Epirubicin Hydrochloride

EPIRUBICIN HYDROCHLORIDE- epirubicin hydrochloride injection, solution
GeneraMedix, Inc.

WARNING

  1. Severe local tissue necrosis will occur if there is extravasation during administration (See PRECAUTIONS). Epirubicin must not be given by the intramuscular or subcutaneous route.

  2. Myocardial toxicity, manifested in its most severe form by potentially fatal congestive heart failure (CHF), may occur either during therapy with epirubicin or months to years after termination of therapy. The probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/m2 , 1.6% at 700 mg/m2 , and 3.3% at 900 mg/m2. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin in excess of 900 mg/m2 ; this cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with Epirubicin Hydrochloride Injection may occur at lower cumulative doses whether or not cardiac risk factors are present.

  3. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. The occurrence of refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7110 patients with breast cancer who received adjuvant treatment with epirubicin-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years and 0.55% at 8 years.

  4. Dosage should be reduced in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).

  5. Severe myelosuppression may occur.

  6. Epirubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

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 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 empirical formula C27 H29 NO11 HCl and a molecular weight of 579.95. The structural formula is as follows:

Image from Drug Label Content

NH2 ∙HCl

CLINICAL PHARMACOLOGY

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 at doses of 60 to 150 mg/m2 in 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.

Table 1. Summary of Mean (±SD) Pharmacokinetic Parameters in Patients1 with Solid Tumors Receiving Intravenous Epirubicin 60 to 150 mg/m2
Dose 2 (mg/m 2 ) C max 3 (mcg/mL) (mcg•h/mL) AUC 4 t 1/2 5 (hours) CL 6 (L/hour) Vss 7 (L/kg)
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
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.

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