Consumer medicine information

Pharmorubicin RD

Epirubicin hydrochloride

BRAND INFORMATION

Brand name

Pharmorubicin

Active ingredient

Epirubicin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pharmorubicin RD.

What is in this leaflet

This leaflet answers some common questions about Pharmorubicin RD.

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 using Pharmorubicin RD against the benefits it is expected to have for you.

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

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

What Pharmorubicin RD is used for

Pharmorubicin RD 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 Pharmorubicin RD has been prescribed for you. Your doctor may have prescribed it for another purpose.

Pharmorubicin RD is only available with a doctor's prescription. It is not addictive.

Before you are given Pharmorubicin RD

When you must not be given it

Do not use Pharmorubicin RD if you have ever had an allergic reaction to epirubicin (the active ingredient in Pharmorubicin RD), 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 Pharmorubicin RD if you are pregnant. Pharmorubicin RD may harm the unborn child.

Do not use Pharmorubicin RD if you are breastfeeding. You should not breastfeed while taking Pharmorubicin RD.

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
    Pharmorubicin RD 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 Pharmorubicin RD.

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 Pharmorubicin RD may interfere with each other. These include:

  • medicines used to treatment cancer such as:
    - 5-fluorouracil
    - cyclophosphamide
    - cisplatin
    - paclitaxel
    - docetaxel
    - trastuzumab
    - other medicines to treat cancer.
  • medicines used to treat angina or high blood pressure such as:
    - nifedipine
    - verapamil
    - diltiazem
    - felodipine
    - amlodipine
    - lercanidipine
    - propranolol.
  • cimetidine ( a medicine used to treat heartburn or stomach ulcers).

You may need to take different amounts of your medicines or you may need to use different medicines. Your doctor will advise you.

How Pharmorubicin RD is given

Treatment will normally take place in a hospital. Pharmorubicin RD 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 Pharmorubicin RD is to be used in the bladder.

Pharmorubicin RD may be given alone or in combination with other medicines.

Your doctor will decide the dose of Pharmorubicin RD to be given. Treatment is usually given every 3 to 4 weeks, in cycles of therapy. However, your doctor may give Pharmorubicin RD 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 Pharmorubicin RD and how it is given.

If you are given too much (overdose)

As Pharmorubicin RD 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 on 13 11 26 for advice, or go to Accident and Emergency at your nearest hospital if you have side effects after being given Pharmorubicin RD. You may need urgent medical attention.

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

While you are using Pharmorubicin RD

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 (birth control) to prevent pregnancy while you or your partner are being treated with Pharmorubicin RD. Pharmorubicin RD may cause birth defects if either the male or female is being treated with Pharmorubicin RD. Men being treated with Pharmorubicin RD must use effective contraceptive methods during treatment and for at least 3.5 months after treatment. Women being treated with Pharmorubicin RD must use effective contraceptive methods during treatment with Pharmorubicin RD and at least 6.5 months after treatment.

Tell your doctor immediately if you become pregnant while taking Pharmorubicin RD.

Tell your doctor if you have an infection or fever. Pharmorubicin RD 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. Pharmorubicin RD may cause nausea and vomiting,

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

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

Things to be careful of

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

PHARMORUBICIN RD 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 Pharmorubicin RD. 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), pain on swallowing or difficulty with swallowing
  • 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.
    Pharmorubicin RD is red and may cause the urine to be a red colour for one or two 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 heartbeat, shortness of breath
  • swelling of ankles, feet, legs or hands
  • bleeding or bruising under the skin
  • cough, difficulty breathing, chest pain, coughing up blood
  • swelling, pain, tenderness and redness of the leg.

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 Pharmorubicin RD

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 Pharmorubicin RD:

  • heart problems, fast or irregular heartbeat, 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 Pharmorubicin RD 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.

Pharmorubicin RD should be stored below 25°C.

Product description

What it looks like

Pharmorubicin RD is a powder that is dissolved in a solution before injection.

Ingredients

The active ingredient in Pharmorubicin RD is epirubicin hydrochloride. It also contains lactose and methyl hydroxybenzoate.

Supplier

Pharmorubicin RD is supplied by:

Pfizer Australia Pty Ltd
Sydney, NSW.
Toll Free Number 1800-675 229.
www.pfizer.com.au .

Australian Registration Numbers

Pharmorubicin RD:
50 mg: AUST R 40220.

Date of preparation

This leaflet was revised in May 2021.

© Pfizer Australia Pty Ltd.

® Registered trademark.

Published by MIMS June 2021

BRAND INFORMATION

Brand name

Pharmorubicin

Active ingredient

Epirubicin hydrochloride

Schedule

S4

 

1 Name of Medicine

Epirubicin hydrochloride.

2 Qualitative and Quantitative Composition

Each vial of Pharmorubicin RD contains 50 mg of epirubicin hydrochloride.
Each vial of Pharmorubicin contains 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL and 200 mg/100 mL of epirubicin hydrochloride (strength 2 mg/mL).

Excipient(s) with known effect.

Methyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.

Pharmorubicin RD is a red/orange freeze-dried crystalline powder that is reconstituted to a clear red solution before use.

Solution for injection.

Pharmorubicin is a clear, red ready for use solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Pharmorubicin 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, Pharmorubicin 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).

4.2 Dose and Method of Administration

Dosage.

Note.

The recommended lifetime cumulative dose limit of Pharmorubicin 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. Pharmorubicin 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 3-4 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 3-4 weeks are recommended. Careful monitoring in regard 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 75-90 mg/m2) for heavily pre-treated patients, patients with pre-existing bone marrow depression or in the presence of neoplastic bone marrow infiltration. If Pharmorubicin is used in combination with other cytotoxic drugs with potentially overlapping toxicities, the recommended dose/cycle should be reduced accordingly.

Preparation of solution.

See Section 4.4 Special Warnings and Precautions for Use.
Pharmorubicin can be used in combination with other anti-tumour agents, but it is not recommended that it be mixed with these drugs in the same container (also see Section 6.2 Incompatibilities).
Storage of the Pharmorubicin ready-to-use 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).
Pharmorubicin contains no antimicrobial preservative. Pharmorubicin are single use only vials and any unused portion must be discarded after use. From a microbiological point of view, the products should be used immediately after first penetration of the rubber stopper.

Compatibility.

Pharmorubicin is compatible with the following infusion media: 0.9% sodium chloride; 5% glucose; and 0.9% sodium chloride with 5% glucose.
Pharmorubicin RD should be dissolved in sterile Water for Injections or Sodium Chloride Injection as indicated in Table 1.
For intravesical administration the desired dose of Pharmorubicin RD should be dissolved in 50 mL of sterile Water for Injections or Sodium Chloride Injection.
Reconstituted solution should be used immediately or as soon as practicable after reconstitution in order to reduce the microbiological hazard. If storage is necessary, store at 2°C to 8°C for not more than 24 hours.
Pharmorubicin RD are single use only vials and any unused portion must be discarded after use. From a microbiological point of view, the products should be used immediately after first penetration of the rubber stopper.
Particular care should be taken to avoid aerosol formation when inserting the needle during reconstitution. Inhalation of any aerosol produced during reconstitution must be avoided. After adding the diluent, the vial should be shaken and the contents allowed to dissolve.

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 Pharmorubicin 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 reconstitution, administration or cleaning, including gloves, should be placed in high risk waste disposal bags for high temperature incineration.
Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water.
All cleaning materials should be disposed of as indicated previously.
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.

Method of administration.

Pharmorubicin is intended for intravenous or intravesical administration only. It must not be administered by the intramuscular, subcutaneous or oral routes.

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, four 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 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.

Intravenous administration.

Care in the intravenous administration of Pharmorubicin will reduce the chance of perivenous infiltration (see Section 4.4 Special Warnings and Precautions for Use, Extravasation). It may also decrease the chance of local reactions, such as urticaria and erythematous streaking.
It is recommended that Pharmorubicin 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. 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 Section 4.4 Special Warnings and Precautions for Use, Extravasation).

Intravesical administration.

Pharmorubicin, 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.

Dosage adjustments.

Renal impairment.

While no specific dose recommendation can be made based 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).

Hepatic impairment.

As clinical toxicity may be increased by the presence of impaired liver function, Pharmorubicin dosage must be reduced if hepatic function is impaired, according to Table 2.

Other special populations.

Haematological toxicity may require dose reduction, delay or suspension of Pharmorubicin therapy. Lower doses may be necessary if Pharmorubicin is used concurrently with other antineoplastic agents.

4.3 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 Pharmorubicin 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 cardiomyopathy, previous myocardial infarction); unstable angina pectoris; 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 problems; haematuria.

4.4 Special Warnings and Precautions for Use

Pharmorubicin 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 Pharmorubicin.
While treatment with high doses of Pharmorubicin (e.g. ≥ 90 mg/m2 every 3-4 weeks) causes adverse events generally similar to those seen at standard doses (e.g. < 90 mg/m2 every 3-4 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 Pharmorubicin requires close observation of the patient and extensive laboratory monitoring including assessment of cardiac function (see Section 4.4 Special Warnings and Precautions for Use, 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 Pharmorubicin treatment.

Warnings.

Both Pharmorubicin solution for injection and powder for injection must be handled with care. If either of the preparations 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.
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 3-4 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 injection into a small vessel or from repeated injections into the same vein.
Pharmorubicin must not be given by the intramuscular or subcutaneous route.
Pharmorubicin is not an antimicrobial agent.

Haematologic toxicity.

As with other cytotoxic agents, epirubicin may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/ neutrophil counts returning to normal values in most cases by day 21. Thrombocytopaenia and anaemia may also occur.
Clinical consequences of severe myelosuppression include fever, infection, sepsis/ septicaemia, septic shock, haemorrhage, tissue hypoxia or death.
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 Section 4.2 Dose and Method of Administration, Dosage adjustment, Other special populations).

Secondary leukaemia.

Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines including epirubicin. Secondary leukaemia is more common when such drugs are given in combination with DNA damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1 to 3 year latency period.

Cardiac function.

Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events. The cardiac abnormalities caused by treatment can be separated into 2 categories: (i) ECG alterations and (ii) congestive heart failure (CHF).

Early (i.e. acute) events.

Early cardiotoxicity of epirubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as nonspecific ST-T wave changes. ECG changes following Pharmorubicin treatment occur in about 10% of patients. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and bradycardia, as well as atrioventricular and bundle branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for the discontinuation of epirubicin treatment.

Late (i.e. delayed) events.

Delayed cardiotoxicity usually develops late in the course of therapy with Pharmorubicin or within 2 to 3 months after treatment termination, but later events several months to years after completion of treatment have also been reported. 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. Pericardial effusion has also been described.
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.
Cardiac function should be assessed before patients undergo treatment with epirubicin and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of left ventricular ejection fraction (LVEF) during the course of treatment with prompt discontinuation of epirubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multigated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
Risk factors for cardiac toxicity include 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 5-fluorouracil). Anthracyclines including epirubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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 variable. Trastuzumab may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with epirubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.
There have been sporadic reports of fetal/neonatal cardiotoxic events including fetal death following in utero exposure to epirubicin (see Section 4.6 Fertility, Pregnancy and Lactation).
It is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive.

Gastrointestinal.

Epirubicin is emetogenic. Nausea and vomiting may be prevented or alleviated by the administration of appropriate antiemetic therapy.
Mucositis/ stomatitis occurs frequently and generally appears early after drug administration, most commonly developing 5 to 10 days after treatment. It is painful and typically begins as a burning sensation in the mouth and pharynx. The mucositis may involve the vagina, rectum and oesophagus, and, if severe, may progress over a few days to mucosal ulcerations with a risk of secondary infection. Most patients recover from this adverse event by the third week of therapy.

Use in hepatic impairment.

The major route of elimination of epirubicin is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with Pharmorubicin. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients (see Section 4.2 Dose and Method of Administration). Patients with severe hepatic impairment should not receive Pharmorubicin (see Section 4.3 Contraindications).

Use in renal impairment.

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of Pharmorubicin excreted by this route. However, serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dL (see Section 4.2 Dose and Method of Administration).

Effects at site of injection.

Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/ thrombophlebitis at the injection site (see Section 4.2 Dose and Method of Administration, Intravenous administration).

Extravasation.

Extravasation of epirubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. The recommended administration procedures should be followed (see Section 4.2 Dose and Method of Administration, Intravenous administration). Should signs or symptoms of extravasation occur during intravenous administration of epirubicin, the drug infusion should be immediately stopped.

Tumour lysis syndrome.

Epirubicin may induce hyperuricaemia because of the extensive purine catabolism that accompanies rapid drug induced lysis of neoplastic cells (tumour lysis syndrome). Blood uric acid levels, potassium, calcium phosphate and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome.

Immunosuppressant effects/ increased susceptibility to infections.

Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents, including epirubicin, may result in serious or fatal infections. 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.

Embryo-fetal toxicity.

Epirubicin can cause genotoxicity. An effective method of contraception is required for both male and female patients during and for a period after treatment with epirubicin (see Section 4.6 Fertility, Pregnancy and Lactation). Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.

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 Pharmorubicin.
Pharmorubicin 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.
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.

Excipients.

Pharmorubicin RD contains methyl hydroxybenzoate. This may cause allergic reactions (which may occur after treatment), and in rare cases, respiratory difficulties.

Intravesical route.

Administration of epirubicin may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterisation problems (e.g. uretheral obstruction due to massive intravesical tumours).

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmorubicin 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 Pharmorubicin with other anti-tumour 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.
Concurrent administration of Pharmorubicin and propranolol may result in an additive cardiotoxic effect.
Cimetidine increased the AUC of Pharmorubicin by 50% and should be stopped during treatment with Pharmorubicin.
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 Pharmorubicin may be associated with enhanced myocardial toxicity of Pharmorubicin.
Pharmorubicin is extensively metabolised by the liver. Changes in hepatic function induced by concomitant therapies may affect Pharmorubicin metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Although no studies have been conducted with Pharmorubicin, it may be expected, like doxorubicin, to cause infertility during the period of drug administration. In women, Pharmorubicin 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 Pharmorubicin, the drug could induce chromosomal damage in human spermatozoa; therefore, males undergoing Pharmorubicin treatment should be advised to use effective contraceptive methods during treatment and for at least 3.5 months after the last dose.
(Category D)
Women of childbearing potential should be advised to avoid becoming pregnant during treatment and to use effective contraceptive methods during treatment and for at least 6.5 months after last dose.
There is no specific information available at present concerning the use of Pharmorubicin 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.
If epirubicin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There have been sporadic reports of fetal and/or neonatal transient ventricular hypokinesia, transient elevation of cardiac enzymes, and of fetal death from suspected anthracycline induced cardiotoxicity following in utero exposure to epirubicin in 2nd and/or 3rd trimesters (see Section 4.4 Special Warnings and Precautions for Use). Monitor the fetus and/or neonate for cardiotoxicity and perform testing consistent with community standards of care.
 It is likely that Pharmorubicin is excreted in breast milk, therefore it is not recommended for nursing mothers unless the expected benefit outweighs any potential risk. Because of the potential for serious adverse reactions in nursing infants from epirubicin, lactating women should be advised not to breastfeed during treatment with epirubicin and for at least 7 days after last dose.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Dose limiting toxicities are myelosuppression and cardiotoxicity (described in detail, see Section 4.4 Special Warnings and Precautions for Use).
Drug-related adverse events that occurred during clinical trials are listed below.

More common reactions (> 5%).

Blood and lymphatic system disorders.

Myelosuppression, leukopenia, neutropenia, febrile neutropenia, thrombocytopenia, mild anaemia, secondary infection.

Cardiac disorders.

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

Gastrointestinal disorders.

Nausea, vomiting, diarrhoea, mucositis (erythema, erosions/ ulcerations, bleeding). Mucositis may appear 5-10 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.

Skin and subcutaneous tissue disorders.

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

General disorders and administration site conditions.

Erythematous streaking along the infused vein.

Metabolism and nutrition disorders.

Dehydration.

Less common reactions (< 5%).

Blood and lymphatic system disorders.

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

Cardiac disorders.

Cardiomyopathy, congestive heart failure, cardiomegaly, atrioventricular and bundle branch block, tachyarrhythmias (premature ventricular contractions, ventricular tachycardia, bradycardia).

Gastrointestinal disorders.

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

Skin and subcutaneous tissue disorders.

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

General disorders and administration site conditions.

Chills, fever, malaise/asthenia, vesication, local pain, severe cellulitis and skin necrosis following perivenous drug extravasation.

Eye disorders.

Conjunctivitis, keratitis.

Immune system disorders.

Anaphylaxis.

Investigations.

Asymptomatic drops in left ventricular ejection fraction, changes in transaminase levels.

Nervous system disorders.

Weakness, dizziness, confusion, depression, paraesthesia.

Metabolism and nutrition disorders.

Hyperuricaemia, anorexia.

Neoplasms benign and malignant.

Acute lymphocytic leukaemia, acute myelogenous leukaemia.

Reproductive system disorders.

Amenorrhoea, azoospermia.

Vascular disorders.

Hot flushes, shock, thromboembolism, arterial embolism, thrombophlebitis, phlebitis, venous sclerosis.

Postmarketing experience.

Infections and infestations.

Pneumonia.

Renal and urinary disorders.

Red coloration of urine for 1 to 2 days after administration.

Respiratory, thoracic and mediastinal disorders.

Pulmonary embolism.

Injury, poisoning and procedural complications.

Chemical cystitis, sometimes haemorrhagic, and bladder constriction (following intravesical administration). Dose reduction (40%) may be necessary in these cases.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

A 36 year old man with non-Hodgkin's lymphoma received a daily 95 mg/m2 dose of epirubicin injection 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 320 mg/m2 dose of epirubicin, 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 Pharmorubicin 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 of 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.
Epirubicin cannot be removed by dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of action of Pharmorubicin 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. Pharmorubicin has proved to be active on the following experimental tumours: L 1210 ascites and P 388 leukaemias, sarcoma SA 180 (solid and ascitic forms), melanoma B 16, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38.
The specificity of Pharmorubicin 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 Pharmorubicin.
Toxicity studies in animals have indicated that on a weight (mg/mg) basis Pharmorubicin has a better therapeutic index and less systemic and cardiac toxicity than doxorubicin.
Pharmorubicin is immunosuppressive in animals. Although there are no clinical data on the immunosuppressive effects of Pharmorubicin, 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 Pharmorubicin 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 70.4% versus 59.5% (p = 0.07). Overall survival at two years was 93% versus 92% 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 Pharmorubicin 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 TTP was significantly longer in study 4 for the higher dose epirubicin regimens.

5.2 Pharmacokinetic Properties

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.

Absorption/distribution.

When Pharmorubicin is administered intravesically, the systemic absorption is minimal. As with doxorubicin, Pharmorubicin may not be expected to cross the blood-brain barrier.

Elimination.

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. Pharmorubicin 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.

5.3 Preclinical Safety Data

Genotoxicity.

Like most other anti-tumour and immunosuppressant agents, Pharmorubicin is mutagenic in animals (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Carcinogenicity.

Pharmorubicin is carcinogenic in animals (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

6 Pharmaceutical Particulars

6.1 List of Excipients

Pharmorubicin RD.

Methyl hydroxybenzoate, lactose.

Pharmorubicin.

Hydrochloric acid, Sodium chloride, Water for injections.

6.2 Incompatibilities

If Pharmorubicin is used in combination with other anti-tumour agents, it should not be mixed with these drugs in the same container.
Epirubicin should not be mixed with other drugs. Contact with any solution of an alkaline pH should be avoided, as it will result in hydrolysis of epirubicin.
Pharmorubicin should not be mixed with heparin as these drugs are incompatible.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Pharmorubicin RD.

Store below 25°C.

Pharmorubicin.

Store at 2°C to 8°C. Refrigerate, do not freeze.

6.5 Nature and Contents of Container

Pharmorubicin RD.

Pharmorubicin RD is supplied in Type 1 glass vials stoppered with chlorobutyl rubber bungs and sealed with aluminum cap in packs of 1 vial.

Pharmorubicin.

Pharmorubicin is supplied in polypropylene vials with halobutyl stoppers and an aluminum cap with a plastic flip-off top in packs of 1 vial.
*These presentations are not supplied.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Structurally, Pharmorubicin differs from Adriamycin (doxorubicin hydrochloride) only in the orientation of the hydroxyl group at the 4 position on the aminoglycoside ring.
The chemical name of epirubicin hydrochloride is (8S, 10S)-10-(3-amino-2,3,6-trideoxy-α-L-arabino-hexopyranosyloxy)-8-glycolloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxynaphthacene-5,12-dione hydrochloride.
Epirubicin hydrochloride is a red-orange, almost odourless, hygroscopic powder, sparingly soluble in water and dilute alcohol.

CAS number.

56390-09-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes