PACKAGE LEAFLET: INFORMATION FOR THE USER

Eposin, concentrate for solution for infusion 20 mg/ml.

etoposide

Read all of this leaflet carefully before you are given your medicine.

It provides a summary of information about your medicine.

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

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

•    This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

•    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.

In this leaflet:

1.    What Eposin is and what it is used for

2.    What you need to know before you are given Eposin

3.    How to use Eposin

4.    Possible side effects

5.    How to store Eposin

6.    Further information

1.    WHAT EPOSIN IS AND WHAT IT IS USED FOR Medicinal product group

Eposin contains the active ingredient of etoposide, which is a cancer chemotherapy drug which slows the process of cell division. Eposin belongs to a class of drugs known as podophyllotoxin derivatives; it slows or stops the growth of cancer cells in your body.

Use for

This medicinal product is used for:

•    Tumours of the testis in combination with other products against cancer.

•    A certain form of lung cancer (small cell lung cancer), in combination with other products against cancer.

•    Certain types of cancer of the blood (acute myelomonocytic and monocytic leukaemia; in combination with other products against cancer.)

2.    WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN EPOSIN Do not use Eposin

•    if you are hypersensitive to etoposide, or one of the other ingredients of the concentrate for solution for intravenous infusion

•    if you have severely reduced function of the liver

•    if you have severe suppression of the functioning of the bone marrow, unless when this is caused by your disease

•    if you are breast-feeding

•    if you will receive yellow fever vaccine or other live vaccines. Live vaccines should not be used in patients whose immune system is less functional.

•    This product contains benzyl alcohol. Must not be given to premature babies or neonates.

Take special care with Eposin

Eposin is only used under strict supervision of a doctor experienced with the use of cytostatics.

Tell your doctor if you have previously been treated with products against cancer or if you have received radiation therapy.

Eposin should be only administered in a vein. If you have a stinging or burning sensation at the place where you have been injected with Eposin, it may be due to leaking of Eposin out of the vein. If this happens please tell your doctor as they will start treatment from a different vein and will monitor the affected area carefully.

Your doctor will regularly check your blood and the functioning of your liver during the use of Eposin.

If you have bone marrow depression caused by radiation therapy or chemotherapy, your doctor will not restart the treatment until your blood tests shows that this is justified.

Also tell your doctor if you think that you have infections.

If you think that you might have an allergic reaction causing flushing, fast heartbeat, difficulty in breathing and a severe reduction in blood pressure (anaphylactic reaction). Tell your doctor immediately of these symptoms, you may need urgent medical attention.

During and for 6 months after the use of Eposin both men and women must use products to prevent pregnancy. Because Eposin can cause infertility, men can have their sperm frozen at the sperm bank before the treatment with Eposin starts.

A bottle with Eposin contains 24 % m/v alcohol. This may be harmful to alcoholics, children, pregnant women and patients with liver diseases, epilepsy or diseases of the brains. Alcohol can influence or increase the effect of other medicinal products.

This product contains benzyl alcohol. May cause toxic reactions and allergic reactions in infants and children up to 3 years old.

Eposin and anthracyclines can negatively affect each other’s action

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

Using other medicines

Note: the following remarks may also be applicable to the use of medicinal products in the past 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 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 concentrate for injection fluid and:

•    Cisplatin can reduce the rate of elimination of Eposin.

•    Phenytoin (a product used in the treatment of epilepsy). The concomitant use of Eposin and phenytoin can reduce the effect of Eposin.

•    products that counteract coagulation of the blood (coumarines like warfarin, acenocoumarol or phenprocoumon), Eposin may increase the effect of these products.

•    Eposin may reduce the effectiveness of the immune system, therefore yellow fever vaccine or other live vaccines should not be used in immunosuppressed patients.

•    certain painkillers (phenylbutazone, sodium salicylate, salicylic acid), the effect and adverse effects of Eposin may increase.

•    cyclosporin (immune system suppressing product); the dose of Eposin should be reduced.

•    bone marrow suppressing products (such as for instance cyclophosphamide, BCNU, CCNU, 5-fluorouracil, vinblastin, doxorubicin, cisplatin); the effect of Eposin and/ or of the concomitantly administered bone marrow suppressing medicine can be increased.

•    anthracyclines (products against cancer); Eposin and anthracyclines can negatively affect each other’s action.

•    other products against cancer (such as for instance bleomycin, cisplatin, ifosfamide, methotrexate); the occurrence of acute leukaemia has been reported.

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

Pregnancy and breast-feeding

Pregnancy

Eposin is not recommended during pregnancy. Women should not get pregnant and men should not father a baby until at the earliest 6 months after the therapy with Eposin. See section “Take special care with Eposin”.

Breast-feeding

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Eposin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

Driving and using machines

The use of this medicinal product can cause nausea and vomiting. Therefore be cautious with activities that require your full attention, such as participating in traffic, operating machines and working at heights. Keep a close eye on children who are using this medicine, when they are playing outside.

3. HOW TO USE EPOSIN

Eposin is an infusion concentrate. This means that it should not be injected into the veins the way it is. It must first be diluted with a physiological salt or glucose solution. Eposin is administered by your doctor in the hospital as an infusion into the veins. The usual dose of Eposin in combination with other chemotherapeutic drugs is 100 -120 mg/m² per day. The administration takes at least 30 minutes. A treatment cycle may exist of one administration per day (=24 hours) for 3 to 5 days, followed by 10 to 20 days of rest. Usually three or four treatment cycles are given, however, the length of the treatment and the number of treatment cycles are determined by the doctor and may be different for each patient.

A dose adjustment should take place with an abnormal renal function.

If you notice that Eposin is working too strong or too weak, consult your doctor or pharmacist.

If you are given more Eposin than you should

If you suspect a severe overdose, you should notify a doctor immediately. Symptoms that may occur are severe bruising and/ or bleeding and inflammation of the mucous membranes. You may be treated with antibiotics or blood transfusions. In case of a hypersensitivity reaction, you will be treated with certain medicinal products (antihistamines and corticosteroids).

If you forget to use Eposin or if you stop using Eposin

Contact your doctor if you think a dose of etoposide has been forgotten.

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

4. POSSIBLE SIDE EFFECTS

Like many other medicines against cancer, Eposin can cause many side effects. Some side effects only occur after some time.

Very common (in more than 1 of 10 patients)

Common (in more than 1 of 100 patients, but in less than 1 of 10 patients)

Uncommon (in more than 1 of 1,000 patients, but in less than 1 of 100 patients)

Rare (in more than 1 of 10,000 patients, but in less than 1 of 1,000 patients)

Very rare (in less than 1 of 10,000 patients)

Not known

System Organ Class (SOC)	Very common	Common	Uncommon	Rare	Very rare	not known
Infections and infestations						Infections (in patients with bone marrow suppression)
Neoplasms benign and malignant		Blood cancer (Secondary leukemia) *				A certain form of blood cancer (Acute promyelocytic leukaemia)
Blood and lymphatic systems	Bone marrow suppressio n (Myelosup-pression), especially a reduction of the number of white blood cells (leucopenia ) and platelets (thrombocytopenia) which makes infections more likely and increases the risk of bleeding or bruising, reduction of red blood cells which can make the skin pale and cause weakness or breathlessn ess

	(anaemia).
Immune system		Hyper sensitivity (Ana phylactic- like reactions) **
Metabolism and nutrition	Lack of appetite (Anorexia)			High concentration of uric acid in the blood (Hyper-uricaemia)
Nervous system		Dizziness	Nerve disorder in the extremities (Peripheral neuropathies )	Insults (seizure**), itching or tingling (paresthesia) , inflammation of the optical nerve involving reduced vision (optical neuritis), taste disturbance. Disorders of the central nervous system (fatigue, somnolence)
Eyes				Reversible loss of vision, transient blindness caused by a disturbance in the cortex (cortical blindness)
Heart		Cardiac arrhythmia, heart infarction (myocardial infarct)	Blue discolouration of the lips, tongue, skin and mucous membranes due to a lack of

			oxygen in the blood (cyanosis).
Blood vessels		Drop in blood pressure after an infusion is administered too rapidly (can be prevented by reducing the rate of the infusion). Haemorrhag e (in patients with severe myeolo-suppression)
Respiratory, system			Contraction of the airways (broncho- spasm), coughing, vocal cord spasm (laryngo- spasms).	Temporarily stopping with breathing (apnoea), pneumonia (interstitial pneumonitis , lung fibrosis).
Gastro intestinal system	Nausea, abdominal pain, constipatio n, loss of appetite	diarrhoea, inflammation of the mucous membrane of the mouth (stomatitis). Inflammation of the gastric and oesophageal mucous membrane (mucositis, oesophagitis ).		Taste disorders, swallowing disorders (dysphagia).
Liver or bile	Liver function disorders.

Skin and subcutaneous tissue disorders	Reversible hair loss (sometimes progressing to total baldness), skin coloring.	Skin rash, hives (urticaria), itching		Localised death of the skin creating blisters (toxic epidermal necrolysis), redness and itching after radiation therapy and the administration of etoposide within the radiated area (radiation-recall-dermatitis), redness and swelling of the palms of your hands or soles of your feet which may cause your skin to peel (hand-foot syndrome),
Kidneys and urinary tract	Etoposide has been observed in high concentrations in the liver and the kidneys, therefore the possibility of an accumulati on of etoposide exists with a disturbed function of these organs.
General administration and administration	General weakness (Asthenia), malaise	Leaking of fluid outside the vessel

site conditions

(extravasation), Inflammation of the vein (phlebitis), occasionally irritation and inflammation of the soft tissues occur, fatigue

*In approximately 1 % of the patients with germ cell tumours after the treatment with etoposide leukaemia could be developed (secondary leukaemia). This leukaemia is characterised by a relatively brief latency time and a good reaction to chemotherapy. The total (cumulative) dose of etoposide has been associated to the higher risk.

**Hypersensitivity (anaphylactoid) reactions characterised by fever, flushing, increased heart rate (tachycardia), contraction of the airways (bronchospasms), breathing difficulties and low blood pressure (hypotension). Also temporary stopping of breathing (apnoea) followed by spontaneous return of breathing after withdrawal of etoposide infusion, increase in blood pressure. The reactions can be managed by discontinuing the etoposide infusion and administration of blood pressure increasing products, corticosteroids, antihistamines and/or volume enlarging products as appropriate. Anaphylactoid-type reactions can occur after the first intravenous administration of etoposide.

Redness of the skin (erythema), swelling (oedema) of the face and tongue, coughing, perspiring, blue discolouration of the lips, tongue, skin and mucous membranes due to a lack of oxygen in the blood (cyanosis), spasms (convulsions), vocal cord spasm (laryngospasms) and high blood pressure (hypertension) were also observed. The blood pressure generally normalises within a few hours after ending the infusion.

Paediatric patients

Anaphylactoid reactions were more often reported in children who received doses that were higher than recommended.

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

5. HOW TO STORE EPOSIN

Keep this medicine out of the sight and reach of children.

Do not use Eposin after the expiry date which is stated on the packaging after “do not use after” or “exp.” The first 2 numbers indicate the month, the last numbers indicate the year.

Store unopened bottles below 25 °C in the tightly closed package. Do not freeze. If stored like this then the medicinal product can be used up to the date mentioned on the package.

After dilution the solution must be administered immediately. If this is not possible the diluted solution may be stored at room temperature (15 -25 °C) for a maximum of 12 hours. The solution may not be stored in the refrigerator (2 -8 °C) as deposits could be formed. Remainders of used solutions should be discarded. Solutions must be clear. Cloudy solutions must not be used.

Prevent unnecessary contact with the solution. Immediately wash the skin after contact with Eposin. Have your doctor or nurse take the bottles, needles and syringes in order to dispose of them according to the regulations.

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 protect the environment.

6. FURTHER INFORMATION What Eposin contains

•    The active substance is 20 mg of etoposide per ml of concentrate for solution for infusion.

•    The other ingredients are macrogol 300, polysorbate 80 (E433), benzyl alcohol (30 mg per ml), ethanol, citric acid anhydrate (E330).

What Eposin looks like and contents of the pack

Eposin is a yellowish viscous liquid in a clear glass bottle with a rubber stopper with an aluminium closing and a plastic snap-cap.

1 bottle with 5 ml of concentrate for solution for infusion contains 100 mg of etoposide.

1 bottle with 25 ml of concentrate for solution for infusion contains 500 mg of etoposide.

A package contains 1 bottle or 10 bottles of Eposin.

Not all mentioned package sizes are marketed.

Marketing Authorisation Holder

Pharmachemie B.V.

Swensweg 5 Postbus 552 2003 RN Haarlem Netherlands

Manufacturer

medac

Gesellschaft fur klinische Spezialpraparate mbH Theaterstr. 6 22880 Wedel Germany

This medicinal product is registered in the member states of the EEA under the following names:

Eposin, concentraat voor oplossing voor infusie 20 mg/ml Eposin, infuusiokonsentraatti, liuosta varten 20 mg/ml Etomedac, Konzentrat zur Herstellung einer Infusionslosung 20 mg/ml Eposin, Concentrado para solu^ao para perfusao 20 mg/ml Etoposido Tevagen 20 mg/ml concentrado para solucion para perfusion Eposin, Concentrate for Solution for Infusion 20 mg/ml

This leaflet has last been approved in 03/2015.