Epirubicin is an anthracycline antineoplastic agent used in the treatment of various malignancies. Breast Cancer, Bladder Cancer, Gastric Cancer, Ovarian Cancer, Soft Tissue Sarcoma, Lung Cancer used in both non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in selected protocols.
Epirucedal® Injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.
Patients should not be treated with Epirucedal® Injection if they have any of the following conditions:
-Cardiomyopathy and/or heart failure, recent myocardial infarction or severe arrhythmias
-Previous treatment with maximum cumulative dose of anthracyclines.
-Hypersensitivity to Epirucedal®, other anthracyclines, or anthracenediones.
Administer Epirucedal® only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with Epirucedal®, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia and generalized infections) of prior cytotoxic treatment. Also, precede initial treatment with Epirucedal® by a careful baseline assessment of blood counts,serum levels of total bilirubin, AST, creatinine and cardiac function as measured by left ventricular ejection function (LVEF). Carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to Epirucedal®.
Injection-Related Reactions:
Epirucedal® is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of Epirucedal® during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Administer Epirucedal® slowly into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100-120 mg/m2 should generally have Epirucedal® infused over 15-20 minutes. For patients who require lower Epirucedal® starting doses due to organ dysfunction or who require modification of Epirucedal® doses during therapy, the Epirucedal® infusion time may be proportionally decreased, but should not be less than 3 minutes. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Immediately terminate infusion and restart in another vein if a burning or stinging sensation indicates perivenous infiltration. Perivenous infiltration may occur without causing pain. Facial flushing, as well as local erythematous streaking along the vein may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis. Give prophylactic antibiotic therapy to patients administered the 120 mg/m2 regimen of Epirucedal® as a component of combination chemotherapy.
Hematologic:
Epirucedal® can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anaemia. myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy.
Cardiac:
Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of Epirucedal® consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity are rarely of clinical importance, and are generally not considered an indication for the suspension of Epirucedal® treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of Epirucedal® and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with Epirucedal® or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported.
Given the risk of cardiomyopathy, exceed a cumulative dose of 900 mg/m2 Epirucedal® only with extreme caution. Risk factors [active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs, especially those with long half-lives (e.g., trastuzumab)] may increase the risk of Epirucedal® cardiotoxicity.
Although not formally tested, it is probable that the toxicity of Epirucedal® and other anthracyclines or anthracenediones is additive. Cardiac toxicity with Epirucedal® may occur at lower cumulative doses whether cardiac risk factors are present.
Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of Epirucedal® at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Perform repeated MUGA or ECHO determinations of LVEF, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with Epirucedal® in patients with impaired cardiac function must be carefully evaluated.
Do not administer Epirucedal® in combination with other cardio toxic agents unless the patient’s cardiac function is closely monitored. Patients receiving Epirucedal® after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity.
Secondary Leukemia:
The occurrence of secondary acute myelogenous leukemia, with or without a pre leukemic phase, has been reported in patients treated with anthracyclines. 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 1-3 year latency period. Epirubicin is mutagenic, clastogenic and carcinogenic in animals.
Hepatic:
The major route of elimination of epirubicin is the hepatobiliary system. Evaluate serum total bilirubin and AST levels before and during treatment with Epirucedal®. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients. Patients with severe hepatic impairment have not been evaluated; therefore, do not use Epirucedal® in this patient population.
Renal:
Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL. Patients undergoing dialysis have not been studied.
Tumor-Lysis Syndrome:
As with other cytotoxic agents, Epirucedal® may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor-lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, consider the potential for tumor-lysis syndrome in potentially susceptible patients and consider monitoring serum uric acid, potassium, calcium, phosphate and creatinine immediately after initial chemotherapy administration.
Hydration, urine alkalinization and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.
Immunosuppressant Effects/Increased Susceptibility to Infections:
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. Avoid vaccination with a live vaccine in patients receiving Epirucedal®. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Gastrointestinal:
Epirucedal® is emetogenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of Epirucedal®, particularly when given in conjunction with other emetogenic drugs.
Thrombophlebitis and Thromboembolic Phenomena:
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of Epirucedal®.
Coadministration with Cimetidine:
Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with Epirucedal®.
Pregnancy:
Epirucedal® can cause fetal harm when administered to a pregnant woman. Epirubicin was embryolethal and teratogenic in rats and rabbits. There are no adequate and well-controlled studies of Epirucedal® in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods.
Male Fertility and Reproductive Outcomes:
Males with female sexual partners of childbearing potential should use contraception during and after cessation of Epirucedal® therapy. Epirucedal® may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain.
Laboratory Testing:
Assess blood counts, including absolute neutrophil counts and liver function, before and during each cycle of therapy with Epirucedal®. Perform repeated evaluations of LVEF during therapy.
Inflammation following Irradiation:
As with other anthracyclines, administration of Epirucedal® after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.
When possible, to reduce the risk of developing cardiotoxicity in patients receiving Epirucedal® after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, Epirucedal® based therapy should be delayed until the other agents have cleared from the circulation.
Administer Epirucedal® by intravenous infusion. Give Epirucedal® in repeated 3- to 4-week cycles. The total dose of Epirucedal® may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of Epirucedal® are as follows:
Recommended Dose
The recommended dose of Epirucedal® is 100 to 120 mg/m2. The following regimens are recommended:
Patients administered the 120 mg/m2 regimen of Epirucedal® should receive prophylactic antibiotic therapy.
Dose Modifications
Epirucedal® dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirucedal® Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to
≤ Grade 1.
Bone Marrow Dysfunction:
Consider administering a lower starting dose (75-90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration. For patients receiving a divided dose of Epirucedal® (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000-100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose.
Hepatic Impairment:
Recommendations regarding use of Epirucedal® in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended:
Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose
Bilirubin > 3 mg/dL or AST > 4 times upper limit of normal 1/4 of recommended starting dose
Renal Impairment:
While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL).
Preparation and Administration Precautions
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 (15º-30ºC).
Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing Epirucedal®. Several guidelines on this subject have been published.
Incompatibilities:
Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix Epirucedal® with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation. Epirucedal® can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.
Preparation of Infusion Solution:
Administer Epirucedal® into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100-120 mg/m2 should generally have Epirucedal® infused over 15-20 minutes. For patients who require lower Epirucedal® starting doses due to organ dysfunction or who require modification of Epirucedal® doses during therapy, the Epirucedal® infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein. Use Epirucedal® within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency is not always defined. Percentages reported as part of combination chemotherapy regimens. Adverse reactions significant percentages as part of combination chemotherapy regimens.
>10%:
1% to 10%:
<1%, postmarketing, case reports, and/or frequency not defined:
Acute lymphoid leukemia (ALL), acute myelogenous leukemia (AML), anaphylaxis, arrhythmia, arterial embolism, ascites, atrioventricular block, bradycardia, bundle-branch block, cardiomyopathy, chills, dehydration, dyspnea, ECG abnormalities, erythema, esophagitis, GI bleeding, GI burning sensation, GI erosions/ulcerations, GI pain, hepatomegaly, hyperpigmentation (oral mucosa, nails, skin), hypersensitivity, hyperuricemia, myelodysplastic syndrome, myocarditis, neutropenic typhlitis, phlebitis, photosensitivity, pneumonia, premature menopause, premature ventricular contractions, pulmonary edema, pulmonary embolism, radiation recall, sepsis, shock, sinus tachycardia, stomatitis, ST-T wave changes (nonspecific), tachyarrhythmias, thromboembolism, thrombophlebitis, toxic megacolon, transaminases increased, urine discoloration (red), urticaria, ventricular tachycardia
OVERDOSAGE:
There is no known antidote for overdoses of Epirubicin. A 36-year-old man with non-Hodgkin’s lymphoma received a daily 95 mg/m2 dose of Epirubicin 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 Epirubicin. 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 Epirubicin. 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 like 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.
Cardioactive Compounds:
Do not administer Epirubicin in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. Concomitant use of Epirubicin with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment.
Cimetidine:
Cimetidine increases the exposure to epirubicin. Stop Cimetidine during treatment with Epirubicin.
Other Cytotoxic Drugs:
epirubicin used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects.
Paclitaxel:
The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone.
Docetaxel:
The administration of epirubicin immediately prior to or after docetaxel did not have an effect on the systemic exposure of epirubicin, but increased the systemic exposure of epirubicinol and 7-deoxydoxorubicin aglycone.
Radiation Therapy:
There are few data regarding the coadministration of radiation therapy and epirubicin. In adjuvant trials of epirubicin-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received epirubicin-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.
Concomitant Therapies-Hepatic Function:
Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity.
Drug/Laboratory Test Interactions:
There are no known interactions between epirubicin and laboratory tests.
Pregnancy Category D.
Epirucedal® can cause fetal harm when administered to a pregnant woman. Administration of 0.8 mg/kg/day intravenously of epirubicin to rats (about 0.04 times the maximum recommended single human dose on a body surface area basis) during Days 5 to 15 of gestation was embryotoxic (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight) but was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 9 and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, dead fetuses and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight. This dose was also teratogenic, causing numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems) and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations.
Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not embryotoxic or teratogenic, but a maternally toxic dose of
0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of embryofetal toxicity or teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior or reproductive performance of the offspring.
There are no adequate and well-controlled studies of Epirubicin in pregnant women. Two pregnancies have been reported in women taking epirubicin. A 34-year-old woman, 28 weeks pregnant at her diagnosis of breast cancer, was treated with cyclophosphamide and Epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of pregnancy and delivered a healthy baby at 35 weeks. A second 34-year-old woman with breast cancer metastatic to the liver was randomized to FEC-50 but was removed from study because of pregnancy. She experienced a spontaneous abortion. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Epirubicin was excreted into the milk of rats treated with 0.50 mg/kg/day of epirubicin during peri- and postnatal periods. It is not known whether this drug is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Epirucedal®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of Epirubicin have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. The pharmacokinetics of Epirubicin in pediatric patients have not been evaluated.
Although a lower starting dose of Epirubicin was not used in trials in elderly female patients, particular care should be taken in monitoring toxicity when Epirubicin is administered to female patients ≥ 70 years of age.
Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. Do not treat patients with severe hepatic impairment with Epirubicin. Reduce the starting dose for patients with less severe hepatic impairment.
No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine < 5 mg/dL. Consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL), as a reduction in plasma clearance was reported in these patients. Patients on dialysis have not been studied.