INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ASPEN EPIRUBICIN 10 mg
ASPEN EPIRUBICIN 50 mg

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ASPEN EPIRUBICIN 10 mg
(powder for solution for injection)
ASPEN EPIRUBICIN 50 mg
(powder for solution for injection)

COMPOSITION:
ASPEN EPIRUBICIN 10 mg:
Epirubicin HCl 10 mg
ASPEN EPIRUBICIN 50 mg: Epirubicin HCl 50 mg
Methyl parahydroxybenzoate 3,2% m/m.

PHARMACOLOGICAL CLASSIFICATION:
A 26 Cytostatic agents

PHARMACOLOGICAL ACTION:
Epirubicin is an anthracycline antibiotic with antineoplastic activity. The exact mechanism of action is unclear, but it appears to be due to intercalation of anthracycline with DNA, eventually inducing DNA cleavage by topoisomerase II. Other cytotoxic mechanisms may be due to inhibition of DNA helicase, thus impairing DNA synthesis and free radical generation. These mechanisms inhibit cellular nucleic acid synthesis and mitosis, resulting in cell death.
Pharmacokinetics:
Epirubicin, after intravenous administration is extensively distributed into tissues, resulting in a triphasic elimination pattern with half-lives of 3 minutes, 2,5 hours and 33 hours (mean half-life of 40 hours). Epirubicin undergoes hepatic biotransformation to less active metabolites or to metabolites with no inherent activity. It is highly bound to plasma albumin (77%) and is excreted via the biliary (35%) and renal (20%) systems. It does not cross the blood-brain barrier.

INDICATIONS:
ASPEN EPIRUBICIN is indicated as mono chemotherapy for the treatment of a wide spectrum of neoplasms including breast and gastric carcinomas, malignant lymphomas and soft tissue sarcomas. It may have some benefit in advanced colorectal carcinoma and in malignant melanoma. When given in combination with other chemotherapeutic agents, ASPEN EPIRUBICIN has been used in the treatment of lung and ovarian cancer.

CONTRA-INDICATIONS:
Hypersensitivity to ASPEN EPIRUBICIN, other anthracyclines or to any components of the formulation.
Patients with myelosuppression induced by previous chemotherapeutic agents or radiation therapy.
Patients treated with maximal cumulative doses of other anthracycline derivatives such as daunorubicin and doxorubicin.
Buccal ulceration –ASPEN EPIRUBICIN should not be administered if present, or if a buccal burning sensation is present, which can precede the onset of buccal ulceration.
Patients with current or previous history of cardiac dysfunction.
Pregnancy, particularly in the first trimester and during lactation.
Severe hepatic function impairment.
Baseline neutrophil count <1,500 cells/mL.

WARNINGS:
ASPEN EPIRUBICIN should be administered under supervision of a doctor experienced in the use of cancer chemotherapeutic agents. Initiation and maintenance of treatment requires careful monitoring of baseline parameters and cardiac function (see SPECIAL PRECAUTIONS).
ASPEN EPIRUBICIN should be given with great care in reduced doses in the elderly and in those with hepatic impairment. Liver function testing should be performed before commencing treatment, and at regular intervals whilst on therapy.
Use of ASPEN EPIRUBICIN in a patient who has previously received daunorubicin, doxorubicin, idarubicin, mitoxantrone or radiation therapy to the mediastinal area may increase the risk of cardiotoxicity.

INTERACTIONS:
ASPEN EPIRUBICIN should not be mixed with heparin as incompatibility and precipitation of the medicines has been reported.
Concomitant administration of ASPEN EPIRUBICIN with blood dyscrasia-causing medications, bone marrow suppressants or radiation therapy may potentiate the risk of bone marrow suppression.
Cimetidine –concomitant administration with ASPEN EPIRUBICIN increases the concentration of ASPEN EPIRUBICIN, by reducing plasma clearance by as much as 30%.
Cardio-active compounds such as calcium channel blockers may contribute to cardiotoxicity and may precipitate cardiac failure.

PREGNANCY AND LACTATION:
Safety and efficacy in pregnancy and lactation have not been established.
Women of childbearing age should be advised not to fall pregnant while taking ASPEN EPIRUBICIN and to consider using contraception.
It is unknown whether ASPEN EPIRUBICIN is excreted into breast milk. Other anthracycline derivatives are excreted into breastmilk and breastfeeding is therefore not recommended because of potential harm to the infant.

DOSAGE AND DIRECTIONS FOR USE:
Safety and efficacy in paediatric patients has not been established.
Regular testing of the haemoglobin, leukocyte count, platelet count and albumin are recommended at the start of therapy and before each subsequent dose.
ASPEN EPIRUBICIN should be administered by intravenous injection only, not intrathecally or intramuscularly. The medicine is not pharmacologically active if given orally.
Monotherapy: 60 to 90 mg/m
2 body surface area.
ASPEN EPIRUBICIN should be given by slow intravenous injection over 3 to 5 minutes and, depending on the bone marrow response, can be repeated after a 21 day cycle.
In the treatment of advanced breast cancer doses of up to 135 mg/m
2 body surface area can be used every 3 to 4 weeks.
Patients with inadequate marrow reserves (e.g. the elderly, doses given prior to other chemotherapy or radiotherapy and patients with neoplastic bone marrow infiltration) should be given lower doses of 60 to 75 mg/m
2 body surface area. In these cases, the total dose per cycle can be divided over 2 to 3 consecutive days.
Combination therapy: When used in combination with other chemotherapeutic agents, the dose of ASPEN EPIRUBICIN needs to be adjusted appropriately. In advanced breast cancer, when used in combination, doses of up to 120 mg/m
2 body surface area can be used every 3 to 4 weeks.
Hepatic dysfunction:
• Moderate liver impairment.
Total serum bilirubin of 24 to 51,3 mmol/L requires a dose reduction of 50%.
Renal dysfunction:
Moderate renal impairment does not require a dosage adjustment for ASPEN EPIRUBICIN because of the limited amount excreted by this route.
Concomitant or previous radiation to the mediastinal or pericardial area:
The maximum cumulative dose should be lowered to 400 to 450 mg/m
2.
Administration precautions:
Caution should be exercised with handling and preparation of ASPEN EPIRUBICIN. A designated area, preferably a laminar flow system, should be used for reconstitution.
The work surface should be covered by plastic-backed absorbent paper. All items used for reconstitution should be placed in high risk, waste-disposable bags for high temperature incineration. Skin reactions with accidental exposure to the powder or solution may occur and use of gloves and masks is recommended. If ASPEN EPIRUBICIN does contact skin or mucosae, the area should be washed copiously with soap and warm water. Eyes should be irrigated with 0,9% saline.
Preparation for intravenous infusion:
ASPEN EPIRUBICIN may be dissolved in sterile water for injection or 0,9% sodium chloride solution and reconstituted as follows:

FREEZE-DRIED PREP DILUENT ADDED FINAL CONCENTRATION
10 mg 5 mL 2 mg/mL
50 mg 25 mL 2 mg/mL
After adding the diluent, shake the vial to ensure all the medicine has been completely dissolved. The reconstituted solution must be used immediately after first penetration of the rubber stopper. Storage of the reconstituted solution is not recommended. Any unused portion of the solution should be discarded. ASPEN EPIRUBICIN should be administered into the tubing of a freely running intravenous infusion set containing normal saline, after checking that the needle is well placed in the vein. If extravasation into the surrounding tissue occurs, severe tissue lesions, including necrosis may occur.
Venous sclerosis may result from injections into small calibre veins or from repeated injections into the same vein.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Side effects:
Haematological:
Frequent: Leukopenia, neutropenia.
Less frequent: Thrombocytopenia, bleeding
Cardiovascular:
Rare: Cardiotoxicity (may manifest as an acute, transient alteration of normal cardiac function, or as a delayed, potentially fatal chronic congestive cardiac failure and may occur up to 6 months after administration), acute life-threatening arrhythmias (during or within a few hours of intravenous administration).
The following side-effects have been reported and frequencies are unknown: Hypotension.
Nervous System:
The following side-effects have been reported and frequencies are unknown: Headache.
Endrocine/Metabolic:
Rare: Hyperuricaemia.
The following side-effects have been reported and frequencies are unknown: Gynaecomastia, suppression of ovarian or testicular function leading to amenorrhoea or inhibition of spermatogenesis respectively.
Gastrointestinal:
Frequent: Buccal ulceration, nausea, vomiting, stomatitis, oesophagitis.
Less frequent: Diarrhoea.
Rare: Anorexia.
The following side-effects have been reported and frequencies are unknown: abdominal pain, gastrointestinal bleeding, ulceration or perforation.
Kidney/Genitourinary:
Frequent: Nephrotoxicity, red discolouration of the urine for 1 to 2 days after administration
Rare: Acute renal failure due to uric acid nephropathy as a result of rapid tumour lysis causing hyperuricaemia.
Musculoskeletal:
Rare: Weakness, malaise.
Ocular:
Less frequent: Conjunctivitis, increased lacrimation.
Skin:
Frequent: Alopecia.
Rare: Erythema (often at sites of prior irradiation), darkening of the soles, palms or nails, tissue necrosis due to extravasation from the vein, thrombophlebitis.
The following side-effects have been reported and frequencies are unknown: Facial flushing, poor wound healing, rashes, pruritus.
Other:
Rare: Allergic reactions, anaphylaxis

Special precautions:
ASPEN EPIRUBICIN has been associated with:-
Bone marrow suppression –Myelosuppression may occur, particularly in those who have previously had chemotherapy or radiotherapy. The nadir in the white cell count is approximately 10 days post administration and usually recovers by day 21.
  If thrombocytopenia occurs as a consequence of administration of ASPEN EPIRUBICIN, patients should be observed carefully for signs of bleeding (skin, intravenous puncture sites, mucosae, unusual bruising, melaena stools, haematuria). Intramuscular injections, alcohol, aspirin and contact sports should be avoided. Platelet transfusions may be required.
Patients who develop leukopenia should be carefully observed for signs of infection.
Antibiotic support may be necessary. In neutropenic patients who develop fever, empiric broad spectrum antibiotics should be initiated, pending bacterial culture results.
Immunisations should be avoided unless approved by the attending doctor.
Cardiac toxicity –The risk of cadiotoxicity appears to be related to prior mediastinal radiation therapy, pre-existing cardiac disease and a total cumulative dose of ASPEN EPIRUBICIN that exceeds 550 mg/m2 body surface area. Cardiac monitoring is strongly recommended with the use of noninvasive techniques such as ECG, echocardiography and if indicated, measurement of ejection fraction by radionuclide angiography. An ECG should be performed before and after each treatment cycle. Alterations in the ECG tracing like flattening or inversion of the T wave, new onset arrhythmias, S-T segment depression may occur, but are not necessarily indicators to stop treatment. Anthracycline-induced cardiomyopathy is characterised by a persistent reduction in the QRS voltages on ECG, prolonged systolic intervals (PEP/LVET) and a diminished ejection fraction. The benefit derived from exceeding the cumulative dose of ASPEN EPIRUBICIN, versus the risk of anthracycline-induced cardiomyopathy and congestive heart failure should be carefully weighed.
Hyperuricaemia – Administration of ASPEN EPIRUBICIN may induce hyperuricaemia from lysis of tumour cells. Uric acid levels should be monitored and appropriately treated if indicated.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
(See SIDE EFFECTS AND SPECIAL PRECAUTIONS)
Treatment of overdose:
Treatment is symptomatic and supportive.

IDENTIFICATION:
A red-orange compact aggregate of fragments with porous appearance.
Appearance of reconstituted solution: Clear, red-orange solution.

PRESENTATION:
ASPEN EPIRUBICIN is presented in 10 ml (for 10 mg) and 30 ml (for 50 mg) clear, colourless type I vials, closed with grey bromobutyl stoppers (Type I), an aluminium cap and a grey polypropylene top.

STORAGE:
Store the freeze-dried product in a dry place below 25ºC. Protect from light. The reconstituted solution must be used immediately after first penetration of the rubber stopper.
Storage of the reconstituted solution is not recommended.
Any unused portion must be discarded.
Do not remove the vial from the carton until required for use.
KEEP OUT OF THE REACH OF CHILDREN

REGISTRATION NUMBER:
ASPEN EPIRUBICIN 10 mg (powder): 42/26/0018
ASPEN EPIRUBICIN 50 mg (powder): 42/26/0019

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
2191

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
18 September

2007 0893 PL 01

PATIENT INFORMATION LEAFLET

Read all of this leaflet carefully before you start taking this medicine
• Keep this leaflet. You may need to read it again.
• If you have further questions, please ask your doctor or your pharmacist.
• This medicine has been prescribed for you personally and you should not share your medicine with other people. It may harm them, even if their symptoms are the same as yours.

Schedule 4

ASPEN EPIRUBICIN 10
(powder for solution for injection)
ASPEN EPIRUBICIN 50
(powder for solution for injection)
Epirubicin HCL

1. WHAT ASPEN EPIRUBICIN 10 MG AND ASPEN EPIRUBICIN 50 MG CONTAIN:
The active substance in ASPEN EPIRUBICIN is Epirubicin hydrochloride.

Each vial contains:-
ASPEN EPIRUBICIN 10: Epirubicin HCl 10 mg with lactose and Methyl parahydroxybenzoate 3,2% m/m.
ASPEN EPIRUBICIN 50: Epirubicin HCl 50 mg with lactose and Methyl parahydroxybenzoate 3,2% m/m.

2. WHAT ASPEN EPIRUBICIN 10 AND ASPEN EPIRUBICIN 50 ARE USED FOR:
The active ingredient in ASPEN EPIRUBICIN 10 and ASPEN EPIRUBICIN 50 belongs to the group of medicines (anthracyclines) known as antineoplastic agents.
ASPEN EPIRUBICIN is used to treat a variety of cancers, either alone or in combination with other drugs. The way in which it is used depends upon the type of cancer that is being treated.
When injected into the bloodstream , ASPEN EPIRUBICIN has been found to be useful in the treatment of cancers of the breast, ovaries, stomach, bowel and lung. In addition ASPEN EPIRUBICIN can be given the same way to treat cancers of the blood forming tissues such as malignant lymphomas, leukaemias and multiple myeloma.
ASPEN EPIRUBICIN contains a medicine that acts upon cells that are actively growing, in such a way as to slow or stop their growth, and increasing the likelihood that the cells die. Cells that actively grow, such as those in cancer are affected most by ASPEN EPIRUBICIN treatment. This helps to selectively kill the cancer tissue rather than normal, healthy tissue.

3. BEFORE YOU TAKE ASPEN EPIRUBICIN 10 AND ASPEN EPIRUBICIN 50:
Do not take ASPEN EPIRUBICIN 10 OR ASPEN EPIRUBICIN 50 if:
You are allergic to epirubicin hydrochloride or any of the other ingredients contained in this medicine.
You are aware that your blood counts are too low, as ASPEN EPIRUBICIN can lower them further.
You are sexually active. You are advised to use effective birth control to prevent pregnancy during treatment.
You are breastfeeding.
Take special care with ASPEN EPIRUBICIN 10 and ASPEN EPIRUBICIN 50:
If you are given medicines containing cimetidine.
If your liver or kidneys are not working properly.
If you are prescribed ASPEN EPIRUBICIN it should only be given to you by doctors or nurses experienced in giving chemotherapy.
Pregnancy and Breast-feeding:
If you are pregnant or breast feeding your baby while taking this medicine, please consult your doctor, pharmacist or other healthcare professional for advice.
ASPEN EPIRUBICIN 10 or ASPEN EPIRUBICIN 50 may not be used at any time during pregnancy or whilst breast-feeding.

Taking other medicines with ASPEN EPIRUBICIN 10 or ASPEN EPIRUBICIN 50:
If you are taking other medicines on a regular basis, including complementary or traditional medicines, the use of ASPEN EPIRUBICIN with these medicines may cause undesirable interactions. Please consult your doctor, pharmacist or other healthcare professional, for advice.
Please inform your doctor or pharmacist
- if you are given medicines containing cimetidine- Cimetidine increases the amount of time epirubicin stays in the body.

4. HOW TO TAKE ASPEN EPIRUBICIN 10 AND ASPEN EPIRUBICIN 50:
Always take ASPEN EPIRUBICIN 10 and ASPEN EPIRUBICIN 50 exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure.
Do not share medicines prescribed for you with any other person.
The dose of ASPEN EPIRUBICIN will be different for different patients. The dose that is used may depend on a number of things, including what the medicine is being used for, the patient’s size, and whether or not other medicines are also being taken. If you have any questions about the proper dose of ASPEN EPIRUBICIN, ask your doctor.
ASPEN EPIRUBICIN should be administered only by intravenous injection. It is not active when given orally and should not be injected intramuscularly or intrathecally.
Your doctor will decide on the dose and number of days’treatment you receive depending on your condition and other treatment you may receive.
While one course of treatment may sometimes be enough, more often your doctor will advise further courses in three or four weeks time. It may take several courses before your illness is under control and you feel better.

If you take more ASPEN EPIRUBICIN 10 or ASPEN EPIRUBICIN 50 than you should:
In the event of overdosage, consult your doctor or pharmacist. If neither is available, seek help at the nearest hospital or poison control center.
You may notice sores in your mouth or the number of white blood cells and platelets (these help the blood to clot) in your blood may decrease. Should this happen, you may need antibiotics or blood transfusions. Mouth ulcers can be treated to make them less uncomfortable as they heal. Heart damage can occur when high doses of ASPEN EPIRUBICIN are given. This may not be detected for several weeks so regular heart monitoring may be required for several weeks after your treatment has stopped.
If you notice any of these symptoms in yourself or any one else that has possibly taken more of this medicine than prescribed, please contact your doctor, pharmacist or nearest hospital immediately.

If you forget to take ASPEN EPIRUBICIN 10 or ASPEN EPIRUBICIN 50:
Do not use a double dose to make up for forgotten individual doses.

5. POSSIBLE SIDE-EFFECTS:
ASPEN EPIRUBICIN 10 and ASPEN EPIRUBICIN 50 can have side effects.
When you are being given ASPEN EPIRUBICIN, if you feel pain, or a burning or stinging sensation at the place where the medicine goes into your vein you must tell your doctor immediately. Allergic reactions can occur as the medicine is given – you may feel feverish, short of breath with a tight chest or throat, or dizzy should this occur. If this happens, tell your doctor or nurse immediately.
Between courses of treatment you may notice the following:
- Reddening of your urine, which is a normal occurrence related to the colour of the medicine, and should stop after a few days.
- Hair loss is common and may be quite severe. Beard growth may stop in men. Hair normally re-grows when treatment course ends.
- Mouth ulcers can occur, and there may be a feeling of sickness (nausea), vomiting or diarrhoea.
- If you feel feverish, suffer chills or rashes it is important you tell your doctor, as you may be allergic to ASPEN EPIRUBICIN.
- Your doctor should test your blood count during treatment to detect anaemia (a low red blood cell count) that can leave you feeling tired and lethargic.
- White blood cell counts can also drop, increasing the chance of infections and a raised temperature or fever.
- Different blood components called platelets can be affected making you bruise more easily, or bleed more than usual if you hurt yourself. It is important to seek medical advice if this happens.
When given in combination with other anti-cancer drugs, some patients have developed a secondary leukaemia after completing treatment. This is rare.
Your doctor will be making regular checks of
- Your blood to check for low blood cell counts that may need treatment.
- Your heart function, as ASPEN EPIRUBICIN can have effects upon this.
- Your liver –again using blood tests –to check that ASPEN EPIRUBICIN is not affecting the way it functions in a harmful way.
Not all side effects reported for this medicine are included in this leaflet. Should your general health worsen while taking this medicine, please consult your doctor, pharmacist or other healthcare professional for advice.
If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

6. STORAGE AND DISPOSING OF ASPEN EPIRUBICIN 10 OR ASPEN EPIRUBICIN 50:
KEEP ALL MEDICINES OUT OF THE REACH AND SIGHT OF CHILDREN.
Keep the medicine away from direct sunlight.
Do not remove the vial from the carton until required for use.
Your doctor must use the ASPEN EPIRUBICIN as soon as it has been made. Vials, which have already been used, should be disposed by your health professional. If ASPEN EPIRUBICIN goes cloudy after preparation, then your health professional will dispose of it safely.
Storage of the reconstituted solution is not recommended. Any unused portion must be discarded.
Do not use after the expiry date stated on the label.
Do not dispose of unused medicine in drains or sewerage systems (eg. toilets)

7. PRESENTATION OF ASPEN EPIRUBICIN 10 AND ASPEN EPIRUBICIN 50:
Aspen Epirubicin is presented in 10 mL (for 10 mg) and 30 mL (for 50 mg) clear, colourless type I vials, closed with grey bromobutyl stoppers (Type I), an aluminium cap and a grey polypropylene top.

8. IDENTIFICATION OF ASPEN EPIRUBICIN 10 AND ASPEN EPIRUBICIN 50 :
A red-orange compact aggregate of fragments with porous appearance.
Appearance of Reconstituted Solution: Clear, red-orange solution.

9. REGISTRATION NUMBER:
ASPEN EPIRUBICIN 10 mg (powder): 42/26/0018
ASPEN EPIRUBICIN 50 mg (powder): 42/26/0019

10. NAME AND ADDRESS OF REGISTRATION HOLDER:
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
2191

11. DATE OF PUBLICATION:
18 September 2007

New addition to this site: April 2010
Source: Pharmaceutical Industry

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