Epirubicin Hydrochloride 2 Mg/Ml Solution For Injection
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Epirubicin Hydrochloride 2 mg/ml solution for injection or infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 2 mg epirubicin hydrochloride.
Each 5/10/25/50/100 ml vial contains 10/20/50/100/200 mg epirubicin hydrochloride. Excipient: Contains sodium 3.54 mg/ml (0.154 mmol).
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Solution for injection or infusion A clear red solution
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Epirubicin is used in the treatment of a range of neoplastic conditions including;
■ Carcinoma of the breast
■ Gastric 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.
• Prophylaxis of recurrences of superficial bladder carcinoma following transurethral resection
4.2 Posology and method of administration
Epirubicin is for intravenous or intravesical use only.
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 (see section 4.4). In case of extravasation, administration should be stopped immediately.
Conventional dose
When epirubicin is used as a single agent, the recommended dosage in adults is 60-90 mg/m2 body area. Epirubicin should be injected intravenously over 3-5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient's haematomedullary 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.
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 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 epirubicin ranging from 100 mg/m2 (as a single dose on day 1) to 120 mg/m (in two divided doses on days 1 and 8) every 3-4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen (in accordance with local guidelines) are recommended.
Lower doses (60-75 mg/m for conventional treatment and 105-120 mg/m 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 epirubicin are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:
|
Epirubicin Dose (mg/m2 )a | ||
|
Cancer Indication |
Monotherapy |
Combination Therapy |
|
Ovarian cancer |
60-90 |
50-100 |
|
Gastric cancer |
60-90 |
50 |
|
SCLC |
120 |
120 |
|
Bladder cancer |
50 mg/50 ml or 80 mg/50 ml | |
(carcinoma in situ)
Prophylaxis:
50 mg/50 ml weekly for 4 weeks then monthly for
__11months__
aDoses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals
Combination therapy
If epirubicin is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above. In establishing the maximal cumulative doses of Epirubicin (usually: 720 - 1000 mg/m2), any concomitant therapy with potentially cardiotoxic drugs should be taken into account.
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:
|
Serum Bilirubin |
AST* |
Dose Reduction |
|
1.4 - 3 mg/100 ml |
50% | |
|
> 3 mg/100 ml |
> 4 times upper normal limit |
75% |
*AST - aspartate aminotransferase
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. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine >450pmol/l).
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 (see section 4.3). 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 distilled sterile water).
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
|
Dose Epirubicin required |
Volume of 2 mg/ml epirubicin hydrochloride injection |
Volume of diluent sterile water for injection or 0.9% sterile saline |
Total volume for bladder installation |
|
30 mg |
15 ml |
35 ml |
50 ml |
|
50 mg |
25 ml |
25 ml |
50 ml |
|
80 mg |
40 ml |
10 ml |
50 ml |
The solution should be retained intravesically for 1- 2 hour. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.
4.3 Contraindications
Epirubicin is contraindicated in:
• Patients who have demonstrated hypersensitivity to the active substance or to any of the excipients, other anthracyclines or anthracenediones.
• Lactation
Intravenous use:
• Patients with persistent myelosuppression
• Patients with marked myelosuppression induced by previous treatment with either other anti-neoplastic agents or radiotherapy to the mediastinal pericardial area and/or who are under medical treatment with potentially cardiotoxic medicinal products (see section 4.5).
• Patients treated with maximal cumulative doses of epirubicin and/or other anthracyclines (e.g. doxorubicin or daunorubicin) and anthracenediones (see section 4.4).
• Patients with current or previous history of cardiac impairment and myocardial infraction.
• Patients with acute systemic infections.
• Sever liver impairment.
• Severe arrhythmias
• Unstable angina pectoris
• Myocardiopathy
Epirubicin is contraindicated for intravesical administration in case of:
• Urinary tract infections.
• Invasive tumours penetrating the bladder.
• Catheterisation problems.
• Inflammation of the bladder.
• Hematuria
4.4 Special warnings and precautions for use
General
Epirubicin should only be administered under the supervision of a qualified physician who is experienced in the use of cytotoxic therapy. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of epirubicin.
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/mucositis 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, and concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab) (see section 4.5).
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.
Haematologic 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 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 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 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 leukaemia's can have a 1- to 3-year latency period. (See section 5.1).
Gastrointestinal - Epirubicin 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 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).
Renal Function - 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).
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 (see section 4.2).
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 drug infusion should be discontinued immediately. The patient’s pain may be relieved by cooling down the area and keeping it cool for 24 hours. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.
Other - As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of epirubicin
Tumor-Lysis Syndrome - 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 alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumour-lysis syndrome.
Immunosuppressant Effects/Increased Susceptibility to Infections- Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. (see section 4.5).
Reproductive system. Epirubicin can cause genotoxicity. Men and women treated with epirubicin 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 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).
Intra-arterial route - 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.
4.5 Interaction with other medicinal products and other forms of interaction
Epirubicin is mainly used in combination with other anti-cancer agents. Additive toxicity may occur especially with regard to bone marrow/hematologic and gastrointestinal 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 Special warnings and precautions for use).
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 half-life of trastuzumab is approximately 28.5 days and may persist in the circulation for up to 24 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to 24 weeks after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
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 400 mg b.i.d given prior to epirubicin 100 mg/m every 3 weeks led to a 50% increase in epirubicin AUC and a 41% increase in epirubicinol AUC (latter p<0.05). The AUC of the 7-deoxy-doxorubicinol aglycone and liver blood flow were not reduced, so results are not explained by reduced cytochrome P-450 activity. Epirubicin used in combination with other cytotoxic agents may result in additive myelotoxicity.
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. Coadministration 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 in to the tissues and may have an influence on the red blood cells partitioning of epirubicin.
The co-administration of interferon a2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin.
The possibility of a marked disturbance of haematopiesis needs to be kept in mind with a (pre-) treatment with agents which influence the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol, diphenylhydantoin, amidopyrinedervatives, antiretroviral agents).
4.6 Fertility, pregnancy and lactation
Impairment of Fertility
Epirubicin could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should use effective contraceptive methods and if appropriate and available, seek advice on sperm preservation due to the possibility of irreversible infertility caused by therapy.
Epirubicin may cause amenorrhea or premature menopause in premenopausal women. Pregnancy
Experimental data in animals suggest that epirubicin may cause foetal harm when administered to a pregnant woman. If epirubicin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.
There are no studies in pregnant women. Epirubicin should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Lactation
It is unknown whether epirubicin is excreted in human breast 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, mothers should discontinue nursing prior to taking this drug.
4.7 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. Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of the ability to drive or operate machines.
4.8 Undesirable effects
The estimation of frequency: 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.
Infections and infestations
Common: Infections
Not known: pneumonia, sepsis and septic shock may occur as a result of myelosuppression.
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Rare: Acute lymphocytic leukaemia, Secondary acute myeloid leukaemia with or without a pre-leukemic phase in patients treated with epirubicin in combination with DNA-damaging antineoplastic agents. These leukaemia’s have short (1-3 years) latency.
Blood and lymphatic system disorder
Very common: Myelosuppression* (leucopoenia, granulocytopenia and neutropenia, anaemia and febrile neutropenia).
Uncommon: Thrombocytopenia.
Not known: Haemorrhage and tissue hypoxia as result of myelosuppression.
* 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 no 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.
Immune system disorders Rare: Anaphylaxis.
Metabolism and nutrition disorders
Common: Anorexia, dehydration.
Rare: Hyperuricaemia (as a result of rapid lysis of neoplastic cells) (see section 4.4).
Nervous system disorders Rare: Dizziness
Eye disorders
Not known: Conjunctivitis, keratitis
Cardiac disorders
Rare: Cardiotoxicity (ECG changes, tachycardia, arrhythmia, cardiomyopathy, congestive heart failure (dyspnoea, oedema, enlargement of the liver, ascites, pulmonary oedema, pleural effusion, gallop rhythm), ventricular tachycardia, bradycardia, AV block, bundle-branch block) (see section 4.4).
Vascular disorders Common: Hot flushes.
Uncommon: Phlebitis, Thrombophlebitis.
Not known: Shock, Coincidental cases of thromboembolic events (including pulmonary embolism (in isolated cases with fatal outcome)) have occurred.
Gastrointestinal disorders
Common: Mucositis may appear 5-10 days after the start of treatment and usually involves stomatitis with areas of painful erosions, ulceration and bleedings, mainly along the side of the tongue and the sublingual mucosa, oesophagitis, vomiting, diarrhoea, nausea
Skin and subcutaneous tissue disorders
Very Common: Alopecia Rare: Urticaria
Not Known: Local toxicity, rash, itch, skin changes, erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction)
Renal and urinary disorders
Very common: Red coloration of urine for 1 to 2 days after administration
Reproductive system and breast disorders
Rare: Amenorrhea, azoospermia.
General disorders and administration site conditions
Common: Redness along the infusion vein. Phlebosclerosis, Local pain and tissue necrosis may occur (following accidental paravenous injection).
Rare: Fever, chills, hyperpyrexia, malaise, asthenia, weakness.
Investigations
Rare: Increased transaminase levels.
Not Known: Asymptomatic drops in left ventricular ejection fraction
Injury, poisoning and procedural complications
Common: Chemical cystitis, in some cases haemorrhagic, is observed following intravesical administration (see section 4.4).
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 (polakisuria).Occasional bacterial or chemical cystitis have been reported (see section 4.4). These ADRs are mostly reversible.
4.9 Overdose
Acute overdosage with epirubicin will result in severe myelosuppression (mainly leucopoenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications. Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment (see section 4.4). Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.
Treatment:
Symptomatic: Treatment should aim to support the patient during this period and should utilize such measures as blood transfusion and reverse barrier nursing. Delayed cardiac failure has been seen with the anthracyclines up to 6 months after the overdose. Patients should be observed carefully and should, if signs of cardiac failure arise, be treated along conventional lines. Epirubicin is not dialyzable.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anthracylines and related substances ATC code: L01D B03.
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).
5.2 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 epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubicinol.
In a pharmacokinetic study of patients with carcinoma in situ in the bladder the plasma levels of epirubicin after intravesical administration are typically low (<10 ng/ml). A significant systemic resorption is therefore not presumed. In patients with mucous membrane lesions in the bladder (e.g. tumour, cystitis, operations) an increased resorption rate may 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 drug.
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 drug does not cross the blood brain barrier
5.3 Preclinical safety data
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 genotoxic, embryotoxic and carcinogenic in rats.
No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, epirubicin must be considered potentially teratogenic.
A local tolerance study in rats and mice showed extravasation of epirubicin causes tissue necrosis.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium Chloride
Hydrochloric acid (For pH adjustment)
Water for Injections
6.2 Incompatibilities
Prolonged contact of the medicinal product with any solution of alkaline pH (including sodium bicarbonate solutions) should be avoided; this will result in hydrolysis (degradation) of the active substance. Only the diluents detailed in section 6.6 should be used.
Neither the injection nor any diluted solution should be mixed with any other drugs. A physical incompatibility with heparin has been reported.
Epirubicin should not be mixed with other drugs.
6.3 Shelf life
Shelf life of the product as package for sale: 2 year.
Shelf life after first opening the container:
The vials are for single use only and any unused portion must be discarded after use. From a microbiological point of view, the product should be used immediately after the first penetration of the rubber stopper. If not used immediately, in use storage times and conditions are the responsibility of the user.
Shelf life after dilution of the solution for injection:
Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted, under aseptic conditions, in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light. For storage after dilution, see section 6.3.
6.5 Nature and contents of container
5 and 10 ml vials: Type I tubular glass vial with either teflon-coated rubber stopper or siliconised rubber stopper with teflon film on plug surface and aluminium flip-off white seal.
25 ml vial: Type I tubular glass vial with either teflon-coated rubber stopper or siliconised rubber stopper with teflon film on plug surface and aluminium flip-off white / royal blue seal.
50 ml vial: Type I clear moulded glass vial with either teflon-coated rubber stopper or siliconised rubber stopper with teflon film on plug surface and aluminium flip-off royal blue seal.
100 ml vial: Type I clear moulded glass vial with either teflon-coated rubber stopper or siliconised rubber stopper with teflon film on plug surface and aluminium flip-off white / royal blue seal.
Pack size: 1 vial.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. For information on the stability of the infusion solutions, please refer to section 6.3.
The solution for injection or infusion contains no preservative and any unused portion of the vial should be discarded 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.
7 MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited,
Sage House, 319, Pinner Road,
North Harrow,
Middlesex, HA1 4HF,
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20075/0024
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19/02/2009
10 DATE OF REVISION OF THE TEXT
18/09/2012