DENZAPINE® 25,50,100 AND 200 mg TABLETS IBRITANNIA

CLOZAPINE

PACKAGE LEAFLET - INFORMATION FOR THE USER

The use of DENZAPINE is restricted to those patients registered with the Denzapine Monitoring Services.

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, 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.

1. WHAT DENZAPINE IS AND WHAT IT IS USED FOR

DENZAPINE contains clozapine, which belongs to a group of medicines called atypical antipsychotics. Antipsychotics are mainly used to treat schizophrenia. Schizophrenia is a psychiatric disorder that affects the way a person thinks and behaves.

DENZAPINE is used:

-    to treat schizophrenia when other antipsychotic medicines have not worked or have caused severe side effects

-    to treat psychotic disorders occurring in patients with Parkinson’s disease, when standard treatment has failed

DENZAPINE is available only with a doctor’s prescription. Ask your doctor if you have any questions about why this medicine has been prescribed for you

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2.    BEFORE YOU TAKE DENZAPINE

DENZAPINE must not be given to anyone who is unconscious or in a coma. Do NOT take DENZAPINE if:

-    You are allergic (hypersensitive) to clozapine or to any of the other ingredients of the DENZAPINE tablets (see section 6, “Further information"). It is important to tell your doctor if you think you have ever had an allergic reaction to any of these ingredients.

Symptoms of an allergic reaction can include:

-    swelling of the face and mouth

-    itchy skin rashes or hives

-    difficulty breathing

-    faintness

-    If you are unable to digest lactose (milk sugar), due to one of the following conditions:

-    galactose intolerance

-    Lapp-lactase deficiency

-    glucose-galactose malabsorption

-    You are unable to undergo regular blood tests

-    You have a low number of white cells in the blood (granulocytopenia/agranulocytosis)

-    You have ever had a low white blood cell count that was unexplained or was caused by medicinal treatment (except anticancer treatment)

-    You are receiving treatment with other medicines that can cause a fall in the number of white blood cells

-    You have suffered from a very low white blood cell count (agranulocytosis) caused by previous treatment with DENZAPINE

You have any of the following diseases:

-    Disorders of the bone marrow (when the bone marrow does not make enough blood cells)

-    Uncontrolled epilepsy (fits or seizures)

-    Acute mental illness caused by alcohol, medicines or other substances

-    Poisoning caused by other medicines

-    Circulatory collapse (a very pronounced fall in blood pressure that may lead to unconsciousness)

-    Disorders affecting the brain that can lead to drowsiness or unconsciousness

-    Severe kidney disease

-    Heart disease (such as myocarditis, pericarditis or cardiomyopathy)

-    Active liver disease with jaundice (yellow colouration of the skin and eyes), feeling sick and loss of appetite

-    Liver failure (very serious liver disease)

-    Paralytic ileus (a disorder of the small intestine)

Take special care with DENZAPINE

Please tell your doctor if you have or have had any medical conditions or illnesses, especially the following:

-    Low number of white blood cells (leukopenia, neutropenia, granulocytopenia, agranulocytosis)

-    High number of a certain type of white blood cells called eosinophil granulocytes (eosinophilia)

-    Low number of platelets in the blood (thrombocytopenia)

-    Pericarditis or pericardial effusion (inflammation of the membranes around the heart)

-    If you or any member of your family have changes on the heart trace (ECG)

-    Orthostatic hypotension (a fall in blood pressure on standing up)

-    Epilepsy or fits, even if they are well controlled

-    Liver disease

-    Enlargement of the prostate

-    Glaucoma (raised pressure in the eye)

-    Constipation, paralytic ileus, disease of the large bowel or operations on the abdomen

-    Fever

-    Neuroleptic Malignant Syndrome, a serious reaction to some anti-psychotic medicines. Symptoms include a sudden increase in body temperature, sweating, a fast heart beat, muscle stiffness and a fluctuating blood pressure. It can lead to coma.

-    Diabetes

-    Stroke (Risk factors of stroke e.g smoking, diabetes and high blood

3.    HOW TO TAKE DENZAPINE

Your dose of DENZAPINE has been determined by your doctor. The dose will depend on how well you respond to the medicine. It will also depend on the other medicines you are taking and other medical conditions you may have. The dose may be altered from time to time.

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-    If you or someone else in your family has a history of blood clots, as medicines like these have been associated with formation of blood clots. If you are not mobile you are at increased risk of developing blood clots while taking DENZAPINE.

Also tell your doctor if you are taking any other antipsychotic medicines (see section “Taking other medicines" below)

Or if you are taking any other medicines that are known to affect the heart DENZAPINE may lower the number of your white blood cells, making you more prone to infections. Before and during your treatment with DENZAPINE, your doctor will monitor your blood count closely to make sure that the number of your white blood cells do not fall under a certain level. Please tell your doctor if you develop any signs of infection, such as fever, sore throat or flu-like symptoms.

If this medicine makes you feel dizzy, light-headed or faint, be careful when getting up from a sitting or lying position. DENZAPINE may lower your blood pressure, especially at the start of treatment. These symptoms can usually be prevented by getting up slowly and flexing leg muscles and toes to get the blood circulating. When getting out of bed, dangle your legs over the side for a minute or two before standing up.

Be careful when drinking alcohol or when taking antihistamines (medicines used for hay fever, allergies or colds), sleeping tablets or tablets to relieve pain while taking this medicine. DENZAPINE can increase drowsiness caused by alcohol and by medicines affecting your nervous system.

DENZAPINE may affect the way your body controls temperature, and it may prevent sweating even in very hot weather. Exercise, hot baths or saunas may make you feel dizzy or faint while you are taking this medicine.

Taking other medicines

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

Some medicines must NOT be used when you are taking DENZAPINE. These include:

-    Medicines that affect the bone marrow. These can decrease the number of blood cells produced by the bone marrow. They include:

-    some antibiotics (e.g. co-trimoxazole, chloramphenicol, sulphonamides)

-    certain pain-killers (e.g. phenylbutazone, oxybutazone, antipyrine, dipyrone)

-    penicillamine (for rheumatoid arthritis)

-    carbamazepine (for epilepsy and for neuralgic pain)

-    cytotoxic (anticancer) medicines

-    Other antipsychotic medicines (neuroleptics), especially when given as a depot (for long-term treatment)

Other medicines can be affected by DENZAPINE or may affect how well DENZAPINE works. Your doctor will tell you what medicines you can take and their doses. Please also consult your doctor if you are taking any of the medicines listed below:

-    Medicines that can make you drowsy e.g. morphine (for pain), benzodiazepines (sleeping pills) and antihistamines (for allergies) such as loratadine, chlorpheniramine

-    Anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness

-    Medicines used to treat high blood pressure, e.g. metoprolol, captopril, enalapril.

-    Medicines used to treat a fast or irregular heart beat (antiarrhythmics, e.g. flecainide, pilsicainide)

-    Medicines that can cause changes on the heart trace (ECG). Your doctor will know which medicines these are

-    Medicines that can cause constipation, particularly certain medicines to treat psychosis, depression or Parkinson’s disease.

Your doctor will know which medicines these are

-    Atropine, a medicine which may be used in some eye drops or

If you have heart, kidney or liver disease, epilepsy or are elderly, or if you are taking any other medicines that may affect the way DENZAPINE works, your doctor may start you on a lower dose to prevent unwanted effects. The dose will be increased slowly.

cough preparations

-    Medicines which may cause excessive salt loss, such as diuretics (water tablets)

-    Adrenaline (epinephrine), a medicine used in emergency situations

-    Warfarin, a medicine to prevent blood clots

-    Digoxin (for heart diseases)

-    Cimetidine, used for stomach ulcers

-    Erythromycin and rifampicin (antibiotics)

-    Medicines to treat fungal infections, such as ketoconazole, itraconazole and miconazole

-    Medicines to treat epilepsy e.g. phenytoin, carbamazepine, valproic acid

-    Medicines for depression, such as fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, amitriptyline, phenelzine, moclobemide, chlorpromazine, mesoridazine orfluphenazine

-    Lithium (for mental disorders)

-    Medicines which affect how your body eliminates clozapine. Your doctor will know which medicines these are.

-    Omeprazole (a drug used to treat excess stomach acid).

-    Ciprofloxacin (a drug used to treat infections)

Your doctor and pharmacist have more information on medicines to be

careful with or avoid while taking DENZAPINE.

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Taking DENZAPINE with food and drink

You can take your DENZAPINE tablets with or without food.

DENZAPINE may increase the effect of alcohol. Therefore, you should not drink alcohol during treatment.

Coffee can affect the levels of clozapine (the active substance of DENZAPINE) in your blood. You may drink coffee. However, if you stop drinking coffee suddenly, the levels of clozapine in your blood may fall. This will make the medicine less effective. Equally, if you start drinking coffee, the levels may rise, increasing the risk of side effects.

Smoking

Smoking can affect the levels of clozapine in your blood. If you stop smoking suddenly, the levels of clozapine in your blood may rise. This may increase the risk of side effects.

Children

DENZAPINE is not recommended for use in children.

Elderly

Please tell your doctor if you have dementia or a family history of dementia

Pregnancy

Tell your doctor if you are or think you may be pregnant or if you are planning to become pregnant.

There is limited information on the safety of DENZAPINE tablets in pregnancy. Your doctor will discuss with you the risks and benefits of taking this medicine during pregnancy.

Some women taking antipsychotic medicines have irregular or no periods. If you have been affected in this way, your periods may return when your medication is changed to DENZAPINE. In these circumstances you should be sure to take adequate contraceptive precautions.

The following symptoms may occur in newborn babies, of mothers that have used Denzapine in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these symptoms you may need to contact your doctor.

Breast-feeding

If you are breast-feeding, DENZAPINE can reach your baby through your breast milk. DENZAPINE should not be used when breast-feeding.

Driving and using machines

You may feel tired, drowsy, dizzy or you may feel faint while taking DENZAPINE, especially during the early stages of treatment. If you have any of these symptoms, do not drive, operate machinery or do any tasks where you need to be alert.

When changing from a previous antipsychotic treatment to DENZAPINE, the first treatment should be gradually withdrawn before starting DENZAPINE.

Continued over the page

Carefully follow all the instructions given to you by your doctor and pharmacist. Their instructions may differ from the information contained in this leaflet. If you do not understand the instructions on the label, ask your doctor or pharmacist for help. Take DENZAPINE exactly as prescribed by your doctor to prevent unwanted side effects.

Do not take more or less DENZAPINE than your doctor has prescribed. If you think the dose is too weak or too strong, talk to your doctor.

Dosage

The total amount of DENZAPINE you take each day is usually divided into two doses. If you have to divide your dose, you should take the larger dose at bed time. However, if your total daily dose is not over 200 mg, it is not necessary to divide the dose. In this case, it is usually taken in the evening.

Swallow DENZAPINE tablets with a full glass of water or other liquid. Taking the tablets at the same time each day will have the best effect and will help you remember to take them.

Schizophrenic patients resistant to other treatments

When you first start taking DENZAPINE, the usual dose is half a 25 mg tablet (12.5 mg) taken once or twice on the first day, followed by one or two 25 mg tablets taken on the second day. If this dose is well tolerated, it may be increased gradually, usually to between 200 mg and 450 mg per day.

However, some people may need a higher dose. The maximum permissible dose is 900 mg per day Once the maximum benefit is achieved, your doctor may reduce the dose gradually to a lower level. Your doctor will determine the most appropriate dose for you. Parkinsonian patients with psychotic disorders that do not respond to standard treatment.

The initial dose is of 12.5 mg (half a 25 mg tablet) taken in the evening. The dose is gradually increased to a maximum of 50 mg per day, taken in the evening. The effective dose is usually between 25 mg and 37.5 mg (one to one-and-a-half 25 mg tablets). If the 50 mg dose is not effective, it can be increased to 100 mg in some patients. This dose (100 mg) must not be exceeded.

Elderly patients:

DENZAPINE tablets can be used in the elderly (over 65 years of age). Treatment usually begins with a lower dose (e.g. 12.5 mg daily), which is then gradually increased.

Duration of treatment:

You should take DENZAPINE for at least 6 months. Do not stop taking this medicine without first talking to your doctor.

WHILE TAKING DENZAPINE

Tell all of the doctors and pharmacists who are treating you that you are taking DENZAPINE.

You must have regular blood tests while taking DENZAPINE.

Blood tests

Before starting DENZAPINE you will have a blood test to make sure that you can take this medicine.

DENZAPINE can cause agranulocytosis. In this condition, the number of white blood cells (which are necessary to fight infection) is too low. If this occurs, you are at risk of suffering infections which may be life-threatening. Warning signs include flu-like symptoms, a sore throat or fever. If you develop these or any other signs suggestive of infection, you should contact your doctor immediately.

There is no way of knowing who is at risk of developing agranulocytosis. Deaths have occurred in severe cases of agranulocytosis, although with regular blood tests, agranulocytosis can be detected early. If DENZAPINE is stopped as soon as a problem is detected, the white blood cell numbers should return to normal. You must understand the importance of regular blood tests by your doctor while taking DENZAPINE.

After starting treatment with DENZAPINE, you will have a blood test once a week for the first 18 weeks. The risk of agranulocytosis is highest in this period. For the rest of the first year of treatment, blood tests will be performed every 2 weeks. After the first year, tests will be performed every 4 weeks for as long as you continue to take DENZAPINE. Tests will also be performed for one month after stopping the medicine. These tests will tell the doctor if there is any problem with the number of white cells in your blood. There are some situations where you may need to have blood tests more often (e.g. twice a week). Your doctor will talk to you about this.

If the number of your white blood cells falls below a critical level, DENZAPINE must be stopped immediately and you must never take any medicines containing clozapine again.

Things which I must not do

-    Do not stop taking DENZAPINE or lower the dosage even if you are feeling better, unless your doctor tells you to do so. Your condition may worsen if you suddenly stop taking it. Your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

-    Do not give DENZAPINE to anyone else even if they have the same symptoms as you. It may harm them even if their condition seems similar to yours.

- Do not use DENZAPINE to treat other complaints unless your doctor tells you to.

If you take more DENZAPINE than you should

If you suspect that you or someone else has taken too many DENZAPINE tablets, contact a doctor immediately or go to the Accident and Emergency Department at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep the telephone numbers for these places handy.

The most common signs and symptoms of overdose include:

-    drowsiness

-    confusion and coma

-    delirium

-    agitation

-    light-headedness

-    a fall in blood pressure

-    collapse

-    shallow or slow breathing or sometimes shortness of breath

-    fast or irregular heartbeat

-    dribbling

-    fits.

If you forget to take DENZAPINE

If it is almost time for your next dose (within four hours), forget the dose you missed and take your next dose at its normal time. Otherwise take it as soon as you remember, and then go back to taking your tablets as you would normally.

If you miss a dose of DENZAPINE do not take a double dose to make up for the missed dose.

If you have stopped taking DENZAPINE for more than two days, you must contact your doctor before starting to take it again. In this case, the medicine must be started again at a low dose and then increased.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If your doctor tells you to stop taking DENZAPINE

If the medicine needs to be stopped abruptly due to side effects, you will be monitored closely for psychotic symptoms. Other symptoms can also arise, including increased sweating, headache, nausea (feeling sick), vomiting and diarrhoea.

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4. POSSIBLE SIDE EFFECTS

Blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing.

If you notice any of these symptoms seek medical advice immediately.

Like all medicines, DENZAPINE can cause side effects although not everybody gets them. The frequency of side effects is based on the following:

The following side effects have been associated with DENZAPINE:

Very common:

Drowsiness

Dizziness

A fast heart beat (tachycardia)

Constipation

Hypersalivation (forming a large volume of saliva)

Common:

A fall in the number of white cells in the blood (leukopenia, neutropenia, granulocytopenia, agranulocytosis) (see Section 3, “Howto take DENZAPINE")

Eosinophilia (an increase in the number of a certain type of white blood cells called eosinophil granulocytes)

Leukocytosis (an increase in the number of white blood cells)

Weight gain Blurred vision Headache Tremor

Stiffness of the limbs (rigidity)

Restlessness (akathisia)

Problems of coordination Epileptic fits (localised or generalised)

Changes on the heart trace (ECG)

High blood pressure (hypertension)

A fall in blood pressure on standing up (orthostatic hypotension)

Fainting

Nausea (feeling sick)

Vomiting

Loss of appetite (anorexia)

Dry mouth

Changes in the blood tests that assess how the liver is working Urinary incontinence

Urinary retention (the inability to pass urine)

Fatigue

Fever

Benign hyperthermia (drug fever; changes in body temperature caused by certain medicines)

Alterations in the body’s control of temperature Alterations of sweating Slurring of words

Uncommon:

Agranulocytosis (a very low number of white cells in the blood) Neuroleptic malignant syndrome (fever, sweating, a fast heart beat, muscle stiffness and changes in blood pressure)

Stammering

Rare:

Impaired glucose tolerance (excess sugar levels in the blood)

Diabetes mellitus Restlessness (agitation)

Confusion

Delirium

Circulatory collapse (a very low blood pressure that can lead to unconsciousness)

Irregular heart beat (arrhythmia)

Ventricular arrhythmias (life-threatening disorders of the heart. These are medical emergencies.)

Inflammation of the heart muscle (myocarditis)

Pericarditis (inflammation of the membranes around the heart)

Pericardial effusion (a collection of liquid in the membranes around

the heart)

Blood clots in the veins that may cause lung problems Inhaling of food into the lungs (aspiration)

Difficulty swallowing (dysphagia)

Inflammation of the liver (hepatitis)

Jaundice (yellow colouration of the skin and eyes)

Inflammation of the pancreas (pancreatitis)

A rise in the CPK values (a blood test)

A low number of red blood cells (anaemia)

Chest infection and pneumonia

Very rare:

A fall in the number of platelets in the blood (thrombocytopenia) Complications of excessive sugar in the blood (severe hyperglycaemia, ketoacidosis, hyperosmolar coma)

Excessive fat in the blood (hypertriglyceridaemia)

Tardive dyskinesia (slow, abnormal movements of the face, tongue and limbs)

Disease of the heart muscle (cardiomyopathy)

Cardiac arrest

Torsades de pointes (a life-threatening disorder of the heart. This is a medical emergency.)

Very slow or shallow breathing (respiratory depression)

Absence of breathing (respiratory arrest)

Enlargement of the parotid glands (salivary glands)

Altered bowel movement (intestinal obstruction, paralytic ileus, faecal impaction)

Death of the liver (fulminant hepatic necrosis)

Skin reactions

Inflammation of the kidney (interstitial nephritis)

A persistent and possibly painful erection (priapism)

Sudden unexplained death

Obsessive thoughts and compulsive behaviours (obsessive compulsive symptoms)

In elderly patients with dementia, a small increase in the number of people dying has been reported for patients taking antipsychotics compared with those who are not taking antipsychotics.

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.

5. HOW TO STORE DENZAPINE

Keep DENZAPINE out of the reach and sight of children.

A locked cupboard at least one and a half metres from the ground is a good place to store medicines.

Do not take DENZAPINE after the expiry date shown on the outer carton or on the blister strip. The expiry date refers to the last day of that month. Do not take DENZAPINE if the packaging is damaged or shows signs of

tampering.

Do not store above 30°C. Store in the original packaging. Keep in the outer carton to protect from light.

Keep your tablets in the original container until it is time to take them.

Do not store DENZAPINE or any medicine in the bathroom or near a sink. Do not leave it in a car or on a window sill. Heat and dampness can

destroy medicines. If your tablets appear to change in their appearance or show any other apparent signs of deterioration, do not take the tablets but refer immediately to the pharmacist.

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.

6. FURTHER INFORMATION

What DENZAPINE contains

-    The active substance is clozapine.

One DENZAPINE 25 mg tablet contains 25 mg clozapine.

One DENZAPINE 50 mg tablet contains 50 mg clozapine.

One DENZAPINE 100 mg tablet contains 100 mg clozapine.

One DENZAPINE 200 mg tablet contains 200 mg clozapine.

-    The other ingredients are

-    Microcrystalline cellulose

-    Lactose monohydrate

-    Povidone

-    Sodium starch glycolate

-    Magnesium stearate

What DENZAPINE looks like and contents of the pack

DENZAPINE 25 mg tablets are small, round, yellow tablets with “25" embossed over a breakline on one face, the other side is plain.

DENZAPINE 50 mg tablets are small, round, yellow tablets with “50" embossed over a breakline on one face, the other side is plain. DENZAPINE 100 mg tablets are small, round, yellow tablets with “100" embossed over a breakline on one face, the other side is plain. DENZAPINE 200 mg tablets are large, oval shaped, yellow tablets with “200" on one side and a breakline on the other side.

The breakline allows the tablet to be broken for easier swallowing. DENZAPINE 25 and 100 mg tablets are supplied in bottles of 100 tablets and in blister packs containing 28 or 84 tablets.

DENZAPINE 50 mg tablets are supplied in bottles of 100 tablets and in blister packs containing 20 or 50 tablets.

DENZAPINE 200 mg tablets are supplied in blister packs containing 50 tablets.

The quantity provided to you by the pharmacy will be determined by your doctor.

The Marketing Authorisation holder and Manufacturer:

Britannia Pharmaceuticals Ltd., ParkView House, 65 London Road, Newbury, Berkshire RG14 1JN, UK.

If you have any further questions about your medicine or are unsure about any of the advice in this leaflet, ask your doctor or pharmacist.

Marketing Authorisation number:

DENZAPINE 25 mg tablets PL 04483/0067

DENZAPINE 50 mg tablets PL 04483/0068

DENZAPINE 100 mg tablets PL 04483/0069

DENZAPINE 200 mg tablets PL 04483/0070

This leaflet was last revised in September 2014.    9249637 XXXX

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