Epirubicin Ebewe

Epirubicin Ebewe

epirubicin

Manufacturer:

EBEWE Pharma

Distributor:

Maxxcare

Marketer:

Mega Lifesciences
Full Prescribing Info
Contents
Epirubicin Hydrochloride.
Description
Excipients/Inactive Ingredients: Sodium chloride, Hydrochloric acid (for pH adjustment), Water for injections.
Action
Pharmacology: Pharmacodynamics: Antineoplastic agents, cytotoxic antibiotics and related substances, anthracyclines and related substances.
The mechanism of action of epirubicin hydrochloride is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin hydrochloride has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).
Pharmacokinetics: In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150mg/m2 of the active substance follow a triexponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway.
The major metabolites that have been identified are epirubicinol (13-OH-epirubicin) and glucuronides of epirubicin and epirubicinol.
The 4'-O-glucuronidation distinguishes epirubicin from doxorubicin and may account for the faster elimination of epirubicin and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH-derivative (epirubicinol) are consistently lower and virtually parallel those of the unchanged substance.
Epirubicin is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution. Urinary excretion accounts for approximately 9-10% 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 active substance does not cross the blood-brain barrier.
Toxicology: Preclinical safety data: The main target organs in rat, rabbit and dog following repeated dosing were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicin hydrochloride was also cardiotoxic in the species tested.
It was genotoxic, and, like other anthracyclines, carcinogenic in rats.
Epirubicin hydrochloride was embryotoxic in rats. No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic medicinal products, epirubicin must be considered potentially teratogenic.
A local tolerance study in rats and mice showed extravasation of epirubicin hydrochloride causes tissue necrosis.
Indications/Uses
Epirubicin hydrochloride is used in the treatment of a range of neoplastic conditions including: Carcinoma of the breast; Gastric cancer.
When administered intravesically, epirubicin hydrochloride has been shown to be beneficial in the treatment of: Papillary transitional cell carcinoma of the bladder; Carcinoma-in-situ of the bladder; lntravesical prophylaxis of recurrences of superficial bladder carcinoma following transurethral resection.
Dosage/Direction for Use
Epirubicin hydrochloride is for intravenous or intravesical use only.
The safety and efficacy of epirubicin hydrochloride in children has not been established.
Intravenous administration: It is advisable to administer epirubicin hydrochloride via the tubing of a freely-running intravenous saline infusion after checking that the needle is properly placed in the vein. This method minimises the risk of drug extravasation and makes sure that the vein is flushed with saline after the administration of the medicinal product. Extravasation of epirubicin hydrochloride from the vein during injection may give rise to severe tissue lesions, even necrosis. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.
Conventional doses: When epirubicin hydrochloride is used as a single agent, the recommended dose in adults is 60-90 mg/m2 body area; the medicinal product should be injected intravenously over 3-5 minutes and, depending on the patient's haematomedullary status, the dose should be repeated at 21-day intervals.
High doses: Epirubicin hydrochloride as a single agent for the treatment of lung cancer at high doses should be administered according to the following regimens: Lung cancer: Small cell lung cancer (previously untreated): 120 mg/m2 epirubicin hydrochloride day 1, every 3 weeks.
Non-small cell lung cancer (squamous, large cell, and adenocarcinoma previously untreated): 135 mg/m2 epirubicin hydrochloride day 1 or 45 mg/m2 epirubicin hydrochloride days 1, 2, 3, every 3 weeks.
Breast cancer: In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin hydrochloride ranging from 100 mg/m2 (as a single dose on day 1) to 120 mg/m2 (in two divided doses on days 1 and 8) every 3-4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen, are recommended.
The medicinal product should be given as an intravenous bolus over 3-5 minutes or as an infusion up to 30 minutes. Lower doses (60-75 mg/m2 for conventional treatment and 105-120 mg/m2 for high dose schedules) are recommended for patients whose bone marrow function has already been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone-marrow infiltration. The total dose per cycle may be divided over 2-3 successive days.
When the medicinal product is used in combination with other antitumour agents, the doses need to be adequately reduced.
Impaired liver function: Since the major route of elimination of epirubicin hydrochloride is the hepatobiliary system, the dose should be reduced in patients with impaired liver function, in order to avoid an increase of overall toxicity. Moderate liver impairment (bilirubin: 1.4 - 3 mg/100 ml) requires a 50% reduction of dose, while severe impairment (bilirubin >3 mg/100 ml) necessitates a dose reduction of 75%.
Impaired renal function: Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin hydrochloride excreted by this route. However dose adjustment may be necessary in patients with serum creatinine >5 mg/dl.
Intravesical administration: Epirubicin hydrochloride can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate. Epirubicin hydrochloride has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences.
While many regimens have been used, the following may be helpful as a guide: for therapy, 8 x weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water). In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg/50 ml is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg/50 ml. For prophylaxis, 4 x weekly administrations of 50 mg/50 ml, followed by 11 x monthly instillations at the same dose, is the schedule most commonly used.
The solution should be retained intravesically for 1 hour. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.
Overdosage
Acute overdose with epirubicin hydrochloride will result in severe myelosuppression (mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications. Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment (see Precautions). Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.
Treatment: Symptomatic. Epirubicin hydrochloride cannot be removed by dialysis.
Contraindications
Hypersensitivity to epirubicin or to any of the excipients, other anthracyclines or anthracenediones.
Lactation.
Intravenous use: persistent myelosuppression; severe hepatic impairment; Myocardiopathy; recent myocardial infarction; severe arrhythmias; previous treatments with maximum cumulative doses of epirubicin and/or other anthracyclines and anthracenediones (see Precautions); patients with acute systemic infections; unstable angina pectoris.
lntravesical use: urinary tract infections; inflammation of the bladder; haematuria; invasive tumours penetrating the bladder; catheterisation problems.
Special Precautions
General: Epirubicin hydrochloride should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy.
Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with epirubicin hydrochloride.
While treatment with high doses of epirubicin hydrochloride (e.g., ≥90 mg/m2 every 3 to 4 weeks) causes adverse events generally similar to those seen at standard doses (<90 mg/m2 every 3 to 4 weeks), the severity of the neutropenia and stomatitis/mucositis may be increased. Treatment with high doses of epirubicin hydrochloride does require special attention for possible clinical complications due to profound myelosuppression.
Cardiac function: Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.
Early (i.e. acute) events: Early cardiotoxicity of epirubicin hydrochloride consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for the discontinuation of epirubicin hydrochloride treatment.
Late (i.e. delayed) events: Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin hydrochloride or within 2 to 3 months after treatment termination, but later events (several months to years after completion of treatment) have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the medicinal product.
The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin hydrochloride in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution (see Pharmacology: Pharmacodynamics under Actions).
Cardiac function should be assessed before patients undergo treatment with epirubicin hydrochloride and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of epirubicin hydrochloride at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m2 epirubicin hydrochloride should be exceeded only with extreme caution.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other medicinal products with the ability to suppress cardiac contractility or cardiotoxic medicinal products (e.g. trastuzumab) (see Interactions) with an increased risk in the elderly.
Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzumab therapy alone or in combination with anthracyclines such as epirubicin hydrochloride. This may be moderate to severe and has been associated with death. Trastuzumab and anthracyclines such as epirubicin hydrochloride should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with trastuzumab treatment, although the risk is lower than with concurrent use of trastuzumab and anthracyclines.
Because the half-life of trastuzumab is approximately 28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as epirubicin hydrochloride after stopping trastuzumab may possibly be at an increased risk of cardio toxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin hydrochloride are used, the patient's cardiac function should be monitored carefully.
If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin hydrochloride therapy, it should be treated with the standard medications for this purpose.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with epirubicin hydrochloride may occur at lower cumulative doses whether or not cardiac risk factors are present.
It is probable that the toxicity of epirubicin hydrochloride and other anthracyclines or anthracenediones is additive.
Haematologic toxicity: As with other cytotoxic agents, epirubicin hydrochloride may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin hydrochloride haematologic toxicity and is the most common acute dose-limiting toxicity of this medicinal product. Leukopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death.
Secondary leukaemia: Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin hydrochloride. Secondary leukaemia is more common when such medicinal products are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic medicinal products, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1- to 3-year latency period (see Pharmacology: Pharmacodynamics under Actions).
Gastrointestinal: Epirubicin hydrochloride is emetogenic. Mucositis/stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.
Liver function: The major route of elimination of epirubicin hydrochloride is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin hydrochloride. Patients with elevated bilirubin or AST may experience slower clearance of medicinal product with an increase in overall toxicity. Lower doses are recommended in these patients (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Patients with severe hepatic impairment should not receive epirubicin hydrochloride (see Contraindications).
Renal function: Serum creatinine should be assessed before and during therapy. Dose adjustment is necessary in patients with serum creatinine >5 mg/dl (see Dosage & Administration).
Effects at site of injection: Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site (see Dosage & Administration).
Extravasation: Extravasation of epirubicin hydrochloride during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of epirubicin hydrochloride, the drug infusion should be immediately discontinued. The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g. dexrazoxane (please refer to relevant labels for use). The patient's pain may be relieved by cooling down the area and keeping it cool using hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.
Other: As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of epirubicin hydrochloride.
Tumour-lysis syndrome: Epirubicin hydrochloride may induce hyperuricaemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour-lysis syndrome.
Immunosuppressant effects/increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin hydrochloride, may result in serious or fatal infections (see Interactions).
Vaccination with a live vaccine should be avoided in patients receiving epirubicin hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Reproductive system: Epirubicin hydrochloride can cause genotoxicity. Men and women treated with epirubicin hydrochloride should adopt appropriate contraceptives. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.
Additional warnings and precautions for other routes of administration: lntravesical route: Administration of epirubicin hydrochloride may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterisation problems (e.g., urethral obstruction due to massive intravesical tumours).
Intra-arterial route: Intra-arterial administration of epirubicin hydrochloride (transcatheter arterial embolisation for the localised or regional therapies of primary hepatocellular carcinoma or liver metastases) may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of epirubicin hydrochloride) localised or regional events which include gastroduodenal ulcers (probably due to reflux of the medicinal products into the gastric artery) and narrowing of bile ducts due to drug-induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.
The safe use of product in latex-sensitive individuals has not been studied.
Effects on ability to drive and use machines: There have been no reports of particular adverse events relating to effects on ability to drive and to use machines.
Use In Pregnancy & Lactation
Fertility: Epirubicin hydrochloride could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin hydrochloride should use effective contraceptive methods and if appropriate and available, seek advice on sperm preservation due to the possibility of irreversible infertility caused by therapy.
Epirubicin hydrochloride may cause amenorrhoea or premature menopause in premenopausal women.
Pregnancy: Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods.
Experimental data in animals suggest that epirubicin hydrochloride may cause foetal harm when administered to a pregnant woman. If epirubicin hydrochloride is used during pregnancy or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to the foetus.
There are no studies in pregnant women. Epirubicin hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breast-feeding: It is not known whether epirubicin hydrochloride is excreted in human milk. Because many medicinal products, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from epirubicin hydrochloride, mothers should discontinue nursing prior to taking this medicinal product.
Adverse Reactions
The following undesirable effects have been observed and reported during treatment with epirubicin hydrochloride with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
More than 10% of treated patients can expect to develop undesirable effects. The most common undesirable effects are myelosuppression, gastrointestinal side effects, anorexia, alopecia, infection.
Infections and infestations: Common: Infection.
Not known: Septic shock, sepsis, pneumonia.
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Rare: Acute lymphocytic leukaemia, acute myelogenous leukaemia.
Blood and the lymphatic system disorders: Very common: Myelosuppression (leukopenia, granulocytopenia and neutropenia, anaemia and febrile neutropenia).
Uncommon: Thrombocytopenia.
Not known: Haemorrhage and tissue hypoxia as result of myelosuppression.
Immune system disorders: Rare: Anaphylaxis.
Metabolism and nutrition disorders: Common: Anorexia, dehydration.
Rare: Hyperuricaemia (see Precautions).
Nervous system disorders: Rare: Dizziness.
Eye disorders: Not known: Conjunctivitis, keratitis.
Cardiac disorders: Rare: Congestive heart failure (dyspnoea, oedema, hepatomegaly, ascites, pulmonary oedema, pleural effusions, gallop rhythm), cardiotoxicity (e.g. ECG abnormalities, arrhythmias, cardiomyopathy), ventricular tachycardia, bradycardia, AV block, bundle-branch block.
Vascular disorders: Common: Hot flushes.
Uncommon: Phlebitis, thrombophlebitis.
Not known: Shock, thromboembolism, including pulmonary emboli.
Gastrointestinal disorders: Common: Mucositis, oesophagitis, stomatitis, vomiting, diarrhoea, nausea.
Not known: Oral mucosa erosion, mouth ulceration, oral pain, mucosal burning sensation, mouth haemorrhage, and buccal pigmentation.
Skin and subcutaneous tissue disorders: Very common: Alopecia.
Rare: Urticaria.
Not known: Local toxicity, rash, itch, skin changes, erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction).
Renal and urinary disorders: Very common: Red colouration of urine for 1 to 2 days after administration.
Reproductive system and breast disorders: Rare: Amenorrhoea, azoospermia.
General disorders and administration site conditions: Common: Infusion site erythema.
Rare: Malaise, asthenia, fever, chills.
Not known: Phlebosclerosis, local pain, severe cellulitis, tissue necrosis after accidental paravenous injection.
Investigations: Rare: Changes in transaminase levels.
Not known: Asymptomatic drops in left ventricular ejection fraction.
Injury, poisoning and procedural complications: Common: Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration (see Precautions).
lntravesical administration: As only a small amount of active ingredient is reabsorbed after intravesical instillation, severe systemic adverse drug reactions as well as allergic reactions are rare. Commonly reported are local reactions like burning sensation and frequent voiding (pollakisuria). Occasional bacterial or chemical cystitis have been reported (see Precautions). These ADRs are mostly reversible.
Drug Interactions
Epirubicin hydrochloride is mainly used in combination with other cytotoxic medicinal products. Additive toxicity may occur especially with regard to bone marrow/haematologic and gastrointestinal effects (see Precautions). The use of epirubicin hydrochloride in combination chemotherapy with other potentially cardiotoxic medicinal products, as well as the concomitant use of other cardioactive compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout treatment.
Epirubicin hydrochloride is extensively metabolised by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin hydrochloride metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity (see Precautions).
Anthracyclines including epirubicin hydrochloride should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity.
Because the half-life of trastuzumab is approximately 28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as epirubicin hydrochloride after stopping trastuzumab may possibly be at an increased risk of cardio toxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin hydrochloride are used, the patient's cardiac function should be monitored carefully.
Vaccination with a live vaccine should be avoided in patients receiving epirubicin hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Cimetidine increased the AUC of epirubicin hydrochloride by 50% and should be discontinued during treatment with epirubicin hydrochloride.
When given prior to epirubicin hydrochloride, paclitaxel can cause increased plasma concentrations of unchanged epirubicin hydrochloride and its metabolites, the latter being, however, neither toxic nor active. Co-administration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin hydrochloride when epirubicin hydrochloride was administered prior to the taxane.
This combination may be used if using staggered administration between the two agents. Infusion of epirubicin hydrochloride and paclitaxel should be performed with at least a 24 hour interval between the 2 agents.
Dexverapamil may alter the pharmacokinetics of epirubicin hydrochloride and possibly increase its bone marrow depressant effects.
One study found that docetaxel may increase the plasma concentrations of epirubicin hydrochloride metabolites when administered immediately after epirubicin hydrochloride.
Quinine may accelerate the initial distribution of epirubicin hydrochloride from blood into the tissues and may have an influence on the red blood cells partitioning of epirubicin hydrochloride.
The co-administration of interferon α2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin hydrochloride.
The possibility of a marked disturbance of haematopoiesis needs to be kept in mind with a (pre) treatment with medications which influences the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivative, antiretroviral agents).
Increase of myelosuppression may occur in patients receiving combination therapy of anthracycline and dexrazoxane.
Caution For Usage
Instructions for use and handling: Epirubicin hydrochloride 2 mg/ml Injection may be further diluted in glucose 5% or sodium chloride 0.9% and administered as an intravenous infusion. The infusion solution should be prepared immediately before use.
For instructions on the administration of the product, see Dosage & Administration.
The injection solution contains no preservative and any unused portion of the vial should be discarded immediately.
Guidelines for the safe handling and disposal of antineoplastic agents: 1. If an infusion solution is to be prepared, this should be performed by trained personnel under aseptic conditions.
2. Preparation of an infusion solution should be performed in a designated aseptic area.
3. Adequate protective disposable gloves, goggles, gown and mask should be worn.
4. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or 0.9% sodium chloride solution. Then seek medical evaluation by a physician.
5. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Always wash hands after removing gloves.
6. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as detailed as follows.
7. Pregnant staff should not handle the cytotoxic preparation.
8. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc) used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Prolonged contact of the medicinal product with any solution of an alkaline pH should be avoided: this will result in hydrolysis (degradation) of the active substance. A physical incompatibility of the product with heparin has been reported. This medicinal product must not be mixed with other medicinal products except those previously mentioned in Instructions for use and handling.
Storage
Store refrigerated (2°C to 8°C).
Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15° to 25°C).
Shelf-life: Medicinal product as packaged for sale: 2 years.
Shelf life after dilution: It would normally not be longer than 24 hours at 2 to 8°C.
ATC Classification
L01DB03 - epirubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.
Presentation/Packing
Soln for inj/infusion (vial) 2 mg/mL x 5 mL x 1's, 5's, 10's, 25 mL x 1's, 5's, 10's.
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