Consumer medicine information

EPIRUBICIN KABI

Epirubicin hydrochloride

BRAND INFORMATION

Brand name

Epirubicin Kabi

Active ingredient

Epirubicin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Epirubicin Kabi.

It does not contain all 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 you using Epirubicin Kabi against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

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

What Epirubicin Kabi is used for

Epirubicin Kabi is used in the treatment of various types of cancer. It may be used alone or with other medicines.

Ask your doctor if you have any questions about why Epirubicin Kabi has been prescribed for you.

Your doctor may have prescribed it for another purpose.

Epirubicin Kabi is only available with a doctor's prescription. It is not addictive.

Before you are given Epirubicin Kabi

When you must not be given it

Do not use Epirubicin Kabi if you have ever had an allergic reaction to epirubicin (the active ingredient in Epirubicin Kabi), other medicines to treat cancer or any of the ingredients listed at the end of this leaflet.

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.

Do not use the medicine for injection into a vein if you have:

  • a low number of red blood cells, white blood cells or platelets in your blood
  • sore, red mouth from previous treatment or radiation therapy
  • an infection
  • severe liver problems
  • heart problems or have ever had heart problems
  • already received the highest dose allowed for medicines such as mitozantrone, mitomycin C, doxorubicin or daunorubicin

Do not use the medicine for injection into the bladder if you have:

  • cancer that has gone into the bladder wall
  • kidney or urinary tract infection
  • swollen or inflamed bladder
  • problems with a catheter (a tube in your bladder)
  • blood in the urine

Do not use Epirubicin Kabi if you are pregnant. Epirubicin Kabi may harm the unborn child.

Do not use Epirubicin Kabi if you are breastfeeding. You should not breastfeed while taking Epirubicin Kabi.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

Before you are given it

You must tell your doctor if you:

  • have heart problems or have ever had heart problems
  • have liver problems
  • have kidney problems
  • have had radiation therapy previously or are having radiation therapy
  • have been treated previously with medicines to treat cancer
  • you are going to be vaccinated (have an injection to prevent a certain disease)
  • are planning to have children

Epirubicin Kabi may decrease the fertility of men and women.

If you have not told your doctor about any of the above, tell your doctor before you start using Epirubicin Kabi.

Taking other medicines

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

Some medicines and Epirubicin Kabi may interfere with each other. Some of these medicines include:

  • 5-fluorouracil
  • cyclophosphamide
  • cisplatin
  • paclitaxel
  • docetaxel
  • trastuzumab
  • other medicines to treat cancer
  • nifedipine
  • verapamil
  • diltiazem
  • felodipine
  • amlodipine
  • lercanidipine
  • propranolol
  • cimetidine

You may need to take different amounts of your medicines or you may need to use different medicines.

Your doctor will advise you.

How Epirubicin Kabi is given

Treatment will normally take place in a hospital. Epirubicin Kabi is usually given as a slow injection or a drip (infusion) into a vein. It might also be injected into the bladder.

Do not drink fluids for 12 hours before treatment if Epirubicin Kabi is to be used in the bladder.

Epirubicin Kabi may be given alone or in combination with other medicines.

Your doctor will decide the dose of Epirubicin Kabi to be given. Treatment is usually given every 3 to 4 weeks, in cycles of therapy. However, your doctor may give Epirubicin Kabi more or less frequently.

Treatment will not be repeated until your blood counts have returned to acceptable levels and any unwanted effects have been controlled.

Your doctor may change your dose during treatment.

Your doctor will let you know how many cycles of treatment you will need.

Ask your doctor if you have any questions about the dose of Epirubicin Kabi and how it is given.

If you take too much (overdose)

As Epirubicin Kabi is likely to be given to you in hospital under the supervision of a doctor, it is unlikely that you will receive too much.

However, immediately tell your doctor or telephone the Poisons Information Centre (Phone Australia 13 11 26) or advice, or go to Accident and Emergency at your nearest hospital if you have side effects after being given Epirubicin Kabi. You may need urgent medical attention.

Symptoms of overdose with Epirubicin Kabi include the side effects below in the 'Side Effects' section, but they are usually of a more severe nature.

While you are using Epirubicin Kabi

Things you must do

Tell your doctor or nurse immediately if the injection stings or hurts while it is being given. The injection may need to be stopped and injected into a different vein.

Make sure you follow your doctor's instructions and keep all appointments. Your doctor will regularly check the function of your heart, liver and kidneys. You will also need to have blood tests.

Use contraception to prevent pregnancy while you or your partner are being treated with Epirubicin Kabi. Epirubicin Kabi may cause birth defects if either the male or female is being treated with Epirubicin Kabi. Both men and women being treated with Epirubicin Kabi and their partners must use a reliable method of contraception (birth control) during treatment with Epirubicin Kabi.

Tell your doctor immediately if you become pregnant while taking Epirubicin Kabi.

Tell your doctor if you have an infection or fever. Epirubicin Kabi lowers your ability to fight infection.

Tell your doctor if you would like to take medicine to prevent or treat nausea (feeling sick) or vomiting. Epirubicin Kabi may cause nausea and vomiting,

Tell any doctor, dentist or pharmacist who treats you that you are being treated with Epirubicin Kabi.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are being treated with Epirubicin Kabi.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert, until you know how Epirubicin Kabi affects you.

Epirubicin Kabi may make some people feel tired or dizzy.

Side Effects

Tell your doctor as soon as possible if you do not feel well while you are being treated with Epirubicin Kabi. All medicines can have unwanted side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. Medicines can affect people in different ways.

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

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

  • nausea (feeling sick) or vomiting
  • diarrhoea
  • sore mouth or tongue, mouth ulcers, redness of mouth, sore vagina or rectum
  • redness of the skin or vein at the site of the injection
  • hair loss, beard stops growing
  • dehydration (thirsty, dry mouth, dry skin, loss of body fluid)
  • sore oesophagus (food pipe)
  • stomach pain or burning feeling in stomach
  • skin rash, itchy skin, hives, sensitive skin, blisters
  • change in colour of skin or nails
  • increased sensitivity to the sun
  • itchy eye, crusty eyelid, sore red eye, blurred vision, conjunctivitis
  • loss of appetite
  • absence of menstrual bleeding (temporary loss of periods)
  • hot flushes
  • weakness, tiredness, dizziness, confusion, depression
  • tingling or numbness of hands or feet; pins and needles
  • gout
  • red coloured urine

Epirubicin Kabi is red and may cause the urine to be a red colour for one or days after treatment. There is no cause for alarm.

Tell your doctor immediately if you get any of the following side effects:

  • stinging, swelling or pain at the site of injection
  • flushing of face while the injection is being given
  • an infection or chills, fever, sore throat, swollen glands, shock
  • heart problems, fast or irregular heart beat, shortness of breath
  • swelling of ankles, feet, legs or hands,
  • bleeding or bruising under the skin

The above side effects may be serious. You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above, such as leukaemia, may also occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using Epirubicin Kabi

Tell your doctor immediately if you notice any of the following side effects, even if they occur several months or years after stopping treatment with Epirubicin Kabi:

  • heart problems, fast or irregular heart beat, shortness of breath
  • swelling of ankles, feet, legs or hands, swelling in the stomach
  • fever or other signs of infection

Leukaemia may occur after treatment with Epirubicin Kabi and other medicines to treat cancer. It is rare.

Storage

This medicine will be stored in the hospital pharmacy and will be looked after by your doctor or pharmacist.

Vials of Epirubicin Kabi Injection should be kept in a refrigerator (2 to 8°C). Do not freeze.

Product Description

What it looks like

Epirubicin Kabi is a red solution.

It is available as a liquid injection in 3 sizes: 10 mg/5 mL, 50 mg/25 mL and 200 mg/100 mL.

Ingredients

The active ingredient in Epirubicin Kabi is epirubicin hydrochloride. It also contains sodium chloride and water for injections.

Supplier

Epirubicin Kabi is supplied in Australia by:
Fresenius Kabi Australia Pty Limited
964 Pacific Highway
Pymble NSW 2073
Telephone: (02) 9391 5555

Australian Registration Numbers

  • 10 mg/5 mL: 175841
  • 50 mg//25 mL: 175839
  • 200 mg/100 mL: 175840

This leaflet was prepared in 01 November 2011

Published by MIMS August 2014

BRAND INFORMATION

Brand name

Epirubicin Kabi

Active ingredient

Epirubicin hydrochloride

Schedule

S4

 

Name of the medicine

Epirubicin hydrochloride.

Excipients.

Sodium chloride in water for injections. Hydrochloric acid is added as necessary to adjust the pH.

Description

Chemical name: (8S, 10S)-10-(3-amino-2,3,6-trideoxy-α-L-arabinohexopyranosyloxy)-8-glycolloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1 methoxynaphthacene-5,12-dione hydrochloride. Molecular formula: C27H29NO11.HCl. MW: 579.99. CAS: 56390-09-1. Structurally, epirubicin hydrochloride differs from doxorubicin hydrochloride only in the orientation of the hydroxyl group at the 4 position on the aminoglycoside ring. Epirubicin hydrochloride is a red orange, almost odourless, hygroscopic powder, sparingly soluble in water and dilute alcohol.

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 per 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/min) 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 indicates 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 2 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 4 years and 303 patients were randomised to receive tamoxifen for 4 years in combination with epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks for 6 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 4 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 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; 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 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, such as 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 problem; haematuria.

Precautions

Epirubicin hydrochloride should be administered only under the supervision of qualified physicians 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 the drug (e.g. greater than or equal to 90 mg/m2 every three to four weeks) causes adverse events generally similar to those seen in 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 3 to 4 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 hydrochloride 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. Leukopenia 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 the drug 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/ anthracenediones. concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic agents such as high dose cyclophosphamide or fluorouracil or trastuzumab. 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 where 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 lifetime 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 S-T 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.

Impaired hepatic function.

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 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).

Impaired renal function.

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin hydrochloride excreted by this route. However, serum creatinine should be assessed before and during therapy as dosage adjustment is necessary in patients with serum creatinine > 5 mg/dL (see Dosage and Administration).

Immunosuppression 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 administered; 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 pharmacologic 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.

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 benefits outweighs any potential risk.

Carcinogenecity, mutagenicity, 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. 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 several 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.

Interactions

Epirubicin hydrochloride is mainly used in combination with other cytotoxic drugs and additive toxicity may occur especially with regard to bone marrow/ haematologic and gastrointestinal effects. In addition, the concomitant use of epirubicin hydrochloride with other antitumour drugs which have been reported as potentially cardiotoxic (e.g. 5-fluorouracil, cyclophosphamide, cisplatin, taxanes, trastuzumab), as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), requires 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 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.

Adverse Effects

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

More common reactions (> 5%).

Haematological.

Myelosuppression, leukopenia, 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 5 to 10 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.

CNS.

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.
During 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.

Serious 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. Leukopenia is the predominant effect with thrombocytopenia and anaemia occurring less frequently. Leukopenia 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, Dose modifications).

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 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 (1 to 3 years) latency period.

Mucositis.

This is frequent and painful and most commonly develops 5 to 10 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 10 days.

Cardiotoxicity.

The cardiac abnormalities caused by treatment can be separated into 2 categories: (i) ECG alterations, and (ii) 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 precordial 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 Warnings). 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 hydrochloride is intended for intravenous or intravesical administration only. It 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 Warnings).

Note.

The recommended lifetime cumulative dose limit of epirubicin hydrochloride 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 physician should determine the choice of dose.
Higher doses, up to 135 mg/m2 as a single agent and 120 mg/m2 in combination, every 3 to 4 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 3 to 4 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 8 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, 4 weekly administrations of 50 mg followed by 11 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 twelve 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.

Pharmaceutical precautions.

The following protective recommendations are given due to the toxic nature of this substance.
Personnel should be trained in good technique for 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.
All items used for administration of 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 hydrochloride is for use in one patient on one occasion only. Discard any residue. Epirubicin hydrochloride 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 epirubicin hydrochloride be slowly administered into the tubing of a freely running intravenous infusion of sodium chloride injection 0.9% or glucose injection 5%. 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 between 3 and 20 minutes to minimise the risk of thrombosis and perivenous extravasation. To minimise the risk of thrombosis or perivenous extravasation, the usual infusion times range between 3 and 20 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 (see Warnings).

Intravesical administration.

Epirubicin hydrochloride, to be instilled using a catheter, should be retained intravesically for 1 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%.
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.

Heparin.

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 a daily 95 mg/m2 dose of epirubicin injection or 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, supporting treatment (including antibiotic therapy, blood and platelet transfusions, colony stimulating factors and intensive case as needed) should be provided until the recovery from toxicities. Delayed cardiac failure may occur up to 6 months after the overdose. Patients should be observed carefully and should, if signs of cardiac failure arise, be treated along conventional lines.
Contact the Poisons Information Centre on 131 126 for advice on the management of overdose.

Presentation

Solution for injection (clear red, ready to use), 10 mg/5 mL (AUST R 175841), 50 mg/25 mL (AUST R 175839), 200 mg/100 mL (AUST R 175840): 1's (single dose vial).

Storage

Store the vials in the original carton between 2 to 8°C. Refrigerate, do not freeze. Single use only. Discard unused portion.
The expiry date (month/ year) is stated on the package after the word EXP.

Poison Schedule

S4.