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Epirubicin (Epirubicin Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Epirubicin hydrochloride injection is an anthracycline cytotoxic agent, intended for intravenous administration. Epirubicin hydrochloride is supplied as a sterile, clear, red solution and is available in single-use 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 qs. 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-α-L-arabino-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula C27 H29 NO11 HCl and a molecular weight of 579.95. The structural formula is as follows:

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

Pharmacokinetics

Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m2 and 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 hydrochloride injection at doses of 60 to 150 mg/m2 in patients with solid tumors are shown in Table 4. 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.

Table 4. Summary of Mean (± SD) Pharmacokinetic Parameters in Patients 1 With Solid Tumors Receiving Intravenous Epirubicin Hydrochloride Injection 60 to 150 mg/m2

Dose 2

(mg/m2)

Cmax 3

(mcg/mL)

AUC 4

(mcg•h/mL)

t1/2 5

(hours)

CL 6

(L/hour)

Vss 7

(L/kg)

60 5.7 ± 1.6 1.6 ± 0.2 35.3 ± 9 65 ± 8 21 ± 2
75 5.3 ± 1.5 1.7 ± 0.3 32.1 ± 5 83 ± 14 27 ± 11
120 9 ± 3.5 3.4 ± 0.7 33.7 ± 4 65 ± 13 23 ± 7
150 9.3 ± 2.9 4.2 ± 0.8 31.1 ± 6 69 ± 13 21 ± 7

1 Advanced solid tumor cancers, primarily of the lung
2 N = 6 patients per dose level
3 Plasma concentration at the end of 6 to 10 minute infusion
4 Area under the plasma concentration curve
5 Half-life of terminal phase
6 Plasma clearance
7 Steady state volume of distribution

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 epirubicin hydrochloride injection 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 hydrochloride injection is administered to female patients > 70 years of age [see Patient Counseling Information (17)].

 

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 epirubicin hydrochloride injection doses of 12.5 to 90 mg/m2. 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 hydrochloride injection dose of 25 mg/m2 (n = 8). Their pharmacokinetics were compared to those of patients with normal serum AST and bilirubin values, who received epirubicin hydrochloride injection doses of 12.5 to 120 mg/m2. 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 [see Dosage and Administration (2.2), and 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) and Dosing and Administration (2.2)]. Patients on dialysis have not been studied.

 

Effect of Paclitaxel

The administration of paclitaxel (175 to 225 mg/m2 as a 3 hour infusion) immediately before or after epirubicin (90 mg/m2 as bolus) caused variable increases in the systemic exposure (mean AUC) of epirubicin ranging from 5% to 109%. At same doses of epirubicin and paclitaxel, the mean AUC of the inactive metabolites of epirubicin (epirubicinol and 7-deoxy-aglycone) increased by 120% and 70%, respectively, when paclitaxel was immediately administered after epirubicin. Epirubicin had no effect on the exposure of paclitaxel whether it was administered before or after paclitaxel.

Effect of Docetaxel

The administration of docetaxel (70 mg/m2 as 1 hour infusion) immediately before or after epirubicin (90 mg/m2 as bolus) had no effect on the systemic exposure (mean AUC) of epirubicin. However, the mean AUC of epirubicinol and 7-deoxy-aglycone increased by 22.5% and 95%, respectively, when docetaxel was immediately administered after epirubicin compared to epirubicin alone. Epirubicin had no effect on the exposure of docetaxel whether it was administered before or after docetaxel.

 

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/m2) by 50% and decreased its plasma clearance by 30%.

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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 to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vitro (chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation and was also clastogenic in vivo (chromosome aberration in mouse bone marrow).

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

Adjuvant Treatment of Breast Cancer

Two randomized, open-label, multicenter studies evaluated the use of epirubicin hydrochloride injection 100 to 120 mg/m2 in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m2 of epirubicin hydrochloride injection per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an epirubicin hydrochloride injection-containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m2 of epirubicin hydrochloride injection per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, 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. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study. Table 5 shows the treatment regimens that the patients received. Relapse-free survival was defined as time to occurrence of a local, regional, or distant recurrence, or disease-related death. Patients with contralateral breast cancer, second primary malignancy, or death from causes other than breast cancer were censored at the time of the last visit prior to these events.

Table 5. Treatment Regimens Used in Phase 3 Studies of Patients With Early Breast Cancer
Treatment Groups Agent Regimen
MA-5 1 CEF-120 (total, 6 cycles) 2 N = 356 Cyclophosphamide 75 mg/m2 PO, d 1 to 14, q 28 days
N = 716 Epirubicin Hydrochloride Injection 60 mg/m2 IV, d 1 & 8, q 28 days
CMF (total, 6 cycles) N = 360 Fluorouracil 500 mg/m2 IV, d 1 & 8, q 28 days
Cyclophosphamide 100 mg/m2 PO, d 1 to 14, q 28 days
Methotrexate 40 mg/m2 IV, d 1 & 8, q 28 days
GFEA-05 3 FEC-100 (total, 6 cycles) Fluorouracil 500 mg/m2 IV, d 1, q 21 days
N = 565 N = 276 Epirubicin Hydrochloride Injection 100 mg/m2 IV, d 1, q 21 days
Cyclophosphamide 500 mg/m2 IV, d 1, q 21 days
FEC-50 (total, 6 cycles) Fluorouracil 500 mg/m2 IV, d 1, q 21 days
N = 289 Epirubicin Hydrochloride Injection 50 mg/m2 IV, d 1, q 21 days
Tamoxifen 30 mg daily x 3 years, postmenopausal women, any receptor status Cyclophosphamide 500 mg/m2 IV, d 1, q 21 days

1 In women who underwent lumpectomy, breast irradiation was to be administered after completion of study chemotherapy.
2 Patients also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluoroquinolone for the duration of their chemotherapy.
3 All women were to receive breast irradiation after the completion of chemotherapy.

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, epirubicin hydrochloride injection-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 = 0.013). The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the epirubicin hydrochloride injection-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 = 0.13). The estimated reduction in the risk of death was 29% at 5 years.

In Study GFEA-05, patients treated with the higher-dose epirubicin hydrochloride injection 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 1-3 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.

Table 6. Efficacy Results from Phase 3 Studies of Patients With Early Breast Cancer 1
MA-5 Study GFEA-05 Study

CEF-120

N = 356

CMF

N = 360

FEC-100

N = 276

FEC-50

N = 289

RFS at 5 yrs (%) 62 53 65 52
   Hazard ratio 2 0.76 0.68
   2-sided 95% CI (0.60, 0.96) (0.52, 0.89)
   Logrank Test (p = 0.013) (p = 0.007)
stratified 3
OS at 5 yrs (%) 77 70 76 65
   Hazard ratio 0.71 0.69
   2-sided 95% CI (0.52, 0.98) (0.51, 0.92)
   Logrank Test (p = 0.043) (p = 0.007)
   stratified (unstratified p = 0.13)
RFS at 10 yrs (%) 51 44 49 43
   Hazard ratio 0.78 0.78
   2-sided 95% CI (0.63, 0.95) (0.62, 0.99)
   Logrank Test (p = 0.017) (p = 0.04)
   stratified (unstratified p = 0.023) (unstratified p = 0.09)
OS at 10 yrs (%) 61 57 56 50
   Hazard ratio 0.82 0.75
   2-sided 95% CI (0.65, 1.04) (0.58, 0.96)
   Logrank Test (p = 0.100) (p = 0.023)
   stratified (unstratified p = 0.18) (unstratified p = 0.039)

1 Based on Kaplan-Meier estimates
2 Hazard ratio: CMF:CEF-120 in MA-5, FEC-50:FEC-100 in GFEA-05
3 Patients in MA-5 were stratified by nodal status (1-3, 4-10, 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 fmol), or unknown status). Patients in GFEA-05 were stratified by nodal status (1-3, 4-10, and > 10 positive nodes).

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.

Figure 3. Relapse-Free Survival in Study MA-5

Figure 3. Relapse-Free Survival in Study MA-5

Figure 4. Overall Survival in Study MA-5

Figure 4. Overall Survival in Study MA-5

Figure 5. Relapse-Free Survival in Study GFEA-05

Figure 5. Relapse-Free Survival in Study GFEA-05

Figure 6. Overall Survival in Study GFEA-05

Figure 6. Overall Survival in Study GFEA-05

See Table 6 for statistics on 5 and 10 year analyses.

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