Antineoplastic Agent, Anthracycline; Antineoplastic Agent, Antibiotic

As a component of adjuvant therapy following primary resection of primary breast cancer in patients with evidence of axillary node tumor involvement

D

Epirubicin is mutagenic and carcinogenic. If a pregnant woman is treated with epirubicin, or if a woman becomes pregnant while receiving this drug, she should be informed of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Excretion in human breast milk is unknown, however other anthracyclines are excreted. Breast-feeding is contraindicated.

Hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; baseline neutrophil count <1500 cells/mm³; severe myocardial insufficiency; recent myocardial infarction; previous treatment with anthracyclines up to the maximum cumulative dose; severe hepatic dysfunction

Should be administered only under the supervision of a physician experienced in the use of chemotherapy. The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. The primary toxicity is myelosuppression, especially of the granulocytic series, with less marked effects on platelets and erythroid series.

Reduce dosage and use with caution in mild to moderate hepatic impairment or in severe renal dysfunction (serum creatinine >5 mg/dL). May cause tumor lysis syndrome or radiation recall. Treatment with anthracyclines may increase the risk of secondary leukemias. May cause premature menopause in premenopausal women. For I.V. administration only, severe local tissue necrosis will result if extravasation occurs. Epirubicin is emetogenic.

Vesicant chemotherapy. Epirubicin infiltration can cause severe inflammation, tissue necrosis, and ulceration. If the drug is infiltrated, consult institutional policy, apply ice to the area, and elevate the limb. Can have ongoing tissue destruction secondary to propagation of free radicals; may require debridement.

Grade 3 and 4 leukopenia may occur in 1.5% to 58.6% of patients, depending on the protocol and dosage of epirubicin. Grade 3 or 4 gastrointestinal toxicity was noted to occur in 22% to 25% of patients.

>10%:

Central nervous system: Lethargy (1% to 46%)

Dermatologic: Alopecia (69% to 95%)

Endocrine & metabolic: Amenorrhea (69% to 72%), hot flashes (5% to 39%)

Gastrointestinal: Nausea, vomiting (83% to 92%), mucositis (9% to 59%), diarrhea (7% to 25%)

Hematologic: Leukopenia (49% to 80%), neutropenia (54% to 80%), anemia (13% to 72%), thrombocytopenia (5% to 49%)

Local: Injection site reactions (3% to 20%)

Ocular: Conjunctivitis (1% to 15%)

Miscellaneous: Infection (15% to 21%)

1% to 10%:

Central nervous system: Fever (1% to 5%)

Cardiovascular: Congestive heart failure (0.4% to 1.5%), decreased LVEF (asymptomatic) (1.4% to 1.8%)

Dermatologic: Rash (1% to 9%), skin changes (0.7% to 5%)

Gastrointestinal: Anorexia (2% to 3%)

Other reactions (percentage not specified): Acute myelogenous leukemia (0.2% at 3 years), acute lymphoid leukemia, increased transaminases, radiation recall, skin and nail hyperpigmentation, photosensitivity reaction, hypersensitivity, anaphylaxis, urticaria, premature menopause in women

Symptoms of overdose are generally extensions of known cytotoxic effects, including myelosuppression, mucositis, gastrointestinal bleeding, lactic acidosis, multiple organ failure, and death. Delayed development of congestive heart failure may also occur. Treatment is supportive.

No systematic evaluation of the potential for interaction with inhibitors or inducers of cytochrome P-450 isoenzymes has been performed. However, cimetidine increased the AUC of epirubicin by 50%.

Store refrigerated (2°C to 8°C/36°F to 46°F). Protect from light. Solution should be used within 24 hours of penetrating the rubber stopper. Incompatible with heparin, fluorouracil, or any solution of alkaline pH.

Epirubicin is an anthracycline cytotoxic agent. The precise mechanism of its cytotoxic and antiproliferative effect has not been elucidated. Epirubicin is known to inhibit DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs; active throughout entire cell cycle. Intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase, and generates cytotoxic free radicals.

Distribution: V_ss 21-27 L/kg

Protein binding: 77% (albumin)

Metabolism: Extensive, via hepatic and extrahepatic (including RBCs) routes

Half-life: Triphasic; mean terminal half-life: 33 hours

Elimination: Biliary and (to a lesser extent) renal excretion

Adults: I.V.:

Recommended starting dose: 100-120 mg/m². Epirubicin is given in repeated 3- to 4-week cycles with the total dose given on day 1 of each cycle or divided equally and given on days 1 and 8 of each cycle. Patients receiving the 120 mg/m² regimen should also receive prophylactic antibiotics with TMP-SMX or a fluoroquinolone.

As a component of adjuvant therapy in patients with axillary-node positive breast cancer:

CEF-120: 60 mg/m² on days 1 and 8 of cycle (in combination with cyclophosphamide and 5-fluorouracil); cycle is repeated every 28 days for 6 cycles

FEC-100: 100 mg/m² on day 1 of cycle (in combination with 5-fluorouracil and cyclophosphamide); cycle is repeated every 21 days for 6 cycles

Dosage adjustment in bone marrow dysfunction:

Patients with heavy pretreatment, pre-existing bone marrow depression, or the presence of neoplastic bone marrow infiltration: Consider lower starting doses of 75-90 mg/m²

Dosage modifications after the first treatment cycle: Nadir platelet counts <50,000/mm³, ANC <250/mm³, neutropenic fever, or grades 3/4 nonhematologic toxicity: Reduce day 1 dose in subsequent cycles to 75% of the current cycle. Day 1 chemotherapy in subsequent courses of treatment should be delayed until platelet counts are greater than or equal to 100,000/mm³, ANC greater than or equal to 1500/mm³, and nonhematologic toxicities have recovered to less than or equal to grade 1.

In addition, for patients receiving divided dose (day 1 and day 8) regimen:

Day 8 platelet counts 75,000-100,000/mm³ and ANC 1000-1499/mm³: Day 8 dose should be 75% of the day 1 dose

Day 8 platelet counts <75,000/mm³, ANC <1000/mm³, or grade 3 or 4 nonhematologic toxicity: Omit day 8 dose

Dosage adjustment in renal impairment: Severe renal impairment (serum creatinine >5 mg/dL): Lower doses should be considered

Dosage adjustment in hepatic impairment:

Bilirubin 1.2-3 mg/dL or AST 2-4 times the upper limit of normal: 50% of recommended starting dose

Bilirubin >3 mg/dL or AST >4 times the upper limit of normal: 25% of recommended starting dose

Elderly: Plasma clearance of epirubicin in elderly female patients was noted to be reduced by 35%. Although no initial dosage reduction is specifically recommended, particular care should be exercised in monitoring toxicity and adjusting subsequent dosage in elderly patients (particularly females >70 years of age).

Administer I.V. into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution) over 3-5 minutes. Avoid extravasation, associated with severe ulceration and soft tissue necrosis; flush with 5-10 mL of I.V. solution before and after drug administration. Should not be mixed with other drugs in the same syringe. Incompatible with heparin, fluorouracil, or any solution of alkaline pH.

Monitor injection site during infusion for possible extravasation or local reactions; CBC with differential and platelet count, liver function tests, renal function, EKG, and left ventricular ejection fraction

No information available to require special precautions

No effects or complications reported

Report any stinging or change in sensation during the infusion. This medication can only be administered I.V. During therapy, do not use alcohol, aspirin-containing products, and OTC medications without consulting prescriber. It is important to maintain adequate nutrition and hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) during therapy; frequent small meals may help. You may experience nausea or vomiting (frequent small meals, frequent mouth care, sucking lozenges, or chewing gum may help). You may experience loss of hair (reversible); you will be more susceptible to infection (avoid crowds and exposure to infection as much as possible). Yogurt or buttermilk may help reduce diarrhea (if unresolved, contact prescriber for medication relief). Frequent mouth care and use of a soft toothbrush or cotton swabs may reduce mouth sores. May discolor urine (red/pink). Report fever, chills, unusual bruising or bleeding, signs of infection, abdominal pain or blood in stools, excessive fatigue, yellowing of eyes or skin, swelling of extremities, difficulty breathing, or unresolved diarrhea. Barrier contraceptive measures are recommended for both males and females while receiving this drug and for at least one month following administration. Risks of treatment include irreversible heart damage, treatment-related leukemia, and premature menopause in women.

Injection: 2 mg/mL (50 mg/25 mL; 200 mg/100 mL)