/m2; exceed this dose with extreme caution.1 Possible toxicity at lower cumulative doses, regardless of whether cardiac risk factors are present.1

Cardiac effects of epirubicin and other anthracyclines or anthracenediones may be additive.1

Cardiovascular Effects

Thrombophlebitis and thromboembolic phenomena, including pulmonary embolism, sometimes fatal, have been reported.1

GI Effects

Possible nausea and vomiting; consider prophylaxis with antiemetics.1

Possible dose-dependent mucositis (e.g., oral stomatitis, esophagitis); may be severe.1

Irradiation

Possible additive cytotoxicity with combined epirubicin and radiation therapy; in clinical studies with epirubicin, radiation therapy was delayed until after completion of the chemotherapy.1

Possible inflammatory recall reaction at the site of prior irradiation.1

Prophylactic Anti-infective Therapy

In clinical studies, prophylactic anti-infective therapy with co-trimoxazole or a fluoroquinolone was used with the 120-mg/m2 regimen (see Dosage under Dosage and Administration).1

Specific Populations

Pregnancy

Category D.1

Lactation

Discontinue nursing because of potential risk to nursing infants.1

Pediatric Use

Safety and efficacy not established.1

Possible increased risk of acute or delayed cardiotoxicity.1

Geriatric Use

Careful monitoring for toxicity is recommended.1

Hepatic Impairment

Use not recommended in severe impairment.1 Dosage adjustment for mild to moderate impairment (see Hepatic Impairment under Dosage and Administration).1

Common Adverse Effects

Alopecia, nausea/vomiting, myelosuppression (leukopenia, neutropenia, anemia, thrombocytopenia), amenorrhea, mucositis, lethargy, hot flushes (flashes), diarrhea, infection, local effects (e.g., venous irritation), conjunctivitis/keratitis, rash/pruritus, skin changes, fever, anorexia.1

Epirubicin Hydrochloride Pharmacokinetics

Distribution

Extent

Rapidly and widely distributed into body tissues following IV administration.1 Appears to concentrate in red blood cells; concentrations in whole blood are approximately twice those in plasma.1 Distributed into milk in rats; not known whether the drug is distributed into milk in humans.1

Plasma Protein Binding

Approximately 77% bound to plasma proteins, principally albumin.1

Elimination

Metabolism

Extensively and rapidly metabolized in the liver; also is metabolized in other organs and cells, including erythrocytes.1 Four main metabolic pathways have been identified.1 Only the metabolite epirubicinol appears to have cytotoxic activity; however, epirubicinol is unlikely to reach in vivo concentrations sufficient to produce cytotoxic effects.1

Elimination Route

Epirubicin and its major metabolites are eliminated in feces via biliary excretion and to a lesser extent in urine.1

Half-life

Plasma concentrations of epirubicin decline in a triphasic manner, with mean half-lives for the α, β, and γ phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.1

Special Populations

Clearance is reduced in geriatric women and in patients with hepatic impairment.1

Stability

Storage

Parenteral

Injection, for IV Use

2–8° C.1 Do not freeze; protect from light.1 Discard unused solution within 24 hours after initial entry into vial.1 HID

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Incompatible with any alkaline pH solution (hydrolysis of drug).1

Solution CompatibilityHID

Compatible

Dextrose 3.3% in sodium chloride 0.3%

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility Admixture Compatibility

Compatible

Ifosfamide

Incompatible

Fluorouracil

Heparin sodium

Irinotecan HCl

Y-Site CompatibilityHID

Compatible

Oxaliplatin

Manufacturer states that epirubicin hydrochloride should not be mixed with other drugs in the same syringe.1

Compatibility in Syringe1HID

Compatible

Ifosfamide

Incompatible

Fluorouracil

Ifosfamide with mesna

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