Package leaflet: Information for the user

Kappalkyl, 2.5 mg/ml, powder for concentrate for solution for infusion

Bendamustine hydrochloride

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

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

-    If you have any further questions, ask your doctor, pharmacist 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.

What is in this leaflet

1.    What Kappalkyl is and what it is used for

2.    What you need to know before you use Kappalkyl

3.    How to use Kappalkyl

4.    Possible side effects

5.    How to store Kappalkyl

6.    Contents of the pack and other information

1.    What Kappalkyl is and what it is used for

Kappalkyl is a medicine which is used for the treatment of certain types of cancer (cytotoxic medicine).

Kappalkyl is used alone (monotherapy) or in combination with other medicines for the treatment of the following forms of cancer:

chronic lymphocytic leukaemia in cases where fludarabine combination chemotherapy is not appropriate for you,

non-Hodgkin lymphomas, which had not, or only shortly, responded to prior rituximab treatment,

multiple myeloma in cases where high-dose chemotherapy with autologous stem cell transplantation, thalidomide or bortezomib containing therapy is not appropriate for you.

2.    What you need to know before you use Kappalkyl

Do not use Kappalkyl

if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);

while breast-feeding;

if you have severe liver dysfunction (damage to the functional cells of the liver);

if you have yellowing of the skin or whites of the eyes caused by liver or blood problems (jaundice);

if you have severely disturbed bone marrow function (bone marrow depression) and serious changes in your number of white blood cells and platelets in the blood (white blood cells and/or platelet values dropped to < 3,000/|Jl or < 75,000/|Jl, respectively.);

if you have had major surgical operations less than 30 days before starting treatment;

if you have an infection, especially one accompanied by a reduction in white blood cells (leucocytopenia);

in combination with yellow fever vaccines.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Kappalkyl

in case of reduced capability of the bone marrow to replace blood cells. You should have your number of white blood cells and platelets in the blood checked before starting treatment with Kappalkyl, before each subsequent course of treatment and in the intervals between courses of treatment.

in case of infections. You should contact your doctor if you have signs of infection, including fever or lung symptoms.

in case of reactions on your skin during treatment with Kappalkyl. The reactions may increase in severity.

in cases of existing heart disease (e.g. heart attack, chest pain, severely disturbed heart rhythms).

in case you notice any pain in your side, blood in your urine or reduced amount of urine. When your disease is very severe, your body may not be able to clear all the waste products from the dying cancer cells. This is called tumour lysis syndrome and can cause kidney failure and heart problems within 48 hours of the first dose of Kappalkyl. Your doctor will be aware of this and may give you other medicines to help prevent it.

in case of severe allergic or hypersensitivity reactions. You should pay attention to infusion reactions after your first cycle of therapy.

Men receiving treatment with Kappalkyl are advised not to conceive a child during treatment and for up to 6 months afterwards. Before starting treatment, you should seek advice on storing sperm because of the possibility of permanent infertility.

Unintentional injection into the tissue outside blood vessels (extravasal injection) should be stopped immediately. The needle should be removed after a short aspiration. Thereafter the affected area of tissue should be cooled. The arm should be elevated. Additional treatments like the use of corticosteroids are not of clear benefit (see section 4).

Children and adolescents

There is no experience in children and adolescents with Kappalkyl.

Other medicines and Kappalkyl

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

If Kappalkyl is used in combination with medicines which inhibit the formation of blood in the bone marrow, the effect on the bone marrow may be intensified.

If Kappalkyl is used in combination with medicines which alter your immune response, this effect may be intensified.

Cytostatic medicines may diminish the effectiveness of live-virus vaccination. Additionally cytostatic medicines increase the risk of an infection after vaccination with live vaccines (e.g. viral vaccination).

Pregnancy, breastfeeding and fertility

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

Kappalkyl can cause genetic damage and has caused malformations in animal studies. You should not use Kappalkyl during pregnancy unless clearly indicated by your doctor. In case of treatment you should have medical consultation about the risk of potential adverse effects of your therapy for the unborn child and genetic consultation is recommended.

If you are a woman of childbearing potential you must use an effective method of contraception both before and during treatment with Kappalkyl. If pregnancy occurs during your treatment with Kappalkyl you must immediately inform your doctor and should have genetic consultation.

Breastfeeding

Kappalkyl must not be administered during breastfeeding. If treatment with Kappalkyl is necessary during lactation you must discontinue breastfeeding.

Fertility

If you are a man, you should avoid fathering a child during treatment with Kappalkyl and for up to 6 months after treatment has stopped. There is a risk that treatment with Kappalkyl will lead to infertility and you may wish to seek advice on storing of sperm before treatment starts.

Driving and using machines

No studies on the effects on the ability to drive and to use machines have been performed. Do not drive or operate machines if you experience side effects, such as dizziness or lack of coordination.

3. How to use Kappalkyl

Kappalkyl is administered into a vein over 30-60 minutes in various dosages, either alone (monotherapy) or in combination with other medicines.

Treatment should not be started if your white blood cells (leukocytes) have fallen to counts below 3,000 cells/pl and/or your blood platelets have fallen to counts below 75,000 cells/pl.

Your doctor will determine these values at regular intervals.

Chronic lymphocytic leukaemia
Kappalkyl 100 mg per square metre of your body surface area (based on your height and weight)	on Days 1+2
Repeat the cycle after 4 weeks

Non-Hodgkin lymphomas
Kappalkyl 120 mg per square metre of your body surface area (based on your height and weight)	on Days 1 + 2
Repeat the cycle after 3 weeks

Multiple myeloma

Kappalkyl 120 - 150 mg per square metre of your body surface area (based on your height and weight)	on Days 1 + 2
Prednisone 60 mg per square metre of your body surface area (based on your height and weight) intravenous or orally	on Days 1 - 4
Repeat the cycle after 4 weeks

Treatment should be terminated if white blood cell (leukocyte) and/or platelet values dropped to <

3,000/pl or < 75,000/pl, respectively. Treatment can be continued after white blood cell values have increased to > 4,000/pl and platelet values to > 100,000/pl.

Impaired liver or kidney function

Dependent on the degree of impairment of your liver function it may be necessary to adjust your dose (by 30% in case of moderate liver dysfunction). Kappalkyl should not be used if you suffer from severe liver dysfunction. No dose adjustment is necessary in case of impairment of kidney function. Your attending doctor will decide whether a dosage adjustment is necessary.

How it is administered

Treatment with Kappalkyl should be undertaken only by doctors experienced in tumour therapy. Your doctor will give you the exact dose of Kappalkyl and use the necessary precautions.

Your attending doctor will administer the solution for infusion after preparation as prescribed. The solution is administered into a vein as a short-term infusion over 30 - 60 minutes.

Duration of use

There is no time limit laid down as a general rule for treatment with Kappalkyl. Duration of treatment depends on disease and response to treatment.

If you are at all worried or have any questions regarding treatment with Kappalkyl, please speak to your doctor or nurse.

If you forget to use Kappalkyl

If a dose of Kappalkyl has been forgotten, your doctor will usually retain the normal dosage schedule.

If you stop using of Kappalkyl

The doctor treating you will decide whether to interrupt the treatment or to change over to a different preparation.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tissue changes (necrosis) have been observed very rarely following unintentional injection into the tissue outside blood vessels (extravascular). A burning sensation where the infusion needle is inserted may be a sign for administration outside the blood vessels. The consequence of administration in this way can be pain and poorly healing skin defects.

The dose-limiting side-effect of Kappalkyl is impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone marrow function increases the risk of infection.

Very common (may affect more than 1 in 10 people):

Common (may affect up to 1 in 10 people)

•    Bleeding (haemorrhage)    •

•    Disturbed metabolism

caused by dying cancer cells    •

releasing their contents into the blood stream (tumour lysis syndrome)

•    Reduction in red blood cells

which can make the skin    •

pale and cause weakness or breathlessness (anaemia)    •

•    Low counts of neutrophils (neutropenia)

•    Hypersensitivity reactions    •

of the skin , such as nettle    •

rash (urticaria)    _•

•    A rise in liver enzymes    •

AST/ALT    •

•    A rise in the enzyme alkaline phosphatase

•    A rise in bile pigment

Uncommon (may affect up to 1 in 100 people):

• Accumulation of fluid in the heart sac (escape of fluid into the pericardial space)

Rare (: may affect up to 1 in 1,000 people):
• Infection of the blood	•	Signs similar to	•	Reddening of the skin
(sepsis)		anaphylactic reactions		(erythema)
• Severe allergic		(anaphylactoid	•	Inflammation of the skin
hypersensitivity reactions		reactions)		(dermatitis)
(anaphylactic reactions)	•	Drowsiness	•	Itching (pruritus)
	•	Loss of voice (aphonia)	•	Skin rash (macular
	•	Acute circulatory		exanthema)
		collapse	•	Excessive sweating (hyperhidrosis)

•    Primary atypical inflammation of the lungs (pneumonia)

•    Break-down of red blood cell

•    Rapid decrease in blood pressure sometimes with skin reactions or rash (anaphylactic shock)

•    Disturbed sense of taste

•    Altered sensations (paraesthesia)

•    Malaise and pain in the limbs (peripheral neuropathy)

•    Disease of the nervous system (anticholinergic syndrome)

•    Neurological disorders

•    Lack of coordination (ataxia)

•    Inflammation of the brain (encephalitis)

•    Increased heart rate (tachycardia)

•    Heart attack, chest pain (myocardial infarct)

•    Heart failure

•    Inflammation of the veins (phlebitis)

•    Formation of tissue in the lungs (fibrosis of the lungs)

•    Bleeding inflammation of the gullet (haemorrhagic oesophagitis)

•    Bleeding of stomach or gut

•    Infertility

•    Multiple organ failure

Not known:

• Liver failure

There have been reports of secondary tumours (myelodysplastic syndrome, acute myeloid leukaemia (AML), bronchial carcinoma) following treatment with Kappalkyl. No clear relationship with Kappalkyl could be determined.

A small number of cases of severe skin reactions ( Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis) have been reported. The relationship with Kappalkyl is unclear.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Kappalkyl

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

Do not use this medicine after the expiry date which is stated on the label and the carton after ‘EXP’ .The expiry date refers to the last day of that month.

Note on shelf-life after opening or preparing the solution

Solutions for infusions prepared according to the directions listed at the end of this leaflet are stable in polyethylene bags at 25° C / 60% relative humidity for 3.5 hours, and in a refrigerator they are stable for 1 day. Kappalkyl contains no preservatives. The solutions should not therefore be used after these lengths of time.

It is the responsibility of the user to maintain aseptic conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Kappalkyl contains

The active substance is bendamustine hydrochloride.

1 vial contains 25 mg of bendamustine hydrochloride.

1 vial contains 100 mg of bendamustine hydrochloride.

After reconstitution 1 ml of the concentrate contains 2.5 mg bendamustine hydrochloride.

The other ingredient is Mannitol.

What Kappalkyl looks like and contents of the pack

Brown glass vials with bromobutyl rubber stopper and plastic aluminium flip-off cap.

The powder appears white and crystalline.

Kappalkyl is available in packs containing

1, 5, 10 and 20 injection vials with 25 mg of bendamustine hydrochloride and 1 and 5 injection vials with 100 mg of bendamustine hydrochloride.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Helm AG Nordkanalstr. 28 20097 Hamburg Germany

Manufacturer (responsible for batch release)

Helm AG Nordkanalstr. 28 20097 Hamburg Germany

S.C. POLISANO PHARMACEUTICALS S.R.L.

Sos. Alba Iulia nr. 156,

Sibiu, Jud. Sibiu, cod 550052 ROMANIA

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

Denmark    Kappalkyl, 2.5 mg/ ml pulver til koncentrat til infusionsv^ske, oplosning

United Kingdom Kappalkyl, 2.5 mg/ ml Powder for concentrate for solution for infusion

This leaflet was last revised in 11/2015.

As with all similar cytotoxic substances, stricter safety precautions apply as far as nursing staff and doctors are concerned, due to the potentially genome-damaging and cancer-causing effect of the preparation. Avoid inhalation (breathing in) and contact with the skin and mucous membranes when handling Kappalkyl (wear gloves, protective clothing, and possibly a face mask!). If any parts of the body become contaminated, clean them carefully with soap and water, and flush the eyes with 0.9% w/v saline solution. If possible, it is advisable to work on a special safety work bench (laminar flow) with a disposable absorbent sheet that is impermeable to liquids. Contaminated articles are cytostatic waste. Please comply with national guidelines on the disposal of cytostatic material! Pregnant staff must be excluded from working with cytostatics. The vials are for single use only.

The solution ready for use must be prepared by dissolving the contents of an injection vial of Kappalkyl exclusively in water for Injections, as follows:

1. Preparation of the concentrate

•    One injection vial of Kappalkyl containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml by shaking

•    One injection vial of Kappalkyl containing 100 mg of bendamustine hydrochloride is first dissolved in 40 ml by shaking

2. Preparation of the solution for infusion

As soon as a clear solution is obtained (generally after 5 - 10 minutes), the total recommended dose of Kappalkyl is immediately diluted with 0.9% w/v saline solution to obtain a final volume of approximately 500 ml. Kappalkyl must not be diluted with other solutions for infusion or injection. Kappalkyl must not be mixed in an infusion with other substances.