ELLENCE- epirubicin hydrochloride_injection, solution
Function and Efficacy
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. Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m 2 2 Table 4. Summary of Mean (+/-SD) Pharmacokinetic Parameters in Patients Advanced solid tumor cancers, primarily of the lung 2 Dose N=6 patients per dose level (mg/m 2 C max Plasma concentration at the end of 6 to 10 minutes infusion (µg/mL) AUC Area under the plasma concentration curve (µg∙h/mL) t 1/2 Half-life of terminal phase (hours) CL Plasma clearance (L/hour) Vss Steady state volume of distribution (L/kg) 60 5. 3 +/- 9 65 +/- 8 21 +/- 2 75 5. 1 +/- 5 83 +/- 14 27 +/- 11 120 9. 7 +/- 4 65 +/- 13 23 +/- 7 150 9. 1 +/- 6 69 +/- 13 21 +/- 7 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. 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: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites. 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. Effect of 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 ELLENCE 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 ELLENCE is administered to female patients > 70 years of age. Effect of 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. Effect of Race The influence of race on the pharmacokinetics of epirubicin has not been evaluated. Effect of 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 ELLENCE doses of 12. 5 to 90 mg/m 2 2 2 [see Dosage and Administration (2. 3) Warnings and Precautions (5. 5) Effect of 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 [see Warnings and Precautions (5. 6) Dosing and Administration (2. 2) Effect of Paclitaxel The administration of paclitaxel (175en dash225 mg/m 2 2 Effect of Docetaxel The administration of docetaxel (70 mg/m 2 2 Effect of 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 2. 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.
Indication
ELLENCE 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) ELLENCE is an anthracycline topoisomerase inhibitor indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer ( 1.
Usage and Dosage
1 2 2. 7 When possible, to reduce the risk of developing cardiotoxicity in patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, delay ELLENCE-based therapy until the other agents have cleared from the circulation [see Warnings and Precautions (5. 1) Antiemetics may reduce nausea and vomiting; consider use of antiemetics before administration of ELLENCE or when clinically indicated, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6. 1) Patients administered the 120 mg/m 2 The recommended dose of ELLENCE is 100 to 120 mg/m 2 [see Dosage and Administration (2. 4) The following regimens are recommended: CEF-120: Cyclophosphamide 75 mg/m 2 ELLENCE 60 mg/m 2 5-Fluorouracil 500 mg/m 2 Repeat every 28 days for 6 cycles FEC-100: 5-Fluorouracil 500 mg/m 2 ELLENCE 100 mg/m 2 Cyclophosphamide 500 mg/m 2 Repeat every 21 days for 6 cycles Administer ELLENCE in repeated 3- to 4-week cycles. The total dose of ELLENCE may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. ELLENCE dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm 3 3 3 3 Cardiac Toxicity Discontinue ELLENCE in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5. 1) Bone Marrow Dysfunction Consider administering a lower starting dose (75en dash90 mg/m 2 [see Warnings and Precautions (5. 4) 3 3 3 3 Hepatic Impairment In patients with elevated serum AST or serum total bilirubin concentrations [see Warnings and Precautions (5. 5) Clinical Pharmacology (12. 3) Renal Impairment Consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL) [see Warnings and Precautions (5. 6) Clinical Pharmacology (12. 3) Preparation 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 (15en dash25°C). Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ELLENCE is a cytotoxic drug. Follow applicable special handling and disposable procedures 1 [see References (15) Incompatibilities Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix ELLENCE with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation. ELLENCE can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe. Administration Administer ELLENCE 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 100en dash120 mg/m 2 For patients who require lower ELLENCE starting doses due to organ dysfunction or who require modification of ELLENCE doses during therapy, the ELLENCE 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 [see Warnings and Precautions (5. 3) Storage Use ELLENCE within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
Label
Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) The most common adverse reactions (>=10%) are leukopenia, neutropenia, anemia, thrombocytopenia, amenorrhea, lethargy, nausea/vomiting, mucositis, diarrhea, infection, conjunctivitis/keratitis, alopecia, local skin toxicity, and rash/itch ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ELLENCE was evaluated in two studies (Studies MA-5 and GFEA-05) evaluating combination regimens in patients with early breast cancer [see Clinical Studies (14. Adverse Reactions in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) Grades 1en dash4 Grades 3/4 Grades 1en dash4 Grades 3/4 Grades 1en dash4 Grades 3/4 FEC & CEF = cyclophosphamide + ELLENCE + 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. Hematologic Leukopenia 80 59 50 1. 5 98 60 Neutropenia 80 67 54 11 96 78 Anemia 72 6 13 0 71 0. 9 Thrombocytopenia 49 5 4. 6 Endocrine Amenorrhea 72 0 69 0 68 0 Hot flashes 39 4 5 0 69 6 Body as a Whole Lethargy 46 1. 3 Fever 5 0 1. 5 0 Gastrointestinal Nausea/vomiting 92 25 83 22 85 6 Mucositis 59 9 9 0 53 1. 9 Diarrhea 25 0. 8 Anorexia 2. 3 Infection Infection 22 1. 6 15 0 26 0. 6 Febrile neutropenia NA 6 0 0 NA 1. 1 Ocular Conjunctivitis/keratitis 15 0 1. 1 0 38 0 Skin Alopecia 96 57 70 19 84 7 Local toxicity 20 0. 4 8 0 Rash/itch 9 0. 4 0 14 0 Skin changes 4. 7 0 7 0 Delayed Events Table 2 describes the incidence of delayed adverse reactions in patients participating in the MA-5 and GFEA-05 trials. Long-Term Adverse Reactions in Patients with Early Breast Cancer Event % of Patients FEC-100/CEF-120 (N=620) FEC-50 (N=280) CMF (N=360) Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving ELLENCE. However, an association between anthracyclines such as ELLENCE and ALL has not been clearly established. Cardiac events Asymptomatic drops in LVEF 2. 1 In study MA-5, cardiac function was not monitored after 5 years. 3 Leukemia AML 0. 3 Hematologic Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with ELLENCE 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, ELLENCE 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. , 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 ELLENCE [see Warnings and Precautions (5. 4) Gastrointestinal A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with ELLENCE. 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 Dosage and Administration (2. 1) 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 ELLENCE; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock. Cardiovascular Serious drug-related cardiovascular adverse events that occurred during clinical trials with ELLENCE, 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 ELLENCE 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. 40) at 3 years, 0. 46% (approximate 95% CI, 0. 65) at 5 years, and 0. 55% (approximate 95% CI, 0. 78) at 8 years. The risk of developing AML/MDS increased with increasing ELLENCE cumulative doses as shown in Figure 2. Risk of AML/MDS in 7110 Patients Treated with ELLENCE 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 ELLENCE (720 mg/m 2 2 Table 3. Cumulative Probability of AML/MDS in Relation to Cumulative Doses of ELLENCE and Cyclophosphamide Years from Treatment Start Cumulative Probability of Developing AML/MDS Cyclophosphamide Cumulative Dose 2 Cyclophosphamide Cumulative Dose 2 ELLENCE Cumulative Dose 2 ELLENCE Cumulative Dose 2 ELLENCE Cumulative Dose 2 ELLENCE Cumulative Dose 2 3 0. 87) Figure 2 The following adverse reactions have been identified during post-approval use of ELLENCE. 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).
Precautions
ELLENCE is contraindicated in patients with: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Adverse Reactions (6. 1) 4 4 4 4 4.
Special Population Medication
3 Risk Summary Based on findings from animal studies and its mechanism of action, ELLENCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12. 1) st nd rd (see Clinical Considerations see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions There have been rare reports of fetal and/or neonatal transient ventricular hypokinesia, transient elevation of cardiac enzymes, and a case of fetal demise from suspected anthracycline-induced cardiotoxicity following in utero exposure to epirubicin in 2 nd rd [see Warnings and Precautions (5. 1) Data Animal Data Intravenous administration of 0. 8 mg/kg/day epirubicin (about 0. 04 times the maximum recommended single human dose on a body surface area basis) to rats during Days 5 to 15 of gestation resulted in embryofetal lethality (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight). Intravenous administration of 2 mg/kg/day epirubicin (about 0. 1 times the maximum recommended single human dose on a body surface area basis) to rats on Days 9 and 10 of gestation resulted in embryo-fetal lethality (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight and numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0. 2 mg/kg/day (about 0. 02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not teratogenic, but a maternally toxic dose of 0. 32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0. 1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of teratogenicity were observed. When doses up to 0. 5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0. 025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring. Risk Summary There are no data on the presence of epirubicin in human milk, the effects on the breastfed child, or the effects on milk production. Epirubicin is present in rat milk (see Data Data Animal Data In a peri- and post-natal study, epirubicin was present in milk of rats treated with 0. 5 mg/kg/day epirubicin (about 0. 025 times the maximum recommended human dose on a body surface area basis). Pregnancy Testing Verify the pregnancy status in female patients of reproductive potential prior to initiating ELLENCE. Contraception Females ELLENCE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8. 1) Males Based on its mechanism of action and genotoxicity studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ELLENCE. Advise male patients with pregnant partners use condoms during treatment and for at least 7 days after the last dose of ELLENCE [see Clinical Pharmacology (12. 1) Nonclinical Toxicology (13. 1) Infertility Females Based on clinical findings and animal studies, ELLENCE may impair female fertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment [see Nonclinical Toxicology (13. 1) Males Based on clinical findings and animal studies, ELLENCE may cause oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Nonclinical Toxicology (13. 1) Safety and effectiveness of ELLENCE have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity or late cardiovascular dysfunction. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated. Clinical experience in patients who were 65 years of age and older who received ELLENCE chemotherapy regimens for primary breast cancer showed no overall differences in safety and effectiveness compared with younger patients. In elderly female patients, closely monitor for increased toxicity due to the risk of decreased clearance of epirubicin [see Clinical Pharmacology (12. 3) Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. Do not treat patients with severe hepatic impairment with ELLENCE [see Contraindications (4) [see Dosage and Administration (2. 2) Clinical Pharmacology (12. 3) No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine 5 mg/dL), as a reduction in plasma clearance was reported in these patients [see Dosage and Administration (2. 3) Clinical Pharmacology (12.
Drug Interactions
2 Closely monitor cardiac function when ELLENCE is used in combination with other cardiotoxic agents. Patients receiving ELLENCE after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may be at an increased risk of developing cardiotoxicity [see Dosage and Administration (2) Warnings and Precautions (5. 1) Concomitant use of ELLENCE with other cardioactive compounds that could cause heart failure (e. , calcium channel blockers), requires close monitoring of cardiac function throughout treatment. Cimetidine increases the exposure to epirubicin [see Clinical Pharmacology (12. 3) ELLENCE used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects. Paclitaxel: The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone [see Clinical Pharmacology (12. 3) Docetaxel: The administration of epirubicin immediately prior to or after docetaxel did not have an effect on the systemic exposure of epirubicin, but increased the systemic exposure of epirubicinol and 7-deoxydoxorubicin aglycone [see Clinical Pharmacology (12. 3) There are few data regarding the coadministration of radiation therapy and ELLENCE. In adjuvant trials of ELLENCE-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received ELLENCE-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of ELLENCE with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.
Other Information
OVERDOSAGE
There is no known antidote for overdoses of ELLENCE. A 36-year-old man with non-Hodgkin''s lymphoma received a daily 95 mg/m 2 2 2 If an overdose occurs, provide supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) until the recovery of toxicities. Delayed CHF has been observed months after anthracycline administration. Observe patients carefully over time for signs of CHF and provided with appropriate supportive therapy.
NONCLINICAL TOXICOLOGY
Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats (about 0.2 times the maximum recommended human dose on a body surface area basis) approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats (about 0.025 times the maximum recommended human dose on a body surface area basis) every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day (about 0.015 times the maximum recommended human dose on a body surface area basis) to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period. Epirubicin was mutagenic in vitro in vitro in vivo In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through Day 7 of gestation. When 0.3 mg/kg/day (about 0.015 times the maximum recommended human single dose on a body surface area basis) was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day (about 0.0015 times the maximum recommended human single dose on a body surface area basis). Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively (both approximately 0.5 times the maximum recommended human dose on a body surface area basis). A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats.
CLINICAL STUDIES
Two randomized, open-label, multicenter studies evaluated the use of ELLENCE 100 to 120 mg/m 2 2 2 Table 5. Treatment Regimens Used in Phase 3 Studies of Patients with Early Breast Cancer Treatment Groups Agent Regimen MA-5 In women who underwent lumpectomy, breast irradiation was to be administered after completion of study chemotherapy. CEF-120 Patients also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluoroquinolone for the duration of their chemotherapy. CMF Cyclophosphamide 75 mg/m 2 2 2 2 2 2 GFEA-05 All women were to receive breast irradiation after the completion of chemotherapy. FEC-100 FEC-50 Fluorouracil 500 mg/m 2 2 2 2 2 2 In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had >= 4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had >= 4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study. Relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results were initially analyzed after up to 5 years of follow-up and these results are presented in the text below and in Table 6. Results after up to 10 years of follow-up are presented in Table 6. In Study MA-5, ELLENCE-containing combination therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus 53%, stratified logrank for the overall RFS p=0. The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the ELLENCE-containing CEF-120 regimen than for the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p=0. 043; non-stratified logrank p=0. The estimated reduction in the risk of death was 29% at 5 years. In Study GFEA-05, patients treated with the higher-dose ELLENCE regimen (FEC-100) had a significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p=0. 007) and OS (estimated 76% versus 65%, logrank for the overall survival p=0. 007) than patients given the lower dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated reduction in the risk of death was 31% at 5 years. Results of follow-up up to 10 years (median follow-up = 8. 8 years and 8. 3 years, respectively, for Study MA-5 and Study GFEA-05) are presented in Table 6. Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1en dash3 node positive and in those with >=4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were observed in both pre-and postmenopausal women treated with FEC-100 compared to FEC-50. Efficacy Results from Phase 3 Studies of Patients with Early Breast Cancer Based on Kaplan-Meier estimates MA-5 Study GFEA-05 Study CEF-120 CMF FEC-100 FEC-50 RFS at 5 yrs (%) 62 53 65 52 Hazard ratio Hazard ratio: CMF:CEF-120 in MA-5, FEC-50:FEC-100 in GFEA-05 0. 68 2-sided 95% CI (0. 89) Logrank Test stratified Patients in MA-5 were stratified by nodal status (1en dash3, 4en dash10, and >10 positive nodes), type of initial surgery (lumpectomy versus mastectomy), and by hormone receptor status (ER or PR positive (>=10 fmol), both negative (10 positive nodes). 013) (p = 0. 007) OS at 5 yrs (%) 77 70 76 65 Hazard ratio 0. 69 2-sided 95% CI (0. 92) Logrank Test stratified (p = 0. 043) (p = 0. 007) (unstratified p = 0. 13) RFS at 10 yrs (%) 51 44 49 43 Hazard ratio 0. 78 2-sided 95% CI (0. 99) Logrank Test stratified (p = 0. 017) (p = 0. 040) (unstratified p = 0. 023) (unstratified p = 0. 09) OS at 10 yrs (%) 61 57 56 50 Hazard ratio 0. 75 2-sided 95% CI (0. 96) Logrank Test stratified (p = 0. 100) (p = 0. 18) (unstratified p = 0. 039) The Kaplan-Meier curves for RFS and OS from Study MA-5 are shown in Figures 3 and 4 and those for Study GFEA-05 are shown in Figures 5 and 6. Relapse-Free Survival in Study MA-5 Figure 4. Overall Survival in Study MA-5 Figure 5. Relapse-Free Survival in Study GFEA-05 Figure 6. Overall Survival in Study GFEA-05 Figure 3 Figure 4 Figure 5 Figure 6.
REFERENCES
1. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html