Innozide

INNOZIDE 20/12.5 mg Tablets

(enalapril maleate/hydrochlorothiazide)

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may want 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 get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What 'Innozide' is and what it is used for


• 2. Before you take 'Innozide'


• 3. How to take 'Innozide'


• 4. Possible side effects


• 5. How to store 'Innozide'


• 6. Further information

What 'Innozide' is and what it is used for

Innozide contains enalapril maleate and hydrocholorothaizide:

• enalapril belongs to a group of medicines known as ACE inhibitors, which work by widening your blood vessels


• hydrochlorothiazide belongs to a group of medicines known as water tablets (diuretics), which increase the volume of urine you produce.

The effect of these medicines is to lower your blood pressure. 'Innozide' is used to treat high blood pressure (hypertension). Taking both medicines that 'Innozide' contains can increase their effect compared to taking just one.

Before you take 'Innozide'

Do not take 'Innozide' if:

• you have ever had an allergic reaction to 'Innozide', a similar medicine or to any of the ingredients (listed in Section 6). The signs may have been itching, nettle rash, wheezing or swelling of your hands, throat, mouth or eyelids



• you are allergic to a type of medicine called ‘sulphonamides'



• you are in the last 6 months of pregnancy, see section headed 'Pregnancy'.



• you are breast feeding



• you are not passing urine



• you have a condition know as renal artery stenosis (narrowing of the arteries that supply the blood to your kidneys).

Do not take 'Innozide' if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking 'Innozide'.

Take special care with 'Innozide'

Check with your doctor or pharmacist before taking your medicine if:

• you have kidney problems, have had a recent kidney transplantation, are a dialysis patient, or are taking water tablets (diuretics)



• you are on a salt restricted diet, or have suffered from excessive vomiting or diarrhoea recently



• you have a heart condition called ‘aortic stenosis', ‘hypertrophic cardiomyopathy' or ‘outflow obstruction'



• you have collagen vascular disease, are taking immunosuppressant therapy (used for the treatment of autoimmune disorders such as rheumatoid arthritis or following transplant surgery)



• you are taking allopurinol, (used for the treatment of gout), or procainamide, (used to treat abnormal heart rhythms). If you develop an infection (symptoms may be high temperature or fever), you should let your doctor know immediately. Your doctor may take a blood sample from time to time to check your white blood cell count



• you have a history of ‘angioedema' while taking other medicines. The signs may have been itching, nettle rash, wheezing or swelling of your hands, throat, mouth or eyelids



• you have diabetes and are taking antidiabetic medicines, including insulin to control your diabetes (you should monitor your blood for low blood glucose levels, especially during the first month of treatment)



• you are taking potassium supplements or potassium containing salt substitutes



• you are taking lithium, used for the treatment of some psychiatric illnesses



• you have been told by your doctor that you have an intolerance to some sugars.



• you think you are pregnant (or might become) pregnant. 'Innozide' is not recommended in early pregnancy and may cause serious harm to your baby after 3 months of pregnancy, see section headed Pregnancy.

If you are about to have any of the following procedures, you should tell your doctor who is treating you that you are taking 'Innozide':

• any surgery or receive anaesthetics (even at the dentist)



• a treatment called LDL apheresis, to remove cholesterol from your blood using a machine



• desensitisation treatment, to reduce the effect of an allergy to bee or wasp stings.

Routine tests

When you first start to take 'Innozide', your doctor will monitor your blood pressure frequently to ensure you have been given the correct dose. In addition, for some patients the doctor may want to do some tests to measure your potassium, sodium, magnesium, creatinine and liver enzyme levels.

Tell you doctor if you have or will take an anti-doping test since this medication can produce a positive result.

Children

Innozide is not recommended for use in children.

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 as some drugs may affect each other's action. This includes herbal medicines. Also some other medicines can affect the way 'Innozide' work:

• potassium sparing water tablets (diuretics) such as spironolactone, eplerenone, triamterene or amiloride, potassium supplements, or potassium-containing salt substitutes. 'Innozide' may increase the levels of potassium in your blood leading to high potassium levels. This causes few signs and is usually seen by a test



• water tablets (diuretics) such as thiazides, furosemide, bumetanide



• other medicines that lower blood pressure, such as nitroglycerine, nitrates, and vasodilators



• lithium, used for the treatment of some psychiatric illnesses. 'Innozide' should not be taken with this drug



• barbiturates (sedatives used for sleeplessness or epilepsy)



• tricyclic antidepressants such as amitriptyline, used for depression, antipsychotics such as phenothiazines, used for severe anxiety



• pain killers such as morphine or anaesthetics, because your blood pressure may become too low



• cholestyramine or colestipol (used to help control cholesterol levels)



• medicines used for, stiffness and inflammation associated with painful conditions, particularly those affecting your muscles, bones and joints:
  
  
  • including gold therapy which can lead to flushing of your face, feeling sick (nausea), vomiting and low blood pressure, when taken with 'Innozide', and
  
  
  
  • non-steroidal anti-inflammatory drugs (NSAIDs), for example diflunisal or diclofenac. They may prevent your blood pressure from being well controlled and may increase the level of potassium in your blood
  
  
  



• medicines such as ephedrine, used in some cough and cold remedies, or noradrenaline and adrenaline used for low blood pressure, shock, cardiac failure, asthma or allergies. If used with 'Innozide' these drugs may keep your blood pressure high




• ACTH (to test whether your adrenal glands are working properly)



• Corticosteroids (used to treat certain conditions such as rheumatism, arthritis, allergic conditions, asthma or certain blood disorders)



• Allopurinol (used to treat gout)



• Ciclosporins (immunosuppressive agents used for autoimmune disorders)



• Medicines for the treatment of cancer



• Antacids (used for indigestion relief)



• Procainamide, amiodarone or sotalol (used to treat abnormal heart rhythms)



• Digitalis (used to treat heart rhythm problems)



• Carbenoxalone (used to treat stomach ulcers)



• Excessive use of laxatives



• antidiabetic medicines such as insulin. 'Innozide' may cause your blood sugar levels to drop even further if you take it with antidiabetics.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking 'Innozide'.

Taking 'Innozide' with food and drink

'Innozide' can be taken with or without food. However, if you drink alcohol while taking 'Innozide', it may cause your blood pressure to drop too much and you may experience dizziness, light-headedness or faintness. You should keep your alcohol intake to a minimum.

Pregnancy and breast-feeding

You must tell your doctor if you think that you are (or might become) pregnant. Usually, your doctor will advise you to take another medicine instead of 'Innozide', as 'Innozide' is not recommended in early pregnancy, and may cause serious harm to your baby if it is used after 3 months of pregnancy.

Appropriate antihypertensive drug must usually replace 'Innozide' before starting a pregnancy. The product should not be used during the 2^nd and 3^rd trimester of pregnancy.

Your doctor will normally advise you to stop taking 'Innozide' as soon as you know you are pregnant. If you become pregnant during therapy with 'Innozide', please inform and see your physician without delay.

Tell your doctor if you are breast feeding. Small amounts of enalapril are found in breast milk. While taking 'Innozide', breast feeding is not recommended.

Driving and using machines

Certain side effects, such as dizziness and weariness, have been reported with 'Innozide' which may affect some patients' ability to drive or operate machinery.

Important information about some of the ingredients of 'Innozide'

'Innozide' contains lactose, which is a type of sugar. It is important to tell your doctor if you suffer from lactose intolerance.

How to take 'Innozide'

Taking this medicine

• You should take this medicine by mouth.


• Always take 'Innozide' exactly as your doctor told you.


• The number of tablets you take each day will depend upon your condition.

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

REMEMBER, this medicine is for you. Do not share it with anyone else. It may not suit them.

The usual dose for many people is:

• One tablet each day.


• Your doctor may increase the dose to two tablets each day.


• Do not take more or less than your doctor has prescribed.

If you take more 'Innozide' than you should

Contact your doctor immediately if you think you have taken more of your tablets than you should. The most common signs and symptoms of an overdose are a fall in blood pressure and stupor (a state of almost complete lack of consciousness). Other symptoms may include dizziness or light-headedness due to a fall in blood pressure, forceful and rapid heartbeat, rapid pulse, anxiety, cough, kidney failure, and rapid breathing.

If you forget to take 'Innozide'

• If you forget to take a tablet, skip the missed dose.


• Take the next dose as usual.


• Do not take a double dose to make up for a forgotten dose.

If you stop taking 'Innozide'

Do not stop taking your medicine, unless your doctor has told you to. If you do your blood pressure may increase. If your blood pressure becomes too high it may affect your heart and kidneys.

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

Innozide Side Effects

Like all medicines 'Innozide' can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

It is vital to stop taking 'Innozide' and seek medical attention immediately if you begin to have the following symptom:

• allergic reaction- you may get an itch, short of breath or wheezy and develop swelling of your hands, mouth, throat, face or eyes.

Stop taking 'Innozide' immediately and see your doctor if you have any of the following side effects

• severe dizziness, light-headedness, especially at the start of treatment or when your dose is increased or when you stand up.

Other possible side effects

Very common (affects more than 1 in 10 people)

• blurred vision, cough, feeling sick (nausea), weakness

Common (affects less than 1 in 10 people)

• headache, depression, low blood pressure, fainting


• chest pain, heart rhythm changes, angina, fast heart beat, shortness of breath


• diarrhoea, pain around your stomach area (abdomen), changes in taste, fluid retention (oedema), feeling tired


• rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported.


• increased blood potassium level, increases in serum creatinine (both are usually detected by a test); increased levels of cholesterol, increased levels of triglycerides, increased levels of uric acid in the blood.

Uncommon (affects less than 1 in100 people)

• anaemia, anxiety, a sense of heightened awareness or a shaky feeling (caused by low blood sugar), confusion, feeling sleepy, difficulty sleeping, feeling nervous, tingling or numbness, feeling like you are spinning (vertigo)



• low blood pressure (which may make you feel dizzy when you stand up), uneven heart beats, heart attack or stroke (in high risk patients)



• runny nose, sore throat and hoarseness, difficulty breathing or asthma



• a blockage in your intestine (ileus), pancreatitis, being sick, indigestion, constipation, not feeling like eating properly (anorexia), stomach irritation, dry mouth, flatulence, gout



• burning, aching pain with an empty feeling and hunger, particularly when the stomach is empty (caused by a peptic ulcer), excessive sweating, itching, hives (urticaria), hair loss, protein in your urine (usually detected by a test)



• impotence, decreased libido, muscle cramps, flushing, ringing in your ears, feeling lethargic, high temperature



• increases in blood urea and decreases in blood sodium levels (usually detected by a test).

Rare (affects less than 1 in 1,000 people)

• strange dreams, sleeping problems


• decreases in your white blood cells, red blood cells, platelets, bone marrow depression (all are usually detected by tests)


• swollen glands, autoimmune diseases, low blood flow to your fingers and toes causing redness and pain (Raynaud's), fluid on your lungs, runny or sore nose


• eosinophilic pneumonia (signs may be cough, high temperature and difficulty breathing)


• pain, swelling or ulcers in your mouth, infection or pain and swelling of your tongue, kidney problems such as lower back pain and reduction in the volume of urine you pass


• liver failure or hepatitis, this may cause yellowing of your skin (jaundice)


• excessive redness of your skin, blisters, skin peeling off in sheets


• development of breasts in men


• increased liver enzymes or blood ‘bilirubin' (usually detected by a blood test), decrease in blood glucose

Very rare (affects less than 1 in 10,000 people)

• intestinal ‘angioedema'. Signs may include stomach pain, feeling sick and vomiting, elevated calcium level in blood

Others (it is unknown how many people may be affected)

A complex side effect has also been reported which may include some or all of the following signs:

• fever, inflammation of your blood vessels, pain and inflammation of muscles or joints


• blood disorders affecting the components of your blood (usually detected by a blood test)


• rash, hypersensitivity to sunlight and other effects on your skin.

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

How to store 'Innozide'

Keep your tablets out of the reach and sight of children.

Do not store above 25°C. Store in the original container.

Do not put them into another container as they might get mixed up.

Do not take them past the expiry date which is clearly marked on the pack.

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.

Further Information

What 'Innozide' contains:

The active ingredients in 'Innozide' Tablets are enalapril maleate and hydrochlorothiazide .Each tablet contains 20 mg enalapril maleate and 12.5 mg hydrochlorothiazide.

The other ingredients in 'Innozide' are Sodium hydrogen carbonate E500, lactose, maize starch, yellow ferric oxide E172, pregelatinised starch, magnesium stearate E572.

What Innozide looks like and the contents of the pack

'Innozide' is available as round, fluted, yellow tablets with ‘MSD 718' on one side and scored on the other.

'Innozide' Tablets are available in blister packs containing 28 tablets.

Marketing Authorisation Holder and Manufacturer

The marketing Authorisation Holder is

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

The product is manufactured by

Merck Manufacturing Division

Merck Sharp & Dohme Limited

Shotton Lane

Cramlington

Northumberland

NE23 3JU

UK

This leaflet was last approved in May 2008

This leaflet gives you some of the most important patient information about 'Innozide'. If you have any questions after you have read it, ask your doctor or pharmacist, who will give you further information.

denotes registered trademark of

Merck & Co., Inc.

Whitehouse Station

NJ

USA

© Merck Sharp & Dohme Limited 2008. All rights reserved.

(logo) MSD

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

PIL.CRN.07.UK.2768

Indigestion Mixture

1. Name Of The Medicinal Product

Indigestion Mixture

2. Qualitative And Quantitative Composition

	per 5ml
Sodium Bicarbonate Ph Eur	225mg
Light Magnesium Carbonate Ph Eur	225mg
Calcium Carbonate Light Ph Eur	175mg

3. Pharmaceutical Form

Suspension

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of occasional indigestion, heartburn, excess acidity and flatulence.

For oral administration.

4.2 Posology And Method Of Administration

Adults and children over 12 years

10ml after meals, at bedtime or when required.

Children 5 to 12 years

5ml after meals, at bedtime or when required.

Children under 5 years

Not recommended.

Elderly

There is no need for dosage reduction.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Caution should be observed in patients with impaired renal function, heart failure, hypertension and in those on a low sodium diet.

If symptoms persist for more than 5 days, talk to your doctor.

Keep medicines out of the sight and reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

This product may interfere with the absorption of tetracyclines when these are given concomitantly. May enhance the cardiac effects of digitalis glycosides. Will alkalinise the urine and reduce the urinary excretion of amphetamines, methadone, quinidine and quinine. Will reduce the effectiveness of hexamine compounds, which are only effective as urinary antiseptics in acid urine. The renal excretion of lithium appears to be increased by sodium bicarbonate and this could lead to reduced plasma levels of lithium and impairment of the therapeutic response.

4.6 Pregnancy And Lactation

Although problems have not been documented with sodium bicarbonate, there are no adequate human data from the use of magnesium carbonate and calcium carbonate in pregnant women. Studies in animals have not been done. Caution should be exercised when taken by pregnant women.

Although some magnesium, calcium and sodium may be secreted in breast milk, the concentration is too small to produce an effect in the neonate.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

The product may cause diarrhoea, flatulence, gastrointestinal irritation and metabolic alkalosis. Prolonged use may lead to elevated serum levels of calcium and magnesium, particularly in the presence of renal impairment.

4.9 Overdose

Symptoms of overdosage include gastrointestinal irritation, diarrhoea, flatulence and metabolic alkalosis. In severe cases, symptoms of hypermagnesaemia and hypercalcaemia may develop. Treatment should be symptomatic and supportive.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Light magnesium carbonate, calcium carbonate and sodium bicarbonate have antacid properties.

5.2 Pharmacokinetic Properties

Magnesium carbonate administered by mouth reacts with gastric acid to form soluble magnesium chloride and carbon dioxide in the stomach. Some magnesium is slowly absorbed from the gastrointestinal tract and is eliminated in the urine, otherwise excretion is via the faeces.

Calcium carbonate is converted is converted to calcium chloride and carbon dioxide by gastric acid. Some of the calcium is absorbed but about 85% is reconverted to insoluble calcium salts, such as the carbonate and is excreted in the faeces.

Sodium bicarbonate is converted to sodium chloride and carbon dioxide by gastric acid. Some sodium is absorbed.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Chloroform

Peppermint oil

Purified water

6.2 Incompatibilities

None

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

None

6.5 Nature And Contents Of Container

White flint glass bottle, with an unlined polypropylene cap or roll-on pilfer proof cap with a flowed in liner or triseal (LDPE/EPE/LDPE) liner.

Pack size: 200ml

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL 00014/5409R

9. Date Of First Authorisation/Renewal Of The Authorisation

First authorisation: 7 October 1988

Date of last renewal: 18 January 1999

10. Date Of Revision Of The Text

February 2003

Indivina

Indivina 1 mg/2.5 mg tablets

Indivina 1 mg/5 mg tablets

Indivina 2 mg/5 mg tablets

estradiol /medroxyprogesterone

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.

In this leaflet:

1. What Indivina is and what it is used for

2. Before you take Indivina

3. How to take Indivina

4. Possible side effects of Indivina

5. How to store Indivina

6. Further information

What Indivina Is And What It Is Used For

The name of your medicine is Indivina. It is a hormone replacement therapy (HRT) used to treat some of the symptoms which occur when the oestrogen levels decline and the periods stop (menopause) by replacing the oestrogen that your body is no longer producing. The tablets contain oestrogen and progestogen. Indivina is only recommended for women whose periods stopped more than three years ago and who still have their womb.

Indivina can also be used to help to prevent osteoporosis (thinning of the bones) if you are at an increased risk of fractures due to osteoporosis but are unable to take other treatments or if other therapies prove to be ineffective. Your doctor should discuss all the available options with you.

There is only limited experience of treating women older than 65 years with Indivina.

Before You Take Indivina

Medical check-ups

Before you start taking Indivina, your doctor will inform you about the risks and benefits of the treatment (see also section 4, “Other side effects of combined HRT”). Before you start treatment and regularly during treatment, your doctor will evaluate whether Indivina is the right treatment for you. Your doctor will tell you how often you should go for periodic check-ups, taking into account your general state of health. If you have any close relative (mother, sister, maternal or paternal grandmother), who has suffered from serious illness, e.g. blood clot or breast cancer, you might be at increased risk. You should therefore always tell your doctor about any close relative suffering from serious illness, and you should also tell your doctor about any changes, you might find in your breasts.

As well as regular check-ups with your doctor, be sure to:

• Regularly check your breasts for any changes, such as dimpling or sinking of the skin, changes in the nipple, or any lumps you can see or feel.


• Go for regular breast screening (mammography) and cervical smear tests.
  
  
  • While you are receiving this medication, you should see your doctor regularly, at least every six to twelve months
  • If you have unusual symptoms such as unexplained pains in the chest, abdomen or legs you must consult your doctor immediately.
  • If you have a family history of breast cancer you should use this medication with great caution.

Do not take Indivina, if:

• you are allergic (hypersensitive) to estradiol valerate or medroxyprogesterone acetate or any of the other ingredients of Indivina (see section 6: Further information)


• you have or have had breast cancer in the past


• you have or have had an oestrogen-dependent tumour such as endometrial cancer (cancer of the lining of the womb)


• you have unusual vaginal bleeding that has not been checked by a doctor


• you have endometrial hyperplasia (abnormal growth of the lining of the womb) that is not being treated


• you have had a recent blood clot of an artery (leading to chest pain or heart attack)


• you have had liver disease and have been told by your doctor that your liver function has not yet returned to normal


• you have or have had a blood clot in a vein in your leg or anywhere else (a “deep vein thrombosis or pulmonary embolism”)


• you have porphyria (a genetic disorder).

Take special care with Indivina

As well as benefits, HRT has some risks which you need to consider when you are deciding whether to take it, or whether to carry on taking it. Tell your doctor if you have any of the following as you may need more frequent check ups’ if:

• you think you might be at risk of oestrogen dependent tumors such as breast cancer or endometrial cancer (see the section below on effects on your risk of developing cancer)


• you have had endometrial hyperplasia (thickening of the lining of the womb)


• you have uterine fibroids or endometriosis


• you feel you might be at risk of developing blood clots (see section below on blood clots)


• you have liver, kidney or heart problems


• you have gallstones


• you have asthma, epilepsy or diabetes


• you have high blood pressure


• you have otosclerosis (hearing problems due to bone overgrowth in the ear)


• you have been told that you have an intolerance to some sugars


• you have systemic lupus erythematosus (SLE)


• you have migraine or severe headaches


• you have been told you have high cholesterol or fat levels in your blood


• you are going to have surgery, make sure your doctor knows about it. You may need to stop taking HRT about 4 to 6 weeks before the operation, to reduce the risk of a blood clot. Your doctor will tell you when you can start taking HRT again.

HRT may change the results of some laboratory tests. If you are going to have any laboratory tests, tell your doctor/nurse that you are taking Indivina.

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.

In particular tell your doctor if you are taking any of the following:

• antibiotics such as rifampicin, rifabutin


• anti-epileptic medicines such as phenytoin, phenobarbital and carbamazepine


• HIV medicines such as nelfinavir, ritonavir, nevirapine and efavirenz


• the herbal preparation St. Johns Wort.

If you are in any doubt about taking other medicines with Indivina, talk to your doctor or your pharmacist.

Taking Indivina with food and drink

Indivina can be swallowed with a glass of water at the same time each day.

Pregnancy and breast-feeding

• Pregnancy – Do not take Indivina if you are pregnant, think you are pregnant or planning to become pregnant


• Breast feeding – Do not take Indivina if you are breast feeding.

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

Driving and using machines

Indivina should not affect your ability to drive or operate machinery.

Important information about some ingredients of Indivina

This medicine contains lactose. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicinal product.

How To Take Indivina

Always take Indivina as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Take one Indivina tablet every day, preferably at about the same time each day. Calendar days are printed on the blister sheet to help you follow your daily tablet intake. Swallow the tablet whole with a drink if necessary. You will normally start on the lowest dose of Indivina and this will be increased, if necessary. Your doctor should aim to prescribe the lowest dose for the shortest time that gives you relief from your symptoms. Talk to your doctor if your symptoms are not better after three months. If you feel that the effect of Indivina is too strong or too weak, do not change the dose or stop taking the tablets yourself, but ask your doctor for advice.

If you are not having periods and you have not previously taken HRT or you are changing from another continuous combined HRT product, treatment with Indivina may be started on any day.

If you switch from a cyclic HRT regimen, start Indivina treatment one week after taking the last tablet of the cyclic HRT. Talk to your doctor or pharmacist if you are unsure.

Whilst taking this medicine

When you first start taking Indivina you may get some bleeding at odd times for a few months (Please also refer to the section above on Endometrial cancer). However, if this is still happening after a few months or if you experience heavy bleeding tell your doctor.

If you take more Indivina than you should:

If you or somebody else has taken too many Indivina tablets, talk to your doctor or pharmacist. An overdose of Indivina could make you feel sick or make you get a headache or uterine bleeding.

If you forget to take Indivina:

It is best to take the tablet at the same time each day. If you forget to take a tablet leave the forgotten tablet. You should then continue by taking the next tablet at your usual time. Missing a tablet or irregular use of Indivina tablets may cause breakthrough bleeding or spotting.

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

If you stop taking Indivina

If you want to stop taking Indivina, talk to your doctor first. He/she will explain the effects of stopping treatment and discuss other possibilities with you.

Indivina Side Effects

Like all medicines, Indivina may cause side effects although not everybody gets them, particularly early on (in the first few months of treatment), for example irregular bleeding may occur. These often disappear with continued treatment.

There are a number of situations in which you may have to stop taking Indivina. Tell your doctor immediately if you develop any of the following conditions:

Common (affecting more than 1 person in 100):

• feeling sick, stomach pain


• headache


• breast tenderness, breast enlargement, breakthrough bleeding


• weight increase or decrease


• changes in mood including anxiety and depressive mood, changes in libido


• increase in size of uterine muscle lumps (fibroids)


• swelling caused by fluid retention

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

• dizziness, migraine


• leg cramps


• increased blood pressure


• vaginal thrush (candidiasis)


• indigestion/heartburn


• wind, vomiting


• gall bladder disease and/or gallstones

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

• skin rash, itching


• blood clots


• hair loss, excessive hair growth (hirsutism)

Other side effects of combined HRT

The following side effects have been reported after taking other oestrogen/progestagen products:

Oestrogen dependent tumours, heart attack, stroke, disorders of skin and underlying tissues.

Endometrial hyperplasia and endometrial cancer

In women with an intact uterus, the risk of excessive growth of the womb lining (endometrial hyperplasia) is increased. Treatment with unopposed oestrogens for long periods of time increases the risk of cancer of the lining of the womb (endometrial cancer). Adding a progestagen, which Indivina contains, greatly reduces this increased risk.

Compare

Looking at women who still have a uterus and who are not taking HRT, on average, 5 in 1000 will be diagnosed with endometrial cancer between the ages of 50 and 65. For women who take oestrogen-only HRT the number will be 2 to 12 times higher, depending on the dose and how long you take it. The addition of progestogen to oestrogen-only HRT substantially reduces the risk of endometrial cancer.

Breast cancer

Every woman is at risk of getting breast cancer whether or not she takes HRT. There is a small increase in this risk for women who have been using HRT compared with women of the same age who have never used HRT. This risk increases with the duration of intake of HRT, but returns to normal within a few (at most five) years of having stopped HRT. The risk seems to be higher for women who use oestrogen in combination with progestagen as compared to oestrogen alone.

Compare:

Looking at women aged 50 who are not taking HRT – on average, 32 in 1000 will be diagnosed with breast cancer by the time they reach the age of 65.

For women who start taking oestrogen-only HRT at age 50 and take it for 5 years, the figure will be between 33 and 34 in 1000 (i.e. an extra 1-2 cases).

If they take oestrogen-only HRT for 10 years, the figure will be, 37 in 1000 (i.e. an extra 5 cases). For women who start taking oestrogen plus progestogen HRT at age 50 and take it for 5 years, the figure will be 38 in 1000 (i.e. an extra 6 cases).

If they take oestrogen plus progestogen HRT for 10 years, the figure will be 51 in 1000 (i.e. an extra 19 cases).

To be able to detect a breast tumour as early as possible, it’s important to regularly check your breasts for any changes and to discuss any changes with your doctor. Also go for regular health check, including mammography. If you are anxious about the risk of developing breast cancer, you should talk to your doctor about the risks and benefits of hormone replacement therapy.

Blood clots in the deep veins

Every woman is at risk of getting a blood clot whether or not she takes HRT.

HRT may increase the risk of blood clots in the veins up to3 times, especially in the first year of taking it.

If you suspect you are suffering from a blood clot, seek immediate medical attention.

You are also more likely to get a blood clot:

• If you are very overweight


• If you have had a blood clot before, or have had any blood clotting problem that needs treatment with a medicine such as Warfarin


• If any of your close family has had blood clots


• If you have had a miscarriage


• If you are off your feet for a long time through surgery, injury or illness


• If you have Systemic Lupus Erythematosus ((SLE) – an autoimmune disease)

Compare

Looking at women in their 50’s who are not taking HRT – on average, over a 5 year period, 3 in 1000 would be expected to get a blood clot.

For women in their 50s who are taking HRT, the figure would be 7 in 1000.

Looking at women in their 60s who are not taking HRT – on average, over a 5 year period, 8 in 1000 would be expected to get a blood clot.

For women in their 60’s who are taking HRT, the figure would be 17 in 1000.

Symptoms that may be indicative of blood clots:

• Pain and swelling in your leg


• Sudden chest pain


• Difficulty breathing.

Seek immediate medical help. Stop taking HRT until your doctor says you can.

Heart disease

If you ever have had angina or heart attack, you should talk to your doctor about the risks and benefits of hormone replacement therapy.

There is no evidence from clinical trials of beneficial effects on the risks of cardiovascular disease with hormone replacement therapy in the menopause. Results from two large clinical studies showed that women, who used another type of oestrogen/progestagen combination, had a slightly increased risk of heart disease in the first year of use.

For other HRT products there are only very limited data from trials examining the effects on the risk of cardiovascular disease.

Stroke

There may be a slightly higher chance of having a stroke if you are taking HRT.

Other things that also increase the risk of stroke are:

• Getting older


• High blood pressure


• Smoking


• Drinking too much alcohol


• An irregular heartbeat.

Compare

Looking at women in their 50’s who are not taking HRT - on average, over a 5 year period, 3 in 1000 would be expected to have a stroke.

For women in their 50s who are taking HRT, the figure would be 4 in 1000.

Looking at women in their 60s who are not taking HRT - on average, over a 5 year period, 11 in 1000 would be expected to have a stroke.

For women in their 60’s who are taking HRT, the figure would be 15 in 1000.

If you get:

• Unexplained migraine-type headaches, with or without disturbed vision.

See a doctor as soon as possible. Stop taking HRT until your doctor says you can.

Ovarian cancer

Long-term (at least 5 or 10 years) use of oestrogen-only HRTs and oestrogen plus progestogen HRTs has been associated with an increased risk of ovarian cancer in some epidemiological studies.

Dementia

HRT will not prevent memory loss. In one study of women who started using combined HRT after the age of 65, a small increase in the risk of dementia was observed.

Effects on the skin

Brown patches in the face (chloasma), skin rashes including red inflammation on the hands or the legs (erythema multiforme), formation of tender, red nodules on the front of the legs/knees (erythema nodosum) or a bruise-like rash (vascular purpura).

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

How To Store Indivina

Keep out of the reach and sight of children. Do not use Indivina after the expiry date which is stated on the pack. Do not store above 30 ºC. Store in the original package in order to protect from moisture. Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Indivina contains:

The active ingredients of Indivina tablets are estradiol valerate and medroxyprogesterone acetate. Three different strengths of tablets are available.

Indivina 1 mg/2.5 mg tablets contain 1 mg of estradiol valerate and 2.5 mg medroxyprogesterone acetate.

Indivina 1 mg/5 mg tablets contain 1 mg of estradiol valerate and 5 mg medroxyprogesterone acetate.

Indivina 2 mg/5 mg tablets contain 2 mg of estradiol valerate and 5 mg medroxyprogesterone acetate.

The other ingredients of all Indivina tablets are lactose monohydrate, maize starch, gelatin, and magnesium stearate

What Indivina looks like and contents of the pack:

Indivina 1 mg/2.5 mg tablets are white, round, bevelled-edge, diameter 7 mm, flat tablets with a code ‘1 + 2.5’on one side.

Indivina 1 mg/5 mg tablets are white, round, bevelled-edge, diameter 7 mm, flat tablets with a code ‘1 + 5’on one side.

Indivina 2 mg/5 mg tablets are white, round, bevelled-edge, diameter 7 mm, flat tablets with a code ‘2 + 5’on one side.

The tablets are packed in a PVC/PVDC-aluminium blister of 28 tablets. The pack sizes available are 1 x 28 tablets and 3 x 28 tablets for all three strengths. All pack sizes may not be available in your country.

Marketing Authorisation Holder:

Orion Corporation

Orionintie 1

FIN-02200 Espoo

FINLAND

Manufactured by:

Orion Corporation

Tengströminkatu 8

FIN-20360 Turku

FINLAND

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

Indivina, Duova

This leaflet was last revised: June 2010

Icthaband (Molnlycke Health Care )

1. Name Of The Medicinal Product

Icthaband.

2. Qualitative And Quantitative Composition

Zinc Oxide BP 15% w/w; Ichthammol BP 2% w/w.

3. Pharmaceutical Form

Open wove bleached cotton bandage impregnated with the paste formulation.

4. Clinical Particulars

4.1 Therapeutic Indications

Icthaband may be used for the following conditions: subacute eczematous conditions; chronic eczema, where tar is not tolerated; subacute gravitational eczema and all other forms of leg eczema; varicose and gravitational ulcers, in conjunction with a compression bandage, when a protective barrier to thin and fragile skin is required.

4.2 Posology And Method Of Administration

For topical use. Adults, the elderly, and children: Frequency of dressing changes is at the discretion of the responsible physician. There are no differences in use between adults, children and the elderly.

4.3 Contraindications

Hypersensitivity to any ingredient of the paste, and acute eczematous lesions.

4.4 Special Warnings And Precautions For Use

Avoid use on grossly macerated skin. The skin of leg ulcers is easily sensitised to topical medicaments including preservatives. Sensitisation should be suspected in patients particularly where there is deterioration of the ulcer or surrounding skin. Such patients should be referred for special diagnosis including patch testing. One of the functions of occlusive bandages is to increase absorption. Care should be taken, therefore, if it is decided to apply topical steroid preparations under these bandages as their absorption may be significantly increased.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

No special precautions required.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Not applicable.

4.9 Overdose

Not applicable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The product is a paste bandage with the active constituent presented in a glycerine, modified starch and castor oil based paste spread onto a cotton bandage. Zinc Oxide as a zinc salt has astringent properties and has been shown to play a role in wound healing. Ichthammol has an antipruritic action and has slight bacteriostatic properties. These substances are well established in use, but only the subject of brief references in recent literature and pharmacopoeias (e.g. Martindale). Much of the therapeutic action of paste bandages is attributable to the bandaging technique, the physical support and protection provided and to the maintenance of moist wound healing conditions.

5.2 Pharmacokinetic Properties

The pharmacokinetics of the active ingredient are those relevant to topical application of the substances through whole or broken skin. Contemporary literature describes the biochemical properties but with the exception of the zinc salts does directly relate these properties to the disease states being treated. Zinc compounds are the subject of current re-appraisal for their role in wound healing.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glycerol

Castor oil

Tapioca starch

Citric acid

Propylhydroxybenzoate

Water purified

Open weaved cotton bandage

6.2 Incompatibilities

None stated.

6.3 Shelf Life

Thirty months.

6.4 Special Precautions For Storage

Store in a dry place not exceeding 25^oC.

6.5 Nature And Contents Of Container

Bandages are wrapped individually in waxed paper or polythene film and then placed in a nylon/foil/polythene laminate bag in a cardboard carton, or a sealed polythene bag in a cardboard carton. 12 cartons are packed per corrugated cardboard outer.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Medlock Medical Ltd., Tubiton House, Oldham, OL1 3HS.

8. Marketing Authorisation Number(S)

PL 21248/0018

9. Date Of First Authorisation/Renewal Of The Authorisation

29^th June 2007.

10. Date Of Revision Of The Text

29^th June 2007.

Ilaris 150mg powder for solution for injection

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

One vial contains 150 mg of canakinumab*.

After reconstitution, each ml of solution contains 150 mg canakinumab.

* fully human monoclonal antibody produced in mouse hybridoma Sp2/0 cells by recombinant DNA technology

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for injection.

The powder is white.

4. Clinical Particulars

4.1 Therapeutic Indications

Ilaris is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS) in adults, adolescents and children aged 4 years and older with body weight above 15 kg, including:

− Muckle-Wells Syndrome (MWS),

− Neonatal-Onset Multisystem Inflammatory Disease (NOMID) / Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA),

− Severe forms of Familial Cold Autoinflammatory Syndrome (FCAS) / Familial Cold Urticaria (FCU) presenting with signs and symptoms beyond cold-induced urticarial skin rash.

4.2 Posology And Method Of Administration

Treatment should be initiated and supervised by a specialist physician experienced in the diagnosis and treatment of CAPS.

After proper training in the correct injection technique, patients may self-inject Ilaris if their physician determines that it is appropriate and with medical follow-up as necessary.

Adults, adolescents and children aged 4 years and older

The recommended dose of Ilaris is 150 mg for CAPS patients with body weight > 40 kg and 2 mg/kg for CAPS patients with body weight

If a satisfactory clinical response (resolution of rash and other generalised inflammatory symptoms) has not been achieved 7 days after treatment start, a second dose of Ilaris at 150 mg or 2 mg/kg can be considered. If a full treatment response is subsequently achieved, the intensified dosing regimen of 300 mg and 4 mg/kg should be maintained. No experience exists for doses > 600 mg every 8 weeks. Clinical experience with dosing at intervals of less than 4 weeks is limited.

Special populations

Paediatric population

Ilaris is not recommended for use in children below 4 years of age or with body weight below 15 kg due to a lack of clinical data.

Elderly

Clinical experience in patients above 65 years is limited, therefore caution is recommended.

Hepatic impairment

Ilaris has not been studied in patients with hepatic impairment.

Renal impairment

No dose adjustment is needed in patients with renal impairment. However, clinical experience in such patients is limited.

For instructions on use and handling of the reconstituted solution, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Active, severe infections (see section 4.4).

4.4 Special Warnings And Precautions For Use

Serious infections

Ilaris may be associated with an increased incidence of serious infections. Therefore patients should be monitored carefully for signs and symptoms of infections during and after treatment with Ilaris. Physicians should exercise caution when administering Ilaris to patients with infections, a history of recurring infections, or underlying conditions which may predispose them to infections. Treatment with Ilaris should not be continued or initiated in patients with severe infections requiring medical intervention.

Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported more frequently with Ilaris than with placebo. All infections responded to standard therapy. In canakinumab-treated patients with serious and systemic infections, a physiological inflammatory response was maintained as evidenced by concomitant C-reactive protein (CRP) elevation and fever. A blunted inflammatory response to infections cannot be excluded and increased vigilance is therefore recommended. No unusual or opportunistic infections were reported with Ilaris.

Concomitant use of Ilaris with tumour necrosis factor (TNF) inhibitors is not recommended because this may increase the risk of serious infections (see section 4.5).

PPD (purified protein derivative) skin test

In approximately 12% of CAPS patients tested with a PPD skin test in clinical trials, follow-up testing yielded a positive test result while treated with Ilaris without clinical evidence of a latent or active tuberculosis infection. Before initiation of therapy, all patients must be evaluated for both active and latent tuberculosis infection. Particularly in adult patients, this evaluation should include a detailed medical history and appropriate screening tests. Patients must be monitored closely for signs and symptoms of tuberculosis during and after treatment with Ilaris. In the event of conversion from a negative to a positive PPD test, especially in high-risk patients, alternative means of screening for a tuberculosis infection should be considered.

Neutropenia

Neutropenia (absolute neutrophil count [ANC] < 1.5 x 10⁹/l) has been observed commonly with another medicinal product that inhibits IL-1 used in a patient population (rheumatoid arthritis) other than CAPS. Neutropenia was observed commonly in patients with rheumatoid arthritis (not an approved use) who were administered Ilaris subcutaneously in clinical studies. Treatment with Ilaris should not be initiated in patients with neutropenia. It is recommended that neutrophil counts be assessed prior to initiating treatment, after 1 to 2 months, and periodically thereafter while receiving Ilaris. If a patient becomes neutropenic the ANC should be monitored closely and treatment discontinuation should be considered.

Malignancies

The risk for the development of malignancies with anti-interleukin (IL)-1 therapy is unknown. A potential risk cannot be excluded in patients treated with Ilaris.

Hypersensitivity reactions

Cases suggestive of hypersensitivity reactions with Ilaris therapy have been reported in clinical trials. The majority of these events were mild in severity. No anaphylactoid or anaphylactic reactions have been reported. However, the risk of severe hypersensitivity reactions, which is not uncommon for injectable proteins, cannot be excluded (see section 4.3).

Hepatic function

Rare, mild, transient and asymptomatic cases of elevations of serum transaminases or bilirubin have been reported in clinical trials.

Vaccinations

No data are available on the risk of secondary transmission of infection by live (attenuated) vaccines in patients receiving Ilaris. Therefore, live vaccines should not be given concurrently with Ilaris unless the benefits clearly outweigh the risks (see section 4.5).

Prior to initiation of Ilaris therapy, adult and paediatric patients should receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine.

Mutation in NLRP3 gene

Clinical experience in patients without a confirmed mutation in the NLRP3 gene is limited.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interactions between Ilaris and other medicinal products have not been investigated in formal studies.

An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Use of Ilaris with TNF inhibitors is not recommended because this may increase the risk of serious infections.

The expression of hepatic CYP450 enzymes may be suppressed by the cytokines that stimulate chronic inflammation, such as IL-1 beta. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as canakinumab, is introduced. This is clinically relevant for CYP450 substrates with a narrow therapeutic index where the dose is individually adjusted. On initiation of canakinumab in patients being treated with this type of medicinal product, therapeutic monitoring of the effect or of the active substance concentration should be performed and the individual dose of the medicinal product adjusted as necessary.

No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving Ilaris. Therefore, live vaccines should not be given concurrently with Ilaris unless the benefits clearly outweigh the risks. Should vaccination with live vaccines be indicated after initiation of Ilaris treatment, the recommendation is to wait for at least 3 months after the last Ilaris injection and before the next one (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

There is a limited amount of data from the use of canakinumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). The risk for the foetus/mother is unknown. Women should use effective contraceptives during treatment with Ilaris and for up to 3 months after the last dose. Women who are pregnant or who desire to become pregnant should therefore only be treated after a thorough benefit-risk evaluation.

Lactation

It is unknown whether canakinumab is excreted in human milk. The decision whether to breast-feed during Ilaris therapy should therefore only be taken after a thorough benefit-risk evaluation.

Animal studies have shown that a murine anti-murine IL-1 beta antibody had no undesirable effects on development in nursing mouse pups and that the antibody was transferred to them (see section 5.3).

Fertility

Formal studies of the potential effect of Ilaris on human fertility have not been conducted.

Canakinumab had no effect on male fertility parameters in marmosets (C. jacchus). A murine anti-murine IL-1 beta antibody had no undesirable effects on fertility in male or female mice (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

The ability to drive and operate machines may be impaired by some symptoms associated with CAPS. Patients who experience vertigo during Ilaris treatment should wait for this to resolve completely before driving or operating machines.

4.8 Undesirable Effects

Summary of the safety profile

Approximately 830 subjects have been treated with Ilaris in blinded and open-label clinical trials in patients with CAPS, patients with other diseases, and healthy volunteers. Safety data from 104 CAPS patients is available. A total of 10 serious adverse reactions that were considered by the investigator as related to treatment were reported during the clinical programme in CAPS, of which the most frequent events were infections (3) and vertigo (2). The most frequently reported adverse events included upper respiratory tract infections and nasopharyngitis across all CAPS studies. Dose and duration of treatment have no impact on the type or frequency of adverse events.

A total of 104 adult and paediatric CAPS patients (including FCAS/FCU, MWS, and NOMID/CINCA) have received Ilaris in clinical trials. The safety of canakinumab compared with placebo was investigated in a pivotal phase III trial that consisted of an 8-week, open-label period (Part I), a 24-week, randomised, double-blind and placebo-controlled withdrawal period (Part II), and a 16-week open label period on canakinumab (Part III). All patients were treated with Ilaris 150 mg subcutaneous or 2 mg/kg if body weight was

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (

Table 1 Tabulated summary of reported adverse drug reactions from pivotal CAPS clinical trial

	Part I	Part II	Part III
	Canakinumab n=35	Canakinumab n=15	Placebo n=16	Canakinumab n=31
Infections and infestations
Very common	Nasopharyngitis	4 (11.4%)	5 (33.3%)	3 (18.8%)	4 (12.9%)
Common	Urinary tract infection	0	2 (13.3%)	0	1 (3.2%)
Upper respiratory tract infection	1 (2.9%)	1 ( 6.7%)	1 (6.3%)	1 (3.2%)
Viral infection	3 (8.6%)	2 (13.3%)	3 (18.8%)	1 (3.2%)
Ear and labyrinth disorders
Very common	Vertigo*	2 (5.8%)	0	0	3 (9.7%)
Skin and subcutaneous tissue disorders
Very common	Injection site reaction#	3 (8.6%)	2 (13.3%)	1 (6.3%)	1 (3.2%)
# Solicited through physician questionnaires * All events resolved despite continued treatment with Ilaris.

Cases suggestive of hypersensitivity reactions with Ilaris therapy have been reported in patients treated with canakinumab in clinical trials. The majority of these events were mild in severity. No anaphylactoid or anaphylactic reactions have been reported.

During clinical trials with canakinumab mean values for hemoglobin increased and decreased for white blood cell, neutrophils and platelets. These changes were potentially due to a decrease in inflammation and not considered to be of clinical relevance.

Elevations of transaminases have been observed rarely in CAPS patients.

Asymptomatic and mild elevations of serum bilirubin have been observed in CAPS patients treated with canakinumab without concomitant elevations of transaminases.

Paediatric population

Twenty-three paediatric CAPS patients (4-17 years of age) demonstrated similar efficacy and safety to adult patients. Specifically, the overall frequency and severity of infectious episodes in paediatric patients were comparable to that in the adult population. Infection of the upper respiratory tract was the most frequently reported infection.

4.9 Overdose

No case of overdose has been reported.

In case of overdose, it is recommended for the patient to be monitored for any signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Interleukin inhibitors, ATC code: L04AC08

This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

Mechanism of action

Canakinumab is a fully human monoclonal anti-human interleukin-1 beta (IL-1 beta) antibody of the IgG1/κ isotype. Canakinumab binds with high affinity specifically to human IL-1 beta and neutralises the biological activity of human IL-1 beta by blocking its interaction with IL-1 receptors, thereby preventing IL-1 beta-induced gene activation and the production of inflammatory mediators.

Pharmacodynamic effects

In clinical studies, CAPS patients who have uncontrolled over-production of IL-1 beta show a rapid response to therapy with canakinumab, i.e. laboratory parameters such as high C-reactive protein (CRP) and serum amyloid A (SAA), high neutrophil and platelet counts, and leukocytosis rapidly returned to normal.

Clinical data

The efficacy and safety of canakinumab have been demonstrated in patients with varying degrees of disease severity and different CAPS phenotypes (including FCAS/FCU, MWS, and NOMID/CINCA). Only patients with confirmed NLRP3 mutation were included in the pivotal study.

In the Phase I/II study, treatment with canakinumab had a rapid onset of action, with disappearance or clinically significant improvement of symptoms within one day after dosing. Laboratory parameters such as high CRP and SAA, high neutrophils and platelet counts normalised rapidly within days of canakinumab injection.

The pivotal study consisted of a 48-week three-part multicentre study, i.e. an 8-week open-label period (Part I), a 24-week randomised, double-blind, placebo-controlled withdrawal period (Part II), followed by a 16-week open-label period (Part III). The aim of the study was to assess efficacy, safety, and tolerability of canakinumab (150 mg or 2 mg/kg every 8 weeks) in patients with CAPS.

− Part I: A complete clinical and biomarker response to canakinumab (defined as composite of physician's global assessment on autoinflammatory and on skin disease

− Part II: In the withdrawal period of the pivotal study, the primary endpoint was defined as the proportion of patients with a disease relapse/flare: none (0%) of the patients randomised to canakinumab flared, compared with 81% of the patients randomised to placebo.

− Part III: Patients treated with placebo in Part II who flared regained and maintained clinical and serological response following entry into the open-label canakinumab extension.

Table 2 Tabulated summary of efficacy in Phase III trial, pivotal placebo-controlled withdrawal period (Part II)

Phase III trial, pivotal placebo-controlled withdrawal period (Part II)
	Canakinumab n=15	Placebo n=16	p-value
Primary endpoint (flare)
Proportion of patients with disease flare in Part II	0 (0%)	13 (81%)	< 0.001
Inflammatory markers*
C-reactive protein, mg/l	1.10 (0.40)	19.93 (10.50)	< 0.001
Serum amyloid A, mg/l	2.27 (-0.20)	71.09 (14.35)	0.002
* mean (median) change from beginning of Part II

Sustained efficacy for more than 3 years was observed for the initial four patients with continued administration of canakinumab.

No antibodies to canakinumab have been detected in CAPS patients treated with canakinumab.

Paediatric population

The CAPS trials with canakinumab included a total of 23 paediatric patients with an age range from 4 to 17 years (approximately half of them treated on an mg/kg basis). Overall, the efficacy, safety and tolerability profile of canakinumab in paediatric patients was comparable to adult patients.

The European Medicines Agency has deferred the obligation to submit the results of studies with Ilaris in one or more subsets of the paediatric population in Cryopyrin Associated Periodic Syndromes (CAPS). See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic Properties

The peak serum canakinumab concentration (C_max) occurred approximately 7 days following single subcutaneous administration of 150 mg in adult CAPS patients. The mean terminal half-life was 26 days. Based on a population pharmacokinetic analysis, the absolute bioavailability of subcutaneous canakinumab was estimated to be 70%. The clearance (CL) and distribution volume (V_ss) of canakinumab varied according to body weight and were estimated to be 0.174 l/day and 6.01 litres, respectively, in a typical CAPS patient of body weight 70 kg. The expected accumulation ratio was 1.3-fold following 6 months of subcutaneous administration of 150 mg canakinumab every 8 weeks. Exposure parameters (such as AUC and C_max) increased in proportion to dose over the dose range of 0.30 to 10.0 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection. There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender or age-related pharmacokinetic differences were observed after correction for body weight.

Paediatric population

Peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of canakinumab 150 mg or 2 mg/kg in paediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on cross-reactivity, repeated dose, immunotoxicity, reproductive and juvenile toxicity studies performed with canakinumab or a murine anti-murine IL-1 beta antibody.

Since canakinumab binds to marmoset (C. jacchus) and human IL-1 beta with a similar affinity, the safety of canakinumab has been studied in the marmoset. No undesirable effects of canakinumab were seen following twice weekly administration to marmosets for up to 26 weeks or in an embryofoetal developmental toxicity study in pregnant marmosets, at exposure in excess of human clinical levels. In addition, no antibodies to canakinumab were detected in these studies. No non-specific tissue cross-reactivity was demonstrated when canakinumab was applied to normal human tissues.

Formal carcinogenicity studies have not been conducted with canakinumab.

In an embryofoetal development study in marmosets canakinumab showed no maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis.

No undesirable effects of a murine anti-murine IL-1 beta antibody were seen in a complete set of reproductive and juvenile studies in mice. Anti-murine IL-1 beta did not elicit adverse events on foetal or neonatal growth when administered throughout late gestation, delivery and nursing (see section 4.6). The high dose used in these studies was in excess of the maximally effective dose in terms of IL-1 beta suppression and activity.

An immunotoxicology study in mice with a murine anti-murine IL-1 beta antibody showed that neutralising IL-1 beta has no effects on immune parameters and caused no impairment of immune function in mice.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sucrose

Histidine

Histidine hydrochloride monohydrate

Polysorbate 80

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

36 months

After reconstitution, from a microbiological point of view, the product should be used immediately. 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°C - 8°C.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

150 mg of powder for solution for injection in a vial (type I glass) with a stopper (coated chlorobutyl rubber) and flip-off cap (aluminium).

Packs containing 1 vial or multipacks containing 4 (4x1) vials.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Instructions for reconstitution

Using aseptic technique, reconstitute each vial of Ilaris at room temperature by slowly injecting 1.0 ml water for injections with a 1 ml syringe and an 18 G x 2 inch (50 mm) needle. Swirl the vial slowly at an angle of about 45° for approximately 1 minute and allow to stand for about 5 minutes. Then gently turn the vial upside down and back again ten times. If possible, avoid touching the rubber stopper with your fingers. Allow to stand for about 15 minutes at room temperature to obtain a clear to opalescent solution. Do not shake. Do not use if particles are present in the solution.

Tap the side of the vial to remove any residual liquid from the stopper. The solution should be free of visible particles and clear to opalescent. The solution should be colourless or may have a slight brownish-yellow tint. If the solution has a distinctly brown discolouration it should not be used. If not used immediately after reconstitution, the solution should be kept at 2°C to 8°C and used within 24 hours.

Instructions for administration

Carefully withdraw the required volume depending on the dose to be administered (0.2 ml to 1.0 ml) and subcutaneously inject using a 27 G x 0.5 inch (13 mm) needle.

The following are suitable injection sites: upper thigh, abdomen, upper arm or buttocks. Broken skin and areas which are bruised or covered by a rash should be avoided. Injection into scar-tissue should be avoided as this may result in insufficient exposure to Ilaris.

Ilaris vials are for single use only.

Disposal

Patients or their caregivers should be instructed on the appropriate procedure for disposal of the vials, syringes and needles in accordance with local requirements.

7. Marketing Authorisation Holder

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/09/564/001-002

9. Date Of First Authorisation/Renewal Of The Authorisation

23.10.2009

10. Date Of Revision Of The Text

16.09.2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

LEGAL CATEGORY

POM

Iglu Gel

1. Name Of The Medicinal Product

IGLÜ^® GEL

2. Qualitative And Quantitative Composition

Lidocaine Hydrochloride 0.66% w/w; Aminoacridine Hydrochloride 0.05% w/w.

For excipients, see section List of Excipients.

3. Pharmaceutical Form

Soft, pale yellow, slightly opalescent oromucosal gel.

4. Clinical Particulars

4.1 Therapeutic Indications

For fast, effective relief from the pain of common mouth ulcers, soreness of gums and denture rubbing.

4.2 Posology And Method Of Administration

For use in the mouth.

For adults, the elderly and children over 7 years old.

Apply sparingly, directly to the affected area(s) with a clean finger tip or a cotton wool bud. Re-apply as necessary – the aim being to keep the affected area(s) protected with a thin layer of gel. As a guide, each application should normally last for an hour or more, although eating and/or drinking may necessitate more frequent re-application. In some cases, applications may remain in place for several hours.

4.3 Contraindications

Do not use in cases of known sensitivity to lidocaine hydrochloride (or other local anaesthetics of the amide-type), aminoacridine hydrochloride or any of the other ingredients.

4.4 Special Warnings And Precautions For Use

Keep Iglü Gel away from the eyes. In case of accidental contact, wash eye immediately with water: keep rinsing for 10 to 15 minutes, holding the eyelids well apart and avoid getting the rinse liquid into the other eye. Consult a doctor if irritation persists.

If symptoms persist consult your doctor or dentist.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

Animal studies are insufficient with respect to effects on pregnancy and lactation (see section Preclinical Safety Data). The potential risk for humans is unknown.

Caution should therefore be exercised before recommending this treatment for use during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Rare instances of hypersensitivity reactions to lidocaine and aminoacridine have been reported.

4.9 Overdose

Overdosage is unlikely to be a problem because of the low formulated concentrations. Severe overdosage (e.g. if a large quantity is swallowed) may impair swallowing and this enhances the risk of aspiration. Likewise, generalised numbness of the tongue or buccal membranes may lead to biting trauma when eating. Systemic adverse reactions to excessive overdosage include excitory and depressant effects on the CNS and depressant cardiovascular reactions. Emergency treatment of such systemic side effects should be directed to assuring adequate ventilation and averting convulsions. In the meantime, use of this product should be discontinued.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Iglü Gel is strongly mucoadhesive, thereby localising the active ingredients in a depot over the site(s) of application and forming a physical barrier to protect the sensitive and delicate underlying lesion as it heals.

Applied topically to mucous membranes, lidocaine hydrochloride produces rapid, local and superficial anaesthesia which lasts for up to 30 minutes. Its mode of action is to prevent initiation of nerve impulses.

Aminoacridine hydrochloride acts as a broad spectrum antiseptic by disrupting microbial metabolic pathways.

5.2 Pharmacokinetic Properties

The active ingredients are readily absorbed through mucous membranes. Both are rapidly metabolised, even when swallowed. This, and the low doses involved, means that systemic effects are very unlikely.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in this SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Carbomer; Hydroxypropylcellulose; White Soft Paraffin; Liquid Paraffin; Peppermint Oil.

6.2 Incompatibilities

None encountered.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

8 g plastic tube and nozzle with polypropylene cap.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Diomed Developments Limited

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

00173/0186.

9. Date Of First Authorisation/Renewal Of The Authorisation

7 March 2001.

10. Date Of Revision Of The Text

August 2010.