Epirubicine mylan

Overdose

Symptoms:

Acute overdosage with Epirubicine Mylan will result in severe myelosuppression within 10-14 days (mainly leucopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and cardiac complications (acute myocardial degeneration within 24 hours). During this period a blood transfusion is required as well as isolation in a sterile room. Latent cardiac failure has been observed with anthracyclines several months (up to 6 months) to years after completion of treatment. Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic.

Epirubicine Mylan cannot be removed by dialysis.

Acute overdosage with epirubicin will result in severe myelosuppression (within 10 - 14 days; mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications (within 24 hours). Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment. Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic. Epirubicin cannot be removed by dialysis.

Contraindications

-

- Lactation

Contraindications to intravenous administration:

- Patients with marked or persistent myelosuppression induced by previous treatment with either other anti-neoplastic agents or radiotherapy,

- Patients with severe hepatic impairment

- Patients treated previously with maximum cumulative doses of Epirubicine Mylan and/or other anthracyclines such as doxorubicin or daunorubicin and anthracenediones

- Patients with current or previous history of cardiac impairment (including 4th degree muscular heart failure, acute heart attack and previous heart attack which led to 3rd and 4th degree muscular heart failure, acute inflammatory heart diseases, severe arrhythmia, myocardiopathy, recent myocardial infarction)

- Patients with acute systemic infections

- Patients with unstable angina pectoris

Contraindications to the intravesical administration of Epirubicine Mylan are:

- Urinary tract infections

- Inflammation of the bladder

- Haematuria

- Invasive tumours penetrating the bladder

- Catheterisation problems

- Large volume of residual urine

- Contracted bladder

Lactation.

Intravenous use:

- Persistent myelosuppression

- severe hepatic impairment

- severe myocardial insufficiency

- recent myocardial infarction

- severe arrhythmias

- previous treatments with maximum cumulative doses of epirubicin and/or other anthracyclines and anthracenediones

- patients with acute systemic infections

- unstable angina pectoris

- myocardiopathy

- acute inflammatory heart diseases

Intravesical use:

- urinary tract infections

- invasive tumours penetrating the bladder

- catheterisation problems

- inflammation of the bladder

- haematuria

- contracted bladder

- big volume of residual urine

Incompatibilities

Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug, which includes sodium bicarbonate containing solutions.

Neither the injection nor any diluted solution should be mixed with any other drugs (a physical incompatibility with heparin has been reported).

Prolonged contact of the medicinal product with any solution of an alkaline pH (including sodium bicarbonate solutions) should be avoided; this will result in hydrolysis (degradation) of the active substance.

A physical incompatibility of the medicinal product with heparin has been reported.

Undesirable effects

The following undesirable effects have been observed and reported during treatment with Epirubicine Mylan 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.

1High doses of Epirubicine Mylan have been safely administered in a large number of untreated patients having various solid tumours and have caused adverse events which are not different from those seen at conventional doses with the exception of reversible severe neutropenia (< 500 neutrophils/mm3 for < 7 days) which occurred in the majority of patients. Only few patients required hospitalisation and supportive therapy for severe infectious complications at high doses.

Intravesical 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. These ADRs are mostly reversible.

Reporting of suspected adverse reactions

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

The following undesirable effects have been observed and reported during treatment with epirubicin with the following frequencies:

Very common (> 1/10)

Common (> 1/100, < 1/10)

Uncommon (> 1/1,000, < 1/100)

Rare (> 1/10,000, < 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.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Secondary acute myeloid leukaemia with or without a pre-leukaemic phase, in patients treated with epirubicin in combination with DNA-damaging antineoplastic agents.

These leukaemias have a short (1 - 3 years) latency.

Blood and lymphatic system disorders:

High doses of epirubicin have been safely administered in a large number of untreated patients having various solid tumours and have caused adverse events which are not different from those seen at conventional doses with the exception of reversible severe neutropenia (< 500 neutrophils/mm³ for < 7 days) which occurred in the majority of patients. Only few patients required hospitalisation and supportive therapy for severe infectious complications at high doses.

Skin and subcutaneous tissue disorders:

Alopecia, normally reversible, appears in 60 - 90 % of treated cases; it is accompanied by lack of beard growth in males.

General disorders and administration site conditions:

Mucositis - may appear 5 - 10 days after the start of treatment, and usually involves stomatitis with areas of painful erosions, ulceration and bleeding, mainly along the side of the tongue and the sublingual mucosa.

Local pain and tissue necrosis (following accidental paravenous injection) may occur.

Intravesical administration:

As only a small amount of active ingredient is reabsorbed after intravesical instillation, severe systemic adverse 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. These ADRs are mostly reversible.

Reporting of suspected adverse reactions

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 www.mhra.gov.uk/yellowcard.

Preclinical safety data

Following repeated dosing with Epirubicine Mylan, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicine Mylan was also cardiotoxic in the rat, rabbit and dog.

Epirubicine Mylan, like other anthracyclines, was mutagenic, genotoxic, embryotoxic and carcinogenic in rats. No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, Epirubicine Mylan must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of Epirubicine Mylan causes tissue necrosis.

Following repeated dosing with epirubicin, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicin was also cardiotoxic in the rat, rabbit and dog.

Epirubicin, like other anthracyclines, was mutagenic, genotoxic and carcinogenic in rats. Embryotoxicity was seen in rats at clinically relevant doses.

No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic active substances, epirubicin must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of epirubicin causes tissue necrosis.

Therapeutic indications

Epirubicine Mylan Hydrochloride 2 mg/ml, solution for injection is used in the treatment of a range of neoplastic conditions including:

- Breast and gastric carcinomas,

When administered intravesically, this medicinal product has been shown to be beneficial in the treatment of:

- Papillary transitional cell carcinoma of the bladder,

- Carcinoma-in-situ,

- Prophylaxis of recurrences after transurethral resection.

Epirubicin is used in the treatment of a range of neoplastic conditions including:

- Carcinoma of the breast

- Advanced ovarian cancer

- Gastric cancer

- Small cell lung cancer

When administered intravesically, epirubicin has been shown to be beneficial in the treatment of:

- Papillary transitional cell carcinoma of the bladder

- Carcinoma-in-situ of the bladder

- Intravesical prophylaxis of recurrences of superficial bladder carcinoma following transurethral resection.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent. ATC code: L01D B03

Epirubicine Mylan is a cytotoxic active antibiotic from the anthracycline group.

The mechanism of action of Epirubicine Mylan 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. Epirubicine Mylan 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).

Pharmacotherapeutic group: Antineoplastic agent. ATC code: L01D B03

Epirubicin is a cytotoxic active antibiotic from the anthracycline group.

The mechanism of action of epirubicin 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 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).

Pharmacokinetic properties

In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m2 of the drug follow a tri-exponential 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 Epirubicine Mylanol (13-OH Epirubicine Mylan) and glucuronides of Epirubicine Mylan and Epirubicine Mylanol.

The 4'-O-glucuronidation distinguishes Epirubicine Mylan from doxorubicin and may account for the faster elimination of Epirubicine Mylan and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (Epirubicine Mylanol) are consistently lower and virtually parallel than those of the unchanged drug.

Epirubicine Mylan 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 drug does not cross the blood brain barrier.

In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m² of the medicinal product follow a tri-exponential 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. Between 60 and 120 mg/m² there is an extensive linear pharmacokinetic, 150 mg/m² is at the margin of dose linearity. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubicinol.

In pharmacokinetic studies of patients with carcinoma in situ of the bladder the plasma levels of epirubicin after intravesical instillation are typically low (< 10 ng/ml). A significant systemic resorption can therefore not be assumed. In patients with lesions of the mucosa of the bladder (e.g. tumour, cystitis, operations), a higher resorption rate can be expected.

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 active 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

General - Epirubicine Mylan should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Diagnostic and treatment facilities should be readily available management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of Epirubicine Mylan.

Epirubicine Mylan is not active when given orally and should not be injected intramuscularly or intrathecally.

Careful baseline monitoring of various laboratory parameters and cardiac function should precede initial treatment with Epirubicine Mylan.

Patients should recover from acute toxicities (such as stomatitis or mucositis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with Epirubicine Mylan.

While treatment with high doses of Epirubicine Mylan (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 Epirubicine Mylan requires 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 Epirubicine Mylan 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 Epirubicine Mylan treatment.

Late (i.e. Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with Epirubicine Mylan 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 Epirubicine Mylan in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution.

Above this level the risk of irreversible congestive heart failure increases greatly.

Heart failure may appear several weeks after discontinuing therapy with Epirubicine Mylan and may be unresponsive to specific medical treatment.

In establishing the maximal cumulative dose of Epirubicine Mylan, consideration should be given to any concomitant therapy with potentially cardiotoxic drugs.

Cardiac function should be assessed before patients undergo treatment with Epirubicine Mylan 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 Epirubicine Mylan 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 Epirubicine Mylan should be exceeded only with extreme caution.

An ECG is recommended before and after each treatment cycle. Alterations in the ECG tracing, such as flattening or inversion of the Twave, depression of the S-T segment, or the onset of arrhythmias, generally transient and reversible, need not necessarily be taken as indications to discontinue treatment. With cumulative doses < 900 mg/m2, there is evidence that cardiac toxicity rarely occurs. In case of cardiac insufficiency, treatment with Epirubicine Mylan should be discontinued.

Cardiomyopathy induced by anthracyclines is associated with persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction. Cardiac monitoring of patients receiving Epirubicine Mylan treatment is highly important and it is advisable to assess cardiac function by non-invasive techniques. Electrocardiogram (ECG) changes may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.

Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors, particularly prior anthracycline or anthracenedione use. However cardiotoxicity with Epirubicine Mylan may occur at lower cumulative doses whether or not risk factors are present. It is probable that the toxicity of Epirubicine Mylan and other anthracyclines or anthracenediones is additive.

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 and/or cardiotoxic drugs (e.g. trastuzumab) with an increased risk in the elderly.

Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzamab therapy alone or in combination with anthracyclines such as Epirubicine Mylan. This may be moderate to severe and has been associated with death.

Trastuzumab and anthracyclines such as Epirubicine Mylan 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.

Because the half-life of trastuzumab is approximately28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as Epirubicine Mylan after stopping trastuzumab may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as Epirubicine Mylan are used, the patient's cardiac function should be monitored carefully.

If symptomatic cardiac failure develops during trastuzumab therapy after Epirubicine Mylan therapy, it should be treated with the standard medications for this purpose.

Haematologic Toxicity- As with other cytotoxic agents, Epirubicine Mylan may produce myelosuppression. Haematological profiles should be assessed before and during each cycle of therapy with Epirubicine Mylan. Red blood cell, differential white blood cell (WBC), neutrophil and platelet counts should be carefully monitored both before and during each cycle of therapy. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestion of Epirubicine Mylan haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia are generally more severe with high-dose schedules reaching a nadir in most cases between the 10th and 14th day after drug administration; this is usually transient with WBC/neutrophil counts returning to normal in most cases by the 21st day. Thrombocytopenia (< 100,000 platelets/mm3) is experienced in very few patients, even following high doses of Epirubicine Mylan. Anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukaemia - Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines, including Epirubicine Mylan. Secondary leukemia 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 leukemias can have a 1- to 3-year latency period..

Gastrointestinal - Epirubicine Mylan is emetigenic. 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 Epirubicine Mylan is the hepatobiliary system. Before starting therapy with Epirubicine Mylan, and during treatment, liver function should be evaluated (SGOT, SGT, alkaline phosphatase, bilirubin, AST). Patients with elevated bilirubin or AST may experience slower clearance of the drug with an increase in overall toxicity. Lower doses are recommended in these patients. Patients with severe hepatic impairment should not receive Epirubicine Mylan.

Renal Function - Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dl.

Epirubicine Mylan may impart a red colour to the urine for one or two days after administration.

Effects at Site of Injection - Phlebosclerosis may result from injection into small vessels or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site.

Extravasation - Extravasation of Epirubicine Mylan from the vein during injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of Epirubicine Mylan, 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, use of 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 Epirubicine Mylan.

Tumor Lysis Syndrome - As with other cytotoxic agents, Epirubicine Mylan may induce hyperuricaemia because of the extensive purine metabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should therefore be evaluated after initial treatment so that this phenomenon may be recognised and properly managed. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimize potential complications of tumor-lysis syndrome.

Immunosuppressant Effects/Increased Susceptibility to Infections - Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including Epirubicine Mylan, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Epirubicine Mylan. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Reproductive system - Epirubicine Mylan can have genotoxic effects. Men and women treated with Epirubicine Mylan should adopt appropriate contraceptive measures. 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

Intravesical route - Administration of Epirubicine Mylan may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumors).

Intra-arterial route - Intra-arterial administration of Epirubicine Mylan (transcatheter arterial embolization 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 Epirubicine Mylan) 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.

Epirubicine Mylan contains sodium.

This medicinal product contains 3.6 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

General - 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, mucositis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment before beginning treatment with epirubicin.

While treatment with high doses of Epirubicine Mylan (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 Epirubicine Mylan 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 transient, reversible and 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 dyspnea, 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 Epirubicine Mylan in excess of 900 mg/m²; this cumulative dose should only be exceeded with extreme caution.

Monitoring of cardiac function. 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 Epirubicine Mylan should be exceeded only with extreme caution.

Cardiomyopathy induced by anthracyclines is associated with persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP) and a reduction of the ejection fraction (LVEF). Electrocardiogram (ECG) changes may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.

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) with an increased risk in the elderly.

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.

It is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive.

Cardiotoxicity in combination with trastuzumab. Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzamab 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.

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 after stopping trastuzumab may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin are used, 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.

Haematological toxicity - 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 leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin 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 administration of the medicinal product; 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. 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.

Gastrointestinal - Epirubicin is emetogenic. Mucositis/stomatitis generally appears early after administration of the medicinal product 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 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 the medicinal product with an increase in overall toxicity. Lower doses are recommended in these patients. Patients with severe hepatic impairment should not receive epirubicin.

Renal function - Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dl.

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 minimize the risk of phlebitis/thrombophlebitis at the injection site.

Extravasation - 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 infusion of the medicinal product 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, use of hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks. If 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.

Tumour-lysis syndrome - Epirubicin may induce hyperuricaemia because of the extensive purine catabolism that accompanies rapid lysis of neoplastic cells (tumour-lysis syndrome) induced by the medicinal product. 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 minimize potential complications of tumour-lysis syndrome.

Immunosuppressant effects/Increased susceptibility to infections - Vaccination with a live vaccine should be avoided in patients immunocompromised by chemotherapeutic agents including epirubicin as it may result in serious or fatal infections. Killed or inactivated vaccines may be administered to patients receiving epirubicin; however, the response to such vaccines may be diminished.

Reproductive system - Epirubicin can cause genotoxicity. Men and women treated with epirubicin 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

Intravesical route - 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., uretheral obstruction due to massive intravesical tumours).

Effects on ability to drive and use machines

There have been no reports of particular adverse events relating to the effects on ability to drive and to use machines.

The effect of Epirubicine Mylan on the ability to drive or use machinery has not been systematically evaluated.

Epirubicine Mylan may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.

The effect of epirubicin on the ability to drive or use machinery has not been systematically evaluated.

Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.

Dosage (Posology) and method of administration

This medicinal product is for intravenous or intravesical use only.

Intravenous administration

It is advisable to administer Epirubicine Mylan hydrochloride via the tubing of a free-running intravenous saline or glucose infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation. In case of extravasation, administration should be stopped immediately.

Conventional dose

When Epirubicine Mylan hydrochloride is used as a single agent, the recommended dosage in adults is 60-90 mg/m2 body area. Epirubicine Mylan hydrochloride should be injected intravenously over 3-5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient's haematomedullar status.

If signs of toxicity, including severe neutropenia/neutropenic fever and thrombocytopenia occur (which could persist at day 21), dose modification or postponement of the subsequent dose may be required.

Breast Cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of Epirubicine Mylan 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.

For high dose treatment, Epirubicine Mylan may be given as an intravenous bolus over 3-5 minutes or as an infusion of up to 30 minutes duration.

Lower doses (60-75 mg/m2 for conventional treatment and 105-120 mg/m2 for high dose treatment) are recommended for patients whose bone marrow function has 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.

The following doses of this medicinal product are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:

a Doses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals

A total cumulative dose of 900 - 1000 mg/m2 should not be exceeded due to a potential risk of cardiotoxicity.

Combination therapy

If Epirubicine Mylan hydrochloride is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above.

Liver impairment The major route of elimination of Epirubicine Mylan hydrochloride is the hepatobiliary system. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

* AST - aspartate aminotransferase

Renal impairment

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of Epirubicine Mylan hydrochloride excreted by this route. However, lower starting doses should be considered in patients with severe renal impairment (serum creatinine > 5 mg/dl).

Paediatric population

The safety and efficacy of this medicinal product in children has not been established.

Intravesical administration

This medicinal product can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be given intravesically for the treatment of invasive tumours that have penetrated the bladder wall, systemic therapy or surgery is more appropriate in these situations. This medicinal product has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water).

If local toxicity (chemical cystitis) is observed: a dose reduction to 30 mg/50 ml is advised.

Carcinoma-in-situ: up to 80 mg/50 ml (depending on individual tolerability of the patient)

For prophylaxis: 4 weekly administrations of 50 mg/50 ml followed by 11 monthly instillations at the same dose.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

The solution should be retained intravesically for 1-2 hours. 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.

Posology

Epirubicin is for intravenous or intravesical use only.

Paediatric population

The safety and efficacy of epirubicin in children has not been established.

Intravenous administration

It is advisable to administer epirubicin via the tubing of a free-running intravenous saline infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation. In case of extravasation, administration should be stopped immediately.

Dosage

In order to avoid cardiac toxicity, a total cumulative dose of 900 - 1,000 mg/m² Epirubicine Mylan should not be exceeded.

Conventional dose

When Epirubicine Mylan is used as a single agent, the recommended dosage in adults is 60 - 90 mg/m² body surface area. Epirubicine Mylan should be injected intravenously over 3 - 5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient's haematological status and bone marrow function.

If signs of toxicity, including severe neutropenia/neutropenic fever and thrombocytopenia occur (which could persist at day 21), dose modification or postponement of the subsequent dose may be required.

High dose

Epirubicin as a single agent for the high dose treatment of lung cancer should be administered according to the following regimens:

- Small cell lung cancer (previously untreated): 120 mg/m² Epirubicine Mylan on day 1, every 3 weeks.

For high dose treatment, epirubicin may be given as an intravenous bolus over 3 - 5 minutes or as an infusion of up to 30 minutes duration.

Breast cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of Epirubicine Mylan 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.

Lower doses (60 - 75 mg/m² for conventional treatment and 105 - 120 mg/m² for high dose treatment) are recommended for patients whose bone marrow function has 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.

The following doses of Epirubicine Mylan are commonly used in monotherapy and combination chemotherapy for various other tumours, as shown:

a Doses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals

Combination therapy

If Epirubicine Mylan is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above.

Impaired liver function

The major route of elimination of epirubicin is the hepatobiliary system. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

Impaired renal function

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route. However, dosage adjustment may be necessary in patients with serum creatinine > 5 mg/dl.

Intravesical administration

Epirubicin can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be given intravesically for the treatment of invasive tumours that have penetrated the bladder wall, systemic therapy or surgery is more appropriate in these situations. Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline or water for injection).

If local toxicity is observed: A dose reduction to 30 mg/50 ml is advised.

Carcinoma-in-situ: Up to 80 mg/50 ml (depending on individual tolerability of the patient)

For prophylaxis: 4 weekly administrations of 50 mg/50 ml followed by 11 monthly instillations at the same dose.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

The solution should be retained intravesically for 1 - 2 hours. 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.

Special precautions for disposal and other handling

As with other potentially toxic compounds, caution should be exercised when handling Epirubicine Mylan (hydrochloride) 2 mg/ml, solution for injection.

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to guarantee the protection of the handler and his surroundings.

Epirubicine Mylan (hydrochloride) 2 mg/ml, solution for 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.

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 below.

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 medicinal product or waste material should be disposed of in accordance with local requirements.

Epirubicine Mylan may be further diluted in glucose 5 % solution or sodium chloride 0.9 % solution and administered as an intravenous infusion.

The injection solution contains no preservative and any unused portion of the vial should be disposed of immediately in accordance with local requirements.

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 below.

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.