Epirubicin Hydrochloride (Page 6 of 8)

10 OVERDOSAGE

There is no known antidote for overdoses of epirubicin hydrochloride injection. A 36-year-old man with non-Hodgkin’s lymphoma received a daily 95 mg/m2 dose of epirubicin hydrochloride 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/m2 dose of epirubicin hydrochloride injection. 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 hydrochloride injection. Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m2. 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, 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.

11 DESCRIPTION

Epirubicin Hydrochloride Injection is an anthracycline cytotoxic agent, intended for intravenous administration. Epirubicin Hydrochloride Injection is supplied as a sterile, clear, red solution and is available in colorless type I glass 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-α-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 molecular formula C27 H29 NO11 HCl and a molecular weight of 579.95. The structural formula is as follows:

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12 CLINICAL PHARMACOLOGY

12.1 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.

12.3 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
Dose b C max c AUC d t 1/2 e CL f V ss g
(mg/m 2 ) (mcg/mL) (mcg•h/mL) (hours) (L/hour) (L/kg)
a Advanced solid tumor cancers, primarily of the lung
b N=6 patients per dose level
c Plasma concentration at the end of 6 to 10 minute infusion
d Area under the plasma concentration curve
e Half-life of terminal phase
f Plasma clearance
g Steady state volume of distribution
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 9.0 ± 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

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 greater than 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 greater than 70 years of age [see Patient Counseling Information (17)].

Effect of Gender

In patients less than or equal to 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 less than 5 mg/dL. A 50% reduction in plasma clearance was reported in four patients with serum creatinine greater than or equal to 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.

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