Epirubicin Hydrochloride Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Epirubicin Hydrochloride Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Cancer, Cancer, Endometrial (Endometrial Cancer), Cancer, lung (Lung Cancer), Cancer, Lung, Small Cell (Small Cell Lung Cancer), Cancer, Non-Hodgkin's Lymphoma (Non-Hodgkin's Lymphoma), Cancer, Ovarian (Ovarian Cancer), Cancer, Ovaries (Ovarian Cancer), Cancer, Pancreatic (Pancreatic Cancer), Cancer, Stomach (Stomach Cancer), Cancer, Uterine (Endometrial Cancer)
Class: Antineoplastic detoxifying agents, Antineoplastics
Form: Liquid solution, Intravenous (IV)
Ingredients: epirubicin hydrochloride, sodium chloride, USP, water for injection, USP

Pharmaceutical Information

Drug Substance

Proper Name epirubicin hydrochloride (USAN)
Chemical Name (8S-cis)-10-[(3-amino-2,3,6-trideoxy-α-L-arabino-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12- naphthacenedione hydrochloride
Molecular Formula C27 H29 NO11 ●HCl
Molecular Weight 579.98
Structural Formula
Physiochemical properties Epirubicin hydrochloride is a semisynthetic anthracycline cytotoxic antibiotic in which the sugar moiety differs from the natural daunosamine (amino sugar present in doxorubicin) in that steric configuration of the hydroxyl bearing C-4 is inverted, thus forming the L-arabino configuration instead of the L-lyxo. The anthracycline ring is lipophilic. The saturated end of the ring system contains hydroxyl groups adjacent to the amino sugar producing a hydrophilic centre. The molecule is amphoteric, containing acidic function in the phenolic ring groups and a basic function in the sugar amino group.
It is a dark red crystalline powder, soluble in water, methanol and ethyl alcohol (50 °C). It is practically insoluble in acetone, chloroform and methylene chloride. Epirubicin hydrochloride has a melting point about 207 °C, pKa in water of 7.7, and pH of 4 to 5.5 in a 0.5% w/v solution in water.

Clinical Trials

Early Stage Breast Cancer Studies

Two randomized, open-label, multi center studies evaluated the use of epirubicin hydrochloride 100 mg/m2 to 120 mg/m2 in combination with cyclophosphamide and fluorouracil for the adjuvant treatment in 1281 women with:

  • axillary-node-positive breast cancer,
  • no evidence of distant metastatic disease (Stage II or III), and
  • no T4 tumors.

Study MA.5 evaluated 120 mg/m2 of epirubicin per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). Pre- and peri-menopausal women with one or more positive lymph nodes were randomized to either the CEF-120 regimen or a CMF regimen.

Study GFEA-05 (FASG-05) evaluated the use of 100 mg/m2 of epirubicin per course in combination with fluorouracil and cyclophosphamide (FEC-100). Pre- and post-menopausal women were randomized to either the FEC-100 or lower-dose FEC-50 regimens. Eligible patients were either required to have 4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3.

Table 1 shows the treatment regimens that the patients received.

Table 1. Treatment Regimens Used in Early Breast Cancer Phase 3 Studies
Treatment Groups Agent Regimen
MA.51
N = 716
CEF-120(total, 6 cycles)2

N=356
Cyclophosphamide 75 mg/m2 p.o.
d 1 to 14, q 28 days
Epirubicin Hydrochloride 60 mg/m2 i.v.
d 1 and 8, q 28 days
Fluorouracil 500 mg/m2 i.v.
d 1 and 8, q 28 days
CMF(total, 6 cycles)

N=360
Cyclophosphamide 100 mg/m2 p.o.
day 1 to 14, q 28 days
Methotrexate 40 mg/m2 i.v.
day 1 and 8, q 28 days
Fluorouracil 600 mg/m2 i.v.
d 1 and 8, q 28 days
GFEA-05
(FASG-05)3
N = 565
FEC-100(total, 6 cycles)

N=276
Fluorouracil 500 mg/m2 i.v.
day 1, q 21 days
Epirubicin Hydrochloride 100 mg/m2 i.v.
day 1, q 21 days
Cyclophosphamide 500 mg/m2 i.v.
day 1, q 21 days
FEC-50(total, 6 cycles)

N=289
Fluorouracil 500 mg/m2 i.v.
day 1, q 21 days
Epirubicin Hydrochloride 50 mg/m2 i.v.
day 1, q 21 days
Tamoxifen 30 mg daily x
3 years, postmenopausal women, any
receptor status.
Cyclophosphamide 500 mg/m2 i.v.
day 1, 21 days

1In women who underwent lumpectomy, breast irradiation was to be administered after completion of study chemotherapy.

2Patients also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluroquinolone for theduration of their chemotherapy.

3All women were to receive breast irradiation after the completion of chemotherapy.

The efficacy endpoints of 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 for endpoints are described in terms of the outcomes over 5 and 10 years.

MA.5 results

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.The median follow-up time was 8.8 years (range: 0.2 to 12.1 years) and 8.7 years (range: 0.7 to 12.1 years) for the CEF and CMF treatment groups, respectively. The epirubicin-containingcombination therapy (CEF-120) demonstrated superior RFS to CMF, both over the 5- and 10-year follow-up (Table 2). The overall reduction in risk of relapse was 24% over 5 years and 22% over 10 years. The 5- and 10-year OS were also greater for the CEF-120 regimen than for the CMF regimen (Table 2). The overall relative reduction in the risk of death was 29% over 5 years and 18% over 10 years.

GFEA-05 (FASG-05) results

The median age was 51 years and approximately half of thepatients 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. The median follow-up time was 7.7 years (range: 0.3 to 12.5 years) and 8.7 years (range: 0.2 to 12.7 years) in the FEC-50 and FEC-100 treatment groups, respectively. Patients treated with the higher-dose epirubicin regimen (FEC-100) had a significantly longer RFS and OS over5- and 10-years (Table 2) than patients given the lower dose regimen (FEC-50). The overall reduction in risk of relapse was 32% over 5 years and 22% over 10 years. The relative reduction in the risk of death was 31% over 5 years and 25% over 10 years.

Although the trials were not powered for subgroup analyses, in the MA.5 study, improvement in favor of CEF-120 vs. CMF were observed over 5- and 10-years in RFS and OS both in patients with 1 to 3 node positive and those with ≥4 node positive tumorinvolvement. In the GFEA-05 (FASG-05) study, improvements in RFS and OS were observed over 5- and 10-years in both pre-and post-menopausal women treated with FEC-100 compared to FEC-50.

Efficacy results for the two studies are shown in Table 2.

Table 2. Efficacy Results from Early Breast Cancer Phase 3 Studies*
MA.5 Study GFEA-05 (FASG-05) Study
CEF-120
N = 356
CMF
N = 360
FEC-100
N = 276
FEC-50
N = 289
RFS over 5 yrs (%) 62 53 65 52
Log-Rank Test (stratified p = 0.013) (p = 0.007)
OS over 5 yrs (%) 77 70 76 65
Log-Rank Test (stratified p = 0.043)
(unstratified p = 0.13)
(p = 0.007)
RFS over 10 yrs (%) 51 44 49 43
Log-Rank Test (stratified) (p = 0.017) (p = 0.040)
OS over 10 yrs (%) 61 57 56 50
Log-Rank Test (stratified) (p = 0.100) (p = 0.023)
*Based on Kaplain-Meier estimates

The Kaplain-Meier curves for RFS and OS from Study MA.5 are shown in Figures 1 and 2 and those for Study GFEA-05 (FASG-05) are shown in Figures 3 and 4.

Detailed Pharmacology

The in vitro cytotoxicity of epirubicin, compared to doxorubicin, was investigated using theHeLa cloning efficiency test, the human tumor stem cell assay and the inhibition of mouse embryo fibroblast proliferation test. In the first test, epirubicin had less activity than doxorubicin. In the other two tests the activity of the two compounds was similar.

The antitumoral activity of epirubicin was compared with doxorubicin on various mouseexperimental tumors. Administered i.p. or i.v. as a single injection (sarcoma 180 ascites, leukemia L1210, leukemia P388, Gross leukemia), the two compounds had the same antitumor effect at the same dose. One sub-line of leukemia P388 resistant to doxorubicin showed crossresistance to epirubicin. Administered i.v. and at the same dose, the two compounds had exactly the same effect on solid sarcoma 180 and on both advanced and early mammary carcinoma.

The antitumoral effect of epirubicin was slightly greater than that of doxorubicin on Lewis lung carcinoma and MS-2 sarcoma lung metastases and also on MSV-induced rhabdomyosarcoma and on colon 38 adenocarcinoma.

Epirubicin was found active on mammary carcinoma, melanoma, epidermoid carcinoma of the lung and soft tissue sarcoma, transplanted to nude mice.

Epirubicin was found active against breast, lung, prostate and ovarian tumors transplanted in nude mice; it showed particularly good activity against melanomas. No statistically significanteffect was observed against colorectal human tumors transplanted into nude mice.

Pharmacokinetic studies in man show an initial rapid elimination of the parent compound from plasma. The terminal half-life of elimination of the parent drug from plasma approximates 30 to40 hours. Urinary excretion accounts for approximately 9% to 10% of the administered dose in 48 hours. Biliary excretion represents the major route of elimination, about 40% of the administered dose being recovered in the bile in 72 hours. The major metabolites that havebeen identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubincol.

Glucuronidation distinguishes epirubicin from doxorubicin and may account for its reducedtoxicity. Other metabolites found are aglycones of 7-deoxydoxorubicin and 7-deoxydoxorubinicol. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol)are consistently lower and virtually parallel to those of the unchanged drug.

Toxicology

The acute toxicity of epirubicin i.v. was studied in the mouse, rat and dog.

In the mouse, single doses caused dose-dependent deaths between the 4th and 180th day after injection. Calculated at stabilization, the LD50 was 15.06 mg/kg.

In the rat, single doses of epirubicin produced dose-dependent mortality between the 4th and 15th day after injection. Calculated at stabilization, the LD50 was 13.95 mg/kg.

In the dog, single doses were lethal at 2 mg/kg, while the lower dose (1 mg/kg) can be held to be just within the safety limit.

Chronic toxicity studies were carried out in the rabbit and in the dog after i.v. courses of three consecutive days per week for a total of 6 weeks on the rabbit and 6 and 13 weeks in the dog.The results showed that, in the rabbit, the pharmacological-toxicological mechanism of action of epirubicin is very similar to that of doxorubicin. In qualitative terms, epirubicin is very similar to that of doxorubicin. In quantitative terms, epirubicin was approximately one-third less toxic than doxorubicin with respect to systemic toxicity and myocardial toxicity.

In the dog, the two drugs had the same toxicity profile. The safe dose of epirubicin can be set at 0.1 mg/kg in this species.

In vitro cardiotoxicity tests showed that epirubicin was less cardiotoxic than doxorubicin (on isolated rabbit heart and guinea pig heart); unlike doxorubicin, sometimes it had no effect atall on myocardial cells from newborn mice.

In vivo cardiotoxicity tests showed that in all the animal species tested (mouse i.v., rat i.p., rabbit i.v.) epirubicin was appreciably less cardiotoxic than doxorubicin.

Ultrastructural studies of myocardial tissue from hamsters treated i.p. with epirubicin and doxorubicin showed that the two drugs produce similar alterations in the same length of time.Carcinogenesis tests in vivo run in newborn rats treated with epirubicin s.c. showed that the drug had considerable carcinogenic activity. Mutagenic activity of epirubicin was investigated in various in vitro and in vivo tests. In the in vitro and in vivo tests, Schizosccharomyces pombe P1, epirubicin showed no mutagenic activity; it was mutagenic, however, in vitro onSalmonella typhimurium.

Epirubicin has not shown teratogenic effects in rats or rabbits; embryotoxicity and/or abortions were seen in both species only at very high doses.