1. Name Of The Medicinal Product
Epirubicin hydrochloride 2 mg/ml solution for injection or infusion
2. Qualitative And Quantitative Composition
1 ml contains 2 mg epirubicin hydrochloride
Each 5 ml vial contains 10 mg epirubicin hydrochloride
Each 10 ml vial contains 20 mg epirubicin hydrochloride
Each 25 ml vial contains 50 mg epirubicin hydrochloride
Each 50 ml vial contains 100 mg epirubicin hydrochloride
Each 100 ml vial contains 200 mg epirubicin hydrochloride
For a full list of excipients, see section 6.1.
1 ml contains 3.5 mg sodium
3. Pharmaceutical Form
Solution for injection or infusion
Red, clear solution
4. Clinical Particulars
4.1 Therapeutic Indications
Intravenous use:
• Breast carcinoma
• Gastric carcinoma
Intravesical use:
• Prophylaxis of recurrences after transurethral resection
4.2 Posology And Method Of Administration
Epirubicin is not active when given orally and is not for intrathecal or intramuscular injection. For instructions on dilution of the product before administration, see section 6.6.
The safety and efficacy of epirubicin in children has not been established.
Intravenous use
It is advisable to give the drug via the tubing of a freely running intravenous infusion after checking that the needle is well placed in the vein. This method minimises the risk of drug extravasation and makes sure that the vein is flushed with infusion solution after the administration of the drug. Extravasation of epirubicin from the vein during injection may give rise to severe tissue lesions, even necrosis. In case of extravasation, administration should be stopped immediately. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.
Discard any unused solution.
Conventional doses
When epirubicin is used as a single agent, the recommended dose in adults is generally 60-90 mg/ m2 body area; the drug should be injected intravenously over 3
Alternatively, 20-30 mg/ m2 may be given weekly during palliative care in order to reduce frequency of adverse reactions or in patients who do not tolerate higher doses in a range as mentioned above.
Dose modification (reduction) following signs of toxicity (specifically severe neutropenia /neutropenic fever and thrombocytopenia, which could persist on day 21 after the first dose) could be required or the following dose could be delayed, as the case of liver impairment.
High doses
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/m²(in two divided doses on days 1 and 8) every 3 - 4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen, are recommended.
The most commonly used dosage schedule of epirubicin in metastatic breast cancer, when employed as a single agent for adults, is up to 135 mg/m2 administered at 212 has been used and has been reported to produce less clinical toxicity than higher doses given every three weeks.
In metastatic breast cancer, epirubicin usually can be used in combination with cyclophosphamide and 5-fluorouracil (FEC), at a dose of up to 120 mg/m2 every 3 weeks.
Epirubicin should be given as an intravenous bolus over 3 2 for conventional dose and 105 2 for high dose schedules) are recommended for patients whose bone marrow function has already been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone-marrow infiltration. The total dose per cycle may be divided over 2 - 3 successive days.
When epirubicin is used in combination with other antitumour agents, the doses need to be adequately reduced.
Impaired liver function
Since the major route of elimination of epirubicin is the hepatobiliary system, the doses should be reduced in patients with impaired liver function, in order to avoid an increase of overall toxicity. Moderate liver impairment (bilirubin: 20 - 50 µmol/l) requires a 50 % reduction of dose, while severe impairment (bilirubin > 50 µmol/l) necessitates a dose reduction of 75 %.
Impaired renal function
Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine > 450 µmol/l).
Intravesical use
Epirubicin may be given by intravesical administration for the treatment of superficial bladder carcinoma and carcinoma-in-situ. It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate. Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences.
While many regimens have been used, the following may be helpful as a guide: for therapy 8 x weekly instillations of 50 mg/25-50 ml (diluted with 0.9 % sodium chloride injection). In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg. For prophylaxis, 4 x weekly administrations of 50 mg/25
For the preparation of the solution for intravesical use see section 6.6.
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.
4.3 Contraindications
Epirubicin is contraindicated in patients with marked myelosuppression induced by previous treatment with other antitumour agents or by radiotherapy and in patients already treated with maximal cumulative doses of other anthracyclines such as Doxorubicin or Daunorubicin.
The drug is contraindicated in 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, arrhythmia with serious heamodynamic consequences).
The drug is contraindicated in patients with acute systemic infections.
Epirubicin is contraindicated in patients with hypersensitivity to epirubicin, other antracyclines and/or anthracenediones or to any of the excipients.
Epirubicin is contraindicated in lactating women.
Additional contraindications to the intravesical use are:
invasive tumors that had penetrated the vesical wall; urinary infections; inflammation of the bladder; catheterization problems; contracted bladder; big volume of residual urine
4.4 Special Warnings And Precautions For Use
Epirubicin therapy should be administered only under the supervision of a qualified physician experienced in antiblastic and cytotoxic therapy. Treatment with high dose epirubicin in particular requires the availability of facilities for the care of possible clinical complications due to myelosuppression.
Initial treatment calls for a careful baseline monitoring of various laboratory parameters and cardiac function.
During each cycle of treatment with epirubicin, patients must be carefully and frequently monitored. Red and white blood cells, neutrophils and platelet counts should be carefully assessed both before and during each cycle of therapy. Leukopenia and neutropenia are usually transient with conventional and high-dose schedules, reaching a nadir between the 10thand 14th day and returning to normal values by the 21st day; they are more severe with high dose schedules. Very few patients, even receiving high doses, experience thrombocytopenia (< 100,000 platelets/mm3).
Patients must have adequately recovered from severe stomatitis or mucositis before starting treatment with epirubicin.
Epirubicin is mainly eliminated via the liver. Therefore it is necessary to evaluate liver function (AST, ALT, alkaline phosphatase, bilirubin) prior to initiating treatment and during treatment. In patients with increased bilirubin levels or AST epirubicin clearance can be reduced, which may lead to increased toxicity. For these patients a dose reduction is recommended (see section 4.2). For patients with reduced renal function serum creatinine levels should be checked regularly prior to and during treatment. For patients with increased serum creatinine (>450µmol/l) a dose reduction is proposed (see section 4.2).
A cumulative dose of 900 2 should only be exceeded with extreme caution with both conventional and high doses.
Above this level the risk of irreversible congestive cardiac failure increases greatly. There is objective evidence that cardiac toxicity may occur rarely below this range. However, cardiac function must be carefully monitored during treatment to minimise the risk of cardiac failure of the type described for other anthracyclines.
Heart failure can appear even several weeks after discontinuing treatment and may prove unresponsive to specific medical treatment. The potential risk of cardiotoxicity may increase in patients who have received concomitant, or prior, radiotherapy to the mediastinal pericardial area.
In establishing the maximal cumulative doses of epirubicin, any concomitant therapy with potential cardiotoxic drugs should be taken into account.
It is recommended that an ECG before and after each treatment cycle should be carried out. Alterations in the ECG tracing, such as flattening or inversion of the T
Cardiomyopathy induced by anthracyclines, is associated with a 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 epirubicin treatment is highly important and it is advisable to assess cardiac function by non-invasive techniques such as ECG, echocardiography and, if necessary, measurement of ejection fraction by radionuclide angiography.
Like other cytotoxic agents, epirubicin may induce hyperuricaemia as a result of rapid lysis of neoplastic ells. Blood uric acid levels should therefore be carefully checked so that this phenomenon may be controlled pharmacologically.
Epirubicin may impart a red colour to the urine for 1
This medicinal product contains 3.5 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion can be used in combination with other anticancer drugs but patients should be monitored for additive toxicity. Concomitant use of other medicinal products that may be cardiotoxic or affect cardiac function should be monitored throughout treatment.
Drug interactions with epirubicin have been observed with cimetidine, verapamil/dexverapamil, dexrazoxane, docetaxel, interferon α2b, paclitaxel and quinine.Cimetidine 400 mg b.i.d given prior to epirubicin 100 mg/m2 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.
Verapamil/Dexverapamil may alter the pharmacokinetics of epirubicin and possibly increase its bone marrow depressant effects.
Prior administration of higher doses (900 mg/m2 and 1200 mg/m2) of dexrazoxane may increase the systemic clearance of epirubicin and result in a decrease in AUC.
One study found that docetaxel may increase the plasma concentrations of epirubicin metabolites when administered immediately after epirubicin.
The co-administration of interferon α2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin.
Paclitaxel may affect the pharmacokinetics of epirubicin and its metabolite, epirubicinol. In one study, haematological toxicity was greater when paclitaxel was administered before epirubicin compared with after epirubicin.
One study has shown that paclitaxel clearance is reduced by epirubicin.
Quinine may accelerate the initial distribution of epirubicin from blood into the tissues and may have an influence on the red blood cell partitioning of epirubicin.
The possibility of a marked disturbance of the haematopoiesis needs to be kept in mind with a (pre-) treatment with medications which influence the bone marrow (i.e. cytostatic agents, sulfonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, antiretroviral agents).
Cardiotoxicity of epirubicin is enhanced by certain radiotherapeutic treatments and by previous or concomitant use of other anthracycline derivates like mitomycin-c, dacarbazine, dactinomycin and possibly cyclophosphamide. Epirubicin can potentate the effect of radiation. Medicinal products that induce the cytochrome P450 system (e.g., rifampicin and barbiturates) can enhance epirubicin metabolism, with consequently reduced efficacy.
4.6 Pregnancy And Lactation
Epirubicin is a potential teratogen and if administered to pregnant women may cause miscarriage, embryotoxicity and foetal death. During pregnancy, particularly the first trimester, cytostatic drugs should only be used on strict indication and when the potential benefits to the mother have been weighed against possible risks to the foetus. Both men and women receiving epirubicin should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during epirubicin therapy, and use effective contraception during treatment with epirubicin.
It is unknown whether epirubicin is excreted in human breast milk. A risk to the breast-feeding infant cannot be excluded. Breast-feeding must be discontinued during treatment with epirubicin.
Fertility
Epirubicin can have genotoxic effects. Therefore, male patients treated with epirubicin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because of the possibility of infertility due to therapy with epirubicin.
Women should not become pregnant during treatment with epirubicin. Men and women should use an effective method of contraception during treatment and for six months thereafter.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed with Epirubicin.
Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.
4.8 Undesirable Effects
Adverse event frequencies have been categorised as follows:
Very common (
Common (
Uncommon (
Rare (
Infections and infestations:
Common: Fever, infections, pneumonia, sepsis and septic shock may occur as a result of myelosuppression.
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Rare: 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 year) latency.
Blood and lymphatic system disorders:
Common: Myelosuppression (leucopenia, granulocytopenia, neutropenia, febrile neutropenia, thrombo-cytopenia, anaemia). Haemorrhage and tissue hypoxia (as a result of myelosuppression) may occur.
High doses of epirubicin have been safely administered in a large number of untreated patients having various solid tumours and have caused adverse effects 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 a few patients required hospitalisation and supportive therapy for severe infectious complications at high doses.
Immune system disorders:
Common: Allergic reactions following intravesical administration.
Uncommon: Sensitivity to light or hypersensitivity in the case of radiotherapy ("recall phenomenon").
Rare: Anaphylaxis (anaphylactic/anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills).
Cardiac disorders:
Rare: Cardiotoxicity (ECG changes, tachycardia, arrhythmia, cardiomyopathy, congestive heart failure (dyspnoea, oedema, enlargement of the liver, ascites, pulmonary oedema, pleural effusions, gallop rhythm), ventricular tachycardia, bradycardia, AV block, bundle-branch block (see Section 4.4).
Vascular disorders:
Uncommon: Thrombophlebitis
Coincidental cases of thromboembolic events (including pulmonary embolism [in isolated cases with fatal outcome]) have occurred.
Gastrointestinal disorders:
Common: Nausea, vomiting, diarrhoea, which can result in dehydration, loss of appetite and abdominal pain. Oesophagitis and hyperpigmentation of the oral mucosa may also occur.
Skin and subcutaneous tissue disorders:
Very common: Alopecia, normally reversible, appears in 60-90 % of treated cases; it is accompanied by lack of beard growth in males.
Common: Hot flushes
Uncommon: Hyperpigmentation of skin and nails. Skin reddening.
Rare: Urticaria.
General disorders and administration site conditions:
Common: 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.
Common: Redness along the infusion vein, local phlebitis, phlebosclerosis, local pain and tissue necrosis (following accidental paravenous injection) may occur.
Uncommon: Headache
Rare: Fever, chills, dizziness, amenorrhea, azoospermia, hyperuricaemia (as a result of rapid lysis of neoplastic cells). Hyperpyrexia, malaise, weakness and increased transaminase levels have also been reported.
Injury, poisoning and procedural complications:
Common: Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration.
4.9 Overdose
Very high single doses of epirubicin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression within 10
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: cytotoxic antibiotics and related substances, anthracyclines. 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 leukemias, 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 i.v. injection of 60 2 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.
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 constantly 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
The drug does not cross the blood-brain-barrier. When epirubicin is administered intravesically the systemic absorption is minimal.
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 mutagenic, 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
Water for injections
Hydrochloric acid (for pH-adjustment)
Sodium chloride
6.2 Incompatibilities
Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion should not be mixed with heparin due to chemical incompatibility which may lead to precipitation when the drugs are in certain proportions.
Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion can be used in combination with other antitumour agents, but it is not recommended that it be mixed with other drugs. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf Life
Unopened container: 2 years
After dilution:
Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion may be further diluted, under aseptic conditions, in Glucose 5 % or Sodium chloride 0.9 %, and administered as an intravenous infusion. The infusion solution is chemically stable when stored in PE infusion bags, prepared under full aseptic conditions:
Sodium chloride 0.9 %: for 2 days at 25°C ± 2°C or for 4 days at 2-8°C protected from light.
Glucose 5 %: for 1 day at 25°C ± 2°C or for 2 days at 2-8°C protected from light.
From the 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 normally not be longer than 24 hours at 2 to 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 'in use' storage conditions, see section 6.3.
6.5 Nature And Contents Of Container
6 ml, 10 ml, 25 ml, 50 ml, 100 ml colourless glass vial (type I) with a rubber (chlorobutyl) stopper.
Package quantities:
Packs of | 1, 5 vials containing | 5 ml |
1, 5 vials containing | 10 ml | |
1, 5 vials containing | 25 ml | |
1, 5 vials containing | 50 ml | |
1, 5 vials containing | 100 ml |
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
The product should be brought to room temperature prior to use.
Epirubicin 2 mg/ml may be further diluted in Glucose 5% or Sodium Chloride 0.9%.
The injection solution contains no preservative and any unused portion of the vial should be disposed of immediately in accordance with local requirements
The following protective recommendations are given due to the toxic nature of this substance:
Personnel should be trained in good technique for reconstitution and handling.
Pregnant staff should be excluded from working with this drug.
Personnel handling Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion should wear protective clothing: goggles, gowns and disposable gloves and masks.
A designated area should be defined for reconstitution (preferably under laminar flow system). The work surface should be protected by disposable, plastic-backed, absorbent paper.
All items used for reconstitution, administration or cleaning including gloves should be placed in high-risk, waste disposal bags for high temperature incineration. 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 indicated previously.
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. In case of contact with the eye(s), hold back the eyelid of the affected eye(s), and flush with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.
Always wash hands after removing gloves.
7. Marketing Authorisation Holder
hameln pharma plus gmbh
Langes Feld 13
31789 Hameln
Germany
8. Marketing Authorisation Number(S)
PL 25215/0017
9. Date Of First Authorisation/Renewal Of The Authorisation
01/08/2008
10. Date Of Revision Of The Text
01/08/2008
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
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