Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3235
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epirubicin hydrochloride (Injection, Solution)
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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. The recommended dosages of epirubicin are as follows:<br/>Starting Doses: The recommended starting dose of epirubicin is 100 to 120 mg/m. 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: Patients administered the 120-mg/mregimen of epirubicin also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra, Bactrim) or a fluoroquinolone.<br/>Bone Marrow Dysfunction: Consideration should be given to administration of lower starting doses (75���90 mg/m) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration .<br/>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: Information regarding experience in patients with hepatic dysfunction is provided in CLINICAL PHARMACOLOGY, Pharmacokinetics In Special Populations.<br/>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).<br/>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/mm, absolute neutrophil counts (ANC)<250/mm, 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/mm, ANC���1500/mm, 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/mmand ANC is 1000 to 1499/mm. If Day 8 platelet counts are<75,000/mm, ANC<1000/mm, or Grade 3/4 nonhematologic toxicity has occurred, the Day 8 dose should be omitted.<br/>Preparation&Administration Precautions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures normally used for proper handling and disposal of anticancer drugs should be considered for use with epirubicin. Several guidelines on this subject have been published.<br/>Protective measures: The following protective measures should be taken when handling epirubicin:<br/>Incompatibilities: Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. epirubicin should not be mixed with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation. Epirubicin can be used in combination with other antitumor agents, but it is not recommended that it be mixed with other drugs in the same syringe.<br/>Preparation of Infusion Solution: Epirubicin is provided as a preservative-free, ready-to-use solution. Epirubicin should be administered 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���120 mg/mshould generally have epirubicin infused over 15���20 minutes. For patients who require lower epirubicin starting doses due to organ dysfunction or who require modification of epirubicin doses during therapy, the epirubicin 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 . Epirubicin should be used within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
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Epirubicin is an anthracycline cytotoxic agent, intended for intravenous administration. Epirubicin is supplied as a sterile, clear, red solution and is available in polypropylene vials containing 50 and 200 mg of epirubicin hydrochloride as a preservative-free, ready-to-use solution. Each milliliter of solution contains 2 mg of epirubicin hydrochloride. Inactive ingredients include sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid, NF. Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin. The chemical name is (8S- cis)-10-[(3-amino-2,3,6-trideoxy-��-L- arabino-hexopyranosyl)oxy]-7,8,9,10- tetrahydro6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula CHNOHCl and a molecular weight of 579.95. The structural formula is as follows:
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Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of epirubicin's cytotoxic and/or antiproliferative properties have not been completely elucidated. Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis. Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms. Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors.<br/>Pharmacokinetics: Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/mand 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 at doses of 60 to 150 mg/min 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.<br/>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.<br/>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:<br/>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.<br/>Pharmacokinetics in Special Populations:<br/>Age: A population analysis of plasma data from 36 cancer patients (13 males and 23 females, 20 to 73 years) showed that age affects plasma clearance of epirubicin in female patients. The predicted plasma clearance for a female patient of 70 years of age was about 35% lower than that for a female patient of 25 years of age. An insufficient number of males>50 years of age were included in the study to draw conclusions about age-related alterations in clearance in males. Although a lower epirubicin starting dose does not appear necessary in elderly female patients, and was not used in clinical trials, particular care should be taken in monitoring toxicity when epirubicin is administered to female patients>70 years of age.<br/>Gender: In patients���50 years of age, mean clearance values in adult male and female patients were similar. The clearance of epirubicin is decreased in elderly women (see Pharmacokinetics in Special Populations - Age).<br/>Pediatric: The pharmacokinetics of epirubicin in pediatric patients have not been evaluated.<br/>Race: The influence of race on the pharmacokinetics of epirubicin has not been evaluated.<br/>Hepatic Impairment: Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. In a study of the effect of hepatic dysfunction, patients with solid tumors were classified into 3 groups. Patients in Group 1 (n=22) had serum AST (SGOT) levels above the upper limit of normal (median: 93 IU/L) and normal serum bilirubin levels (median: 0.5 mg/dL) and were given epirubicin doses of 12.5 to 90 mg/m. Patients in Group 2 had alterations in both serum AST (median: 175 IU/L) and bilirubin levels (median: 2.7 mg/dL) and were treated with an epirubicin dose of 25 mg/m(n=8). Their pharmacokinetics were compared to those of patients with normal serum AST and bilirubin values, who received epirubicin doses of 12.5 to 120 mg/m. The median plasma clearance of epirubicin was decreased compared to patients with normal hepatic function by about 30% in patients in Group 1 and by 50% in patients in Group 2. Patients with more severe hepatic impairment have not been evaluated.<br/>Renal Impairment: No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine<5 mg/dL. A 50% reduction in plasma clearance was reported in four patients with serum creatinine���5 mg/dL . Patients on dialysis have not been studied.<br/>Drug-Drug Interactions:<br/>Taxanes: The administration of epirubicin (90 mg/m) immediately prior to paclitaxel (175 mg/m) or docetaxel (70 to 80 mg/m) did not affect the pharmacokinetics of epirubicin but did result in increases in systemic exposure to epirubicin's inactive metabolites epirubicinol and 7-deoxy doxorubicin aglycone. When paclitaxel (175 mg/m) was administered prior to epirubicin (90 mg/m) an increase in the AUCs of epirubicin, epirubicinol and 7-deoxy doxorubicin aglycone was seen .<br/>Cimetidine: Coadministration of cimetidine (400 mg twice daily for 7 days starting 5 days before chemotherapy) increased the mean AUC of epirubicin (100 mg/m) by 50% and decreased its plasma clearance by 30% .<br/>Drugs metabolized by cytochrome P-450 enzymes: No systematic in vitro or in vivo evaluation has been performed to examine the potential for inhibition or induction by epirubicin of oxidative cytochrome P-450 isoenzymes.
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Patients should not be treated with epirubicin injection if they have any of the following conditions: baseline neutrophil count<1500 cells/mm; severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias; previous treatment with anthracyclines up to the maximum cumulative dose; hypersensitivity to epirubicin, other anthracyclines, or anthracenediones; or severe hepatic dysfunction .
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Epirubicin injection is available in polypropylene single-use vials CYTOSAFE���containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths: 50 mg/25 mL single-use vial NDC 59762-5091-1200 mg/100 mL single-use vial NDC 59762-5093-1 Store refrigerated between 2��C and 8��C (36��F and 46��F). Do not freeze. Protect from light. Discard unused portion. 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���25��C).
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WARNING:
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A 36-year-old man with non-Hodgkin's lymphoma received a daily 95 mg/mdose 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/mdose 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/m. 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.
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epirubicin hydrochloride
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epirubicin hydrochloride (Injection, Solution)
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On-Study Events: Integrated safety data are available from two studies evaluating epirubicin-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose epirubicin regimen (FEC-100/CEF-120), 280 patients received the lower dose epirubicin regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 5. FEC&CEF = cyclophosphamide + epirubicin + fluorouracil; CMF = cyclophosphamide + methotrexate + fluorouracil NA = not available Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF.<br/>Delayed Events: Table 6 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials. 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.<br/>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 . 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.
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Epirubicin Injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.
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epirubicin hydrochloride
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