Epirubicin Hydrochloride (Page 4 of 8)

6.2 Overview of Acute and Delayed Toxicities


Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with epirubicin hydrochloride injection 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, use appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy with epirubicin hydrochloride injection [see Warnings and Precautions (5.2)].


A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with epirubicin hydrochloride injection. Clinical manifestations of mucositis may include a pain or burning sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations; most patients recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; consider prophylactic use of antiemetics before therapy [see Warnings and Precautions (5.10)].

Cutaneous and Hypersensitivity Reactions

Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3 months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and anaphylaxis have been reported in patients treated with epirubicin hydrochloride injection; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.


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 injection (Figure 1). The estimated risk of epirubicin hydrochloride injection-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 hydrochloride injection cumulative dose of 900 mg/m2 [see Warnings and Precautions (5.4)].

Figure 1. Risk of CHF in 9144 Patients Treated with Epirubicin Hydrochloride Injection

(click image for full-size original)

In another retrospective survey of 469 epirubicin hydrochloride injection-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 [see Warnings and Precautions (5.3)].

Other serious drug-related cardiovascular adverse events that occurred during clinical trials with epirubicin hydrochloride injection, administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism.

Secondary Leukemia

An analysis of 7110 patients who received adjuvant treatment with epirubicin hydrochloride injection 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 hydrochloride injection cumulative doses as shown in Figure 2.

Figure 2. Risk of AML/MDS in 7110 Patients Treated with Epirubicin Hydrochloride Injection

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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 hydrochloride injection (720 mg/m2) or cyclophosphamide (6,300 mg/m2), as shown in Table 3.

Table 3. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of Epirubicin Hydrochloride Injection and Cyclophosphamide
Years from Cumulative Probability of Developing AML/MDS
Treatment % (95% CI)
Start Cyclophosphamide Cumulative Dose Cyclophosphamide Cumulative Dose
≤6,300 mg/m2 >6,300 mg/m2
Epirubicin Hydrochloride Injection Cumulative Epirubicin Hydrochloride Injection Cumulative Epirubicin Hydrochloride Injection Cumulative Epirubicin Hydrochloride Injection Cumulative
Dose Dose Dose Dose
≤720 mg/m2 >720 mg/m2 ≤720 mg/m2 >720 mg/m2
N=4760 N=111 N=890 N=261
3 0.12 (0.01 to 0.22) 0.00 (0.00 to 0.00) 0.12 (0.00 to 0.37) 4.37 (1.69 to 7.05)
5 0.25 (0.08 to 0.42) 2.38 (0.00 to 6.99) 0.31 (0.00 to 0.75) 4.97 (2.06 to 7.87)
8 0.37 (0.13 to 0.61) 2.38 (0.00 to 6.99) 0.31 (0.00 to 0.75) 4.97 (2.06 to 7.87)

Injection-Site Reactions [see Warnings and Precautions (5.9)].

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of epirubicin hydrochloride injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: sepsis, pneumonia

Immune system disorders: anaphylaxis

Metabolism and nutrition disorders: dehydration, hyperuricemia

Vascular disorders: shock, hemorrhage, embolism arterial, thrombophlebitis, phlebitis

Respiratory, thoracic and mediastinal disorders: pulmonary embolism

Gastrointestinal disorders: erosions, ulcerations, pain or burning sensation, bleeding, hyperpigmentation of the oral mucosa

Skin and subcutaneous tissue disorders: erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin(radiation-recall reaction), urticaria

Renal and urinary disorders: red coloration of urine for 1 to 2 days after administration

General disorders and administration site conditions: fever, chills

Injury, poisoning and procedural complications: chemical cystitis (following intravesical administration)

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