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Doxorubin 0.2%

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Prescriber Information Leaflet

DOXORUBIN 0.2%

doxorubicin hydrochloride

Product Summary

1.    Trade Name of the Medicinal Product

Doxorubin 0.2%

2.    Qualitative and Quantitative Composition

Doxorubin 0.2% injection contains doxorubicin hydrochloride 2 mg/ml.

3.    Pharmaceutical Form

Solution for Injection.

4.    Clinical Particulars

4.1    Therapeutic Indications

In combination with other antineoplastic drugs, doxorubicin is intended for the treatment of acute lymphocytic leukaemia (except acute lymphatic leukaemia of low risk in children), acute myeloid leukaemia, Hodgkin- and non-Hodgkin lymphomas, osteosarcoma, Ewing sarcoma, adult soft tissue sarcoma, metastatic breast carcinoma, gastric carcinoma, small-cell lung cancer, neuroblastoma, Wilms tumour and bladder carcinoma. Doxorubicin may be used intravesically as a single agent for treatment and prophylaxis of superficial bladder carcinoma.

4.2    Posology and Method of Administration Dosage depends on tumour type, hepatic function and concurrent chemotherapy. The commonly recommended dosage schedule as a single agent is 60-75 mg/m2 by intravenous injection once every 3 weeks. An alternative dose schedule is 20 mg/m2 intravenously, on 3 consecutive days, once every 3 weeks.

In combination with other cytotoxic agents doses of 50-75 mg/m2 are administered.

Myelosuppression may be more pronounced because of the additive effects of the drugs.

The risk of development of cardiomyopathy gradually increases with the dosage. A cumulative dose of 550 mg/m2 should not be exceeded. The administration of doxorubicin should be monitored by electrocardiography, echocardiography and carotid pulse curve: where the voltage of the QRS wave decreases by 30 % or at a fractional shortening of 5 %, it is recommended that treatment is stopped.

If a patient has received mediastinal irradiation, has concomitant heart disease, or is also being treated with other cardiotoxic, non-anthracycline cytotoxic agents, a maximal cumulative dose of 400 mg/m2 is recommended.

Doxorubicin dosage should be reduced if the bilirubin is elevated as follows: serum bilirubin 12 to 30 mg/ml - give 1/2 of the normal dose, bilirubin > 30 mg/l -give 1/4 of the normal dose.

In general, impaired renal function does not require a dose reduction.

Doxorubicin may be given by intravenous bolus injection, or as a continuous infusion. Bolus injection causes higher peak plasma concentrations and therefore is probably more cardiotoxic.

Doxorubicin should not be administered intramuscularly or subcutaneously. Intravenous administration occurs preferably through a running intravenous infusion, over 3 to 5 minutes.

Patients at increased risk of cardiotoxicity should be considered for treatment with a 24 hours continuous infusion, rather than a bolus injection. In this way, cardiotoxicity may be less frequent, without a reduction in therapeutic efficacy. In these patients, the ejection fraction should be measured before each course. Dosage in children:

Dosage in children may be lowered, since they have an increased risk for late cardiotoxicity. Myelotoxicity should be anticipated, with nadirs at 10 to 12 days after start of treatment, but is usually followed by a rapid recovery due to the large bone marrow reserve of children as compared to adults.

Superficial bladder carcinoma and bladder carcinoma in situ:

The recommended dosage is 50 mg in 50 ml normal saline, administered via a sterile catheter.

Initially, this dose is given weekly, later on, monthly. The optimal duration of treatment has not yet been determined; it ranges from 6 to 12 months.

Restrictions regarding the maximal cumulative dose, as with intravenous administration, do not apply to intravesical administration, because systemic absorption of doxorubicin is negligible.

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4.3    Contra-indications

Myelosuppression, pre-existing heart disease, previous treatment with complete cumulative doses of doxorubicin or other anthracyclines.

Doxorubicin should not be used intravesically for the treatment of bladder carcinoma in patients with urethral stenosis who cannot be catheterised.

4.4    Special warnings and special precautions for use

Nausea, vomiting and mucositis are often severe and should be treated appropriately. Doxorubicin should not be administered intramuscularly or subcutaneously. Extravasation results in a severe and progressive tissue necrosis. If extravasation occurs, the injection should be terminated immediately and restarted in another vein. Flooding with normal saline, local infiltration with corticosteroids, or sodium hydrogen carbonate solution (8.4%), and application of dimethylsulphoxide have been reported with varying success. The advice of the plastic surgery consultant should be asked for, and wide excision of the involved area should be considered. Exceeding the maximum cumulative dose of 550 mg/m2 increases the risk of severe, irreversible and therapy-resistant cardiomyopathy and resulting congestive heart failure. Age over 70 or below 15 years should be considered a risk factor, as well as concomitant heart disease. In addition, ECG changes may occur including a reduction in the voltage of the QRS wave, and a prolongation of the systolic time interval, and the ejection fraction may be reduced.

In patients previously treated with other anthracyclines or cyclophosphamide, mitomycin C or dacarbazine, and patients who received radiotherapy to the mediastinal area, cardiotoxicity may occur at doses lower than the recommended cumulative limit.

Acute severe arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.

Heart function should be assessed before, during and after doxorubicin therapy, e.g. by ECG, echocardiography or determination of the ejection fraction. The high incidence of bone marrow depression requires careful haematologic monitoring. Doxorubicin therapy should not be started or continued when polynuclear granulocyte counts are below 2000/mm3, except in the treatment of acute leukaemia, where lower limits may be applied.

Careful haematologic monitoring is also required because of the risk of secondary leukaemias after treatment with cytotoxic agents (see section 4.8: "Undesirable effects"). These leukaemias can be cured when detected at an early stage. Hepatic function should be evaluated before and during therapy. Doxorubicin may induce hyperuricaemia. The blood uric acid level should be monitored; sufficient fluid intake should be ascertained (with a daily minimum of 3 l/m2). If necessary, a xanthine-oxidase inhibitor (allopurinol) may be administered.

Men as well as women should take effective contraceptive measures during and for at least 3 months after doxorubicin therapy.

Doxorubicin may impart a red colouration to the urine.

4.5    Interaction with other medicaments and other forms of interaction

Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines, mitomycin C, dacarbazine, dactinomycin and, possibly, cyclophosphamide.

Doxorubicin may cause exacerbations of haemorrhagic cystitis caused by previous cyclophosphamide therapy. The effects of radiation may be enhanced, and recall of these reactions may occur with doxorubicin therapy, even some time after termination of radiotherapy. Inducers of the enzyme cytochrome P-450 (e.g. rifampicin and barbiturates) may stimulate the metabolism of doxorubicin, with a possible decrease in efficacy.

Inhibitors of cytochrome P-450 (e.g. cimetidine) may decrease the metabolism of doxorubicin, with a possible increase in toxic effects.

4.6    Pregnancy and lactation

Clinical evidence suggests a possible adverse effect on the foetus. In animals doxorubicin has embryotoxic and teratogenic effects. Doxorubicin is excreted in breast milk. Usage during pregnancy and lactation is therefore not recommended.

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TEUZD

HOSPITALS

PACKAGE LEAFLET: INFORMATION FOR THE USER

DOXORUBIN 0.2%

Doxorubicin Hydrochloride

Read all of this leaflet carefully before you start using this medicine.

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

•    If you have any further questions, ask your doctor or nurse.

•    If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

IN THIS LEAFLET:

1. What Doxorubin is and what it is used for

2. Before you receive Doxorubin

3. How to receive Doxorubin

4. Possible side effects

5. How to store Doxorubin

6. Further information

OWHAT DOXORUBIN IS AND WHAT IT IS USED FOR

Doxorubicin is an anthracycline glycoside, which belongs to a group of medicines called cytotoxics which are used to treat cancer.

Doxorubin is used to treat:

•    acute lymphocytic leukaemia (cancer of the blood cells made by lymph glands)

•    acute myeloid leukaemia (cancer of the blood cells made by bone marrow)

•    Hodgkin and non-Hodgkin lymphoma (cancer of the lymph glands)

•    osteosarcoma (bone cancer)

•    Ewing sarcoma (bone cancer in teenagers)

•    adult soft tissue sarcoma (cancer of the soft tissues)

•    advanced breast cancer

•    stomach cancer

•    small-cell lung cancer

•    neuroblastoma (cancer of the nerve tissue)

•    Wilms tumour (a kidney cancer)

•    bladder cancer.

In all these types of cancer normal cell growth is disturbed. The cells grow uncontrolled which causes your cancer. The types of cancer listed above depends on the place in your body where these cells grow.

Leukaemia is a cancer of the cells in your body which produce the various components of your blood.

Doxorubicin attacks and destroys the diseased cells. Unfortunately, the growth of normal cells is also affected. This may result in some of the side effects which are discussed later in this leaflet. Before treatment, you should discuss the risks and benefits of this medicine with your doctor.

BEFORE YOU RECEIVE DOXORUBIN

Do NOT receive Doxorubin if you:

•    are allergic (hypersensitive) to doxorubicin hydrochloride or any of the other ingredients of this medicine

•    have problems with your bone marrow not working properly (a problem with blood cell production)

•    have heart problems

•    have previously received treatment with doxorubicin or similar medicines e.g. epirubicin

•    have problems urinating

•    are pregnant, planning to become pregnant or breast-feeding.

Please discuss any worries you may have about the above warnings with your doctor immediately. Your doctor may, however, decide that your treatment is essential.

Take special care with Doxorubin

Tell your doctor or nurse before you start to take this medicine if you:

•    have received radiation therapy to the chest

•    have liver problems

•    have a history of gout.

You should also talk to your doctor before you receive Doxorubin if you are over 70 or under 15 years of age.

Your doctor will want to monitor you with heart, blood and liver tests before and during your treatment with Doxorubin.

Men and women should use an effective method of contraception during therapy and for at least 3 months afterwards.

Taking other medicines

Talk to your doctor or nurse if you are taking any of the following:

•    rifampicin (an antibiotic)

•    barbiturates e.g. phenobarbital

•    cimetidine (used to treat certain conditions caused by too much acid being produced in the stomach).

Talk to your doctor or nurse if you:

•    have previously been treated with cyclophosphamide, mitomycin C, dactinomycin or dacarbazine (used to treat cancer).

Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Doxorubin is not recommended if you are pregnant, trying to become pregnant or breast-feeding. If you become pregnant or suspect that you may be pregnant during therapy, you must tell your doctor immediately.

Driving and using machines

Doxorubin may cause frequent nausea and vomiting. If affected do not drive or operate machinery.

HOW TO RECEIVE DOXORUBIN

Your medicine will be administered by a doctor or nurse as an injection into one of your veins. The injection should never be given under the skin or into a muscle. The site of injection should not be covered or bandaged. In the case of cancer of the bladder, Doxorubin is administered through a catheter. Doxorubin may be given alone or in combination with other medicines.

If you experience any pain, swelling or warmth around the vein where Doxorubin is being injected, tell your nurse or doctor immediately. This may be a sign that the injection has leaked into the surrounding tissue.

If you notice that your face is red while the injection is being given to you, tell your doctor or nurse immediately. This may be a sign that the injection is being given too quickly.

How much Doxorubin will you receive and how often:

Adults

•    The dosage will depend on the type of cancer being treated, other medicines you are receiving, your age, height, weight and your general medical condition

•    The most commonly used dosage is 60 - 75 mg/m2 every 3 weeks

•    If you are being treated for cancer of the bladder the usual dose is 50 mg/50 ml every week and later on, every month

•    Your treatment schedule may be modified depending on your body's response or other medication you are receiving

•    While you are being given Doxorubin your doctor may want to monitor your heart function. Your condition will also be closely monitored during treatment. This will involve

blood tests

• Other medicines may be given during a course of Doxorubin to treat or prevent side effects. Children

Children may be given lower doses than those used in adults.

If you have any questions about your treatment ask your doctor or nurse.

If you receive more Doxorubin than you should

As a doctor or nurse will be giving you your medicine, it is unlikely that you will receive an incorrect dose. If you receive too much Doxorubin you may suffer from side effects sooner. Tell your doctor or nurse if you have any concerns about the amount of medicine that you receive.

If you miss a dose of Doxorubin

It is important that you do not miss an appointment/injection. If you do miss an injection, you should ensure that you receive your missed dose as soon as possible.

If you have any further questions on the use of this product, ask your doctor or nurse.


Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard By reporting side effects you can help provide more information on the safety of this medicine.


HOW TO STORE DOXORUBIN


Keep out of the reach and sight of children. The

vials should be stored in a fridge and be protected from light. Diluted solutions of Doxorubin should be stored in a fridge for 24 hours, and be protected from light. Do not use Doxorubin after the expiry date that is stated on the outer packaging. The expiry date refers to the last day of that month.


FURTHER INFORMATION


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POSSIBLE SIDE EFFECTS


Like all medicines, Doxorubin can cause side effects. You should discuss them with your doctor who will explain the risks and benefits of your treatment. Some of the side effects can be lessened or treated by other medicines or therapy.

Although not all of these side effects may occur, if they do occur, they may need medical attention.


Tell your doctor immediately if any of the following occur:

•    blood problems, characterised by fever or chills, sore throat, ulcers in the mouth or throat, tiredness or weakness, unusual bleeding or unexplained bruising

•    heart problems, characterised by irregular heartbeat, problems with the heart muscle.

After you have completed your course of treatment, you should tell your doctor or nurse immediately if you notice difficulty in breathing, swelling of the feet or legs, or an irregular or rapid heart beat.

The following side effects have also been reported:

•    inflammation, ulceration or swelling of the nose, mouth, or throat

•    flushing of the face

•    inflammation of a vein with a blood clot

•    conjunctivitis

•    pain, swelling or warmth around the vein where Doxorubin is being injected

•    allergic reactions e.g. fever, nettle rash, increased heartbeat, breathing problems, dizziness

•    stomach problems, nausea, vomiting, diarrhoea

•    kidney and bladder problems e.g. inflammation and bleeding of the bladder, blood in the urine, changed pattern of urination, pain during urination

•    liver problems, e.g. yellow eyes and skin, abnormal liver enzymes, inflamed liver.

There is a chance that Doxorubin might cause unwanted effects that may not occur until months or years after the medicine is used. These delayed effects may include certain types of cancer, such as leukaemia. Discuss these possible effects with your doctor.

Doxorubin may cause your urine to turn red in colour for a couple of days after each dose. Medicines like Doxorubin often cause temporary hair loss. After treatment your normal hair growth should return.


What Doxorubin contains:

•    The active ingredient is doxorubicin hydrochloride

•    The other ingredients are sodium chloride, hydrochloric acid/sodium hydroxide and water for injections.

What Doxorubin looks like and contents of the

pack:

•    Doxorubin 0.2% comes as a red-orange solution for injection in vials of 5 ml

(10 mg doxorubicin hydrochloride per vial),

10 ml (20 mg doxorubicin hydrochloride per vial), 25 ml (50 mg doxorubicin hydrochloride per vial) and 100 ml (200 mg doxorubicin hydrochloride per vial)

•    Doxorubin 0.2% is supplied in packs of 1 or 10 vials.


Marketing Authorisation Holder and Manufacturer

Marketing Authorisation holder and company responsible for manufacture: Pharmachemie B.V., Haarlem, The Netherlands.

This leaflet was last revised: June 2015


PL 04946/0016


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4.7    Effects on ability to drive and use machines

Due to the frequent occurrence of nausea and vomiting, driving and operation of machinery should be discouraged.

4.8    Undesirable effects

Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity.

Myelosuppression includes a transient leukopenia, anaemia and thrombocytopenia, reaching its nadir at 10 to 14 days after treatment.

Cardiotoxicity may occur as arrhythmias directly following drug administration; ECG changes, including T-wave flattening and S-T depression, may last up to

2    weeks after administration.

The risk of cardiomyopathy increases at cumulative doses higher than 550 mg/m2. Age over 70 or below 15 years should be regarded as a risk factor. Also, concomitant or previous treatment with mitomycin C, cyclophosphamide or dacarbazine has been reported to potentiate doxorubicin induced cardiomyopathy. Cardiotoxicity may be encountered several weeks or months after discontinuation of doxorubicin therapy. Other adverse reactions reported are: a generally reversible alopecia; gastrointestinal disturbances, including nausea, vomiting and diarrhoea. Mucositis (stomatitis or oesophagitis) may occur 5 to 10 days after administration.

Hypersensitivity reactions, such as fever, urticaria and anaphylaxis have been occasionally reported. Doxorubicin influences and potentiates normal tissue reactions to radiation. Also, late ("recall") reactions may occur when doxorubicin is administered some time after irradiation. Facial flushing may occur if the injection is given too rapidly Thrombophlebitis and conjunctivitis have been reported.

Slight transient increases of liver enzymes have been reported. Concomitant irradiation of the liver may cause severe hepatoxicity, sometimes progressing to cirrhosis. As with other cytotoxic agents, myelodysplastic syndrome and acute myeloid leukaemia have been observed after treatment with combination therapy including doxorubicin. With topoisomerase II inhibitors, secondary leukaemias have been reported more frequently than expected in the form of acute myeloid leukaemia classification 2, 3 and 4. These forms of leukaemia can have a short period of latency (1 to

3    years). They can be cured when detected at an early stage and with an appropriate curative treatment (see section 4.4 "Special warnings and special precautions for use").

Intravesical administration may cause the following adverse reactions: haematuria, vesical and urethral irritation, stranguria and pollakisuria. These reactions are usually of moderate severity and of short duration. Intravesical administration of doxorubicin may cause a sometimes haemorrhagic cystitis; this may cause a decrease in bladder capacity.

Doxorubicin may impart a red colouration to the urine. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9    Overdosage

Acute overdosage of doxorubicin enhances the toxic effects of mucositis, leukopenia and thrombocytopenia. Overdosage at intravesical administration may cause severe cystitis. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalisation, antibiotics and transfusions after consultation with an oncologist.

Chronic overdosage with cumulative doses exceeding 550 mg/m2 increases the risk of cardiomyopathy and resultant congestive heart failure. Treatment consists of vigorous management of congestive heart failure with digitalis preparations and diuretics.

Administration of a very high single dose may cause myocardial degeneration within 24 hours.

5. Pharmacological Properties 5.1 Pharmacodynamic properties Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. Animal studies have shown a cytotoxic action in several solid and haematologic tumours. The


mechanism of action is not completely elucidated. A major mechanism is probably inhibition of topoisomerase II, resulting in DNA breakage. Intercalation and free-radical formation is probably of minor importance. Drug resistance, due to increased expression of the MDR-1 gene encoding for a multidrug efflux pump, has been reported regularly.

5.2    Pharmacokinetic properties

The intravenous administration of doxorubicin is followed by a rapid plasma clearance (t1/2 = 10 min.) and significant tissue binding. The terminal half-life is approximately 30 hours. Doxorubicin is partly metabolised, mainly to doxorubicinol and to a lesser extent, to the aglycon, and is conjugated to the glucuronide and sulphate. Biliary and faecal excretion presents the major excretion route. About 5 % of the dose is eliminated by renal excretion. Plasma protein binding of doxorubicin ranges from 50-85 %. The volume of distribution is 800-3500 l/m2.

Doxorubicin is not absorbed after oral administration; it does not cross the blood-brain barrier. Impairment of liver function may decrease the clearance of doxorubicin and its metabolites.

5.3    Preclinical safety data None stated.

6.    Pharmaceutical Particulars

6.1    List of excipients

Sodium chloride, hydrochloric acid/sodium hydroxide, water for injections.

6.2    Incompatibilities

Doxorubicin should not be mixed with 5-fluorouracil or heparin. Contact with aluminium should be avoided.

6.3    Shelf-life

Following the special precautions for storage (see section 6.4) the shelf-life of the 5 ml, and 25 ml vials is 36 months and the shelf-life of the 100 ml vial is 24 months as printed on the label.

The injection may be diluted with 0.9% sodium chloride solution or 5% glucose solution.

Chemical and physical in-use stability has been demonstrated for 7 days at room temperature (15-25°C) and protected from light.

From a biological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution (etc) has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Doxorubin 0.2%, injection should be stored at 2-8°C, protected from light.

6.5    Nature and contents of container

Doxorubicin 0.2%, injection is supplied as a red-orange, sterile solution in injection vials containing 5 ml (10 mg), 25 ml (50 mg), or 100 ml (200 mg), respectively, of doxorubicin hydrochloride 2 mg/ml.

6.6    Instructions for use/handling

Any contact with the solution should be avoided. During preparation and reconstitution a strictly aseptic working technique should be used; protective measures should include the use of gloves, mask, safety goggles and protective clothing. Use of a vertical laminar airflow (LAF) hood is recommended. Gloves should be worn during administration. Waste-disposal procedures should take into account the cytotoxic nature of this substance.

If the doxorubicin solution contacts skin, mucosae or eyes, immediately wash thoroughly with water. Soap may be used for skin cleansing.

7.    Marketing Authorisation Holder Pharmachemie B.V.,

Swensweg 5,

Postbus 552,

2003 RN Haarlem,

The Netherlands.

8.    Marketing Authorisation Number

PL 04946/0016

9.    Date of First Authorisation/Renewal of Authorisation

4 January 1996.

10.    Date of (Partial) Revision of the Text

June 2015

Distributed by TEVA UK Limited, Eastbourne, BN22 9AG.

67918-L

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