Pharmacokinetics

Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m2 and plasma clearance is not affected by the duration of infusion or administration schedule. Pharmacokinetic parameters for epirubicin following 6 to 10 minute, single-dose intravenous infusions of epirubicin hydrochloride at doses of 60 to 150 mg/m2 in patients with solid tumors are shown in Table 1. The plasma concentration declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.

Distribution. Following intravenous administration, epirubicin is rapidly and widely distributed into the tissues. Binding of epirubicin to plasma proteins, predominantly albumin, is about 77% and is not affected by drug concentration. Epirubicin also appears to concentrate in red blood cells; whole blood concentrations are approximately twice those of plasma.

Metabolism. Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells. Four main metabolic routes have been identified: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites.

Excretion. Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion. Mass-balance data from 1 patient found about 60% of the total radioactive dose in feces (34%) and urine (27%). These data are consistent with those from 3 patients with extrahepatic obstruction and percutaneous drainage, in whom approximately 35% and 20% of the administered dose were recovered as epirubicin or its major metabolites in bile and urine, respectively, in the 4 days after treatment.

Pharmacokinetics in Special Populations

Hematologic Toxicity. A dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with epirubicin and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21 after drug administration. As with other cytotoxic agents, epirubicin hydrochloride injection at the recommended dose in combination with cyclophosphamide and fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive complications occur, appropriate supportive measures (e.g., intravenous antibiotics, colony stimulating factors, transfusions) may be required. Myelosuppression requires careful monitoring. Total and differential WBC, red blood cell (RBC), and platelet counts should be assessed before and during each cycle of therapy with epirubicin hydrochloride injection.

Cardiac Function. 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 consists mainly of sinus tachycardia and/or 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 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.

In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of epirubicin hydrochloride (Figure 5). The estimated risk of epirubicin hydrochloride-treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an epirubicin cumulative dose of 900 mg/m2.

Figure 5. Risk of CHF in 9144 Patients treated with Epirubicin

In another retrospective survey of 469 epirubicin-treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients.

Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m2 epirubicin hydrochloride injection should be exceeded 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) may increase the risk of cardiac toxicity. Although not formally tested, it is probable that the toxicity of epirubicin 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. Electrocardiogram (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 eva luation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac eva luation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, 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 eva luated.

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. An analysis of 7110 patients who received adjuvant treatment with epirubicin in controlled clinical trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14 to 0.40) at 3 years, 0.46% (approximate 95% CI, 0.28 to 0.65) at 5 years and 0.55% (approximate 95% CI, 0.33 to 0.78) at 8 years. The risk of developing AML/MDS increased with increasing epirubicin cumulative doses as shown in Figure 6.

Figure 6. Risk of AML/MDS in 7110 Patients Treated with Epirubcin

The cumulative probability of developing AML/MDS was found to be particularly increased in patients who received more than the maximum recommended cumulative dose of epirubicin (720 mg/m²) or cyclophosphamide (6,300 mg/m²), as shown in Table 4.

Epirubicin hydrochloride is mutagenic, clastogenic, and carcinogenic in animals (see next section, Carcinogenesis, Mutagenesis and Impairment of Fertility).

Carcinogenesis, Mutagenesis & Impairment of Fertility. Treatment-related acute myelogenous leukemia has been reported in women treated with epirubicin-based adjuvant chemotherapy regimens (see above section, WARNINGS, Secondary Leukemia