Ellence


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epirubicin hydrochloride

Ellence, Pharmorubicin PMS (CA)

Pharmacologic class: Anthracycline

Therapeutic class: Antibiotic antineoplastic

Pregnancy risk category D

FDA Box Warning

• Extravasation during administration causes severe local tissue necrosis; don't give epirubicin hydrochloride by I.M. or subcutaneous route.

• Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy or months to years after therapy ends. Probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. In adjuvant treatment of breast cancer, maximum cumulative dose used in clinical trials was 720 mg/m2. Risk of developing CHF increases rapidly with increasing total cumulative doses above 900 mg/m2; exceed this cumulative dose only with extreme caution. Active or dormant cardiovascular disease, previous or concurrent radiotherapy to mediastinal or pericardial area, previous anthracycline or anthracenedione therapy, or concurrent use of other cardiotoxic drugs may increase cardiac toxicity risk. Toxicity may occur at lower cumulative doses even if patient has no cardiac risk factors.

• Secondary acute myelogenous leukemia (AML) has been reported in breast cancer patients who have been treated with anthracyclines, including epirubicin. Refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastics, when patients have been heavily pretreated with cytotoxic drugs, or when epirubicin dosage has been escalated. Cumulative risk of developing treatmentrelated AML or myelodysplastic syndrome (MDS), in 7,110 patients with breast cancer who received adjuvant treatment with epirubicin-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years.

• Reduce dosage in patients with hepatic impairment.

• Drug may cause severe myelosuppression.

• Give under supervision of physician experienced in cancer chemotherapy.

Action

Unknown. Forms complex with DNA by intercalation with nucleotide base pairs, causing inhibition of DNA, RNA, and protein synthesis.

Availability

Injection: 2 mg/ml, in 5 ml-, 25 ml-, 75 ml-, and 100-ml vials

Powder for injection (lyophilized): 50-mg single-dose vial

Indications and dosages

Adjunctive therapy in patients with axillary-node tumor involvement after resection of primary breast cancer

Adults: 100 to 120 mg/m2 by I.V. infusion over 3 to 5 minutes on first day of each cycle or divided equally in two doses on days 1 and 8 of each cycle; repeat cycle q 3 to 4 weeks for six cycles in conjunction with cyclophosphamide and fluorouracil.

Dosage adjustment

• Hepatic and severe renal impairment
• Hematologic or Grade 3 or 4 non-hematologic toxicity and neutropenic fever

Off-label uses

• Cancer of bladder, lung, nasopharynx, endometrium, and ovaries

Contraindications

• Hypersensitivity to drug, other anthracyclines, or anthracenediones
• Severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias
• Severe hepatic dysfunction
• Baseline neutrophil count below 1,500/mm3
• Previous treatment with anthracyclines up to the maximum cumulative doses

Precautions

Use cautiously in:
• heart disease, hepatic, or renal disease
• previous or recent radiation therapy
• hyperuricemia
• concurrent use of cimetidine, other cardiotoxic drugs, or live or live-attenuated vaccines
• elderly patients (female patients age 70 and older)
• pregnant or breastfeeding patients
• children.

Administration

• Be aware that drug may be given with antibiotics.
• Know that previous anthracycline use must be considered when determining dosage because of increased risk of heart failure.
• Follow facility policy for administration and disposal of carcinogenic drugs.
• Assess blood counts, including absolute neutrophil count, serum creatinine, and liver function before and during each cycle of therapy.
• Consider prophylactic use of antiemetics before administration, particularly when given in conjunction with other emetogenic drugs.

Avoid extravasation. If patient complains of burning or stinging, switch infusion to a different vein.
• Administer premixed solution over 3 to 5 minutes into tubing of free-flowing I.V. line containing dextrose 5% in water or normal saline solution. Don't mix with other drugs in same syringe.
• Direct I.V. push is not recommended because of extravasation risk.
• If patient develops facial flushing or red streak in the vein being infused, slow infusion rate.
• Be aware that refrigerated storage of solution for injection can result in formation of a gelled product. Gelled product will return to a slightly viscous to mobile solution after 2- to a maximum of 4-hour equilibration at controlled room temperature (15° to 25° C [59° to 77° F]).

Adverse reactions

CNS: lethargy

CV: cardiomyopathy, cardiotoxicity, heart failure

EENT: conjunctivitis, keratitis

GI: nausea, vomiting, diarrhea, mucositis

GU: reddish urine, amenorrhea

Hematologic: anemia, leukopenia, neutropenia, thrombocytopenia secondary acute myelogenous leukemia, thrombophlebitis, thromboembolic phenomena

Metabolic: hyperuricemia

Respiratory: pulmonary embolism

Skin: alopecia; rash; pruritus; darkening of soles, palms, or nails

Other: increased appetite, infection, fever, hot flashes, tissue necrosis, injection-related reactions, tumorlysis syndrome

Interactions

Drug-drug.Cardioactive compounds that could cause heart failure (such as calcium channel blockers): increased risk of heart failure

Cimetidine: increased epirubicin blood level

Live or live-attenuated vaccines: increased risk of serious or fatal infection

Trastuzumab, other cardiotoxic drugs: increased risk of cardiotoxicity

Drug-diagnostic tests.Hemoglobin, neutrophils, platelets, white blood cells: decreased values

Patient monitoring

Monitor vital signs, left ventricular ejection fraction, and cardiovascular status carefully. Watch for signs and symptoms of cardiomyopathy and heart failure.
• Assess nutritional status and hydration in light of GI adverse effects.

Monitor CBC with white cell differential and watch for signs and symptoms of blood dyscrasias.
• Check temperature. Stay alert for fever and other signs or symptoms of infection.

Consider the possibility of tumor lysis syndrome in potentially susceptible patients and monitor serum uric acid, potassium, calcium, phosphate, and creatinine levels immediately after initial chemotherapy. Be aware that hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.
• Continue to monitor serum total bilirubin, AST, and serum creatinine levels during treatment.

Patient teaching

• Inform patient that drug may cause tissue damage at injection site. Tell him to report pain, burning, or swelling.

Instruct patient to immediately report sudden weight gain, swelling, or shortness of breath.

Tell patient to promptly report unusual bruising or bleeding, fever, or signs and symptoms of infection or tumor lysis syndrome.
• Advise patient to avoid receiving live vaccines while taking this drug.
• Explain that drug will cause hair loss but that hair should grow back within a few months after therapy.
• Advise female patient that drug may cause premature menopause or permanent cessation of menses.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

epirubicin

(ep-i-roo-bi-sin) ,

Ellence

(trade name),

Pharmorubicin PFS

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: anthracyclines
Pregnancy Category: D

Indications

A component of adjuvant therapy for evidence of axillary tumor involvement following resection of primary breast cancer.

Action

Inhibits DNA and RNA synthesis by forming a complex with DNA.

Therapeutic effects

Death of rapidly replicating cells, particularly malignant ones.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.
Distribution: Rapidly and widely distributed; concentrates in RBCs.
Metabolism and Excretion: Extensively and rapidly metabolized by the liver and other tissues.
Half-life: 35 hr.

Time/action profile (effect on WBCs)

ROUTEONSETPEAKDURATION
IVunknown10–14 days21 days

Contraindications/Precautions

Contraindicated in: Hypersensitivity to epirubicin, other anthracyclines, or related compounds;Baseline neutrophil count <1500 cells/mm3;Heart failureRecent MI;Severe arrhythmiasPrevious treatment with anthracyclines up to the maximum cumulative dose;Severe hepatic dysfunction;Concurrent cimetidine therapy; Obstetric / Lactation: Significant risk for fetal or infant harm.
Use Cautiously in: Cardiovascular disease, prior or concomitant radiation therapy to mediastinal or pericardial area, previous therapy with anthracyclines, or concomitant use of cardiotoxic drugs (↑ risk of cardiotoxicity);Severe renal impairment (serum creatinine >5 m g/dL); consider ↓ dose;Hepatic impairment (dose ↓ recommended for bilirubin >1.2 m g/dL or AST >2.2 m–4 times upper limit of normal);Depressed bone marrow reserve; Obstetric: Warn patients with child-bearing potential to avoid pregnancy during treatment; Pediatric: Safety not established; ↑ risk of acute cardiotoxicity and chronic HF; Geriatric: ↑ risk of toxicity in female patients ≥70 yr.

Adverse Reactions/Side Effects

Central nervous system

  • lethargy

Cardiovascular

  • cardiotoxicity (dose-related) (life-threatening)
  • bradycardia
  • heart block
  • thromboembolism
  • ventricular tachycardia

Gastrointestinal

  • nausea (most frequent)
  • vomiting (most frequent)
  • anorexia
  • diarrhea
  • mucositis

Dermatologic

  • alopecia (most frequent)
  • flushing
  • itching
  • photosensitivity
  • radiation-recall reaction
  • rash
  • skin/nail hyperpigmentation

Endocrinologic

  • gonadal suppression

Hematologic

  • leukopenia (life-threatening)
  • anemia
  • thrombocytopenia
  • treatment-related leukemia/myelodysplastic syndromes

Local

  • injection site reactions
  • phlebitis at IV site
  • tissue necrosis

Metabolic

  • hot flashes
  • hyperuricemia

Miscellaneous

  • anaphylaxis (life-threatening)
  • infection (life-threatening)

Interactions

Drug-Drug interaction

Cimetidine ↑ blood levels and risk of serious toxicity; avoid concurrent use.Additive hematologic and gastrointestinal toxicity with other antineoplastics or radiation therapy.Use with other cardiotoxic drugs may ↑ risk of cardiotoxicity; avoid concurrent use.May ↓ antibody response to live-virus vaccines and ↑ risk of adverse reactions.Trastuzumab may ↑ risk of cardiotoxicity; avoid epirubicin for ≥24 wk after stopping trastuzumab therapy.

Route/Dosage

Intravenous (Adults) 100–120 mg/m2 repeated in 3–4 wk cycles (total dose may be given on day 1 or split and given in equally divided doses on day 1 and day 8 of each cycle (combination regimens may employ concurrent 5-fluorouracil and cyclophosphamide).

Hepatic Impairment

Intravenous (Adults) Bilirubin 1.2–3 mg/dL or AST 2–4 times upper limit of normal—use 50% of recommended starting dose; bilirubin >3 m g/dL or AST >4 times upper limit of normal—use 25% of recommended starting dose.

Availability (generic available)

Powder for injection: 50 mg/vial
Solution for injection (red): 2 mg/mL

Nursing implications

Nursing assessment

  • Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, guaiac stools, urine, and emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension.
  • Severe nausea and vomiting may occur. Administer parenteral antiemetic agents 30–45 min prior to therapy and routinely around the clock for the next 24 hr as indicated. Monitor amount of emesis and notify health care professional if emesis exceeds guidelines to prevent dehydration.
  • Measure cardiac function, using ECG and a multigated radionuclide angiography (MUGA) scan or an ECHO, prior to therapy. Perform repeated evaluations of left ventricular ejection fraction during therapy. Monitor for development of signs of cardiac toxicity, which may occur early (ST-T wave changes, sinus tachycardia, and extrasystoles) or late (may occur mo to yr after termination of therapy). Delayed cardiac toxicity is characterized by cardiomyopathy, tachycardia, peripheral edema, dyspnea, rales/crackles, weight gain, hepatomegaly, ascites, pleural effusion. Toxicity is usually dependent on cumulative dose.
  • Assess injection site frequently for redness, irritation, or inflammation. Burning or stinging during infusion may indicate infiltration and infusion should be discontinued and restarted in another vein. Epirubicin is a vesicant but may infiltrate painlessly even if blood returns on aspiration of infusion needle. Severe tissue damage may occur if epirubicin extravasates. If extravasation occurs, stop infusion immediately, restart, and complete dose in another vein.
  • Assess oral mucosa frequently for development of stomatitis (pain, burning, erythema, ulcerations, bleeding, infection). Increased dosing interval and/or decreased dosing is recommended if lesions are painful or interfere with nutrition.
  • Lab Test Considerations: Monitor CBC and differential before and during each cycle of therapy. Epirubicin should not be administered to patients with a baseline neutrophil count <1500 cells/mm3. The WBC nadir occurs 10–14 days after administration, and recovery usually occurs by the 21st day. Severe thrombocytopenia and anemia may also occur.
    • Monitor renal (BUN and creatinine) and hepatic (AST, ALT, LDH, and serum bilirubin) function prior to and periodically during therapy. Dose reduction is required for bilirubin >1.2 m g/dL, AST 2–4 times the upper limit of normal, or serum creatinine >5 m g/dL.

Potential Nursing Diagnoses

Risk for infection (Adverse Reactions)
Decreased cardiac output (Adverse Reactions)

Implementation

  • high alert: Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order, calculations and infusion pump settings. Epirubicin should be administered only under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.
  • Prepare solution in a biologic cabinet. Wear gloves, gown, and mask while handling medication. Discard IV equipment in specially designated containers.
    • Administer prophylactic anti-infective therapy with trimethoprim/sulfamethoxazole or a fluoroquinolone and antiemetic therapy prior to administration of epirubicin.
    • Do not administer subcut or IM.
  • Intravenous Administration
  • Intermittent Infusion: Diluent: Administer undiluted. Solution is clear red. Use epirubicin within 24 hr of penetration of rubber stopper. Discard unused solution.Concentration: 2 mg/mL.
  • Rate: Administer initial dose of 100–120 mg/m2 over 15–20 min through Y-site of a free-flowing infusion of 0.9% NaCl or D5W. Lower doses may be infused for shorter periods, but not less than over 3 min. Do not administer via direct IV push. Facial flushing and erythema along involved vein frequently occur when administration is too rapid. Venous sclerosis may result from injection into a small vein or repeated injections into the same vein. Avoid veins over joints or in extremities with compromised venous or lymphatic drainage.
  • Y-Site Compatibility: alemtuzumab, alfentanil, amifostine, amikacin, aminocaproic acid, anidulafungin, argatroban, atracurium, aztreonam, bivalirudin, bleomycin, bumetanide, buprenorphine, butorphanol, calcium chloride, calcium gluconate, carboplatin, caspofungin, cefazolin, cefotaxime, chlorpromazine, ciprofloxacin, cisatracurium, cisplatin, clindamycin, cyclophosphamide, cyclosporine, daptomycin, dexrazoxane, digoxin, diltiazem, diphenhydramine, dobutamine, docetaxel, dolasetron, dopamine, doxacurium, doxacycline, droperidol, enalaprilat, ephedrine, epinephrine, erythromycin, etoposide, etoposide phosphate, famotidine, fenoldopam, fentanyl, fluconazole, gemcitabine, gentamicin, granisetron, haloperidol, hydrocortisone sodium succinate, hydromorphone, ifosfamide, imipenem cilastatin, insulin, isoproterenol, labetalol, levofloxacin, levorphanol, lidocaine, linezolid, lorazepam, mannitol, meperidine, mesna, methotrexate, metoclopramide, metoprolol, metronidazole, midazolam, milrinone, mitomycin, morphine, moxifloxacin, nalbuphine, naloxone, nesiritide, nicardipine, nitroglycerin, nitroprusside, norepinephrine, octreotide, ondansetron, oxaliplatin, paclitaxel, palonosetron, pancuronium, pentamidine, pentazocine, phenylephrine, potassium chloride, procainamide, prochlorperazine, promethazine, propranolol, quinapristin/dalfopristin, ranitidine, remifentanil, rocuronium, sodium acetate, succinylcholine, sufentanil, tacrolimus, teniposide, theophylline, thiotepa, tirofiban, tobramycin, vancomycin, vasopressin, vecuronium, verapamil, vinblastine, vincristine, vinorelbine, voriconazole, zidovudine, zolendronic acid
  • Y-Site Incompatibility: acyclovir, allopurinol, aminophylline, amphotericin B colloidal, amphotericin B lipid complex, amphotericin B liposome, ampicillin, ampicillin/sulbactam, azithromycin, cefepime, cefoperazone, cefotetan, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, dexamethasone sodium phosphate, diazepam, ertapenem, fluorouracil, foscarnet, fosphenytoin, furosemide, ganciclovir, heparin, hydrocortisone sodium phosphate, ketorolac, leucovorin, magnesium sulfate, meropenem, methohexital, methylprednisolone, nafcillin, pantoprazole, pemetrexed, pentobarbital, phenobarbital, phenytoin, piperacillin/tazobactam, potassium phosphates, sodium bicarbonate, sodium phosphates, thiopental, ticarcillin/clavulanate, tigecycline, trimethoprim/sulfamethoxazole

Patient/Family Teaching

  • Instruct patient to notify health care professional promptly if fever; sore throat; signs of infection; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; increased fatigue; dyspnea; or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls. Patient should be cautioned not to drink alcoholic beverages or take medication containing aspirin or NSAIDs, because these may precipitate gastric bleeding.
  • Instruct patient to report pain at injection site immediately.
  • Instruct patient to inspect oral mucosa for erythema and ulceration. If ulceration occurs, advise patient to use sponge brush, rinse mouth with water after eating and drinking, and confer with health care professional if mouth pain interferes with eating. Pain may require treatment with opioid analgesics. Patients usually recover by the third week of therapy.
  • Advise patient that this medication may have teratogenic effects. Contraception should be used during and for at least 4 mo after therapy is concluded. Inform patient before initiating therapy that this medication may cause irreversible gonadal suppression.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to avoid concurrent use of alcohol or OTC medications and herbal products, especially cold preparations, without consulting health care professional, especially cimetidine.
  • Instruct patient to notify health care professional immediately if vomiting, dehydration, fever, evidence of infection, symptoms of HF, or pain at injection site occurs. Patients should be informed of the risk of irreversible cardiac damage and treatment-related leukemia.
  • Discuss the possibility of hair loss with patient. Explore methods of coping. Regrowth usually occurs 2–3 mo after discontinuation of therapy.
  • Instruct patient not to receive any vaccinations without advice of health care professional.
  • Inform patient that medication may cause urine to appear red for 1–2 days.
  • Instruct patient to notify health care professional if skin irritation occurs at site of previous radiation therapy. May cause hyperpigmentation of the skin and nails. Advise patient to use sunscreen and protective clothing to prevent photosensitivity reactions.
  • Advise patient that this medication may have teratogenic effects. Contraception should be used during and for at least 4 mo after therapy is concluded. Inform patient before initiating therapy that this medication may cause irreversible gonadal suppression.
  • Emphasize the need for periodic lab tests to monitor for side effects.

Evaluation/Desired Outcomes

  • Decrease in size or spread of malignancies in patients with axillary node tumor involvement following resection of primary breast cancer.

Ellence

(ĕl′əns)
A trademark for the drug epirubicin hydrochloride.
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Drugs that have reached the market with no listed patents, but only regulatory exclusivity, include: Mefloquine HCl (mefloquine hydrochloride), Clozaril (clozapine), Hexalen (altretamine), Leustatin (cladribine), Trasylol (aprotinin bovine), Sclerosol (talc), and Ellence (epirubicin hydrochloride).
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including Ellence, cyclophosphamide, and fluorouracil (CEF), Ellence and
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Epirubicin hydrochloride injection (generic equivalent to Ellence , distributed by Pfizer Oncology) is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.
Ellence (epirubicin hydrochloride injection) is part of a chemotherapy regimen used to treat the early stages of breast cancer when the cancer has spread to the lymph nodes.
Teva's product is the AP-rated generic equivalent of Pfizer's Ellence Injection, a product indicated for use as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.