Epirubicin Hydrochloride (Page 6 of 7)

Delayed Events

Table 6 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.

Table 6. Long-Term Adverse Events in Patients with Early Breast Cancer
Event % of Patients
FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360)
*
In study MA-5 cardiac function was not monitored after 5 years.
Cardiac events Asymptomatic drops in LVEF CHF 2.1* 1.5 1.40.4 0.8* 0.3
Leukemia AML 0.8 0 0.3

Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving epirubicin. However, an association between anthracyclines such as epirubicin and ALL has not been clearly established.

Overview of Acute and Delayed Toxicities

Hematologic

See WARNINGS.

Gastrointestinal

A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with epirubicin. 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; prophylactic use of antiemetics should be considered before therapy (see PRECAUTIONS).

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; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock.

Cardiovascular

See WARNINGS.

Secondary Leukemia

See WARNINGS.

Injection-Site Reactions

See PRECAUTIONS.

OVERDOSAGE

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 similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care.

If an overdose occurs, supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) should be provided until the recovery of toxicities. Delayed CHF has been observed months after anthracycline administration. Patients must be observed carefully over time for signs of CHF and provided with appropriate supportive therapy.

DOSAGE AND ADMINISTRATION

Epirubicin Injection is administered to patients by intravenous infusion. Epirubicin is given in repeated 3- to 4-week cycles. The total dose of Epirubicin Hydrochloride Injection 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 epirubicin are as follows:

Starting Doses

The recommended starting dose of epirubicin is 100 to 120 mg/m2. The following regimens were used in the trials supporting use of epirubicin as a component of adjuvant therapy in patients with axillary-node positive breast cancer:

CEF-120: Cyclophosphamide epirubicin 5-Fluorouracil Repeated every 28 days for 6 cycles 75 mg/m2 PO D 1–14 60 mg/m2 IV D 1, 8 500 mg/m2 IV D 1, 8
FEC-100: 5-Fluorouracil epirubicin Cyclophosphamide 500 mg/m2 100 mg/m2 500 mg/m2
All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles

Patients administered the 120-mg/m2 regimen of epirubicin also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra® , Bactrim®) or a fluoroquinolone.

Bone Marrow Dysfunction

Consideration should be given to administration of lower starting doses (75–90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration (see WARNINGS and PRECAUTIONS).

Hepatic Dysfunction

Definitive recommendations regarding use of epirubicin in patients with hepatic dysfunction are not available because patients with hepatic abnormalities were excluded from participation in adjuvant trials of FEC-100/CEF-120 therapy. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions were recommended in clinical trials, although few patients experienced hepatic impairment:

  • 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

Information regarding experience in patients with hepatic dysfunction is provided in CLINICAL PHARMACOLOGY, Pharmacokinetics In Special Populations.

Renal Dysfunction

While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, lower doses should be considered in patients with severe renal impairment (serum creatinine > 5 mg/dL).

Dose Modifications

Dosage adjustments after the first treatment cycle should be made based on hematologic and nonhematologic toxicities. Patients experiencing during treatment cycle nadir platelet counts <50,000/mm3 , absolute neutrophil counts (ANC) <250/mm3 , neutropenic fever, or Grades 3/4 nonhematologic toxicity should have the Day 1 dose in subsequent cycles reduced to 75% of the Day 1 dose given in the current cycle. Day 1 chemotherapy in subsequent courses of treatment should be delayed until platelet counts are ≥100,000/mm3 , ANC ≥1500/mm3 , and nonhematologic toxicities have recovered to ≤ Grade 1.

For patients receiving a divided dose of epirubicin (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 Grade 3/4 nonhematologic toxicity has occurred, the Day 8 dose should be omitted.

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