Epirubicine HCl Strides 2mg/ml, oplossing voor injectie/infusie

Medicinal product group

Epirubicin belongs to the group of cytostatics (products to fight cancer).

Epirubicin makes sure that cancer cells cannot grow any more, which eventually kills them.

Epirubicin is administered for the treatment of:

• breast cancer;
• stomach cancer;
• Epirubicin is also used intravesically (directly into the bladder) to treat early (superficial) urinary bladder cancer and help prevent recurrence of bladder cancer after surgery.

Epirubicin is often used concomitantly with other cancer fighting medicinal products (in so- called po1ychemotherapy schedules).

Do not use Epirubicin Strides

• if you are allergic (hypersensitive) to epirubicin, similar medicines (called anthracyclines, see below) or any of the other ingredients of Epirubicin Strides;
• if you have been treated before with high doses of some other anti-cancer medicines including doxorubicin and daunorubicin which belong to the same group of drugs as Epirubicin Strides (called anthracyclines). They have similar side effects (including those effects on the heart);
• if you suffered or currently have heart problems;
• if you are breast feeding;

Strides Arcolab International Ltd. Epirubicin Strides 2 mg/ml solution for injection or infusion PILE – 2/14 July 2011

• if you have a low blood count;
• if you have a severe liver function disorder;
• if you suffer from an acute severe infection.

When administered intravesically (directly into the bladder), Epirubicin Strides should not be used if:

• the cancer has penetrated the bladder wall;
• you have an infection in your urine tract;
• you have pain or inflammation in your bladder;
• your doctor has problems inserting a catheter (tube) into your bladder;
• there is a large volume of urine left in your bladder after you attempt to empty it;
• if your urine contains blood;
• if you have a contracted bladder.

Take special care with Epirubicin Strides

• if you are elderly or a child, because of the higher risk of severe cardiac side effects. Your cardiac function will be checked before and after the treatment with epirubicin.
• if you have had problems with your heart in the past or if you are currently experiencing such problems. You should inform your doctor. The dose of epirubicin will have to be adjusted. Your doctor will regularly check if your heart is working properly.
• if you have previously been treated with products to fight cancer (such as with doxorubicin or daunorubicin or anthracenedion derivatives) or if you have had radiation, because the risk of severe cardiac side effects is greater. Inform your doctor because this is included in determining the total dose of epirubicin you will be administered.
• if you have a liver or kidney disorder. This may cause an increase in side effects. Both the kidney function and the liver function will be checked regularly and if needed the dose will be adjusted.
• if you desire to have children. Both men and women should use effective contraceptive measures both during and for 6 months after the treatment. Men are advised to request information about the possibility of storing sperm by means of freezing before the treatment.
• if you suffer from infections or bleedings. Epirubicin may affect the bone marrow. The number of white blood cells in your blood will be reduced, which makes you more susceptible to infections (leucopoenia). Bleedings can occur more easily (thrombocytopenia). These side effects are temporary in nature. The reduction of the number of white blood cells is greatest 10-14 days after the administration and usually returns to normal 21 days after the administration.
• if you have recently received or want to receive any vaccination.
• to check the level of uric acid in your blood. Your doctor will check this.
• to ensure the number of cells in your blood does not drop too low. Your doctor will regularly check this.
• if you are experiencing severe inflammation or ulcers in your mouth.
• if you have received or are receiving radiotherapy to the chest area.
• if you get a burning feeling at the site of the administration. This could indicate that epirubicin is leaking outside the blood vessel. Warn your doctor about this.

Please consult your doctor if one of the above mentioned warnings is applicable to you, or has been applicable to you in the past.

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Using other medicines

Attention: the following remarks may also be applicable to the recent use of medicinal products or their use in the near future.

The medicines mentioned in this section may be known to you under a different name, often the brand name. In this section only the active ingredient(s) of the medicinal product is mentioned, not the brand name! Therefore always carefully read on the package or in the patient leaflet what the active ingredient is of the medicines you are using.

An interaction means that (medicinal) products that are used together can influence each other's effect and/ or side effect. An interaction can occur with the concomitant use of this solution and:

• the harmfulness to the heart can increase with prior or concomitant administration of other products related to epirubicin, so-called anthracyclines (for instance the cancer fighting medicines mitomycin-C, dacarbazine, dactinomycin and cyclophosphamide)or other medicines that may affect the heart (for instance the cancer fighting medicines 5-fluorouracil, cyclophosphaminde, cisplatin, taxanes). Extra monitoring of the heart is then necessary.
• epirubicin can increase the effect of radiation and even after quite some time after the radiation it can cause serious side effects in the irradiated area.
• rifampicin (product used for the treatment of tuberculosis) and barbiturates (products that are used for insomnia or epilepsy, such as for instance phenobarbital); these products decrease the amount of epirubicin in the blood, which could lead to a reduced effect of epirubicin.
• paclitaxel and docetaxel (products that are used for some cancers); when paclitaxel is administered before epirubicin or docetaxel is administered immediately after epirubicin, the amount of epirubicin in the blood is increased, which could lead to an increase of the side effects.
• dexverapamil (a product that is used to treat some cardiac disorders); when used together with epirubicin it may have a negative effect on bone marrow.
• interferon a2b (a product used in some cancers and lymphomas and some forms of hepatitis).
• quinine (a product used for treatment of malaria and for leg cramps); quinine may speed up the distribution of epirubicin into the body, which may have a negative effect on the red blood cells.
• dexrazoxane (a product sometimes used with doxorubicin to reduce the risk of heart problems); the time that epirubicin is present in the body may be decreased, which could lead to decreased effect of epirubicin.
• cimetidine (a product to reduce the acid in your stomach); the amount of epirubicin in the blood is increased, which could lead to an increase of the side effects.
• previous or concomitant treatment with other products which influence the bone marrow (for instance other products to treat cancer, sulfonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, products against certain virus); the formation of blood cells can be disturbed.
• products that cause heart failure.
• products that influence the liver function; the degradation of epirubicin by the liver may be influenced, which may cause a reduced effect of epirubicin or an increase of the side effects.
• live vaccines; there is risk of fatal disease therefore this combination is not recommended.

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• cyclosporine (a product that suppresses the immune system); the immune system may be suppressed to much.

Please tell your doctor or pharmacist if you are using or have recently used any other medicines, including medicines obtained without a prescription.

Using Epirubicin Strides with food and drink

You should not drink within 12 hours before application when epirubicine will be administered in the bladder.

Pregnancy and breast-feeding

Pregnancy

Medicines to fight cancer are only administered during pregnancy in extreme cases. The benefits for the mother must be weighed against the possible danger to the unborn child. In animal studies epirubicin proved to be harmful to the unborn child and can cause deformities. Both men and women should use good contraceptive measures (pill, condom) both during and for 6 months after the use of this medicine to prevent pregnancy.

You should also prevent pregnancy if you partner is treated with epirubicin.

If pregnancy occurs during treatment with epirubicin, genetic counselling is recommended.

Men who wish to father children in the future should seek advice about freezing sperm before treatment with epirubicin is started.

Breast feeding

It is not known whether epirubicin is excreted in the breast milk. You should discontinue breast-feeding during treatment with Epirubicin Strides.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Because many people get very nauseous or have to vomit during the treatment, driving and using machines is not recommended.

Important information about some of the ingredients of Epirubicin Strides

This medicinal product contains 3.5 mg sodium per ml solution for injection or infusion. To be taken into consideration by patients on a controlled sodium diet.

Epirubicin Strides will only be given to you under supervision of a doctor specialised in this type of treatment. You should check with your doctor or pharmacist if you are not sure.

The dose you are administered will depend on the type of cancer you have, your health, your age, how well your liver functions and other medicines you are taking.

The usual dose is

Depending on your general health and possible previous treatments the dose schedule is determined, whereby your length and your weight are taken into account. The amounts in the dose schedule are expressed in numbers of milligrams per square metre of body surface area. This medicine will be administered as

• an injection in a vein for 3 - 5 minutes

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or

• an infusion in a vein for a maximum of 30 minutes.

If only epirubicin is administered, so without other cancer medicines, the recommended dose is 60-90 mg/m² of body surface area. This dose is administered as a single dose or distributed over 2-3 consecutive days. This is repeated every 21 days. In combination with other cancer medicines the dose is reduced.

The administration occurs via a catheter or side line of a free running infusion of a sodium chloride or glucose (sugar solution).

Higher doses are used for the treatment of

• lung cancer: 120 mg/m² of body surface area and
• might be given for the treatment breast cancer: 100 - 120 mg/m² of body surface area.

Administration via the bladder (intravesical administration)

The product can be given directly into the bladder (for the treatment of bladder cancer) by means of a catheter. If this method is used, you must not drink any liquids for 12 hours before the treatment, so your urine will not dilute the medicine too much. The dissolved medicine should be kept in your bladder for 1 hour after it has been administered. You will have to change your position occasionally to make sure the medicine reaches all parts of your bladder.

When you empty your bladder after the medicine has been given, make sure that your urine does not get in contact with your skin. In case contact does take place, thoroughly wash the site of contact with water and soap but do not scrub.

While epirubicin is being administered to you your doctor will perform blood tests. This is to measure the effect of the medicine. Your doctor will also perform tests to see how your heart functions. Both blood test and heart function tests are done before and during treatment with epirubicin.

If you notice that Epirubicin Strides is too strong or too weak, consult your doctor or pharmacist.

If more Epirubicin Strides was administered than should have been

Because this medicine is administered by medical personnel the risk of an overdose is unlikely. Immediately contact your doctor if you suspect that too much Epirubicin Strides has been administered.

If you forget to use Epirubicin Strides

Because this medicine is administered by medical personnel it is unlikely that a dose is missed.

You should check with your doctor if you are not sure.

If you stop using Epirubicin Strides

Consult your doctor.

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

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Like all medicines Epirubicin Strides can cause side effects, although not everybody gets them.

If any of the side effects gets serious, or if you notice any side effect not listed in this leaflet, please tell your doctor or pharmacist immediately.

The following side effects can, amongst others, occur:

Very common: affects more than 1 user in 10

Common: affects 1 to 10 users in 100

Uncommon: affects 1 to 10 users in 1,000

Rare: affects 1 to 10 users in 10,000

Very rare: affects less than 1 user in 10,000

Not known: frequency cannot be estimated from the available data

More than 10% of treated patients can expect to develop undesirable effects. The most common undesirable effects are

• myelosuppression,
• gastrointestinal side effects,
• anorexia,
• alopecia,
• infection.

System Organ Class	Frequency	Undesirable effects
Infections	Common	Infection
	Not Known	Blood poisoning (sepsis) and
		shock as a result of blood
		poisoning, pneumonia
Blood	Very Common	Bone	marrow	depression	is
		an abnormality in the blood,
		which means that fewer new
		blood	cells	are	produced
		(resulting in a shortage of
		white blood cells, red blood
		cells,	platelets;		reduced
		number of a type of white
		blood		cell	(neutrophilic
		granulocytes)	with	fever),
		and	which	involves	an
		increased	sensitivity	to
		infections (due to a shortage
		of	white	blood	cells
		(leucopoenia))	and	anaemia.
		Your blood must be checked
		regularly.
	Uncommon	bruising	and	a tendency	to

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		bleed (due to shortage of
		platelets (thrombocytopenia))
	Not known	Bleeding, shortage of oxygen
		in tissue
Immune system	Rare	Severe,	immediate	allergic
		reaction
		(anaphylactic/anaphylactoid
		reaction) with	or	without
		shock including skin rash and
		itching; fever and chills.
	Common	Allergic		reactions			after
		intravesical	administration
		(directly into the bladder).
Nervous system	Rare	Dizziness
	Not known	Certain disorder of the nerves
		(peripheral		neuropathy),
		headache
Eyes	Not known	Inflammation	of	the	eye
		(conjunctivitis or keratitis)
Heart	Rare	Risk of a reduced effect of
		the heart with as a result
		congestion	of		the		blood
		(congestive	heart	failure),
		heart fai1ure	(	dyspnoea;
		accumulation of fluid in the
		whole	body	(	oedema),
		enlargement of	the	liver,
		accumulation of fluid in the
		lungs (ascites), accumulation
		of fluid in the lungs
		(pulmonary	oedema,		pleural
		effusions),	abnormal	rhythm
		of the heart (gallop rhythm)
		cardiotoxicity	(e.g.		ECG
		abnormalities,	arrhythmias,
		heart	muscle		disease
		(cardiomyopathy)), increased
		frequency	of	heart		beat
		arising from lower chambers
		of the	heart	(ventricular
		tachycardia),	slow		heart
		rhythm			(bradycardia),
		cessation	of		impulse
		transmission in the heart (AV
		block, bundle-branch block).
	Not known	Decrease of fraction of blood
		pumped out of a ventricle
		with	each	heart			beat
		(asymptomatic	drops	in	left

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		ventricular ejection fraction)
Blood vessels	Common	Hot	flashes,	thickening	or
		hardening of the walls of the
		veins (phlebosclerosis)
	Uncommon	Redness	along	the	veins
		(phlebitis),			vascular
		inflammation		with	the
		forming of a blood clot, often
		felt as a painful somewhat
		hard core with above it red
		skin (thrombophlebitis)
	Not known	Shock,	forming	of	blood
		clots		(thromboembolism),
		including		blood	clot
		formation	in	the	lungs
		(pulmonary	emboli, in	very
		rare cases this resulted in
		death)
Gastrointestinal system	Common	Mucous membrane
		inflammation (mucositis (can
		occur 5 to 10 days after the
		start of the treatment)),
		inflammation of the mucous
		membrane of the oesophagus
		(esophagitis), inflammation
		of the mucous membrane of
		the mouth (stomatitis),
		vomiting, diarrhoea which
		can result in dehydration,
		nausea (nausea and vomiting
		often occur within the first
		24 hours (in nearly all
		patients),loss of appetite
		(anorexia)
Skin	Very Common	Hair loss (alopecia, in 60-
		90% of treated cases. It
		involves	poor	beard growth
		in men. Hair loss is dose-
		dependent and in most cases
		reversible)
	Rare	Skin rash with formation of
		little	bumps	(urticaria)	or
		with severe itching (pruritis),
		redness along the vein that
		was used for the injection.
	Not Known	Local	reactions,	rash,	itch,
		skin		changes,	redness,
		flushes, changes in skin and
		nail		(hyperpigmentation),

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		sensitivity		to				light
		(photosensitivity)	or	allergic
		reaction in the case of
		radiation	(radiation-recall
		reaction)
Kidneys and urinary tract	Very common	Red coloration of urine for 1
		to 2 days after administration
	Common	Bladder				infection,
		inflammation of the bladder,
		sometimes	bleeding,	local
		reactions	like		burning
		sensations and frequent urge
		to	urinate	have		been
		observed after administration
		into the bladder
	Rare	Increased	bloodlevel	of	uric
		acid (hyperurecemia)
	Not known	Increased amount of proteins
		in	urine	(proteinuria)	in
		patients	who	were	treated
		with a high dose
Sexual organs	Rare	Absence	of	menstruation,
		lack of sperm cells in sperm
Other	Common	Redness at infusion site
	Rare	Concomitant	administration
		of	certain medicines		for
		fighting cancer (so-called
		DNA-damaging
		antineoplastic	substances)
		can in rare cases lead to
		certain forms of cancer of the
		blood	(secondary		acute
		myeloid	leukaemia	(AML)
		with			or			without
		pre1eucaemic	phase). These
		certain forms of cancer of the
		blood can only be observed
		after 1-3 years, Malaise,
		weakness,	(extremely	high)
		fever,	chills,	changes	in
		levels of	certain	enzymes
		(transaminase)

Severe side effects which affect the whole body and allergic reactions are rare when Epirubicin Strides is given into the bladder.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

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Store in a refrigerator (2°C - 8°C).

Store and transport refrigerated.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

After first opening the product should be used immediately.

After dilution (in 0,9 % (9 mg/ml) sodium chloride or 5 % (50 mg/ml) glucose solution) to a concentration of 0,1 mg/ml chemical and physical in-use stability has been demonstrated for 4 days at 25°C and for 14 days at 2-8°C.

After dilution (in 0,9 % (9 mg/ml) sodium chloride or 5 % (50 mg/ml) glucose solution) to a concentration of 1.0 mg/ml chemical and physical in-use stability has been demonstrated for 7 days at 25°C and for 14 days (0,9 % (9 mg/ml) sodium chloride) or 7 days (5 % (50 mg/ml) glucose solution) at 2-8°C.

From a microbiological point of view, the product should be used immediately after first penetration of the rubber stopper. 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.

Storage of the 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 a mobile solution after two to a maximum of four hours equilibration at controlled room temperature (15-25°C).

Keep out of the reach and sight of children!

Do not use Epirubicin Strides after the expiry date mentioned on the package after “exp.” The first 2 numbers indicate the month; the last numbers indicate the year. The expiry date refers to the last day of that month.

Do not use Epirubicin Strides if you see visual signs of deterioration

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What Epirubicin Strides contains

• The active substance is epirubicin hydrochloride; 1 ml contains 2 mg epirubicin hydrochloride.
• The other ingredients (excipients) are sodium chloride, hydrochloric acid and water for injections.

What Epirubicin Strides looks like and contents of the pack

Epirubicin Strides is a medicine in the form of a clear red solution for injection or infusion. It is delivered in glass injection vials with 25 ml (50 mg) or 100 ml (200 mg) of solution for injection or infusion.

Not all pack sizes may be marketed.

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Marketing Authorisation Holder

Strides Arcolab International Limited

Unit 4, Metro Centre

Tolpits Lane, Watford

Herts

WD18 9SS

United Kingdom

Manufacturer

Strides Arcolab Polska Sp z o o

10, Daniszewska Str

03-230 Warsaw

Poland

RVG 108078

This medicinal product is authorised in the Member States of the EEA under the following names:

Luxemburg:	Epirubicine Strides
The Netherlands:	Epirubicine HCl Strides

This leaflet was last approved in januari 2012

<[To be completed nationally]>

The following information is intended for medical and healthcare professional only:

PREPARATION GUIDE FOR USE WITH EPIRUBICIN STRIDES, SOLUTION FOR INJECTION OR INFUSION

It is important that you read the entire contents of this procedure prior to the preparation of either the Epirubicin Strides solution for injection or infusion.