Ellence (Epirubicin) is a cytotoxic or antineoplastic chemotherapeutic drug classified as "anthracycline anticancer antibiotic". It is indicated for the treatment of cancers including breast cancer as adjuvant chemotherapy.

Indications of Epirubicin (Ellence):

• Breast cancer (adjuvant treatment):

  • It is used as adjuvant therapy component for primary breast cancer in patients with evidence of axillary node involvement after tumor resection.

• Off Label Use of Epirubicin in Adults:

  • Esophageal cancer
  • Gastric cancer
  • Osteosarcoma
  • Soft tissue sarcoma

Epirubicin (Ellence) dose in adults:

Note:

• Prophylactic antibiotic therapy with sulfamethoxazole/trimethoprim or a fluoroquinolone should be given to patients receiving 120 mg/m²/cycle as part of combination therapy (CEF-120 regimen).
• Patients who are heavily pretreated, patients with preexisting myelosuppression, or with bone marrow involvement should be treated with the lower initial dose.
• Epirubicin therapy should be delayed until the clearance of other cardiotoxic agents with long half-lives (eg, trastuzumab).
• The recommended lifetime maximum dose is 900 mg/m².
• Antiemetics are recommended to prevent nausea and vomiting due to the high emetic potential of epirubicin.

Epirubicin (Ellence) dose in the treatment of Breast cancer (as adjuvant therapy):

• Usual dose: 100 to 120 mg/m²  IV per 3- or 4-week treatment cycle as follows:
  • 60 mg/m² on days 1 and 8 every 28 days for 6 cycles in combination with cyclophosphamide and fluorouracil  or
  • 100 mg/m² on day 1 every 21 days for 6 cycles in combination with cyclophosphamide and fluorouracil (FEC-100 regimen).

Epirubicin (Ellence) dose in the treatment of Breast cancer (off-label regimens):

• EC regimen:

  • 100 mg/m IV on day 1 every 21 days for 8 cycles in combination with cyclophosphamide or

• EP or EC regimen:

  • 75 mg/m² IV on day 1 every 21 days for up to 6 cycles in combination with either paclitaxel or cyclophosphamide  or

• FEC regimen ± paclitaxel:

  • 90 mg/m² IV on day 1 every 21 days for 6 cycles in combination with fluorouracil and cyclophosphamide or for 4 cycles in combination with fluorouracil and cyclophosphamide followed by paclitaxel OR

• FEC regimen followed by pertuzumab + trastuzumab + docetaxel:

  • 100 mg/m² IV on day 1 every 21 days for 3 cycles in combination with fluorouracil and cyclophosphamide, followed by 3 cycles of pertuzumab, trastuzumab, and docetaxel  OR

• CEF regimen:

  • 50 mg/m² IV on days 1 and 8 every 21 or 28 days for 6 to 9 cycles in combination with cyclophosphamide and fluorouracil

Epirubicin (Ellence) dose in the treatment of Esophageal cancer (off-label): IV:

• ECF, ECX, EOF, and EOX regimens:

  • 50 mg/m² IV on day 1 every 21 days for up to 8 cycles in combination with cisplatin (C), oxaliplatin (O), fluorouracil (F), and/or capecitabine (X)  or

• ECF regimen:

  • 50 mg/m² IV on day 1 every 21 days for 3 preoperative and 3 postoperative cycles in combination with cisplatin and fluorouracil

Epirubicin (Ellence) dose in the treatment of Gastric cancer (off-label): 

• ECF, ECX, EOF, and EOX regimens:

  • 50 mg/m² IV on day 1 every 21 days for up to 8 cycles in combination with cisplatin (C), oxaliplatin (O), fluorouracil (F), and/or capecitabine (X)  or

• ECF regimen:

  • 50 mg/m IV on day 1 every 21 days for 3 preoperative and 3 postoperative cycles in combination with cisplatin and fluorouracil

Epirubicin (Ellence) dose in the treatment of Osteosarcoma (off-label use):

• 90 mg/m² IV on day 1 every 21 days for 3 cycles before surgery and 90 mg/m² on day 1 every 28 days for 3 cycles after surgery (in combination with cisplatin, ifosfamide, and mesna).

Ellence (Epirubicin) dose in the treatment of Soft tissue sarcoma (off-label):

• 25 mg/m² IV on days 1, 2, and 3 every 28 days for 4 cycles (in combination with ifosfamide and mesna) or
• 60 mg/m² on days 1 and 2 every 21 days for 5 cycles (in combination with ifosfamide, mesna, and filgrastim).

Use in Children:

Not indicated

Ellence (Epirubicin) Pregnancy Risk Factor D

• Animal reproduction studies revealed adverse outcome.
• During therapy, effective contraception should be used in women of childbearing age.
• Men undergoing treatment should use effective contraception.
• Irreversible amenorrhea in premenopausal women can occur due to epirubicin.
• Limited information is available from a retrospective study of women who received epirubicin (in combination with cyclophosphamide or weekly as a single-agent) during the second or third (prior to week 35) trimester for the treatment of pregnancy-associated breast cancer and from a study of women who received epirubicin (weekly as a single-agent) at gestational weeks 16 through 30 for the treatment of pregnancy-associated breast cancer.
• During pregnancy,some pharmacokinetic properties of epirubicin may be altered.
• The European Society for Medical Oncology (ESMO) has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy,recommending referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team).
• Chemotherapy should not be given in the first trimester, but may begin in the second trimester.
• The interval between the last chemotherapy dose and anticipated delivery should at least be 3 weeks and chemotherapy should not be administered beyond week 33 of gestation.

Epirubicin use during breastfeeding:

• Epirubicin secretion in breast milk is not known, however, other anthracyclines are present in breast milk.
• Due to the potential for serious adverse reactions in the breastfed infant,  decision be made to discontinue breastfeeding or to discontinue the drug, depends on the importance of treatment to the mother as per manufacturer.

Epirubicin (Ellence) Dose adjustment in renal disease:

The manufacturer's labeling recommends lower doses (dose not specified) in patients with severe renal impairment (serum creatinine >5 mg/dL). Other sources suggest no dosage adjustment is needed for CrCl <50 mL/minute. 

Epirubicin (Ellence) Dose adjustment in liver disease:

• The manufacturer's labeling recommends the following adjustments (based on clinical trial information):
  • Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times the upper limit of normal:
    • Administer 50% of recommended starting dose
  • Bilirubin >3 mg/dL or AST >4 times the upper limit of normal:
    • Administer 25% of recommended starting dose
  • Severe hepatic impairment:
    • Use is not recommended.

Side effects of Epirubicin (Ellence):

Percentages reported as part of combination chemotherapy regimens.

• Cardiovascular:

  • Decreased Left Ventricular Ejection Fraction
  • Cardiac Failure
  • Atrioventricular Block
  • Bradycardia
  • Bundle Branch Block
  • Cardiac Arrhythmia
  • Cardiomyopathy
  • ECG Abnormality
  • Myocarditis
  • Non-Specific T Wave On ECG
  • Sinus Tachycardia
  • ST Segment Changes On ECG
  • Tachyarrhythmia
  • Thromboembolism
  • Ventricular Premature Contractions
  • Ventricular Tachycardia

• Central Nervous System:

  • Lethargy

• Dermatologic:

  • Alopecia
  • Skin Rash
  • Skin Changes

• Endocrine & Metabolic:

  • Amenorrhea
  • Hot Flash

• Gastrointestinal:

  • Nausea And Vomiting
  • Mucositis
  • Diarrhea
  • Anorexia
  • Abdominal Pain
  • Esophagitis
  • Neutropenic Enterocolitis
  • Stomatitis
  • Toxic Megacolon

• Genitourinary:

  • Menopause

• Hematologic & Oncologic:

  • Neutropenia
  • Leukopenia
  • Anemia
  • Thrombocytopenia
  • Febrile Neutropenia
  • Acute Lymphocytic Leukemia
  • Acute Myelocytic Leukemia
  • Myelodysplastic Syndrome

• Hepatic:

  • Ascites
  • Hepatomegaly
  • Increased Serum Transaminases

• Hypersensitivity:

  • Hypersensitivity Reaction

• Infection:

  • Infection

• Local:

  • Injection Site Reaction

• Ophthalmic:

  • Conjunctivitis

• Respiratory:

  • Dyspnea
  • Pulmonary Edema

• Miscellaneous:

  • Fever

Contraindications to Epirubicin (Ellence):

• Hypersensitivity to epirubicin, other anthracyclines, anthracenediones, or any component of the formulation
• Cardiomyopathy and/or heart failure, recent myocardial infarction, severe arrhythmias
• Previous treatment with anthracyclines up to the maximum cumulative dose

Canadian labeling: Additional contraindications (not in the US labeling):

• Significant myelosuppression induced by previous treatment with other chemotherapy agents or by radiotherapy
• Severe hepatic impairment.

Warnings and Precautions

• Bone marrow suppression: [US Boxed Warning]:

  • Epirubicin can lead to myelosuppression including anemia, leukopenia, and thrombocytopenia.
  • Regular monitoring of blood count is necessary.
  • Patients should recover from myelosuppression due to prior chemotherapy treatment before beginning treatments.
  • Supportive treatment is needed in case of severe neutropenia and severe infections.

• Cardiomyopathy: [US Boxed Warning]:

  • Epirubicin therapy can result in cardiac toxicity, including fatal heart failure during or after many months of treatment.
  • Patients who have received prior anthracyclines (or anthracenediones), previous or concomitant chest irradiation, preexisting cardiac disease (active or dormant), concomitant cardiotoxic medications, elderly and children are at increased risk of cardiotoxicity.
  • Early toxicity can present with tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia.
  • Delayed toxicity presents with decreased left ventricular ejection fraction and/or signs/symptoms of heart failure such as tachycardia, dyspnea, pulmonary edema, edema, hepatomegaly, ascites, pleural effusion, and gallop rhythm.
  • Children are at increased risk of delayed cardiotoxicity.
  • Electrocardiographic changes including ST-T wave changes, atrioventricular and bundle-branch block can be seen.
  • In patients with cardiac risk factors or impaired cardiac function, regular monitoring of cardiac function is necessary.
  • Therapy should be stopped with the appearance of early signs of decreased LVEF.
  • The half-life of other cardiotoxic agents (eg, trastuzumab) must be considered in sequential therapy.
  • The risk of developing clinically evident heart failure is ~0.9% at a cumulative dose of 550 mg/m², ~1.6% at a cumulative dose of 700 mg/m , and ~3.3% at a cumulative dose of 900 mg/m².
  • Lower cumulative doses with or without risk factors can also cause cardiotoxicity.
  • The risk of cardiotoxicity increases more steeply with cumulative doses >900 mg/m², and this dose should be exceeded only with extreme caution.
  • The maximum cumulative dose used in studies of adjuvant treatment of breast cancer was 720 mg/m².
  • Previous therapy with other anthracyclines or anthracenediones, previous or concomitant treatment with other cardiotoxic agents or radiotherapy of the chest should be taken into account for total cumulative dose.
  • Irreversible cardiotoxicity can be seen with any dose level.
  • ASCO has developed guidelines for prevention and monitoring of cardiac dysfunction in adult survivors of cancer.
  • According to the guidelines, the risk of cardiac dysfunction is increased with the following:
    • High-dose anthracycline therapy (eg, doxorubicin ≥250 mg/m², epirubicin ≥600 mg/m²).
    • High-dose radiotherapy (≥30 Gy) with the heart in the treatment field.
    • Lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) in combination with lower-dose radiotherapy (<30 Gy) with the heart in the treatment field.
    • Lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) or trastuzumab alone AND any of the following risk factors:
      • multiple cardiovascular risk factors (≥2 risk factors), including smoking, HTN, DM, dyslipidemia, and obesity (during or after completion of therapy),
      • elderly (≥60 years) at cancer treatment, or
      • A compromised cardiac function such as borderline low LVEF [50% to 55%], history of MI, moderate or higher valvular heart disease before or during treatment.
    • Treatment with lower-dose anthracycline (eg, doxorubicin <250 mg/m², epirubicin <600 mg/m²) followed by trastuzumab (sequential therapy).
    • Other risk factors for anthracycline-induced cardiotoxicity include age 60 and older at the time of treatment and 2 or more cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, or obesity) during or after treatment.
  • A detailed assessment in patients with cancer that includes a history and physical examination and screening for cardiovascular disease risk factors, such as hypertension, diabetes, dyslipidemia, obesity, and smoking is recommended as per ASCO.
  • Before starting cardiotoxic therapy,an echocardiogram should be done.
  • An echocardiogram is recommended for diagnostic workup during therapy in patients showing signs and symptoms of cardiac dysfunction.
  • A cardiac MRI (preferred) or multigated acquisition (MUGA) scan can be done if the echo is not feasible.
  • Serum cardiac biomarkers in addition to referral to a cardiologist is required.
  • Before therapy, the management of modifiable risk factors (smoking, hypertension, diabetes, dyslipidemia, and obesity) should be done.
  • Patients receiving high dose anthracyclines might be given cardioprotectants (eg, dexrazoxane).

• Extravasation: [US Boxed Warning]:

  • Epirubicin should only be given via IV route.
  • It has vesicant properties.
  • Severe local tissue damage and necrosis can be seen with extravasation.
  • Venous sclerosis can occur due to injection into a small vein or repeated administration in the same vein.
  • proper needle or catheter placement is necessary before and during infusion to avoid extravasation.
  • The infusion should be immediately stopped in case of perivenous infiltration and restarted in another vein.

• Gastrointestinal toxicity:

  • Antiemetics are needed to prevent nausea and vomiting due to moderate to the high emetic potential of epirubicin.

• Secondary malignancy: [US Boxed Warning]:

  • The risk of secondary acute myeloid leukemia (AML) is significantly increased with anthracycline therapy.
  • Other risk factors include combination with other antineoplastic agents, patients receiving multiple courses of previous chemotherapy, or escalated anthracycline doses.
  • In breast cancer patients, the risk for treatment-related AML or myelodysplastic syndrome (MDS) was estimated at 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years after treatment.
  • The latency period for secondary leukemias may be short (1 to 3 years).

• Thromboembolic events:

  • Epirubicin is known to cause thrombophlebitis and thromboembolic phenomena (including pulmonary embolism).

• Tumor lysis syndrome:

  • Tumor lysis syndrome can rarely occur with epirubicin therapy.
  • Monitoring of serum uric acid, potassium, calcium, phosphate, and serum creatinine after initial administration is necessary for patients at risk.
  • Tumour lysis syndrome can be prevented with adequate hydration and anti-hyperuricemic prophylaxis.

• Hepatic impairment: [US Boxed Warning]:

  • In patients with mild-to-moderate hepatic impairment, dose adjustment is necessary, while its use should be avoided in severe hepatic impairment.
  • Hepatic function tests should be checked before and during treatment.
  • Epirubicin is predominantly eliminated via the liver, increased exposure and toxicity can occur with impaired liver function.

• Renal impairment:

  • In patients with serum creatinine >5 mg/dL, dose adjustment is required.
  • Renal function should be monitored before and during treatment.
  • Has not been studied in patients on dialysis.

Epirubicin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Baseline and repeated measurements of CBC with differential
• Liver function tests
• Renal function tests
• Serum electrolytes
• ECG, and LVEF.
• The method used for the assessment of LVEF (echocardiogram or MUGA) should be consistent during routine monitoring.
• Injection site monitoring during the infusion for possible extravasation or local reactions.

• Cardiovascular monitoring:

  • Before therapy, comprehensive assessment including a history and physical examination and screening for cardiovascular disease risk factors, such as hypertension, diabetes, dyslipidemia, obesity, and smoking, echocardiogram.
  • In patients who develop signs/symptoms of cardiac dysfunction during therapy, an echocardiogram is recommended for diagnostic workup.
  • Cardiac biomarkers, cardiac MRI or multigated acquisition (MUGA) scan should be done if echo is not feasible.

How to administer Epirubicin (Ellence)?

Antiemetics can be used to prevent nausea and vomiting from the moderate to high emetic potency of epirubicin.

Administration intravenous:

• Allow to infuse for 15 to 20 minutes, or slowly push intravenously with a free-flowing IV solution (normally saline or glucose water).
• Infusion time may be reduced if lower doses are given due to dose reduction.
• Do not let the mixture infuse for more than 3 minutes.
• It shouldn't be infused into veins that cross over joints, or in extremities where there is impaired venous and lymphatic drainage.
• To avoid extravasation, it is important to properly place the needles or catheters before and during infusion.

What to do if the injection is injected into an extra artery?

• In case of extravasation, the infusion should be stopped immediately.
• You should gently aspirate the extravasated solution without flushing it.
• You should remove the needle/cannula and elevate your extremity.
• Initiate antidote [dexrazoxane, dimethyl sulfate]
• For 20 minutes, apply dry cold compression four times per day for one to two days.
• Withhold cooling starting 15 minutes prior to dexrazoxane injection; continue withholding cooling until fifteen minutes after infusion.
• Topical DMSO should never be used in conjunction with dexrazoxane. It can decrease dexrazoxane's efficacy.

Dexrazoxane

• 1,000 mg/m2 (maximum dosage: 2,000 mg) IV (administered in a large vein distant from the site of extravasation) for 1 to 2 hour days 1 and 2. Then 500 mg/m2 IV (maximum dosing: 1,000 mg) for 1 to 2 hour days 3;
• Start within 6 hours after extravasation
• Day 2 and day 3 should be taken at the same time (+-3 hours) as day 1.

Notification:

• Patients with severe or moderately impaired renal function (CrCl 40mL/minute) should reduce their dose of dexrazoxane by 50%.

DMSO:

• You should apply it topically to the area twice as large, every 8 hours, for 7 days. It should be applied within 10 minutes of extravasation and without dressing.

Mechanism of action of Epirubicin (Ellence).

• Epirubicin, an anthracycline anti-inflammatory agent, inhibits DNA and RNA formation by steric obstruction.
• It is active throughout the cell cycle. Intercalation causes DNA cleavage via topoisomerase II.
• It also inhibits DNA helicase, and produces cytotoxic free radicals.

Protein binding:

• Albumin is bound at a rate of 77%

Metabolism:

• It is extensively metabolized via extrahepatic and hepatic routes (including RBCs).

Triphasic is the best way to eliminate half-life

• The average terminal half-life time is 33 hours.

Excretion:

• Feces (34%-35%);
• Urine (20% to 27%)

International Brand Names of Epirubicin:

• Ellence
• Pharmorubicin PFS
• PMS-EpiRUBicin
• 4-Epeedo-50
• Adricin
• Ai Da Sheng
• Anthracin
• Binarin
• Bioepicyna
• Canrub
• Ciazil
• P.Mycin
• Eberubi
• Ecclepia
• Epi-Cell
• Epicin
• Epidoxo
• Epifil
• Epilem
• Epilim
• Epirol
• Epiruba
• Episindan
• Epivid
• Epizin
• Ericina
• Farmorrubicina RTU
• Farmorubicin
• Farmorubicin CSU
• Farmorubicin PFS
• Farmorubicin RD
• Farmorubicina
• Farmorubicina CS
• Farmorubicina R.D.
• Farmorubicine
• Favicin
• Grubin
• Neoquabin
• Panbicin
• Pharmarubicin RD
• Pharmorubicin
• Pharmorubicin CS
• Pharmorubicin PDF
• Pharmorubicin PFS
• Pharmorubicin RD
• Riboepi
• Rubisandin

Epirubicin Brand Names in Pakistan: