EPICORD INJ 2MG/ML (25ML)

Indications

• Breast cancer
• Bladder cancer
• Sarcomas
• Ovarian cancer
• Lung cancer

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients, as dosing may vary significantly based on age, weight, and specific indications.

Adults: Refer to the BNF for specific dosing recommendations based on the type of cancer being treated, patient's performance status, and renal function.

Mechanism of action

Epirubicin exhibits antimitotic and cytotoxic activity through several mechanisms. It intercalates between DNA base pairs, which inhibits nucleic acid synthesis and stabilizes the DNA-topoisomerase II complex, disrupting the ligation-religation reaction essential for DNA repair. Additionally, it inhibits DNA helicase activity, preventing DNA replication and transcription. The drug also generates cytotoxic free radicals, contributing to its antiproliferative effects.

Pharmacodynamics

Epirubicin is classified as an antineoplastic agent within the anthracycline class, known for its ability to interact with DNA in various ways, such as intercalation, inducing DNA strand breaks, and inhibiting topoisomerase II. It is recognized for its broad-spectrum antitumor activity against both grafted and spontaneous tumors. However, like other anthracyclines, it lacks specificity and may produce significant toxicity, impacting normal cells along with cancer cells.

Pharmacokinetics

Epirubicin's pharmacokinetics involve rapid distribution and metabolism. It is primarily metabolized in the liver, with renal excretion of its metabolites. The drug demonstrates a large volume of distribution, indicating significant tissue binding. Its half-life can vary based on the dosing regimen and patient factors. Monitoring of renal and hepatic function is important, as these can influence epirubicin's clearance and toxicity.

Adverse effects

• Myelosuppression
• Nausea
• Vomiting
• Alopecia
• Cardiotoxicity
• Mucositis
• Radiation recall phenomenon

Interactions

• cimetidine+epirubicin: Severe (increases exposure)
• ciclosporin+epirubicin: Unknown (increases concentration)

Precautions

• Use with caution in patients with pre-existing heart disease
• Monitor cardiac function during treatment
• May cause severe myelosuppression, monitor blood counts
• Avoid use in patients with active infections

Pregnancy

Epirubicin is contraindicated in pregnancy due to potential harm to the fetus. It is classified as a category D drug, indicating evidence of human fetal risk.

Breast-feeding

It is not known whether epirubicin is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at 2 to 8 degrees Celsius. Protect from light. Do not freeze.

Formulations

• Epirubicin hydrochloride injection
• Epirubicin liposomal formulation

Indications

• Breast cancer
• Bladder cancer (intravesical use)
• Soft tissue sarcomas
• Rhabdomyosarcoma
• Acute lymphoblastic leukaemia

Dosage

Children: Epirubicin is not licensed for use in children. Consult local protocols for any unlicensed use, especially for conditions like rhabdomyosarcoma or acute lymphoblastic leukaemia.

Adults: The dosage for adults varies based on the specific malignancy and treatment protocol. For breast cancer, epirubicin is often given as 60-90 mg/m2 by intravenous infusion every 21 days. For bladder cancer, refer to local protocols for intravesical administration.

Mechanism of action

Epirubicin exerts its antitumor activity through intercalation into DNA, inhibiting topoisomerase II, which prevents DNA unwinding and replication. This mechanism leads to the formation of DNA double-strand breaks and ultimately results in cell death, particularly in rapidly dividing cancer cells.

Pharmacodynamics

Epirubicin shows dose-dependent cytotoxicity and its effectiveness is linked to its ability to penetrate tumor tissues and achieve high concentrations at the site of action. It is known to induce apoptosis in cancer cells and has a broad spectrum of activity against various tumors, particularly those that are sensitive to anthracyclines.

Pharmacokinetics

Epirubicin is administered intravenously and exhibits a volume of distribution of approximately 50 L/m2, indicating extensive tissue binding. It has a plasma half-life of about 30-40 hours, and its metabolism primarily occurs in the liver, with renal excretion of metabolites. The drug's clearance can be affected by liver function, necessitating careful dosage adjustments in patients with hepatic impairment.

Contra-indications

• Bladder inflammation (when used as a bladder instillation)
• Haematuria (when used as a bladder instillation)
• Invasive tumours penetrating the bladder (when used as a bladder instillation)
• Previous treatment with maximum cumulative doses of epirubicin or other anthracyclines
• Myocardial disease

Adverse effects

• Alopecia
• Anemia
• Gastrointestinal disorders
• Nausea
• Vomiting
• Mucositis
• Leukopenia
• Thrombocytopenia
• Skin reactions
• Discoloration of urine
• Asthenia
• Embolism
• Thrombosis
• Sepsis
• Hyperuricaemia
• Bone marrow depression
• Cardiac toxicity
• Photosensitivity reactions

Interactions

• Increased risk of infection with myelosuppressive agents
• Caution with other cardiotoxic drugs, including doxorubicin

Precautions

• Caution in handling due to irritant properties
• Monitor cardiac function during treatment
• Assess patients with echocardiography before treatment

Pregnancy

Avoid use as it is carcinogenic in animal studies.

Breast-feeding

Not recommended due to potential risk to the infant.

Storage

Store below 25°C. Protect from light. Do not freeze.

Formulations

• Solution for injection (2 mg/ml, 10 mg/5 ml, 50 mg/25 ml)
• Solution for infusion (200 mg/100 ml)

Mechanism of action

Epirubicin has antimitotic and cytotoxic activity. It inhibits nucleic acid (DNA and RNA) and protein synthesis through a number of proposed mechanisms of action: Epirubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. It also interferes with DNA replication and transcription by inhibiting DNA helicase activity. 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 fights cancer through topoisomerase II inhibition, hence producing DNA strand breaks that finally lead to cell apoptosis. But anthracyclines produce free radicals that may explain their adverse effects. Dexrazoxane--an iron chelator--was proven to decrease free radical production and anthracycline cardiotoxicity. In this article, we report the concentrations of cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) relative to 2'-deoxyguanosine (dGuo), and comet assay results from a study including 20 cancer patients treated with epirubicin. Plasma concentrations of vitamins A, E, C and carotenoids are also reported. All data were obtained before and immediately after epirubicin infusion. The ratios of 8-Oxo-dGuo to dGuo were measured in leukocyte DNA by HPLC-coulometry after NaI extraction of nucleic acids. Vitamins A and E and carotenoids were measured by HPLC-spectrophotometry. Vitamin C was measured by HPLC-spectrofluorimetry. Median 8-oxo-dGuo/dGuo ratios increased significantly from 0.34 to 0.48 lesions per 100,000 bases while per cent of tail DNA increased from 3.47 to 3.94 after chemotherapy 8-Oxo-dGuo/dGuo and per cent of tail DNA medians remained in the normal range. Only vitamin C decreased significantly from 55.4 to 50.3 microM Decreases in vitamins A, E, lutein and zeaxanthin were not significant, but concentrations were below the lower limit of the normal range both before and after chemotherapy. Only the correlation between comet assay results and vitamin C concentrations was significant (rho =-0.517, p = 0.023). This study shows that cellular DNA is damaged by epirubicin-generated free radicals which produce the mutagenic modified base 8-oxo-dGuo and are responsible for strand breaks. However, strand breaks are created not only by free radicals but also by topoisomerase II inhibition. In a previous study we did not find any significant change in urinary 8-oxo-dGuo excretion after adriamycin treatment. However, 8-oxo-dGuo may have increased at the end of urine collection as DNA repair and subsequent kidney elimination are relatively slow processes. In another study, authors used GC-MS to detect 8-oxo-dGuo in DNA and did not find any change after prolonged adriamycin infusion. Reasons for these apparent discrepancies are discussed.

Pharmacodynamics

Epirubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Epirubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Epirubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific.