EPIRUBICIN HYDROCHLORIDE- epirubicin hydrochloride injection
Hikma Pharmaceuticals USA Inc.
WARNING: RISK OF TISSUE NECROSIS, CARDIAC TOXICITY, SECONDARY ACUTE MYELOGENOUS LEUKEMIA, AND MYELOSUPPRESSION
- Severe local tissue necrosis will occur if there is extravasation during administration. Epirubicin hydrochloride must not be given by the intramuscular or subcutaneous route [see Warnings and Precautions (5.9) ].
- Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with epirubicin hydrochloride 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 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 may occur at lower cumulative doses whether or not cardiac risk factors are present [see Warnings and Precautions (5.3)] .
- 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-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)].
- Severe myelosuppression may occur [see Warnings and Precautions (5.2)].
Epirubicin Hydrochloride Injection, USP is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer [see Clinical Studies (14.1 )].
When possible, to reduce the risk of developing cardiotoxicity in patients receiving epirubicin hydrochloride injection after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, epirubicin hydrochloride injection-based therapy should be delayed until the other agents have cleared from the circulation [see Warnings and Precautions (5.3)].
Administer epirubicin hydrochloride injection by intravenous infusion. Give epirubicin hydrochloride injection 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 hydrochloride injection are as follows:
The recommended dose of epirubicin hydrochloride injection is 100 to 120 mg/m2. The following regimens are recommended:
Repeated every 28 days for 6 cycles
75 mg/m2 PO D 1 to 14
60 mg/m2 IV D 1, 8
500 mg/m2 IV D 1, 8
All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles.
Patients administered the 120 mg/m2 regimen of epirubicin hydrochloride injection should receive prophylactic antibiotic therapy.
Epirubicin hydrochloride injection dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3 , absolute neutrophil counts (ANC) <250/mm3 , neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce epirubicin hydrochloride injection Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥ 100,000/mm3, ANC ≥ 1500/mm3 , and nonhematologic toxicities have recovered to ≤ Grade 1.
Bone Marrow Dysfunction
Consider administering a lower starting dose (75 to 90 mg/m2) for heavily pretreated patients, patients with preexisting bone marrow depression, or in the presence of neoplastic bone marrow infiltration [see Warnings andPrecautions (5)]. For patients receiving a divided dose of epirubicin hydrochloride injection (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000 to 100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3 , or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose.
Recommendations regarding use of epirubicin hydrochloride injection in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials [see Warnings and Precautions (5.5 ) and Clinical Pharmacology (12.3)].In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended:
• 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
While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ].
Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15 to 25ºC).
Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing epirubicin hydrochloride. Several guidelines on this subject have been published.1-4 [see References (15)].
Take the following protective measures when handling epirubicin hydrochloride injection:
• Train personnel in appropriate techniques for reconstitution and handling.
• Exclude pregnant staff from working with this drug.
• Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling epirubicin hydrochloride injection.
• Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper.
• Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration.
• Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves.
Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix epirubicin hydrochloride injection with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.
Epirubicin hydrochloride injection can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.
Preparation of Infusion Solution
Administer epirubicin hydrochloride injection into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). 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. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein [see Warnings and Precautions (5.9)]. Use epirubicin hydrochloride injection within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
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