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PACKAGE LEAFLET: INFORMATION FOR THE USER

Temozolomide 5mg hard capsules Temozolomide 20mg hard capsules Temozolomide 100mg hard capsules Temozolomide 140mg hard capsules Temozolomide 180mg hard capsules Temozolomide 250mg hard capsules

Read all of this leaflet carefully before you start

taking this medicine.

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

-    If you have any further questions, 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. See section 4.

In this leaflet:

1.    What temozolomide is and what it is used for

2.    Before you take temozolomide

3.    How to take temozolomide

4.    Possible side effects

5.    How to store temozolomide

6.    Further i nformation

Male fertility

Temozolomide may cause permanent infertility.

Male patients should use effective contraceptions and not father a child for up to 6 months after “ stopping treatment. It is recommended to seek advice on conservation of sperm prior to treatment.

Driving and using machines

Temozolomide may make you feel tired or sleepy. In this case, do not drive or use any tools or machines or cycle until you see how this medicine affects you (see section 4).

Temozolomide contains lactose

Temozolomide hard capsules contain lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE TEMOZOLOMIDE

1. WHAT TEMOZOLOMIDE IS AND WHAT IT IS

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Dosage and duration of treatment

Your doctor will work out your dose of temozolomide. This is based on your size (height and weight) and if you have a recurrent tumour and have had cnemotherapy treatment in tne past.

You may be given other medicines (anti-emetics) to take before and/or after taking temozolomide to prevent or control nausea and vomiting.

USED FOR

The name of your medicine is Temozolomide 5mg, 20mg, 100mg, 140mg, 180mg or 250mg hard capsules (referred to as temozolomide throughout this leaflet).

Temozolomide is an antitumour agent.

Temozolomide is used for the treatment of specific forms of brain tumours:

-    In adults with newly-diagnosed glioblastoma multiforme. Temozolomide is first used together with radiotherapy (concomitant phase of treatment) and after that alone (monotherapy phase of treatment).

-    In children 3 years and older and adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma. Temozolomide is used in these tumours if they

---return or get worse after standard treatment. ^_

2. BEFORE YOU TAKE TEMOZOLOMIDE

Do not take temozolomide

-    if you are allergic to temozolomide or any of the other ingredients of this medicine (listed in section 6).

__- if you have had an allergic reaction to

dacarbazine (an anticancer medicine sometimes called DTIC). Signs of allergic reaction include feeling itchy, breathlessness or wheezing, swelling of the face, lips, tongue or throat.

-    if certain kinds of blood cells are severely reduced (myelosuppression), such as your white

___blood cell count and platelet count. These blood

cells are important for fighting infection and for proper blood clotting. Your doctor will check your blood to make sure you have enough of these cells before you begin treatment.

Patients with newly-diagnosed glioblastoma multiforme:

If you are a newly-diagnosed patient, treatment will occur in two phases:

-    treatment together with radiotherapy (concomitant phase) first

-    followed by treatment with only temozolomide (monotherapy phase).

During the concomitant phase, your doctor will start temozolomide at a dose of 75mg/m² (usual dose). You will take this dose every day for 42 days (up to 49 days) in combination with radiotherapy. The temozolomide dose may be delayed or stopped, depending on your blood counts and how you tolerate your medicine during the concomitant phase.

Once the radiotherapy is completed, you will interrupt treatment for 4 weeks. This will give your body a chance to recover. Then, you will start the monotherapy phase.

During the monotherapy phase, the dose and way you take temozolomide will be different. Your doctor will work out your exact dose. There may be up to 6 treatment periods (cycles). Each one lasts 28 days. You will take your new dose of temozolomide alone once daily for the first 5 days (“dosing days”) of each cycle. The first dose will be 150mg/m². Then you will have 23 days without temozolomide. This adds up to a 28- day treatment cycle.

After Day 28, the next cycle will begin. You will again _ take temozolomide once daily for 5 days followed by 23 days without temozolomide. The temozolomide dose may be adjusted, delayed or stopped depending on your blood counts and how you tolerate your medicine during each treatment cycle.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking temozolomide

-    as you should be observed closely for the development of a serious form of pneumonia called Pneumocystis jirovecii pneumonia (PCP).

If you are a newly-diagnosed patient (glioblastoma multiforme) you may be receiving temozolomide for 42 days in combination with radiotherapy. In this case, your doctor will also prescribe medicine to help you prevent this type of pneumonia (PCP).

-    if you have ever had or might now have a hepatitis B infection. This is because temozolomide could cause hepatitis B to become active again, which can be fatal in

____some cases_Patients will -bexarefully.____

checked by their doctor for signs of this infection before treatment is started.

-    if you have low counts of red blood cells (anaemia), white blood cells and platelets, or blood clotting problems before starting the treatment, or if you develop them during treatment. Your doctor may decide to reduce the dose, interrupt, stop or change your treatment. You may also need other treatments.

In some cases, it may be necessary to stop treatment with temozolomide. Your blood will be tested frequently during treatment to monitor the side effects of temozolomide on your blood cells.

-    as you may have a small risk of other changes in blood cells, including leukaemia.

-    if you have nausea (feeling sick in your stomach) and/or vomiting which are very common side effects of temozolomide (see section 4), your doctor may prescribe you a medicine (an anti-emetic) to help prevent vomiting. If you vomit frequently before or during treatment, ask your doctor about the best time to take temozolomide until the vomiting is under control. If you vomit after taking your dose, do not take a second dose on the same day.

-    if you develop fever or symptoms of an infection contact your doctor immediately.

-    if you are older than 70 years of age, you might be more prone to infection, bruising or bleeding.

-    if you have liver or kidney problems, your dose of temozolomide may need to be adjusted.

Children and adolescents

Do not give this medicine to children under the age of 3 years because it has not been studied. There is limited information in patients over 3 years of age who have taken temozolomide.

Other medicines and temozolomide

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

Pregnancy, breast-feeding and fertility

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

This is because you must not be treated with temozolomide during pregnancy unless clearly indicated by your doctor.

Effective contraceptive precautions must be taken by both male and female patients who are taking temozolomide (see also “Male fertility” below).

You should stop breast-feeding while receiving treatment with temozolomide.

Patients with tumours that have returned or worsened (malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma) taking temozolomide only:

A treatment cycle with temozolomide lasts 28 days. You will take temozolomide alone once daily for the first 5 days. This daily dose depends on whether or not you have received chemotherapy before.

If you have not been previously treated with chemotherapy, your first dose of temozolomide will be 200mg/m2 once daily for the first 5 days. If you have been previously treated with chemotherapy, your first dose of temozolomide will be 150mg/m2 once daily for the first 5 days.

Then, you will have 23 days without temozolomide. This adds up to a 28-day treatment cycle.

After Day 28, the next cycle will begin. You will again receive temozolomide once daily for 5 days, followed by 23 days without temozolomide.

Before each new treatment cycle, your blood will be tested to see if the temozolomide dose needs to be adjusted. Depending on your blood test results, your doctor may adjust your dose for the next cycle.

How to take temozolomide

Take your prescribed dose of temozolomide once a day, preferably at the same time each day.

Take the capsules on an empty stomach; for example, at least one hour before you plan to eat breakfast. Swallow the capsule(s) whole with a glass of water.

Do not open, crush or chew the capsules. If a capsule is damaged, avoid contact with your skin, eyes or nose. If you accidently get some in your eyes or nose, flush the area with water.

Depending on the prescribed dose, you may have to take more than one capsule together, eventually with different strengths (content of active substance, in mg). The colour of the capsule cap is different for each strength (see in the table below).

You should make sure you fully understand and remember the following:

•    how many capsules you need to take every dosing day. Ask your doctor or pharmacist to write it down (including the colour).

•    which days are your dosing days.

Review the dose with your doctor each time you start a new cycle, since it may be different from the last cycle.

Always take temozolomide exactly as your doctor has told you. It is very important to check with your doctor or pharmacist if you are not sure. Errors in how you take this medicine may have serious health consequences.

If you take more temozolomide than you should

If you accidentally take more temozolomide capsules than you were told to, contact your doctor or pharmacist immediately.

If you forget to take temozolomide

Take the missed dose as soon as possible during the same day. If a full day has gone by, check with your doctor. Do not take a double dose to make up for a forgotten dose, unless your doctor tells you to do so.

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

4. POSSIBLE SIDE EFFECTS

5. HOW TO STORE TEMOZOLOMIDE

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

Contact your doctor immediately it you have any of the following:

-    a severe allergic (hypersensitive) reaction (hives, wheezing or other breathing difficulty),

-    uncontrolled bleeding,

-    seizures (convulsions),

-    fever,

-    a severe headache that does not go away.

Temozolomide treatment can cause a reduction in certain kinds of blood cells. This may cause you to have increased bruising or bleeding, anaemia (a shortage of red blood cells), fever, and reduced resistance to infections. The reduction in blood cell counts is usually short-lived. In some cases, it may be prolonged and may lead to a very severe form of anaemia (aplastic anaemia). Your doctor will monitor your blood regularly for any changes, and will decide if any specific treatment is needed. In some cases, your temozolomide dose will be reduced or treatment stopped.

Side effects from clinical studies:

Temozolomide in combination treatment with radiotherapy in newly-diagnosed glioblastoma Patients receiving temozolomide in combination with radiotherapy may experience different side effects than patients taking temozolomide alone.

The following side effects may occur, and may require medical attention.

Very common (may affect more than 1 in 10 people): loss of appetite, headache, constipation (difficulty passing stools), nausea (feeling sick in your stomach), vomiting, rash, hair loss, tiredness.

Common (may affect up to 1 in 10 people): oral infections, wound infection, reduced number of blood cells (neutropenia, thrombocytopenia, lymphopenia, leukopenia), increased sugar in the blood, loss of weight, change in mental status or alertness, anxiety/depression, sleepiness, difficulty speaking, impaired balance, dizziness, convulsions, confusion, forgetfulness, difficulty concentrating, inability to fall asleep or stay asleep, tingling sensation, bruising, shaking, abnormal or blurry vision, double vision, hearing impairment, shortness of breath, cough, blood clot in the legs, fluid retention, swollen legs, diarrhoea, stomach or abdominal pain, heartburn, upset stomach, difficulty swallowing, dry mouth, skin irritation or redness, dry skin, itching, muscle weakness, painful joints, muscle aches and pains, frequent urination, difficulty with holding your urine, allergic reaction, fever, radiation injury, face swelling, pain, abnormal taste, abnormal liver function tests.

Uncommon (may affect up to 1 in 100 people): flu-like symptoms, red spots under the skin, appearance of a swollen face or muscle weakness, low potassium level in the blood, weight gain, mood swings, hallucination and memory impairment, partial paralysis, impaired coordination, difficulty swallowing, impaired sensations, partial loss of vision, dry or painful eyes, deafness, infection of the middle ear, ringing in the ears, earache, palpitations (when you can feel your heart beat), blood clot in the lung, high blood pressure, pneumonia, inflammation of your sinuses, bronchitis, a cold or the flu, swollen stomach, difficulty controlling your bowel movements, haemorrhoids, peeling skin, increased skin sensitivity to sunlight, change in skin colour, increased sweating, muscle damage, back pain, difficulty in urinating, vaginal bleeding, sexual impotence, absent or heavy menstrual periods, vaginal irritation, breast pain, hot flushes, shivering, discolouration of your tongue, change in your sense of smell, thirst, tooth disorder.

Temozolomide monotherapy in recurrent or progressive glioma

The following side effects may occur, and may require medical attention.

Very common (may affect more than 1 in 10 people): reduced number of blood cells (neutropenia or lymphopenia, thrombocytopenia), loss of appetite, headache, vomiting, nausea (feeling sick in your stomach), constipation (difficulty passing stools), tiredness.

Common (may affect up to 1 in 10 people): loss of weight, sleepiness, dizziness, tingling sensation, shortness of breath, diarrhoea, abdominal pain, upset stomach, rash, itching, hair loss, fever, weakness, shivering, feeling unwell, pain, change in taste.

Uncommon (may affect up to 1 in 100 people): reduced number of blood cell counts (pancytopenia, anaemia, leukopenia).

Rare (may affect up to 1 in 1,000 people): cough, infections including pneumonia.

Very rare (may affect up to 1 in 10,000 people): skin redness, urticaria (hives), skin eruption, allergic reactions.

Other side effects:

Cases of elevations of liver enzymes have been commonly reported. Cases of increased bilirubin, problems with bile flow (cholestasis), hepatitis and injury to the liver, including fatal liver failure, have been uncommonly reported.

Very rare cases of severe rash with skin swelling, including on the palms of the hands and soles of the feet, or painful reddening of the skin and/or blisters on the body or in the mouth have been observed. Tell your doctor immediately if this occurs.

Very rare cases of lung side effects have been observed with temozolomide. Patients usually present with shortness of breath and cough. Tell your doctor if you notice any of these symptoms.

In very rare cases, patients taking temozolomide and medicines like it may have a small risk of developing secondary cancers, including leukaemia.

New or reactivated (recurring) cytomegalovirus infections and reactivated hepatitis B virus infections have been uncommonly reported.

Cases of diabetes insipidus have been uncommonly reported. Symptoms of diabetes insipidus include passing a lot of urine and feeling thirsty.

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.

Keep out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be - lethal for children.

Do not use temozolomide after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.

HDPE Bottle presentation Store below 30^oC

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

5mg, 20mg

Store below 25^oC

100mg, 140mg, 180mg, 250mg

Store below 30^oC

Tell your pharmacist if you notice any change in the appearance of the capsules.

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

6. FURTHER INFORMATION

What temozolomide contains

-    5mg: The active substance is temozolomide.

Each capsule contains 5mg temozolomide.

-    20mg: The active substance is temozolomide. Each capsule contains 20mg temozolomide.

-    100mg: The active substance is temozolomide. --Each capsule contains 100mg temozolomide.

-    140mg: The active substance is temozolomide. Each capsule contains 140mg temozolomide.

-    180mg: The active substance is temozolomide. Each capsule contains 180mg temozolomide.

-    250mg: The active substance is temozolomide. Each capsule contains 250mg temozolomide.

The other ingredients are:

Capsule content

Lactose Anhydrous, Silica, Colloidal Anhydrous, Sodium Starch Glycollate (Type A), Tartaric Acid, Stearic Acid Capsule shell, Size 0:

5mg: gelatin, titanium dioxide (E 171). yellow iron oxide (E 172), indigotine FD & C blue 2 (E132) 20mg: gelatin, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172)

100mg: gelatin, titanium dioxide (E 171), indigotine FD&C blue2 (E 132), red iron oxide (E172)

140mg: Gelatin, titanium dioxide (E 171), indigotine FD&C blue 2 (E 132)

180mg: Gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)

250mg: gelatin, titanium dioxide (E 171)

Printing ink

Shellac, propylene glycol, purified water, sodium

__ammonia solution, potassium hydroxide, black

iron oxide (E 172)

What temozolomide looks like and the contents of the pack

5mg: Hard gelatin capsules size 0 (green opaque cap/white opaque body) with 5 printed in black ink on the body.

_20mg: Hard gelatin capsules size 0 (orange opaque cap /white opaque body) with 20 printed in black ink on the body.

100mg: Hard gelatin capsules size 0 (purple opaque cap /white opaque body) with 100 printed in black ink on the body

140mg: Hard gelatin capsules size 0 (blue opaque _ cap /white opaque body) with 140 printed in black ink on the body

180mg: Hard gelatin capsules size 0 (chocolate brown opaque cap /white opaque body) with 180 printed in black ink on the body

250mg: Hard gelatin capsules size 0 (white opaque cap /white opaque body) with 250 printed in black ink on the body

HDPE Bottle presentation White opaque High Density Polyethylene Bottles with Polpropylene push lock assembly closure, with polyester coil and dessicant containing 5 capsules. Sachet presentation

Sachets composed of paper on linear low density - polyethylene (outermost layer), aluminum and ethylene acrylic acid co-polymer (innermost layer). Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Zentiva, One Onslow Street, Guildford, Surrey, GU1

4YS, UK

Manufacturer:

_ EirGen Pharma Limited, Westside Business Park Old Kilmeaden Road, Waterford, Ireland This leaflet was last revised in May 2015

’Zentiva’ is a registered trademark © 2015 Zentiva