Consumer medicine information

EPIRUBICIN ACT

Epirubicin hydrochloride

BRAND INFORMATION

Brand name

Epirubicin ACT Solution for injection

Active ingredient

Epirubicin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using EPIRUBICIN ACT.

What is in this leaflet?

This leaflet answers some common questions about Epirubicin ACT.

It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of using Epirubicin ACT against the benefits it is expected to have for you.

If you have any concerns about using Epirubicin ACT, ask your doctor or pharmacist.

Keep this leaflet. You may want to read it again.

What Epirubicin ACT is used for

This medicine is used to treat the following types of cancer:

  • breast cancer
  • gastric (stomach) cancer
  • ovarian cancer
  • small cell lung cancer
  • lymphoma (non-Hodgkin's lymphoma), a cancer of the lymph glands
  • sarcoma
  • bladder cancer.

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines. Epirubicin ACT is an anthracycline-type of chemotherapy.

This medicine works by killing cancer cells and stopping cancer cells from growing and multiplying.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

Epirubicin ACT may be used alone or in combination with other medicines to treat cancer.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Before you are given Epirubicin ACT

When you must not be given it

You must not be given Epirubicin ACT if you have an allergy to:

  • any medicine containing epirubicin
  • any of the ingredients listed at the end of this leaflet
  • any other similar medicines, including anthracyclines.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching, or hives on the skin.

Females: tell your doctor or pharmacist if you are pregnant or intend to become pregnant.

Like most cytotoxic medicines, epirubicin is not recommended for use during pregnancy. If there is any need to consider epirubicin during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Males: tell your doctor if your partner intends to become pregnant while you are being given epirubicin or shortly after you have stopped treatment with epirubicin.

Epirubicin may cause birth defects if either the male or female is using it at the time of conception. It is recommended that you use some kind of birth control while you are being treated with epirubicin and for at least 12 weeks after you stop treatment. A barrier method of birth control, such as a condom, should be used while you are being given epirubicin and for 12 weeks after the end of treatment. Your doctor will discuss this with you.

Do not breast-feed while being treated with this medicine. Epirubicin may pass into breast milk and there is a possibility that your baby may be affected.

You must not be given this medicine if you have, or have had, any of the following medical conditions:

  • heart problems, including a heart attack
  • severe or significant liver problems
  • a persistently low number of blood cells or platelets due to previous chemotherapy or radiotherapy
  • a very inflamed and sore mouth due to previous chemotherapy or radiotherapy

You must not be given this medicine as an infusion into the bladder if you have:

  • a tumour that has penetrated the bladder wall.
  • a urinary infection
  • inflammation of the bladder.

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

You must not be given this medicine if you have already received the maximum, long-term dose of epirubicin or another anthracycline medicine.

You must not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are going to be vaccinated (have an injection to prevent a certain disease).

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • mild liver problems
  • any blood disorder with a reduced number of red or white blood cells and/or reduced number of platelets
  • high uric acid levels in your blood which may cause gout
  • lowered immunity due to treatment with medicines such as corticosteroids, cyclosporin or other medicines used to treat cancer (including radiation therapy)
  • lowered immunity due to diseases including HIV/AIDS.

If you have not told your doctor about any of the above, tell him/her before you are given epirubicin.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and epirubicin may interfere which each other.

These include:

  • other medicines used to treat cancer, radiation therapy, or any other treatment which lowers your immune system
  • some heart medication, such as propranolol or calcium channel blockers
  • cimetidine
  • trastuzumab
  • other medicines that may affect how well your liver works
  • some vaccines (ask your doctor).

These medicines may be affected by epirubicin, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are being treated with this medicine.

How Epirubicin ACT is given

How much is given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight, liver function, kidney function and other chemotherapy medicines you are being given.

Epirubicin ACT may be given alone or in combination with other drugs.

Several courses of epirubicin therapy may be needed depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled.

Ask your doctor if you want to know more about the dose of epirubicin you receive.

How it is given

Epirubicin ACT must only be given by a doctor or nurse.

This medicine is usually given as a slow injection into a vein. This medicine might also be infused into the bladder through a tube (called a catheter).

How long it is given

Epirubicin may be given every 3 to 4 weeks, sometimes in combination with other medicines. This is called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need, and the length between cycles.

Overdose

As epirubicin is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any severe side effects after being given epirubicin, tell your doctor immediately or go to Accident and Emergency at the nearest hospital.

You may need urgent medical attention.

Symptoms of an epirubicin overdose may include bleeding and infections due to a very low level of blood cells, and heart problems.

While you are being given Epirubicin ACT

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given epirubicin.

Tell any other doctors, dentists and pharmacists who treat you that you are being given this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given this medicine.

It may affect other medicines used during surgery.

If you become pregnant while being given this medicine, or soon after, tell your doctor immediately.

Keep all your doctor's appointments so your progress can be checked.

Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and to detect any unwanted side effects.

Your doctor will monitor your heart regularly before, during and after you are given this medicine.

Epirubicin can affect your heart, particularly after being given high doses or for a long period of time.

Keep follow up appointments with your doctor.

It is important to have your follow-up doses of epirubicin at the appropriate times to get the best effects from your treatments.

You will be asked to not drink fluids for 12 hours before treatment if this medicine is to be infused into the bladder. This is to reduce dilution of the medicine by the urine.

Tell your doctor if you have any infection or fever before, during or after you are given epirubicin.

This medicine will lower your ability to fight infections.

Epirubicin can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding.

The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate.
  • Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
  • Avoid contact sports or other situations where you may bruise or get injured.

Your body breaks down epirubicin and uses it to fight cancer. The breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen.

In general, precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period by:

  • Flushing the toilet twice to dispose of any body fluids and waste
  • Wearing gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet.
  • Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water.
  • Place soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage.
  • For sexual intercourse, use a barrier method such as a condom.

Things to be careful of

Be careful driving or operating machinery until you know how epirubicin affects you.

This medicine may cause dizziness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Be careful when drinking , alcohol while you are taking this medicine.

If you drink alcohol, dizziness or light-headedness may be worse.

Try to stay out of direct sunlight after treatment with epirubicin.

Epirubicin can increase your sensitivity to the sun.

Side Effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with epirubicin.

Like other medicines that treat cancer, epirubicin may have unwanted side effects, some of which may be serious. You may need medical treatment if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

  • nausea and vomiting
  • diarrhoea
  • mouth ulcers
  • loss of appetite
  • fever and chills
  • weakness, dizziness, confusion
  • hair loss (alopecia)
  • increased sensitivity to the sun
  • skin rash, itching
  • urine discolouration (do not be alarmed if epirubicin colours your urine red for 1-2 days after treatment).

The above list includes the more common side effects of this medicine.

Tell your doctor or nurse as soon as possible if you notice any of the following:

  • inflammation or burning in the nose, throat, vagina or rectum
  • facial flushing
  • any pain, tingling, redness or burning at the site of injection, both during the injection and for the following 24 hours
  • painful joints
  • painful urination or difficulty urinating, lower, back or side pain.

The above list includes serious side effects which may require medical attention.

If any of the following happen, tell your doctor or nurse immediately, or go to Accident and Emergency at your nearest hospital:

  • any signs of infection such as fever, chills, sore throat or cough
  • unusual bleeding or bruising (such as dark stools, blood in urine)
  • irregular heart beat or symptoms of heart failure (such as shortness of breath, swelling of the ankles)
  • signs of an allergic reaction (such as those listed at the start of the leaflet)

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

If the epirubicin is being injected into the bladder, tell your doctor or pharmacist if you notice any of the following:

  • stomach pain
  • blood in the urine
  • pain on passing urine
  • frequent urination or difficulty urinating.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some people. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

The benefits and side effects of epirubicin may take some time to occur, Therefore even after you have finished your epirubicin treatment you should tell your doctor immediately if you notice any of the side effects listed in this section.

After using Epirubicin ACT

Storage

Epirubicin ACT will be stored in the pharmacy or on the ward. The injection is kept in the refrigerator where the temperature stays between 2-8°C and is protected from light.

Product Description

What it looks like

Epirubicin ACT is a red solution in a glass vial. It is supplied in vials as single packs.

Ingredients

Epirubicin hydrochloride.

Also contains: Sodium chloride and water for injection

It does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Actavis Pty Ltd
Level 5, 117
Harrington St,
The Rocks NSW 2000

Australian Registration

  • Epirubicin ACT epirubicin hydrochloride 10 mg/5 ml concentrated injection vial:
    AUST R 146578
  • Epirubicin ACT epirubicin hydrochloride 20 mg/10 ml concentrated injection vial:
    AUST R 146596
  • Epirubicin ACT epirubicin hydrochloride 50 mg/25 ml concentrated injection vial:
    AUST R 146597
  • Epirubicin ACT epirubicin hydrochloride 100 mg/50 ml concentrated injection vial:
    AUST R 146598
  • Epirubicin ACT epirubicin hydrochloride 200 mg/100 ml concentrated injection vial:
    AUST R 146599

This leaflet was updated in December 2013.

BRAND INFORMATION

Brand name

Epirubicin ACT Solution for injection

Active ingredient

Epirubicin hydrochloride

Schedule

S4

 

Name of the medicine

Epirubicin hydrochloride.

Excipients

Sodium chloride, water for injections.

Description

Chemical name: (8S, 10S)-10-(3-amino-2,3,6-trideoxy-alpha-L- arabino- hexopyranosyloxy)-8-glycolloyl-7,8,9,10-tetrahydro- 6,8,11-trihydroxy- 1-methoxynaphthacene- 5,12-dione hydrochloride. Molecular formula: C27H29NO11HCl. MW: 580. CAS: 56390-09-1. Epirubicin hydrochloride is a red orange, almost odourless, hygroscopic powder, sparingly soluble in water and dilute alcohol. Structurally, epirubicin hydrochloride differs from doxorubicin hydrochloride only in the orientation of the hydroxyl group at the 4 position on the aminoglycoside ring.

Pharmacology

The mechanism of action of epirubicin hydrochloride has not been fully elucidated but is probably related to its ability to bind DNA. Cell culture studies have shown cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin hydrochloride has proved to be active on the following experimental tumours: L 1210 ascites and P388 leukaemias, sarcoma SA 180 (solid and ascitic forms), melanoma B 16, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38.
The specificity of epirubicin hydrochloride toxicity appears to be related primarily to proliferative activity of normal tissue. Thus bone marrow, gastrointestinal tract, lymphoid organs and the gonads are the main normal tissues damaged. Degenerative or functional alterations in liver and kidneys were also seen in animals dosed with epirubicin hydrochloride.
Like most other antitumour and immunosuppressant agents, epirubicin hydrochloride, under experimental conditions, has mutagenic properties and is carcinogenic in laboratory animals (see Precautions, Use in pregnancy).
Toxicity studies in animals have indicated that on a weight (mg/mg) basis epirubicin hydrochloride has a better therapeutic index and less systemic and cardiac toxicity than doxorubicin.

Pharmacokinetics.

In patients with normal hepatic and renal function, plasma levels after intravenous injection of 75 to 90 mg/m2 of the drug follow a triexponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. Plasma levels of the drug's main metabolite, the 13-OH derivative, are constantly somewhat lower and virtually parallel to those of the unchanged drug. Epirubicin hydrochloride is eliminated mainly through the liver; high plasma clearance values (0.9 L/minute), indicate that the slow elimination of epirubicin is due to extensive tissue distribution. Urinary excretion accounts for approximately 11% of the administered dose in 48 hours. However, like doxorubicin, biliary excretion is likely to be the major excretion route. Impairment of liver function delays plasma clearance. As with doxorubicin, epirubicin hydrochloride may not be expected to cross the blood brain barrier. When epirubicin hydrochloride is administered intravesically, the systemic absorption is minimal.
There is evidence for a dose response and dose toxicity relationship for epirubicin in breast cancer and, to a lesser extent, for lymphoma. This relationship is steeper and therefore more evident for doses of epirubicin above 90 mg/m2. Current data indicate that an increase in dose (for dose intensity) produces greater response rates.
Epirubicin hydrochloride is immunosuppressive in animals. Although there are no clinical data on the immunosuppressive effects of epirubicin hydrochloride, effects similar to those seen with doxorubicin may be expected.

Clinical Trials

Early breast cancer.

Data from two multicentre, randomised phase III studies support the use of epirubicin hydrochloride 100 to 120 mg/m2 for the adjuvant treatment of patients with axillary node positive breast cancer and no evidence of distant metastatic disease (stage II or III). In one study, an intensive cyclophosphamide/ epirubicin/ fluorouracil (CEF-120) regimen (epirubicin given in a dose of 60 mg/m2 on days 1 and 8) was compared with a conventional cyclophosphamide/ methotrexate/ fluorouracil (CMF) regimen. A total of 716 patients were randomised, 356 to CEF and 360 to CMF. Both disease free survival and overall survival were significantly prolonged in the CEF arm at five years. Disease free survival was 62% for CEF versus 53% for CMF (p = 0.01) and overall survival was 77% for CEF versus 70% for CMF (p = 0.043).
In the second study, 301 patients were randomised to receive tamoxifen 20 mg/day alone for four years and 303 patients were randomised to receive tamoxifen for four years in combination with epirubicin 50 mg/m2 on days 1 and 8 every four weeks for six cycles. Although there was no significant difference between the two arms with regard to disease free survival and overall survival, there was a trend in favour of the combined use of epirubicin and tamoxifen. Disease free survival at two years was 85.1 versus 77.9%, and at five years was 78.8 versus 72.9%.

Advanced breast cancer.

Data from four open label, multicentre, phase III studies support the use of epirubicin hydrochloride for the treatment of patients with locally advanced or metastatic breast cancer. In study 1, an intensified cyclophosphamide/ epirubicin/ fluorouracil (CEF-100) regimen (epirubicin given in a dose of 50 mg/m2 on days 1 and 8) was compared with a conventional CMF regimen (n = 461). Studies 2 and 3 compared cyclophosphamide/ epirubicin/ fluorouracil regimens where only the dose of epirubicin varied. In both of these, epirubicin was given in a dose of 50 mg/m2 on day 1 and compared with either 100 mg/m2 on day 1 (n = 456) or 50 mg/m2 on days 1 and 8 (n = 164). High dose epirubicin (135 mg/m2) was compared to conventional dose epirubicin (75 mg/m2) in study 4 (n = 151).
The efficacy endpoints included response rate (RR), duration of response (DR), time to tumour progression (TTP), time to treatment failure (TTF), and overall survival (OS). In study 1, the CEF-100 regimen produced a significantly higher RR, a significantly longer TTP and a significantly longer TTF than the CMF regimen. In studies 2, 3 and 4, the higher dose epirubicin containing regimens produced a significantly greater RR than the lower dose epirubicin containing regimens. DR and TTF were also significantly longer in study 3 and TPP was significantly longer in study 4 for the higher dose epirubicin regimens.

Indications

Epirubicin hydrochloride has produced responses in a wide spectrum of neoplastic diseases, and is indicated for the treatment of breast cancer, gastric cancer, ovarian cancer, small cell lung cancer, lymphoma (non-Hodgkin's lymphoma), advanced/ metastatic soft tissue sarcoma and superficial bladder cancer (Tis, Ta).
In bladder cancer, epirubicin hydrochloride is also indicated in the prophylaxis of recurrence after transurethral resection of stage T1 papillary cancers and stage Ta multifocal papillary cancers (grade 2 and 3).

Contraindications

Hypersensitivity to epirubicin hydrochloride or any other component of the product, other anthracyclines or anthracenediones.
Situations in which patients should not be treated with intravenous epirubicin hydrochloride are: persisting myelosuppression or severe stomatitis induced by previous drug therapy or radiotherapy; presence of generalised infections; marked liver function impairment; previous history of, or in the presence of, cardiac impairment (severe arrhythmias and myocardial insufficiency, previous myocardial infarction); previous treatments with maximum cumulative doses of mitozantrone, mitomycin C or other anthracyclines, e.g. doxorubicin or daunorubicin; pregnancy and lactation.
Contraindications for intravesical use are: invasive tumours that have penetrated the bladder wall; urinary infections; inflammation of the bladder; catheterisation problems; haematuria.

Precautions

Epirubicin hydrochloride should be administered only under the supervision of qualified doctors experienced in cytotoxic therapy. Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia and generalised infections) of prior cytotoxic treatment before beginning treatment with epirubicin hydrochloride.
While treatment with high doses of epirubicin hydrochloride (e.g. greater than or equal to 90 mg/m2 every three to four weeks) causes adverse events generally similar to those seen at standard doses (e.g. < 90 mg/m2 every three to four weeks), the severity of neutropenia and stomatitis/ mucositis may be increased. In particular, treatment with high doses of the drug requires special attention for possible clinical complications due to profound myelosuppression.
Initial treatment with epirubicin hydrochloride requires close observation of the patient and extensive laboratory monitoring including assessment of cardiac function. During each cycle of treatment patients must be carefully and frequently monitored. A blood count, renal and liver function tests should be carried out prior to each epirubicin hydrochloride treatment. The routine assessment of cardiac function may include electrocardiogram (ECG) and the evaluation of left ventricular ejection fraction (LVEF).

Warnings.

Epirubicin hydrochloride must be handled with care. If the preparation comes in contact with the skin or mucosae, the appropriate areas should be washed immediately and thoroughly with soap and water or sodium bicarbonate solution.
Epirubicin hydrochloride is intended for use under the direction of those experienced in cytotoxic therapy. The rate of administration is dependent on the size of the vein and the dosage. It is important that the dose be administered in not less than three to four minutes. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration.
Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein. Severe local tissue necrosis will occur if there is extravasation during administration. Venous sclerosis may result from infection into a small vessel or from repeated injections into the same vein.
Epirubicin ACT must not be given by the intramuscular or subcutaneous route.
Epirubicin hydrochloride is not an antimicrobial agent.

Haematological considerations.

Haematological monitoring should be undertaken regularly in view of the possibility of severe bone marrow depression which may occur. Leucopenia is usually transient with the recommended dosage schedules, reaching a nadir between 10 and 14 days after administration. A return to normal blood values usually occurs within 21 days from administration.
Secondary acute myelogenous leukaemia, with or without a preleukaemic phase, had been reported in patients treated with topoisomerase II inhibitors, including anthracyclines such as epirubicin (see Adverse Effects).

Anthracycline induced cardiotoxicity.

Patients receiving epirubicin hydrochloride should be monitored for anthracycline induced cardiotoxicity.
Heart function should be carefully monitored during treatment in order to minimise the risk of cardiac failure, of the type described for other anthracycline compounds. Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin hydrochloride or within two to three months post-treatment. Cardiomyopathy induced by anthracyclines is associated with persistent QRS voltage reduction, prolongation beyond normal limits of the systolic time interval (PEP/LVET) and a reduction of the ejection fraction 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.
The onset of cardiac failure may be sudden and early recognition may increase the likelihood of benefit from treatment. Heart failure has been reported even several weeks to several months after discontinuing treatment and the risk may be higher in patients with active or dormant cardiovascular disease, concomitant or previous radiation of the mediastinal pericardial area, hypertensive cardiomyopathy, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic agents (e.g. trastuzumab, high dose cyclophosphamide or fluorouracil). 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.
In such patients a reduction of the total cumulative dose may be required and the monitoring of cardiac function must be particularly strict. The risk/ benefit of continuing epirubicin hydrochloride treatment under conditions of impaired cardiac function has to be carefully evaluated. However cardiotoxicity with epirubicin hydrochloride may occur in lower cumulative doses whether or not cardiac risk factors are present. It is probable that the toxicity of epirubicin hydrochloride and other anthracyclines or anthracenediones is additive.
The total (cumulative) dose levels of epirubicin hydrochloride do correlate with the incidence of drug induced congestive cardiac failure (cardiomyopathy). At a cellular level the nature of epirubicin hydrochloride induced cardiac toxicity appears to be similar to that of doxorubicin. Limitation of the total dose of epirubicin hydrochloride to 900 mg/m2 in good risk patients reduces the likelihood of drug induced cardiomyopathy. It is suggested that an ECG be taken before treatment. Alterations of the ECG, such as flattening or inversion of the T wave, depression of the ST segment, or the onset of arrhythmias, are generally transient and reversible and need not necessarily indicate that treatment should be stopped. It is also advisable to assess cardiac function by other techniques, such as echocardiography and measurement of the ejection fraction by radionuclide angiography. The technique should be consistent throughout follow-up.

Hepatotoxicity.

As toxicity of epirubicin hydrochloride is enhanced by impaired liver function or bile outflow, the major route of elimination being the hepatobiliary system, dosages should be reduced in patients with impaired hepatic function (see also Dosage and Administration). Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin hydrochloride. Patients with severe hepatic impairment should not receive epirubicin hydrochloride (see Contraindications).

Renal toxicity.

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin hydrochloride excreted by this route.
Patients with severe renal impairment (serum creatinine concentration exceeding 5 mg/dL) may require dosage reductions. The drug has not been studied in those undergoing dialysis (see Dosage and Administration).

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. Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administration; however, the response to such vaccines may be diminished.

Other.

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidently reported with the use of epirubicin hydrochloride.
Epirubicin hydrochloride may enhance radiation induced toxicity such as skin reactions and mucositis and may potentiate the toxicity of other anticancer therapies. This has to be taken into account particularly when using the drug in high doses and the availability of supportive care and facilities has to be considered before initiating high dose intensive regimens.
Like other cytotoxic drugs, epirubicin hydrochloride may induce hyperuricaemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacological measures as might be necessary to control this problem.
Epirubicin may impart a red colour to the urine for one to two days after administration. Patients should be advised that such an event is not a cause for alarm.

Use in pregnancy.

(Category D)
There is no specific information available at present concerning the use of epirubicin hydrochloride in human pregnancy. However, as it has been shown to be embryotoxic and fetotoxic in animals, it should not be used in patients who are pregnant or are likely to become pregnant.
Although no studies have been conducted with epirubicin hydrochloride, it may be expected, like doxorubicin, to cause infertility during the period of drug administration. In women, epirubicin hydrochloride may cause amenorrhoea. After termination of therapy, ovulation and menstruation may be expected to return in a few months, often accompanied by normal fertility. Premature menopause may also occur.
In male patients, oligospermia or azoospermia may be permanent, although fertility may return more than five years after ceasing therapy. Given the mutagenic potential of epirubicin hydrochloride, the drug could induce chromosomal damage in human spermatozoa; therefore, males undergoing epirubicin hydrochloride treatment should employ contraceptive measures.

Use in lactation.

It is likely that epirubicin hydrochloride is excreted in breast milk, therefore it is not recommended for nursing mothers unless the expected benefit outweighs any potential risk.

Carcinogenesis, mutagenesis, impairment of fertility.

Although no studies have been conducted with epirubicin hydrochloride, it may be expected, like doxorubicin, to cause infertility during the period of drug administration. After termination of therapy, ovulation and menstruation may be expected to return in a few months, often accompanied by normal fertility. Premature menopause may occur.
Secondary acute myelogenous leukemia (AML) has been reported in patients treated with anthracyclines; risk of refractory AML increases when epirubicin is combined with other DNA damaging antineoplastics, when patients have had extensive exposure to cytotoxic drugs, or when anthracycline doses have been escalated. The cumulative risk for adjuvant epirubicin therapy related leukemia is estimated as 0.2 and 0.8% at three and five years, respectively.
Epirubicin is mutagenic, clastogenic and carcinogenic in animals.

Interactions

Epirubicin hydrochloride is mainly used in combination with other cytotoxic drugs and additive toxicity may occur especially with regard to bone marrow/ haematological and gastrointestinal effects. In addition, the concomitant use of epirubicin hydrochloride with other antitumour drugs which have been reported as potentially cardiotoxic (e.g. fluorouracil, cyclophosphamide, cisplatin, taxanes, trastuzumab), as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), required a close monitoring of cardiac function throughout treatment.

Propranolol.

Concurrent administration of epirubicin hydrochloride and propranolol may result in an additive cardiotoxic effect.
Cimetidine increased the area under the curve (AUC) of epirubicin hydrochloride by 50% and should be stopped during treatment with epirubicin hydrochloride.
When given prior to epirubicin, paclitaxel can cause increased plasma concentrations of unchanged epirubicin. Coadministration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin, when epirubicin was administered prior to the taxane.
Concurrent mediastinal radiotherapy and epirubicin hydrochloride may be associated with enhanced myocardial toxicity of epirubicin hydrochloride.
Epirubicin hydrochloride is extensively metabolised by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin hydrochloride metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity.

Cardiotoxic drugs.

Concurrent administration of epirubicin hydrochloride and cardiotoxic drugs such as propranolol and calcium channel blockers may precipitate congestive heart failure.

Live vaccines.

The use of live attenuated vaccines in the presence of immunosuppression may increase the risk and severity of infection in response to the vaccine. Such vaccinations should only be administered with due regard for these theoretical risks.

Adverse Effects

Dose limiting toxicities are myelosuppression and cardiotoxicity (described in detail under Precautions).
Adverse effects observed are as follows.

More common reactions > 5%.

Haematological.

Myelosuppression, leucopenia, neutropenia, thrombocytopenia, mild anaemia, secondary infection.

Cardiovascular.

Transient ECG changes, including low QRS voltage, tachycardia, arrhythmias, T wave flattening, ST depression and T inversion.

Gastrointestinal.

Nausea, vomiting, diarrhoea and mucositis (erythema, erosions/ ulcerations, bleeding). Mucositis may appear five to ten days after the start of treatment and usually involves stomatitis with areas of painful erosions, mainly along the sides of the tongue and on the sublingual mucosa.

Dermatological.

Alopecia, including the interruption of beard growth, usually reversible, occurs in 60 to 90% of treated cases.

Application site.

Erythematous streaking along the infused vein.

General.

Dehydration.

Less common reactions < 5%.

Haematological.

Severe thrombocytopenia, anaemia, severe myelosuppression, pancytopenia, sepsis, septicaemia, septic shock, tissue hypoxia, haemorrhage and death.

Cardiovascular.

Cardiomyopathy, congestive heart failure, cardiomegaly, atrioventricular and bundle branch block, tachyarrhythmias (premature ventricular contractions, ventricular tachycardia, bradycardia), asymptomatic drops in left ventricular ejection fraction.

Gastrointestinal.

Oesophagitis, bleeding, hyperpigmentation of oral mucosa and abdominal pain or burning sensation.

Dermatological.

Local toxicity, rash/ itch, transient urticaria, flushes, skin and nail hyperpigmentation, photosensitivity and hypersensitivity of irradiated skin.

Application site.

Vesication, phlebitis, thrombophlebitis and venous sclerosis. Local pain, severe cellulitis and skin necrosis following perivenous drug extravasation.

Ocular.

Conjunctivitis, keratitis.

Hepatic.

Changes in transaminase levels.

General.

Chills, shock, fever, anorexia, amenorrhoea, azoospermia, malaise/ asthenia, hot flushes. Anaphylaxis may occur.

Central nervous system.

Weakness, dizziness, confusion, depression, paraesthesia.
Hyperuricaemia may occur as a consequence of the extensive purine catabolism which accompanies drug induced rapid cell kill of highly chemosensitive neoplasms (tumour lysis syndrome). Hydration, urine alkalinisation and allopurinol administration will help to prevent or minimise the adverse effects of hyperuricaemia.

Intravesicular administration.

As drug absorption is minimal, systemic side effects are rare; more frequently chemical cystitis, sometimes haemorrhagic, and bladder constriction has been observed. Dose reduction (40%) may be necessary in these cases.

Severe or life threatening reactions.

Myelosuppression.

This accompanies effective epirubicin hydrochloride treatment in almost 100% of patients and represents the acute dose limiting toxicity of this drug. Leucopenia is the predominant effect with thrombocytopenia and anaemia occurring less frequently. Leucopenia is usually more severe after administration of high dose regimens. Under these conditions appropriate bone marrow support (e.g. peripheral blood progenitor cells and/or colony stimulating factors) may be required. Intravenous antibiotics should be given in the presence of febrile neutropenia.
Myelosuppression is more common in patients who have had extensive radiotherapy, bone marrow infiltration by tumour or impaired liver function (when appropriate dosage reduction has not been adopted) (see Dosage and Administration).

Other haematological.

The occurrence of secondary acute myelogenous leukaemia, with or without a preleukaemic phase, has been reported in patients treated with topoisomerase II inhibitors, including anthracyclines such as epirubicin. Secondary leukaemia is more common when such drugs are given in combination with DNA damaging antineoplastic agents, or when patients have been heavily pretreated with cytotoxic drugs or when the doses of the anthracyclines have been escalated. This complication has been reported in 1 to 2% of patients receiving epirubicin containing combination chemotherapy as adjuvant therapy in breast cancer. These leukaemias can have a short (one to three year) latency period.

Mucositis.

This is frequent and painful and most commonly develops five to ten days after treatment. It typically begins as a burning sensation in the mouth and pharynx. The mucositis may involve the vagina, rectum and oesophagus, and progress to ulceration with a risk of secondary infection. Nausea and vomiting may be prevented or alleviated by the administration of appropriate antiemetic therapy. The mucositis usually subsides in ten days.

Cardiotoxicity.

The cardiac abnormalities caused by treatment can be separated into two categories: ECG alterations and congestive heart failure (CHF).
ECG changes following epirubicin hydrochloride treatment occur in about 10% of patients. The changes are usually reversible and do not appear to be related to the subsequent development of congestive cardiac failure.
Epirubicin, like other members of this class of drugs, may cause congestive cardiac failure (cardiomyopathy). This effect is cumulative dose dependent and represents the cumulative dose limiting toxicity of the drug. The following measures may identify patients with early anthracycline cardiomyopathy: progressive flattening or inversion of the T waves (mainly in the left praecordial leads), low QRS voltage, prolonged systolic time interval, reduced ejection fraction (echocardiography or by cardiac gated pool scanning) or cardiac biopsy showing characteristic electromicroscopic changes. Early diagnosis and management may control the heart failure. Epirubicin hydrochloride induced cardiomyopathy can be fatal (see Precautions). Delayed cardiac toxicity is represented by a characteristic cardiomyopathy which clinically is manifested by symptoms/ signs of ventricular dysfunction/ CHF (such as dyspnoea, pulmonary oedema, dependent oedema, hepatomegaly, ascites, pleural effusion, gallop rhythm).
Delayed cardiotoxicity mainly develops during the course of therapy with epirubicin and up to two to three months afterwards, but late events (several months to years after treatment termination) have occurred. Pericardial effusion has also been described.

Dosage and Administration

Epirubicin ACT solution for injection is intended for intravenous or intravesical administration only. They must not be administered by the intramuscular, subcutaneous or oral routes.
Care in the intravenous administration of epirubicin hydrochloride will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions, such as urticaria and erythematous streaking (see Precautions).

Note.

The recommended lifetime cumulative dose limit of epirubicin hydrochloride is 900 mg/m2 body surface area.
Under conditions of normal recovery from drug induced toxicity (particularly bone marrow depression and stomatitis), the recommended dosage schedule in adults, as described below, is as a single intravenous injection administered at 21 day intervals.
Standard doses are 75 to 90 mg/m2. Epirubicin hydrochloride produces predominantly haematological dose limiting toxicities which are predicted from the known dose response profile of the drug. Based on the patient's haematological status the doctor should determine the choice of dose.
Higher doses, up to 135 mg/m2 as a single agent and 120 mg/m2 in combination, every three to four weeks have been effective in the treatment of breast cancer. In the adjuvant treatment of early breast cancer patients with positive lymph nodes, doses ranging from 100 mg/m2 to 120 mg/m2 every three to four weeks are recommended. Careful monitoring in regards to increased myelosuppression, nausea, vomiting and mucositis are recommended in this high dose setting.
Consideration should be given to the administration of lower starting doses (not exceeding 75 to 90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression or in the presence of neoplastic bone marrow infiltration. If epirubicin hydrochloride is used in combination with other cytotoxic drugs with potentially overlapping toxicities, the recommended dose per cycle should be reduced accordingly.
While no specific dose recommendation can be made on the limited available data in patients with renal impairment, lower starting doses should be considered in patients with severe renal impairment (serum creatinine > 5 mg/dL).

Intravesical administration.

For the treatment of papillary transitional cell carcinoma of the bladder, a therapy of eight weekly instillations of 50 mg is recommended.
In the case of local toxicity (chemical cystitis) a dose reduction up 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 of recurrences after transurethral resection of superficial tumours, four weekly administrations of 50 mg followed by eleven monthly instillations at the same dosage are recommended.
To avoid undue dilution with the urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation.
Intravesical administration is not suitable for the treatment of invasive tumours which have penetrated the muscular layer of the bladder wall.

Dose modifications.

As clinical toxicity may be increased by the presence of impaired liver function, epirubicin hydrochloride dosage must be reduced if hepatic function is impaired, according to Table 1.
Haematological toxicity may require dose reduction, delay or suspension of epirubicin hydrochloride therapy. Lower doses may be necessary if epirubicin hydrochloride is used concurrently with other antineoplastic agents.

Preparation of solution (See Precautions).

Epirubicin is available as a ready to use solution (Epirubicin ACT Solution for injection 10, 20, 50 100 and 200 mg at strength of 2 mg/mL).
Storage of the Epirubicin ACT Solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after two (to a maximum of four) hours equilibration at room temperature (15-25°C).

Pharmaceutical precautions.

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 should wear protective clothing: goggles, gowns and disposable gloves and masks.
A designated area should be defined for reconstitution (preferably under a laminar flow containment system). The work surface should be protected by disposable plastic backed absorbent paper.
All items used for 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.
Accidental contact with the eyes or skin should be treated immediately. Copious lavage with water is appropriate treatment for contact with the eyes, whereas water or soap and water, or sodium bicarbonate solution may be used on the skin; medical attention should be sought.
Epirubicin ACT Solution for injection should be stored refrigerated at 2 to 8°C. Do not freeze. The product contains no antimicrobial preservative.
Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug.

Intravenous administration.

It is recommended that the solution of epirubicin hydrochloride be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection USP or 5% Glucose Injection USP. The tubing should be attached to a butterfly needle inserted preferably into a large vein. The rate of administration is dependent on the size of the vein and the dosage. However, the dosage should be administrated in not less than three to four minutes to minimise the risk of thrombosis and perivenous extravasation. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein (see Precautions, Warnings).

Intravesical administration.

The solution of epirubicin hydrochloride, to be instilled using a catheter, should be retained intravesically for one hour. The patient should be instructed to void at the end of this time. During instillation, the pelvis of the patient should be rotated to ensure extensive contact of the solution with the vesical mucosa.

Compatibility.

Epirubicin hydrochloride is compatible with the following infusion media: sodium chloride 0.9%, glucose 5%, sodium chloride 0.9% with 5% glucose.
Epirubicin hydrochloride can be used in combination with other antitumour agents, but it is not recommended that it be mixed with these drugs in the same container.
Epirubicin hydrochloride should not be mixed with heparin as these drugs are incompatible. Until specific compatibility data are available, it is not recommended that epirubicin hydrochloride be mixed with other drugs.

Overdosage

A 36 year old man with non-Hodgkin's lymphoma received daily epirubicin injection 95 mg/m2 for five consecutive days. Five days later, he developed bone marrow aplasia, grade 4 mucositis and gastrointestinal bleeding. No signs of acute cardiac toxicity were observed. He was treated with antibiotics, colony stimulating factors and antifungal agents and recovered completely. A 63 year old woman with breast cancer and liver metastasis received a single dose of epirubicin 320 mg/m2, which resulted in hyperthermia, multiple organ failure (respiratory and renal), lactic acidosis, increased lactate dehydrogenase and anuria, and death within 24 hours of administration.
Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m2. The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care.
Very high single doses of epirubicin hydrochloride may be expected to cause acute myocardial degeneration within 24 hours, and severe myelosuppression (mainly leukopenia and thrombocytopenia) within 10 to 14 days and also gastrointestinal toxic effects (mainly mucositis).
If an overdose occurs, supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony stimulating factors and intensive care as needed) should be provided until the recovery from toxicities. Delayed cardiac failure may occur up to six months after the overdose. Patients should be observed carefully and should, if signs of cardiac failure arise, be treated along conventional lines.
The Poisons Information Centre, telephone number 131 126, should be contacted for advice on the management of an overdosage.

Presentation

Concentrate for injection (clear red), 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, 100 mg/50 mL, 200 mg/100 mL: 1's (colourless glass vial).

Storage

Solution.

Store refrigerated at 2 to 8°C. Do not freeze. Protect from light.

Poison Schedule

S4.