Epilek

Epilek 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.

This medicinal product is for intravenous or intravesical use only.

Intravenous administration

It is advisable to administer Epilek 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 Epilek hydrochloride is used as a single agent, the recommended dosage in adults is 60-90 mg/m² body area. Epilek 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 Epilek 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, Epilek 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 Epilek 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 Epilek 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 Epilek 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.

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- 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 Epilek 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 Epilek are:

- Urinary tract infections

- Inflammation of the bladder

- Haematuria

- Invasive tumours penetrating the bladder

- Catheterisation problems

- Large volume of residual urine

- Contracted bladder

General - Epilek 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 Epilek.

Epilek 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 Epilek.

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

While treatment with high doses of Epilek (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 Epilek 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 Epilek 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 Epilek treatment.

Late (i.e. Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with Epilek 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 Epilek 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 Epilek and may be unresponsive to specific medical treatment.

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

Cardiac function should be assessed before patients undergo treatment with Epilek 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 Epilek 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 Epilek 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 Epilek 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 Epilek 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 Epilek may occur at lower cumulative doses whether or not risk factors are present. It is probable that the toxicity of Epilek 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 Epilek. This may be moderate to severe and has been associated with death.

Trastuzumab and anthracyclines such as Epilek 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 Epilek 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 Epilek are used, the patient's cardiac function should be monitored carefully.

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

Haematologic Toxicity- As with other cytotoxic agents, Epilek may produce myelosuppression. Haematological profiles should be assessed before and during each cycle of therapy with Epilek. 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 Epilek 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 10^th and 14^th day after drug administration; this is usually transient with WBC/neutrophil counts returning to normal in most cases by the 21^st day. Thrombocytopenia (< 100,000 platelets/mm³) is experienced in very few patients, even following high doses of Epilek. 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 Epilek. 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 - Epilek 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 Epilek is the hepatobiliary system. Before starting therapy with Epilek, 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 Epilek.

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

Epilek 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 Epilek 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 Epilek, 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 Epilek.

Tumor Lysis Syndrome - As with other cytotoxic agents, Epilek 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 Epilek, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Epilek. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Reproductive system - Epilek can have genotoxic effects. Men and women treated with Epilek 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 Epilek 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 Epilek (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 Epilek) 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.

Epilek contains sodium.

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

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

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

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

The following undesirable effects have been observed and reported during treatment with Epilek 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 Epilek 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

Symptoms:

Acute overdosage with Epilek 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.

Epilek cannot be removed by dialysis.

Pharmacotherapeutic group: Antineoplastic agent. ATC code: L01D B03

Epilek is a cytotoxic active antibiotic from the anthracycline group.

The mechanism of action of Epilek 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. Epilek 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).

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 Epilekol (13-OH Epilek) and glucuronides of Epilek and Epilekol.

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

Epilek 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.

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

Epilek, 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, Epilek must be considered potentially teratogenic.

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

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).

As with other potentially toxic compounds, caution should be exercised when handling Epilek (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.

Epilek (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.