Posology : מינונים

4.2 Posology and method of 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 may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. To minimize the risk of thrombosis or perivenous extravasation. The usual infusion times range between 3 and 20 minutes depending upon dosage and volume of the infusion solution. The needle should be properly placed in the vein. This reduces the risk of thrombosis and extravasation that could lead to severe cellulitis and necrosis. In case of extravasation, administration should be stopped immediately. Injection in small veins and repeated injection in the same vein can lead to venous sclerosis.

The recommended dosages of epirubicin are as follows:
Starting Doses
The recommended starting dose of epirubicin is 60 to 120 mg/m². The following regimens were used in trials supporting use of epirubicin as a component of adjuvant therapy in patients with axillary-node positive breast cancer
CEF-120* Cyclophosphamide                      75 mg/m² PO D 1-14
Epirubicin                        60 mg/m² IV D 1, 8
5-Fluorouracil                    500 mg/m² IV D 1, 8
Repeated every 28 days for 6 cycles

FEC-100**: 5-Fluorouracil                      500 mg/m²
Epirubicin                          100 mg/m²
Cyclophosphamide                    500 mg/m²

* Study evaluating epirubicin 120 mg/m² per course in combination with cyclophosphamide and fluorouracil.
** Study evaluating epirubicin 100 mg/m² per course in combination with fluorouracil and cyclophosphamide.
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, 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.

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.

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).

High starting dose regimens
High starting doses of epirubicin may be used in the treatment of breast and lung cancer. As a single agent, the recommended high starting dose of epirubicin per cycle in adults (up to 135 mg/m²) should be administered on day 1 or in divided doses on days 1, 2, 3, every 3 to 4 weeks. In combination therapy, the recommended high starting dose (up to 120 mg/m²) should be administered on day 1, every 3 to 4 weeks.

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.

Intravesical Administration
Epirubicin should be instilled using a catheter and retained intravesically for 1 hour. During instillation, the patient should be rotated to ensure that the vesical mucosa of the pelvis recelvos the most extensive contact with the solution. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. The patient should be instructed to void at the end of the instillation.
Intravesical administration is not suitable for the treatment of invasive tumors which have penetrated the muscular layer of the bladder wall.

Superficial bladder tumors
Single instillation: A single instillation of 80-100 mg immediately following transurethral resection (TUR) is recommended.

4-8 weeks course followed by monthly instillation: Eight weekly instillations of 50 mg (in 25-50 ml of saline solution) starting 2-7 days following TUR are recommended. In the case of local toxicity (chemical cystitis), the dose should be reduced to 30 mg. Patients may receive 4 weekly administrations of 50 mg followed by 11 monthly instillations at the same dosage.