Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Hypersensitivity to epirubicin or to any of the excipients listed in section 6.1, other anthracyclines or anthracenediones.
Intravenous use:
Intravesical use:
Epirubicin 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 generalized infections) of prior cytotoxic treatment before beginning treatment with epirubicin.
While treatment with high doses of epirubicin (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/mucosal inflammation may be increased. Treatment with high doses of epirubicin 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 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 treatment.
Late (i.e., Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin 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 drug.
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 (see section 5.1).
Cardiac function should be assessed before patients undergo treatment with epirubicin and must be monitored throughout therapy to minimize 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 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 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 drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab) (see section 4.5) 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. This may be moderate to severe and has been associated with death.
Trastuzumab and anthracyclines such as epirubicin 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 traztuzumab and anthracyclines.
The reported half-life of trastuzumab is variable. The substance may persist in circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If this is not possible, the patient’s cardiac function should be monitored carefully.
If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin 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 may occur at lower cumulative doses whether or not cardiac risk factors are present.
There have been sporadic reports of foetal/neonatal cardiotoxic events including foetal death following in utero exposure to epirubicin (see section 4.6).
It is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive.
As with other cytotoxic agents, epirubicin 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 leucopoenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopoenia 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 pyrexia, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death.
Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin. Secondary leukaemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1- to 3-year latency period. (See section 5.1).
Epirubicin is emetigenic. Mucosal inflammation /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.
The major route of elimination of epirubicin is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients (see sections 4.2 and 5.2). Patients with severe hepatic impairment should not receive epirubicin (see section 4.3).
Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL (see section 4.2).
Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see section 4.2).
Extravasation of epirubicin 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, 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.
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
Epirubicin may induce hyperuricemia 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 hyperuricemia may minimize potential complications of tumour-lysis syndrome.
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections, (see section 4.5). Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Epirubicin can cause genotoxicity. Men and women treated with epirubicin should adopt appropriate contraceptives during and for a period after treatment with epirubicin (see section 4.6). Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.
Administration of epirubicin 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 catheterization problems (e.g., ureteral obstruction due to massive intravesical tumours).
Intra-arterial administration of epirubicin (transcatheter arterial embolisation for the localized 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) localized or regional events which include gastro-duodenal ulcers (probably due to reflux of the drugs 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.
This medicinal product may be further prepared for administration with sodium containing solutions (see section 4.2 and section 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.
Pharmorubicin 10 mg/5 ml (2 mg/ml) solution for injection or infusion contains 17.7 mg of sodium in each 5 ml vial, equivalent to 0.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Pharmorubicin 20 mg/10 ml (2 mg/ml) solution for injection or infusion contains 35.4 mg of sodium in each 10 ml vial, equivalent to 1.77% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Pharmorubicin 50 mg/25 ml (2 mg/ml) solution for injection or infusion contains 88.5 mg of sodium in each 25 ml vial, equivalent to 4.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Pharmorubicin 200 mg/100 ml (2 mg/ml) solution for injection or infusion contains 354 mg of sodium in each 100 ml vial, equivalent to 17.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Epirubicin is mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/haematologic and gastro-intestinal effects (see section 4.4). The use of epirubicin in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout treatment.
Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity (see section 4.4).
Anthracyclines including epirubicin 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. The reported half-life of trastuzumab is variable. The substance may persist in circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If this is not possible, the patient’s cardiac function should be monitored carefully.
Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Cimetidine increased the AUC of epirubicin by 50% and should be discontinued during treatment with epirubicin
When given prior to epirubicin, paclitaxel can cause increased plasma concentrations of unchanged epirubicin and its metabolites, the latter being, however, neither toxic nor active. Co-administration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin when epirubicin was administered prior to the taxane.
This combination may be used if using staggered administration between the two agents. Infusion of epirubicin and paclitaxel should be performed with at least a 24 hour interval between the 2 agents.
Dexverapamil may alter the pharmacokinetics of epirubicin and possibly increase its bone marrow depressant effects.
One study found that docetaxel may increase the plasma concentrations of epirubicin metabolites when administered immediately after epirubicin.
Quinine may accelerate the initial distribution of epirubicin from blood into the tissues and may have an influence on the red blood cells partitioning of epirubicin.
The co-administration of interferon α2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin.
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-derivate, antiretroviral agents).
Increase of myelosuppression may occur in patients receiving combination therapy of anthracycline and dexrazoxane.
There are no studies in pregnant women. Experimental data in animals suggest that epirubicin may cause foetal harm when administered to a pregnant woman, particularly in the first trimester.
If epirubicin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus. There have been sporadic reports of foetal and/or neonatal transient ventricular hypokinesia, transient elevation of cardiac enzymes, and of foetal death from suspected anthracycline-induced cardiotoxicity following in utero exposure to epirubicin in 2nd and/or 3rd trimesters (see section 4.4). Monitor the foetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care.
Epirubicin should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether epirubicin is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from epirubicin, lactating women should be advised not to breastfeed during treatment with epirubicin and for at least 7 days after last dose.
Epirubicin could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should seek advice on sperm preservation due to the possibility of irreversible infertility caused by therapy.
Epirubicin may cause amenorrhea or premature menopause in premenopausal women.
Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and to use effective contraceptive methods during treatment and for at least 6.5 months after last dose.
Men undergoing treatment with epirubicin should be advised to use effective contraceptive methods during treatment and for at least 3.5 months after the last dose.
There have been no reports of particular adverse events relating to effects on ability to drive and to use machines.
The following undesirable effects have been observed and reported during treatment with epirubicin 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, Frequency not known (cannot be estimated from the available data)
Very Common: Infection, Conjunctivitis
Uncommon: Sepsis*, Pneumonia*
Uncommon: Acute myeloid leukaemia, Acute lymphocytic leukaemia
Very Common: Anaemia, Leukopenia, Neutropenia, Thrombocytopenia, Febrile neutropenia
Rare: Anaphylactic reaction*
Common: Decreased appetite, Dehydration*
Rare: Hyperuricaemia*
Very Common: Keratitis
Common: Ventricular tachycardia, Atrioventricular block, Bundle branch block, Bradycardia, Cardiac failure congestive
Very Common:Hot flush, Phlebitis*
Common: Haemorrhage*, Flushing*
Uncommon: Embolism, Embolism arterial*, Thrombophlebitis*
Frequency not known: Shock*
Uncommon: Pulmonary embolism*
Very Common:Nausea, Vomiting, Stomatitis, Mucosal inflammation, Diarrhoea
Common: Gastrointestinal pain*, Gastrointestinal erosion*, Gastrointestinal ulcer*
Uncommon: Gastrointestinal haemorrhage*
Frequency not known: Abdominal discomfort, Pigmentation buccal*
Very Common:Alopecia, Skin toxicity
Common: Rash/Pruritus, Nail pigmentation*, Skin disorder, Skin hyperpigmentation*
Uncommon: Urticaria*, Erythema*
Frequency not known: Photosensitivity reaction*
Very Common:Chromaturia*†
Very Common:Amenorrhoea
Very Common:Malaise, Pyrexia*
Common: Chills*
Uncommon: Asthenia
Very Common:Transaminases abnormal
Common: Ejection fraction decreased
Very Common:Chemical cystitis*§
Frequency not known: Recall phenomenon*Δ
* ADR identified post-marketing.
† Red coloration of urine for 1 to 2 days after administration.
§ Following intravesical administration.
Δ Hypersensitivity to irradiated skin (radiation-recall reaction).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug.
Pharmorubicin should not be mixed with heparin due to chemical incompatibility which may lead to precipitation when the drugs are in certain proportions.
Pharmorubicin can be used in combination with other antitumour agents, but it is not recommended that it be mixed with other drugs.
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