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Epirubicin (Epirubicin Hydrochloride) - Warnings and Precautions

 
 



WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION

  1. Severe local tissue necrosis will occur if there is extravasation during administration. Epirubicin hydrochloride injection must not be given by the intramuscular or subcutaneous route [see Warnings and Precautions (5.9)].
  2. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with epirubicin hydrochloride injection or months to years after termination of therapy. The 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 the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin hydrochloride injection in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with epirubicin hydrochloride injection may occur at lower cumulative doses whether or not cardiac risk factors are present [see Warnings and Precautions (5.3)].
  3. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. The occurrence of refractory 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 anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7110 patients with breast cancer who received adjuvant treatment with epirubicin hydrochloride injection-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years [see Warnings and Precautions (5.4)].
  4. Severe myelosuppression may occur [see Warnings and Precautions (5.2)].
 

WARNINGS AND PRECAUTIONS

Administer epirubicin hydrochloride injection only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with epirubicin hydrochloride injection, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, precede initial treatment with epirubicin hydrochloride injection by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and 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 epirubicin hydrochloride injection.

Injection-Related Reactions

Epirubicin hydrochloride injection 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 epirubicin hydrochloride injection during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Administer epirubicin hydrochloride injection slowly into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100 to 120 mg/m2 should generally have epirubicin hydrochloride injection infused over 15 to 20 minutes. For patients who require lower epirubicin hydrochloride injection starting doses due to organ dysfunction or who require modification of epirubicin hydrochloride injection doses during therapy, the epirubicin hydrochloride injection infusion time may be proportionally decreased, but should not be less than 3 minutes [see Dosage and Administration ( 2.3  )]. 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 epirubicin hydrochloride injection as a component of combination chemotherapy [see Clinical Studies ( 14.1   ) and Dosage and Administration ( 2.1 )].

Hematologic

Epirubicin hydrochloride injection can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anemia [see Adverse Reactions ( 6.1 )], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration ( 2.2   , 2.3  )].

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 epirubicin hydrochloride injection 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 epirubicin hydrochloride injection 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 epirubicin hydrochloride injection and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with epirubicin hydrochloride injection 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 epirubicin hydrochloride injection 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 epirubicin hydrochloride injection cardiotoxicity [see Drug Interaction ( 7.4   ) and Dosage and Administration ( 2 )]. Although not formally tested, it is probable that the toxicity of epirubicin hydrochloride injection and other anthracyclines or anthracenediones is additive. Cardiac toxicity with epirubicin hydrochloride injection may occur at lower cumulative doses whether or not 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 epirubicin hydrochloride injection 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 epirubicin hydrochloride injection in patients with impaired cardiac function must be carefully evaluated.

Do not administer epirubicin hydrochloride injection in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving epirubicin hydrochloride injection 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. Avoid epirubicin hydrochloride injection-based therapy for up to 24 weeks after stopping trastuzumab when possible. If epirubicin hydrochloride injection is used before this time, monitor cardiac function carefully [see Dosage and Administration ( 2  )].

Secondary Leukemia

The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic 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 to 3 year latency period.

Epirubicin hydrochloride injection is mutagenic, clastogenic, and carcinogenic in animals [see Nonclinical Toxicology ( 13.1  )].

Hepatic

The major route of elimination of epirubicin is the hepatobiliary system [see Clinical Pharmacology (12.3)]. Evaluate serum total bilirubin and AST levels before and during treatment with epirubicin hydrochloride injection. 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 [see Dosage and Administration (2.2)]. Patients with severe hepatic impairment have not been evaluated; therefore, do not use epirubicin hydrochloride injection in this patient population.

Renal

Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dL [see Dosage and Administration (2.2)]. Patients undergoing dialysis have not been studied.

Tumor-Lysis Syndrome

As with other cytotoxic agents, epirubicin hydrochloride injection 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 epirubicin hydrochloride injection. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Gastrointestinal

Epirubicin hydrochloride injection is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of epirubicin hydrochloride injection, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6.2)].

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 epirubicin hydrochloride injection.

Coadministration With Cimetidine

Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with epirubicin hydrochloride injection [see Clinical Pharmacology ( 12.3  )].

Pregnancy

Epirubicin hydrochloride injection 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 epirubicin hydrochloride injection 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 [see Use in Specific Populations ( 8.1  )].

Male Fertility and Reproductive Outcomes

Males with female sexual partners of childbearing potential should use contraception during and after cessation of epirubicin hydrochloride injection therapy. Epirubicin hydrochloride injection 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 [see Nonclinical Toxicology ( 13.1  )].

Laboratory Testing

Assess blood counts, including absolute neutrophil counts, and liver function before and during each cycle of therapy with epirubicin hydrochloride injection. Perform repeated evaluations of LVEF during therapy [see Warnings and Precautions ( 5.5   and 5.6  )].

Inflammation following Irradiation

As with other anthracyclines, administration of epirubicin hydrochloride injection after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects

Pregnancy category D

See "Warnings and Precautions" section.

Epirubicin hydrochloride injection 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, and 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 hydrochloride injection 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 [see Warnings and Precautions (5.12)].

Nursing Mothers

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 epirubicin hydrochloride injection, 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.

Pediatric Use

Safety and effectiveness of epirubicin hydrochloride injection 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.

Geriatric Use

Although a lower starting dose of epirubicin hydrochloride injection was not used in trials in elderly female patients, particular care should be taken in monitoring toxicity when epirubicin hydrochloride injection is administered to female patients ≥ 70 years of age [see Clinical Pharmacology (12.3)].

Hepatic Impairment

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 hydrochloride injection. Reduce the starting dose for patients with less severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Renal 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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Patients on dialysis have not been studied.

Page last updated: 2013-04-11

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