SINGULAIR PAEDIATRIC 4 mg GRANULES

SINGULAIR Paediatric 4 mg Granules

montelukast

Read all of this leaflet carefully before your child starts 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 your child. Do not pass it on to others. It may harm them, even if their symptoms are the same as your child’s.


• 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 SINGULAIR Paediatric is and what it is used for

2. Before SINGULAIR Paediatric is taken

3. How to take SINGULAIR Paediatric

4. Possible side effects

5. How to store SINGULAIR Paediatric

6. Further information

What SINGULAIR Paediatric is and what it is used for

SINGULAIR Paediatric is a leukotriene receptor antagonist that blocks substances called leukotrienes. Leukotrienes cause narrowing and swelling of airways in your lungs. By blocking leukotrienes, SINGULAIR Paediatric improves asthma symptoms and helps control asthma.

Your doctor has prescribed SINGULAIR Paediatric to treat your child’s asthma, preventing asthma symptoms during the day and night.

• SINGULAIR Paediatric is used for the treatment of 6 months to 5 year old patients who are not adequately controlled on their medication and need additional therapy.



• SINGULAIR Paediatric may also be used as an alternative treatment to inhaled corticosteroids for 2 to 5 year old patients who have not recently taken oral corticosteroids for their asthma and have shown that they are unable to use inhaled corticosteroids.



• SINGULAIR Paediatric also helps prevent the narrowing of airways triggered by exercise for patients 2 years of age and older.

Your doctor will determine how SINGULAIR Paediatric should be used depending on the symptoms and severity of your child's asthma.

What is asthma?

Asthma is a long-term disease.

Asthma includes:

• difficulty breathing because of narrowed airways. This narrowing of airways worsens and improves in response to various conditions.


• sensitive airways that react to many things, such as cigarette smoke, pollen, cold air, or exercise.


• swelling (inflammation) in the lining of the airways.

Symptoms of asthma include: Coughing, wheezing, and chest tightness.

Before SINGULAIR Paediatric is taken

Tell your doctor about any medical problems or allergies your child has now or has had.

Do not give SINGULAIR Paediatric to your child if he/she

• is allergic (hypersensitive) to montelukast or any of the other ingredients of SINGULAIR Paediatric (see 6. Further information).

Take special care with SINGULAIR Paediatric

• If your child’s asthma or breathing gets worse, tell your doctor immediately.



• Oral SINGULAIR Paediatric is not meant to treat acute asthma attacks. If an attack occurs, follow the instructions your doctor has given you for your child. Always have your child’s inhaled rescue medicine for asthma attacks with you.



• It is important that your child take all asthma medications prescribed by your doctor. SINGULAIR Paediatric should not be used instead of other asthma medications your doctor has prescribed for your child.



• If your child is on anti-asthma medicines, be aware that if he/she develops a combination of symptoms such as flu-like illness, pins and needles or numbness of arms or legs, worsening of pulmonary symptoms, and/or rash, you should consult your doctor.



• Your child should not take acetyl-salicylic acid (aspirin) or anti-inflammatory medicines (also known as non-steroidal anti-inflammatory drugs or NSAIDs) if they make his/her asthma worse.

Taking other medicines

Some medicines may affect how SINGULAIR Paediatric works, or SINGULAIR Paediatric may affect how your child's other medicines work.

Please tell your doctor or pharmacist if your child is taking or has recently taken other medicines, including those obtained without a prescription.

Tell your doctor if your child is taking the following medicines before starting SINGULAIR Paediatric:

• phenobarbital (used for treatment of epilepsy)


• phenytoin (used for treatment of epilepsy)


• rifampicin (used to treat tuberculosis and some other infections)

Taking SINGULAIR Paediatric with food and drink

SINGULAIR Paediatric granules can be taken without regard to the timing of food intake.

Pregnancy and breast-feeding

This subsection is not applicable for the SINGULAIR Paediatric 4 mg granules since they are intended for use in children 6 months to 5 years of age, however the following information is relevant to the active ingredient, montelukast.

Use in pregnancy

Women who are pregnant or intend to become pregnant should consult their doctor before taking SINGULAIR. Your doctor will assess whether you can take SINGULAIR during this time.

Use in breast-feeding

It is not known if SINGULAIR appears in breast milk. You should consult your doctor before taking SINGULAIR if you are breast-feeding or intend to breast-feed.

Driving and using machines

This subsection is not applicable for the SINGULAIR Paediatric 4 mg granules since they are intended for use in children 6 months to 5 years of age, however the following information is relevant to the active ingredient, montelukast.

SINGULAIR is not expected to affect your ability to drive a car or operate machinery. However, individual responses to medication may vary. Certain side effects (such as dizziness and drowsiness) that have been reported very rarely with SINGULAIR may affect some patients’ ability to drive or operate machinery.

How to take SINGULAIR Paediatric

• This medicine is to be given to a child under adult supervision. Your child should take SINGULAIR Paediatric every evening.


• It should be taken even when your child has no symptoms or if he/she has an acute asthma attack.


• Always have your child take SINGULAIR Paediatric as your doctor has told you. You should check with your child’s doctor or pharmacist if you are not sure.


• To be taken by mouth

For children 6 months to 5 years of age:

One sachet of SINGULAIR Paediatric 4 mg granules to be taken by mouth each evening.

If your child is taking SINGULAIR Paediatric, be sure that your child does not take any other products that contain the same active ingredient, montelukast.

For children 6 months to 2 years old, SINGULAIR Paediatric 4 mg granules are available.

For children 2 to 5 years old, SINGULAIR Paediatric 4 mg chewable tablets and SINGULAIR Paediatric 4 mg granules are available. The SINGULAIR Paediatric 4 mg granules formulation is not recommended below 6 months of age.

How should I give SINGULAIR Paediatric granules to my child?

• Do not open the sachet until ready to use.



• SINGULAIR Paediatric granules can be given either:
  
  
  • directly in the mouth;
  
  
  • OR mixed with a spoonful of cold or room temperature soft food (for example, applesauce, ice cream, carrots and rice).
  
  



• Mix all of the contents of the SINGULAIR Paediatric granules into a spoonful of cold or
  room temperature soft food, taking care to see that the entire dose is mixed with the food.



• Be sure the child is given the entire spoonful of the granule/food mixture immediately (within 15 minutes). IMPORTANT: Never store any granule/food mixture for use at a later time.



• SINGULAIR Paediatric granules are not intended to be dissolved in liquid. However, your child may take liquids after swallowing the SINGULAIR Paediatric granules.



• SINGULAIR Paediatric granules can be taken without regard to the timing of food intake.

If your child takes more SINGULAIR Paediatric than he/she should

Contact your child’s doctor immediately for advice.

There were no side effects reported in the majority of overdose reports. The most frequently occurring symptoms reported with overdose in adults and children included abdominal pain, sleepiness, thirst, headache, vomiting, and hyperactivity.

If you forget to give SINGULAIR Paediatric to your child

Try to give SINGULAIR Paediatric as prescribed. However, if your child misses a dose, just resume the usual schedule of one sachet once daily.

Do not give a double dose to make up for a forgotten dose.

If your child stops taking SINGULAIR Paediatric

SINGULAIR Paediatric can treat your child’s asthma only if he/she continues taking it.

It is important for your child to continue taking SINGULAIR Paediatric for as long as your doctor prescribes. It will help control your child’s asthma.

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

Possible side effects

Like all medicines, SINGULAIR Paediatric can cause side effects, although not everybody gets them.

In clinical studies with SINGULAIR Paediatric 4 mg granules, the most commonly reported side effects (occurring in at least 1 of 100 patients and less than 1 of 10 paediatric patients treated) thought to be related to SINGULAIR Paediatric were:

• diarrhoea


• hyperactivity


• asthma


• scaly and itchy skin


• rash

Additionally, the following side effects were reported in clinical studies with either SINGULAIR 10 mg film-coated tablets, SINGULAIR Paediatric 5 mg or 4 mg chewable tablets:

• abdominal pain


• headache


• thirst

These were usually mild and occurred at a greater frequency in patients treated with SINGULAIR than placebo (a pill containing no medication).

Additionally, while the medicine has been on the market, the following have been reported:

• upper respiratory infection


• increased bleeding tendency


• allergic reactions including rash, swelling of the face, lips, tongue, and/or throat which may cause difficulty in breathing or swallowing


• behaviour and mood related changes [dream abnormalities, including nightmares hallucinations, irritability, feeling anxious, restlessness, agitation including aggressive behaviour or hostility, tremor, depression, trouble sleeping, sleep walking, suicidal thoughts and actions (in very rare cases)]


• dizziness, drowsiness, pins and needles/numbness, seizure


• palpitations


• nosebleed


• diarrhoea , dry mouth, indigestion, nausea, vomiting


• hepatitis (inflammation of the liver)


• bruising, itching, hives, tender red lumps under the skin most commonly on your shins (erythema nodosum)


• joint or muscle pain, muscle cramps


• tiredness, feeling unwell, swelling, fever.

In asthmatic patients treated with montelukast, very rare cases of a combination of symptoms such as flu-like illness, pins and needles or numbness of arms and legs, worsening of pulmonary symptoms and/or rash (Churg-Strauss syndrome) have been reported. You must tell your doctor right away if your child gets one or more of these symptoms.

Ask your doctor or pharmacist for more information about side effects. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your child’s doctor or pharmacist.

How to store SINGULAIR Paediatric

• Keep out of the reach and sight of children.


• Do not use this medicine after the date shown by the six numbers following EXP on the sachet. The first two numbers indicate the month; the last four numbers indicate the year. This medicine expires at the end of the month shown.


• Store in the original package in order to protect from light and moisture.


• 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 SINGULAIR Paediatric contains

• The active substance is montelukast. Each sachet of granules contains montelukast sodium which corresponds to 4 mg of montelukast.


• The other ingredients are: Mannitol, hyprolose (E 463), and magnesium stearate.

What SINGULAIR Paediatric looks like and contents of the pack

SINGULAIR Paediatric 4 mg granules are white granules.

Cartons of 7, 20, 28 and 30 sachets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

The Manufacturer is

Merck Sharp & Dohme BV

Waarderweg 39

PO Box 581

2003 PC Haarlem

The Netherlands

Information is given by

In UK:

Asthma UK

Providence House

Providence Place

London

N1 ONT

Alternatively phone the Asthma UK Adviceline on 08457 010203, Monday to Friday 9 am to 5 pm, calls charged at local rate.

In Ireland:

The Asthma Society of Ireland

Eden House

15-17 Eden Quay

Dublin 1

Alternatively phone The Asthma Live Line on 01 8788122, Monday, Wednesday, Thursday 10am to 1pm, or 01 8788511 9am to 5pm, or The Asthma Line on callsave 1850 44 5464.

(The Asthma UK and The Asthma Society of Ireland are independent charities working to conquer asthma and are not associated with Merck Sharp & Dohme Limited.)

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

Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxemburg, Malta, Netheralnds, Norway, Poland, Portugal, Romania, Slovenia, Slovak Republic, Spain, Sweden, United Kingdom:

SINGULAIR

This leaflet was last approved in June 2010

denotes registered trademark of

Merck Sharp & Dohme Corp.

a subsidiary of Merck & Co., Inc.

Whitehouse Station

NJ

USA

© Merck Sharp & Dohme Limited 2010. All rights reserved.

PIL.SGA-OG-4mg.09.UK.3072.II-051

Syprol Oral Solution 50mg / 5ml

1. Name Of The Medicinal Product

Propranolol Hydrochloride 50mg/5ml Oral Solution

Syprol 50mg/5ml

2. Qualitative And Quantitative Composition

Propranolol Hydrochloride 50mg/5ml.

3. Pharmaceutical Form

Oral Solution

A clear bright orange liquid with odour of orange/tangerine.

4. Clinical Particulars

4.1 Therapeutic Indications

Propranolol is indicated in:

- the control of hypertension

- the management of angina pectoris

- the long term prophylaxis against reinfarction after recovery from acute myocardial infarction

- the control of most forms of cardiac arrhythmia

- the prophylaxis of migraine

- the management of essential tremor

- relief of situational anxiety and generalised anxiety symptoms, particularly those of the somatic type

- prophylaxis of upper gastro-intestinal bleeding in patients with portal hypertension and oesophageal varices

- the adjunctive management of thyrotoxicosis and thyrotoxic crisis

- management of hypertrophic obstructive cardiomyopathy

- management of phaeochromocytoma perioperatively (with an alpha-adrenoceptor blocking drug).

4.2 Posology And Method Of Administration

For oral administration only.

Adults:

Hypertension – A starting dose of 80mg twice a day may be increased at weekly intervals according to response. The usual dose range is 160 – 320mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.

Angina, migraine and essential tremor – A starting dose of 40mg two or three times daily may be increased by the same amount at weekly intervals according to patient response. An adequate response in migraine and essential tremor is usually seen in the range 80-160mg/day and in angina in the range 120-240mg/day.

Situational and generalised anxiety – A dose of 40mg daily may provide short term relief of acute situational anxiety. Generalised anxiety, requiring longer term therapy, usually responds adequately to 40mg twice daily which, in individual cases, may be increased to 40mg three times daily. Treatment should be continued according to response. Patients should be reviewed after six to twelve months treatment.

Arrhythmias, anxiety, tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis – A dosage range of 10-40mg three or four times a day usually achieves the required response.

Post myocardial infarction - Treatment should start between days 5 and 21 after myocardial infarction with an initial dose of 40mg four times a day for 2 or 3 days. In order to improve compliance the total daily dosage may thereafter be given as 80mg twice daily.

Portal hypertension:

Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Dosage should begin with 40mg twice daily, increasing to 80mg twice daily depending on heart rate response. If necessary, the dose may be increased incrementally to a maximum of 160mg twice daily.

Phaeochromocytoma (Used only with an alpha-receptor blocking drug)- Pre-operative: 60mg daily for three days is recommended. Non-operable malignant cases: 30mg daily.

Children

Arrhythmias, phaeochromocytoma, thyrotoxicosis – Dosage should be individually determined and the following is only a guide: 250 – 500 micrograms per Kilogram three or four times daily as required.

Migraine

– Under the age of 12: 20mg two or three times daily Over the age of 12: the adult dose

Fallot's tetralogy – The value of propranolol in this condition is confined mainly to the relief of right-ventricular outflow tract shut-down. It is also useful for treatment of associated arrhythmias and angina. Dosage should be individually determined and the following is only a guide: Up to 1mg/Kg repeated three or four times a day as required..

Elderly

With regard to the elderly the optimum dose should be individually determined according to the clinical response.

4.3 Contraindications

Propranolol must not be used if there is a history of bronchial asthma or bronchospasm.

The product label states the following warning: “Do not take propranolol if you have a history of asthma or wheezing”. A similar warning appears in the patient information leaflet.

Bronchospasm can usually be reversed by beta₂-agonist bronchodilators such as salbutamol. Large doses of the beta₂-agonist bronchodilator may be required to overcome the beta-blockade produced by propranolol and the dose should be titrated according to the clinical response; both intravenous and inhalational administration should be considered. The use of intravenous aminophylline and/or the use of ipratropium (given by nebuliser) may also be considered. Glucagon (1 to 2mg given intravenously) has also been reported to produce a bronchodilator effect in asthmatic patients. Oxygen or artificial ventilation may be required in severe cases.

Propranolol as with other beta-adrenoceptor blocking drugs must not be used in patients with any of the following:

hypersensitivity to propranolol hydrochloride or any of the ingredients; the presence of second or third degree heart block; in cardiogenic shock; metabolic acidosis; after prolonged fasting; bradycardia; hypotension; severe peripheral arterial circulatory disturbances; sick sinus syndrome; untreated phaeochromocytoma; uncontrolled heart failure or Prinzmetal's angina.

Propranolol must not be used in patients prone to hypoglycaemia, i.e., patients after prolonged fasting or patients with restricted counter-regulatory reserves. Patients with restricted counter-regulatory reserves may have reduced autonomic and hormonal responses to hypoglycaemia which includes glycogenolysis, gluconeogenesis and /or impaired modulation of insulin secretion. Patients at risk for an inadequate response to hypoglycaemia includes individuals with malnutrition, prolonged fasting, starvation, chronic liver disease, diabetes and concomitant use of drugs which block the full response to catecholamines.

4.4 Special Warnings And Precautions For Use

Although contra-indicated in uncontrolled heart failure, propranolol may be used where the signs of heart failure have been controlled by the use of appropriate concomitant medication. Propranolol should be used with caution in patients whose cardiac reserve is poor.

Treatment should not be discontinued abruptly in patients with ischaemic heart disease. Either the equivalent dose of another beta-adrenoceptor blocking drug may be substituted or the withdrawal of propranolol should be gradual.

Propranolol should not be used in combination with calcium channel blockers with negative inotropic effects (e.g. verapamil, diltiazem), as it can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

Propranolol may block/modify the signs and symptoms of hypoglycaemia (especially tachycardia). Propranolol occasionally causes hypoglycaemia, even in non-diabetic patients, e.g., neonates, infants, children, elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with propranolol has rarely presented with seizures and/or coma in isolated patients. Caution must be exercised in the concurrent use of propranolol and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin (see section 4.3).

When a patient is scheduled for surgery and a decision is made to discontinue beta-blocker therapy, this should be done at least 24 hours prior to the procedure. The risk/benefit of stopping beta blockade should be made for each patient

Propranolol should not be used in untreated phaeochromocytoma. However, in patients with phaeochromocytoma, an alpha-blocker may be given concomitantly.

Although contra-indicated in severe peripheral arterial circulatory disturbances, propranolol may also aggravate less severe peripheral arterial circulatory disturbances.

One of the pharmacological actions of propranolol is to reduce the heart rate. Therefore the dosage should be reduced in those rare cases where symptoms are attributable to a slow heart rate.

Due to propranolol having a negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.

Since the half life may be increased in patients with significant hepatic or renal impairment, caution must be exercised when starting treatment and selecting the initial dose.

In patients with portal hypertension, liver function may deteriorate and hepatic encephalopathy may develop. There have been reports suggesting that treatment with propranolol may increase the risk of developing hepatic encephalopathy.

Propranolol may cause a more severe reaction to a variety of allergens, when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.

Propranolol may mask the signs of thyrotoxicosis.

Propranolol must be used with caution in patients with decompensated cirrhosis.

Laboratory Tests: Propranolol has been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using fluorescence.

Excipient Warnings

This product contains parahydroxybenzoates which may cause allergic reactions (possibly delayed)

This product also contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

In addition, this product contains Sunset Yellow (E110) which may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Hypoglycaemic agents: Tachycardia associated with hypoglycaemia may be modified by propranolol. Use of propranolol alongside hypoglycaemic therapy in diabetic patients should be with caution since it may prolong the hypoglycaemic response to insulin.

Clonidine: Caution should be exercised when transferring patients from clonidine to beta-adrenoceptor blocking drugs. If propranolol and clonidine are given concurrently, clonidine should not be discontinued until several days after the withdrawal of the beta blocker. If replacing clonidine by beta-adrenoceptor blocking drug therapy, the introduction of the beta-adrenoceptor blocking drugs should be delayed for several days after clonidine administration has stopped.

Anti-arrhythmics: Care should be taken when prescribing a beta-adrenergic blocking drug with Class 1 anti-arrhythmic agents such as disopyramide. Flecainaide may have additive cardiac depressant effects.

Calcium Channel Blockers: Combined use of beta-adrenoceptor blocking drugs and calcium channel blockers with negative inotropic effects (eg, verapamil, diltiazem) can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither drug should be administered intravenously within 48 hours of discontinuing the other.

Concomitant therapy with dihydropyridine calcium channel blockers eg, nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Drugs with hypotensive effects: Dynamic interactions between propranolol and other drugs with hypotensive effects are to be expected. Reactions are sometimes severe and careful monitoring is advised in co-administration of propranolol with other drugs including ACE inhibitors, diuretics, angiotensin II receptor antagonists, vasodilator antihypertensives, diazoxide, adrenergic neurone blockers, alpha blockers, moxisylyte, moxonidine, nitrates and methyldopa.

Anaesthesia: Caution must be exercised when using anaesthetic agents with propranolol. The anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible. Use of beta-adrenoceptor blocking drugs with anaesthetic drugs may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.

Neostigmine and other anticholinesterases: Propranolol reduces the efficacy of these compounds in treatment of myasthenia gravis.

Sympathomimetic Agents and Parenteral Adrenaline: Concomitant use of sympathomimetic agents e.g. adrenaline, may counteract the effect of beta-adrenoceptor blocking drugs. Caution should be taken in the parenteral administration of preparations containing adrenaline to people taking beta-adrenoceptor blocking drugs as, in rare cases, vasoconstriction, hypertension and bradycardia may result.

Muscle relaxants (e.g. balcofen): Concomitant use may result in a fall in blood pressure. Tizanidine may also result in bradycardia.

Antidepressants, anxiolytics and hypnotics: Plasma levels of propranolol can be increased by fluvoxamine. Anxiolytics, hypnotics and MAOIs when given with propranolol may have an enhanced hypotensive effect. Propranolol may increase plasma concentration of imipramine. Barbiturates may reduce the plasma concentration of propranolol.

Corticosteroids: Can antagonise the effects of beta-blockers.

Dihydropyridines: Concomitant therapy with dihydropyridines e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Digitalis Glycosides: These preparations in association with beta-adrenoceptor blocking drugs, may increase atrio-ventricular conduction time.

Lignocaine: Administration of propranolol during infusion of lignocaine may increase the plasma concentration of lignocaine by approximately 30%. Patients already receiving propranolol tend to have higher lignocaine levels than controls. The combination should be avoided.

Ergotamine: Caution should be exercised if ergotamine, dihydroergotamine or related compounds are given in combination with propranolol since vasospastic reactions have been reported in a few patients.

Prostaglandin Synthetase Inhibiting Drugs: Concomitant use of these e.g. ibuprofen or indomethacin, may decrease the hypotensive effects of propranolol.

Chlorpromazine: Concomitant administration with propranolol may result in an increase in plasma levels of both drugs. This may lead to an enhanced antipsychotic effect for chlorpromazine and an increased antihypertensive effect for propranolol.

Mefolquine: May lead to an increased risk of bradycardia.

Cimetidine, hydralazine, alcohol: Concomitant use of cimetidine and hydralazine will increase, whereas concomitant use of alcohol will decrease, the plasma level of propranolol.

Dopaminergics (e.g. Levodopa), Aldesleukin, Prostaglandins (alprostadil): May have an enhanced hypotensive effect when used concomitantly with propranolol.

Oestrogens: May antagonise the hypotensive effect of propranolol.

5HT₁ agonists: Propranolol may increase plasma concentrations of rizatriptan.

Pharmacokinetic studies have shown that the following agents may interact with propranolol due to effects on enzyme systems in the liver which metabolise propranolol and these agents: quinidine, propafenone, rifampicin, theophylline, warfarin, thioridazine and dihydropyridine calcium channel blockers such as nifedipine, nisoldipine, nicardipine, isradipine and lacidipine. Owing to the fact that blood concentrations of either agent may be affected, dosage adjustments may be needed according to clinical judgement. (See also the interaction above concerning the concomitant therapy with dihydropyridine calcium channel blockers).

4.6 Pregnancy And Lactation

As with all drugs, propranolol should not be given in pregnancy unless absolutely essential. There is no evidence of teratogenicity with propranolol. However, beta adrenoceptor blocking agents reduce placenta perfusion, which may result in intra-uterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia in the neonate and bradycardia in the foetus) may occur. There is an increased risk of cardiac and pulmonary complications in the neonate in the post-natal period.

Most beta-adrenoceptor blocking drugs particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of these compounds.

4.7 Effects On Ability To Drive And Use Machines

Use is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur.

4.8 Undesirable Effects

Propranolol is usually well tolerated, however, listed below are the side effects that may occur:-

Cardiovascular: Bradycardia, heart failure deterioration, postural hypotension which may be associated with syncope, heart block and congestive cardiac failure, exacerbation of claudication, cold extremities, Raynaud's phenomenon.

Respiratory: Bronchospasm (especially in patients with a history of asthma), sometimes with fatal outcome (see Section 4.3).

Neurological and CNS: Confusion, dizziness, mood changes, nightmares, psychoses and hallucinations, sleep disturbances, paraesthesia especially of the hands.

Haematological: Purpura, thrombocytopenia.

Endocrine: Hypoglycaemia in neonates, infants, children, , elderly patients, patients on haemodialysis, patients on concomitant antidiabetic therapy, patients with prolonged fasting and patients with chronic liver disease has been reported (see section 4.3, 4.4 and 4.5). The frequency of hypoglycaemia is not known. Seizures have been linked to hypoglycaemia.

Gastro-intestinal: Gastro-intestinal disturbance, nausea, diarrhoea.

Integumentary: Alopecia, dry eyes, psoriasiform skin reactions and exacerbation of psoriasis, skin rashes.

Senses: Visual disturbances.

Others: Muscle fatigue, lassitude, insomnia, an increase in ANA (antinuclear antibodies) although the clinical relevance of this has not been established. Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported in patients administered propranolol.

If these effects occur, thought should be given to withdrawing the drug. However, it should be withdrawn gradually.

Bradycardia and hypotension are usually a sign of overdosage but may be rarely linked to intolerance. If this occurs the drug should be withdrawn and overdosage treatment initiated.

4.9 Overdose

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

General treatment should include: close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Excessive bradycardia can be countered with atropine 1-2mg intravenously and/or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10mg/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta-adrenoceptor stimulant such as dobutamine 2.5 to 10 micrograms/Kg/minute by intravenous infusion may be given. Dobutamine, because of its positive inotropic effect could also be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta-blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Propranolol is a competitive antagonist at both beta₁ and beta₂-adrenoceptors.

It has no agonist activity at the beta-adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1-3mg/litre, though such concentrations are rarely achieved during oral therapy. Competitive beta-adrenoceptor blockade has been demonstrated in man by a parallel shift to the right in the dose-heart rate response curve to beta-agonists such as isoprenaline.

Propranolol, as with other beta-adrenoceptor blocking drugs, has negative inotropic effects, and is therefore contra-indicated in uncontrolled heart failure.

Propranolol is a racemic mixture and the active form is the S(-) isomer. With the exception of inhibition of the conversion of thyroxine to triiodothyronine it is unlikely that any additional ancillary properties possessed by R(+) propranolol, in comparison with the racemic mixture will give rise to different therapeutic effects.

Propranolol is effective and well tolerated in most ethnic populations, although the response may be less in black patients.

5.2 Pharmacokinetic Properties

Following intravenous administration, the plasma half-life of propranolol is about 2 hours and the ratio of metabolites to parent drug in the blood is lower than after oral administration. In particular, 4-hydroxypropranolol is not present after intravenous administration.

Propranolol is completely absorbed after oral administration and peak plasma concentrations occur 1-2 hours after dosing in fasting patients. The liver removes up to 90% of an oral dose with an elimination half-life of 3 to 6 hours. Propranolol is widely and rapidly distributed throughout the body with highest levels occurring in the lungs, liver, kidney, brain and heart.

Propranolol is highly protein bound (80-95%).

5.3 Preclinical Safety Data

Propranolol is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid monohydrate, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene glycol, liquid maltitol, sunset yellow E110, orange/tangerine flavour (including ethanol (0.12%v/v) and butylhydroxyanisol E320) and purified water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months unopened

3 months opened.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature And Contents Of Container

Amber (Type III) glass bottles
Closures:-	a) Aluminium, EPE wadded, roll-on pilfer-proof screw cap. b) HDPE, EPE wadded, tamper evident screw cap. c) HDPE, EPE wadded, tamper evident, child resistant closure.

Pack Size: 150ml

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK.

8. Marketing Authorisation Number(S)

PL 00427/0124

9. Date Of First Authorisation/Renewal Of The Authorisation

11^th December 2000, Renewal 30^th August 2006

10. Date Of Revision Of The Text

8^th September 2011

11. LEGAL CATEGORY

POM

Synacthen Depot

Synacthen Depot Ampoules 1mg/ml

tetracosactide acetate

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

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



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



• 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.

The information in this leaflet has been divided into the following sections:

• 1. What Synacthen Depot is and what it is used for


• 2. Check before you receive Synacthen Depot


• 3. How Synacthen Depot is given to you


• 4. Possible side effects


• 5. How to store Synacthen Depot


• 6. Further information

What Synacthen Depot is and what it is used for

Synacthen Depot belongs to a group of medicines called pituitary hormones.

The pituitary gland is a small gland inside the brain which controls many other glands in the body, including the thyroid and adrenal glands. The pituitary gland produces hormones which send chemical messages to various parts of the body and affect many bodily functions such as blood pressure, blood sugar levels, growth and menstrual cycle.

The adrenal glands are found on top of the kidneys and make the body’s natural steroids which can affect blood pressure and the way the body handles the sugars, protein and fats absorbed from food. They also make adrenaline which controls the body’s response to different types of stress.

Synacthen Depot is similar to the hormone that the pituitary gland normally produces (called ACTH) to make the adrenal glands produce certain steroids. When Synacthen depot is injected it works on the adrenal glands by ‘telling’ them to produce more steroids.

Synacthen Depot is used in place of medicines like prednisolone or cortisone (types of steroids) to treat a number of different conditions, including ulcerative colitis, Crohn's disease and rheumatoid arthritis. It is usually only given for a
short time.

Synacthen Depot is also used as a test to find out if the pituitary and adrenal glands are working normally.

Check before you receive Synacthen Depot

You should not be given Synacthen Depot if:

• you are allergic (hypersensitive) to adrenocorticotropic hormone (ACTH), tetracosactide acetate or any of the ingredients of Synacthen Depot (see Section 6 Further information)



• you suffer from any allergies, including allergies to any medicines



• you suffer from any serious mood or mental health disorders



• you have or have you ever had TB (tuberculosis)



• you have currently got any infections



• you suffer from any known hormone problems, e.g. Cushing’s syndrome or Addison’s disease (over or under active adrenal glands)



• you have an ulcer in your stomach or small intestine



• you suffer from any serious heart disease



• you suffer from asthma



• you are pregnant, trying to become pregnant, or breast-feeding.

Synacthen Depot is not for use in children under 3 years of age.

If any of the above applies to you, or if you are not sure, speak to your doctor or pharmacist before you are given Synacthen Depot.

Take special care with Synacthen Depot

Before you are given Synacthen Depot tell your doctor if:

• you have been vaccinated recently or are planning to have a vaccination



• your immune system is not working properly



• you have any disorder of the intestines, e.g. ulcerative colitis, diverticulitis



• you have recently had surgery on your intestines (bowel)



• you suffer from high blood pressure



• you have suffered from a blood clot in the past



• you suffer from any serious liver or kidney disease



• you suffer from osteoporosis (thinning of the bones)



• you suffer from myasthenia gravis (an illness causing muscle weakness)



• you have an under active thyroid gland which can cause tiredness or weight gain.

If any of the above applies to you, or if you are not sure, speak to your doctor before you are given Synacthen Depot.

Taking other medicines

Tell your doctor or pharmacist if you are taking/using or have recently taken/used any of the following medicines as they may interfere with Synacthen Depot:

• medicines to control high blood pressure


• medicines to control diabetes.

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

Taking with food and drink

Since Synacthen Depot can cause salt and water retention, your doctor may advise a low-salt diet during treatment.

Pregnancy and breast-feeding

You should not receive Synacthen Depot if you are pregnant, trying to become pregnant or breast-feeding.

Driving and using machines

If you feel dizzy or get blurred vision after you have been given Synacthen Depot, do not drive or operate machinery until these effects have worn off.

Important information about some of the ingredients of Synacthen Depot

Synacthen Depot contains benzyl alcohol. Benzyl alcohol can cause toxic reactions and allergic reactions in children less than 3 years old.

Synacthen Depot is essentially ‘sodium-free’ - it contains less than 1 mmol sodium (23 mg) per 1mg.

How Synacthen Depot is given to you

Your treatment with Synacthen Depot will take place in a hospital, under the supervision of a doctor. The doctor will be monitoring your progress carefully during your treatment with Synacthen Depot.

Treatment with Synacthen Depot

Your doctor will decide on a suitable dose of Synacthen Depot depending on your condition. The liquid in the ampoule will be drawn up into a syringe and injected into a muscle by your doctor or nurse.

Adults including elderly patients will usually start treatment with 1mg once or twice daily for about three days. As your condition improves, this dose will then be reduced over a period of several weeks, to 0.5mg every two to three days or 1mg once a week.

Children aged 3 -12 years will be given a lower dose based on their age and weight. They will start with an injection every day. This will then be reduced to once every 2 to 8 days.

Your doctor may monitor growth or organise heart scans in children who are given this medicine for a long period of time.

Synacthen Depot is not suitable for children under three years of age.

Diagnostic Tests with Synacthen Depot

You will be given one, two or three injections followed by a number of blood tests.

What to do if you think you have received more Synacthen Depot than you should

As this medicine is given to you in hospital, it is very unlikely that an overdose will happen. If anyone receives this medicine by accident, tell the hospital accident and emergency department or a doctor immediately. Show any left over medicines or the empty packet to the doctor.

If you forget to take Synacthen Depot

As a doctor or nurse is giving you this medicine, you are unlikely to miss a dose.

If you have any worries, tell a doctor or nurse.

Synacthen Depot Side Effects

Do not worry. Like all medicines, Synacthen Depot can cause side effects, although not everyone gets them.

Very rarely, Synacthen Depot can cause an allergic reaction with skin irritation and swelling, faintness, wheezing or flushing. For this reason, you should be monitored carefully for 30 minutes after each injection. If you get a reaction like this when you are not under medical supervision, contact your doctor or nearest
hospital accident and emergency department immediately. Once you have had an allergic reaction like this, you should never be treated with Synacthen Depot or similar medicines again.

You are unlikely to get any of the following rare side effects but if you do, tell your doctor as soon as possible.

• menstrual (period) problems



• swelling of the face (moon face)



• increased thirst



• mood changes or fits



• decreased or blurred vision



• high blood pressure



• inflammation of the pancreas which causes severe stomach and back pain



• acne, other skin problems or unusual bruising



• muscle cramps or pain, muscle weakness



• pain in back, hips, arms, shoulders or legs



• heart problems which can cause shortness of breath or ankle swelling



• inflammation of the blood vessels (sometimes with a rash, arthritis or kidney failure)



• poor healing of wounds



• bleeding into the adrenal gland (small glands above the kidneys) which may result in sudden stomach or back pain, weakness, fainting, loss of appetite and feeling or actually being sick.

Other common side effects (that affect less than 1 person in 10) that may occur include:

• increased chance of infection



• abscess



• increase in the number of white blood cells which can cause bleeding, fever, infection or inflammation



• unusual increase in hair growth on body or face



• diabetes mellitus (increased sugar levels in your urine)



• fluid retention



• low levels of potassium which can cause muscle weakness, muscle twitching or abnormal heart beat or low levels of calcium which can cause muscle cramps, stomach cramps or spasms. Your doctor may want to take a blood test to measure your blood levels of potassium or calcium



• increased appetite



• headache



• protrusion of the eye-balls in their sockets



• glaucoma/blurred vision



• a feeling of dizziness or “spinning”



• blood clot



• blood in your stools



• blood in your urine



• blood in your vomit



• stomach pain or a bloated stomach



• inflammation of the gullet (food pipe)



• small, round, dark red spots on the skin



• bruising



• facial flushing



• darkening or lightening of skin colour



• increased sweating



• bone thinning and fractures of the bones



• ruptured tendon, the symptoms of which include severe pain, inability to use the affected arm or leg and rapid bruising at the site



• slowing of the rate of growth in children



• weight increase.

Very rare side effects include (that affect less than 1 person in 1000):

• long term use in children up to 5 years may cause changes to the heart.

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

How to store Synacthen Depot

Synacthen Depot will be stored in the hospital pharmacy.

Keep out of the reach and sight of children.

Do not use Synacthen Depot after the expiry date which is stated on the ampoule. The expiry date refers to the last day of that month after Exp/Lot.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist on how to dispose of medicines no longer required. These measures will help protect the environment.

Further information

What is in Synacthen Depot?

The active ingredient in this medicine is tetracosactide acetate.

The other ingredients are zinc chloride, sodium phosphate, benzyl alcohol (50 mg/5 ml), sodium chloride, sodium hydroxide and water.

What Synacthen Depot looks like and contents of the pack

Synacthen Depot comes in packs of 10 ampoules.

Marketing Authorisation Holder and Manufacturer

The product licence holder is:

Alliance Pharmaceuticals Ltd

Avonbridge House

Chippenham

Wiltshire

SN15 2BB

UK

Synacthen Depot is manufactured by

Nycomed Austria GmbH

St-Peter-Strasse 25

A-4020 Linz

Austria

The information in this leaflet applies only to Synacthen Depot. If you have any questions or you are not sure about anything, ask your doctor or a pharmacist.

This leaflet was last approved in:

26^th November 2008

Alliance, Alliance Pharmaceuticals and associated devices are registered Trademarks.

© Alliance Pharmaceuticals Ltd 2008.

SYNACTHEN is a registered trademark of Novartis Pharmaceuticals Limited and is used under licence by Alliance Pharmaceuticals Limited.

UK PIL 006 v5a

Saizen 3.33mg

1. Name Of The Medicinal Product

Saizen 3.33 mg powder and solvent for solution for injection

2. Qualitative And Quantitative Composition

Each vial of Saizen 3.33 mg contains somatropin* (recombinant human growth hormone).

*produced by recombinant DNA technology in mammalian cells

After reconstitution with the enclosed solvent, each vial shall contain

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection

Appearance of the powder: white lyophilised powder.

Appearance of the solvent: clear colourless solution.

The pH of the reconstituted solution is 7.4 - 8.5.

4. Clinical Particulars

4.1 Therapeutic Indications

Saizen is indicated in the treatment of:

Children:

	- Growth failure in children caused by decreased or absent secretion of endogenous growth hormone.
	- Growth failure in girls with gonadal dysgenesis (Turner Syndrome), confirmed by chromosomal analysis.
	- Growth failure in prepubertal children due to chronic renal failure (CRF).
	- Growth disturbance (current height SDS <-2.5 and parental adjusted height SDS <-1) in short children born small for gestational age (SGA) with a birth weight and/or length below -2 SD, who failed to show catch-up growth (HV SDS <0 during the last year) by 4 years of age or later.

Adults:

- Replacement therapy in adults with pronounced growth hormone deficiency as diagnosed by a single dynamic test for growth hormone deficiency. Patients must also fulfil the following criteria:

	- Childhood Onset: Patients who were diagnosed as growth hormone deficient during childhood, must be retested and their growth hormone deficiency confirmed before replacement therapy with Saizen is started.
	- Adult Onset: Patients must have growth hormone deficiency as a result of hypothalamic or pituitary disease and at least one other hormone deficiency diagnosed (except for prolactin) and adequate replacement therapy instituted, before replacement therapy using growth hormone may begin.

4.2 Posology And Method Of Administration

Benzyl alcohol as a preservative in bacteriostatic sodium chloride solution may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates. Saizen may be reconstituted with Sodium Chloride Injection BP or Sterile Water for Injections for immediate use when administering to children under 3 years of age.

Saizen 3.33 mg is intended for multiple dose use.

Saizen dosage should be individualised for each patient based on body surface area (BSA) or on body weight (BW).

It is recommended that Saizen be administered at bedtime according to the following dosage:

Children and adolescents:

	- Growth failure due to inadequate endogenous growth hormone secretion: 0.7-1.0 mg/m2 body surface area (BSA) per day or 0.025-0.035 mg/kg body weight (BW) per day by subcutaneous or intramuscular administration.
	- Growth failure in girls due to gonadal dysgenesis (Turner Syndrome) 1.4 mg/m2 body surface area (BSA) per day or 0.045-0.050 mg/kg body weight (BW) per day by subcutaneous administration.
	- Concomitant therapy with non-androgenic anabolic steroids in patients with Turner Syndrome can enhance the growth response.
	- Growth failure in prepubertal children due to chronic renal failure (CRF): 1.4 mg/m2 body surface area (BSA), approximately equal to 0.045-0.050 mg/kg body weight (BW), per day by subcutaneous administration.
	- Growth failure in short children born small for gestational age (SGA): The recommended daily dose is 0.035 mg/kg body weight (or 1 mg/m2/day, equal to 0.1 U/kg/day or 3 IU/m2/day) per day, by subcutaneous administration.
	Treatment should be discontinued when the patient has reached a satisfactory adult height, or the epiphyses are fused.
	For growth disturbance in short children born SGA, treatment is usually recommended until final height is reached. Treatment should be discontinued after the first year if height velocity SDS is below +1. Treatment should be discontinued when final height is reached (defined as height velocity <2 cm/year), and if confirmation is required if bone age is>14 years (girls) or>16 years (boys), corresponding to closure of the epiphyseal growth plates.

Adults:

- Growth Hormone Deficiency in adults: At the start of somatropin therapy, low doses of 0.15-0.3 mg are recommended, given as a daily subcutaneous injection. The dose should be adjusted stepwise, controlled by Insulin-like Growth Factor 1 (IGF-1) values. The recommended final GH dose seldom exceeds 1.0mg/day. In general the lowest efficacious dose should be administered. In older or overweight patients, lower doses may be necessary.

The powder for solution for injection should be used with the enclosed solvent for parenteral use. The reconstituted solution for injection should be clear with no particles. For instructions for preparation, please see section 6.6.

4.3 Contraindications

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

Somatropin should not be used for growth promotion in children with closed epiphyses.

Any evidence of active malignant tumours. Intracranial neoplasm must be inactive and antitumor therapy should be completed prior to institution of therapy.

Patients with acute critical illness suffering complications following open heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with somatropin.

In children with chronic renal disease, treatment with somatropin should be discontinued at renal transplantation.

4.4 Special Warnings And Precautions For Use

Treatment should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of patients with growth hormone deficiency.

Patients with an intra or extracranial neoplasia in remission who are receiving treatment with growth hormone should be examined carefully and at regular intervals by the physician.

Patients with growth hormone deficiency secondary to an intracranial tumour should be examined frequently for progression or recurrence of the underlying disease process.

Prader-Willi Syndrome

Saizen is not indicated for the long-term treatment of paediatric patients who have growth failure due to genetically confirmed Prader-Willi Syndrome, unless they also have a diagnosis of growth hormone deficiency. There have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone in paediatric patients with Prader-Willi Syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.

Leukaemia

Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposing factors.

Insulin sensitivity

Because somatropin may reduce insulin sensitivity , patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin containing product therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy.

Stable background retinopathy should not lead to discontinuation of somatropin replacement therapy. In case of development of preproliferative changes and the presence of proliferative retinopathy somatropin replacement therapy should be discontinued.

Thyroid function

Growth hormone increases the extra thyroid conversion of T4 to T3 and may, as such, unmask incipient hypothyroidism. Monitoring of thyroid function should therefore be conducted in all patients. In patients with hypopituitarism, standard replacement therapy must be closely monitored when somatropin therapy is administered.

Benign intracranial hypertension

In case of severe or recurrent headache, visual problems, nausea and/or vomiting, fundoscopy for papille oedema is recommended. If papille oedema is confirmed a diagnosis of benign intracranial hypertension (or pseudotumor cerebri) should be considered and if appropriate, Saizen treatment should be discontinued. At present there is insufficient evidence to guide clinical decision-making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary

Antibodies

As with all somatropin containing products, a small percentage of patients may develop antibodies to somatropin. The binding capacity of these antibodies is low and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

Slipped capital femoral epiphysis is often associated with endocrine disorders such as growth hormone deficiency and hypothyroidism, and with growth spurts. In children treated with growth hormone, slipped capital femoral epiphysis may either be due to underlying endocrine disorders or to the increased growth velocity caused by the treatment. Growth spurts may increase the risk of joint-related problems, the hip joint being under particular strain during the prepubertal growth spurt. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in children treated with Saizen.

Patients with growth failure due to chronic renal failure should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy and it is uncertain whether these problems are affected by growth hormone therapy. X-rays of the hip should be obtained prior to initiating therapy.

In children with chronic renal failure, renal function should have decreased to below 50% of normal before therapy is instituted. To verify the growth disturbance, growth should have been followed for a year before institution of therapy. Conservative treatment for renal insufficiency (which includes control of acidosis, hyperparathyroidism and nutritional status for one year prior to the treatment) should have been established and should be maintained during treatment. Treatment should be discontinued at the time of renal transplantation.

In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.

For SGA patients it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, increased body mass index, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.

For SGA patients it is recommended to measure IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I/IGFBP-3 ratio could be taken into account to consider dose adjustment.

Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty. Experience with SGA patients with Silver-Russel syndrome is limited.

Some of the height gain obtained with treating short children born SGA with somatropin may be lost if treatment is stopped before final height is reached.

Fluid retention is expected during growth hormone replacement therapy in adults.

In case of persistent oedema or severe paraesthesia the dosage should be decreased in order to avoid the development of carpal tunnel syndrome.

The injection site should be varied to prevent lipoatrophy.

Benzyl alcohol as a preservative in bacteriostatic sodium chloride solution may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates. Saizen may be reconstituted with Sodium Chloride Injection BP or Sterile Water for Injections for immediate use when administering to children under 3 years of age.

Growth Hormone Deficiency in the Adult is a lifelong condition and should be treated accordingly, however experience with patients over sixty years and experience with prolonged treatment is limited

In all patients developing acute critical illness, the possible benefit of treatment with somatropin must be weighed against the potential risk involved.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of somatropin containing products. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth hormone.

Data from an interaction study performed in growth hormone deficient adults, suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P 450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6 Pregnancy And Lactation

Pregnancy:

Animal studies are insufficient and/or animal data is not available with regard to effects on pregnancy, embryofoetal development, parturition or postnatal development (See section Preclinical safety data 5.3) No clinical data on exposed pregnancies are available. Therefore, somatropin containing products are not recommended during pregnancy and in woman of childbearing potential not using contraception

Lactation:

There have been no clinical studies conducted with somatropin in breast-feeding women. It is not known whether somatropin is excreted in human milk. Therefore caution should be exercised when somatropin is administered to breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

Somatropin-containing products have no influence on the ability to drive and use machines.

4.8 Undesirable Effects

Up to 10 % of patients may experience redness and itching at the site of injection, particularly when the subcutaneous route is used.

Fluid retention is expected during growth hormone replacement therapy in adults. Oedema, joint swelling, arthralgias, myalgias and paresthesias may be clinical manifestations of fluid retention. However, these symptoms / signs are usually transient and dose dependent.

Adult patients with growth hormone deficiency, following diagnosis of growth hormone deficiency in childhood, reported side-effects less frequently than those with adult onset growth hormone deficiency.

Antibodies to somatropin can form in some patients; the clinical significance of these antibodies is unknown, though to date the antibodies have been of low binding capacity and have not been associated with growth attenuation except in patients with gene deletions. In very rare instances, where short stature is due to deletion of the growth hormone gene complex, treatment with growth hormone may induce growth attenuating antibodies.

Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposing factors.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Common (	Uncommon (	Very rare (<1/10,000)	Frequency unknown
Nervous system disorders		Idiopathic intracranial hypertension (benign intracranial hypertension) Carpal tunnel syndrome		(Isolated) headache
Musculoskeletal and connective tissue disorders			Slipped capital femoral epiphysis (Epiphysiolysis capitis femoris), or avascular necrosis of the femoral head
Endocrine disorders			Hypothyroidism
Metabolism and nutrition disorders	In adults: Fluid retention: peripheral oedema, stiffness, arthralgia, myalgia, paresthesia.	In children: Fluid retention: peripheral oedema, stiffness, arthralgia, myalgia, paresthesia.		Insulin resistance can result in hyperinsulinism and in rare cases in hyperglycemia.
General disorders and administration site conditions	Injection site reactions: Localized lipoatrophy, which can be avoided by varying the site of injection

4.9 Overdose

No cases of acute overdose has been reported. However, exceeding the recommended doses can cause side effects. Overdosage can lead to hypoglycaemia and subsequently to hyperglycaemia. Moreover, somatropin overdose is likely to cause manifestations of fluid retention.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Anterior pituitary lobe hormones and analogues, ATC code: H01AC01.

Saizen contains recombinant human growth hormone produced by genetically engineered mammalian cells.

It is a peptide of 191 amino acids identical to human pituitary growth hormone with respect to aminoacid sequence and composition as well as peptide map, isoelectric point, molecular weight, isomeric structure and bioactivity.

Growth hormone is synthesised in a transformed murine cell line that has been modified by the addition of the gene for pituitary growth hormone.

Saizen is an anabolic and anticatabolic agent, which exerts effects not only on growth but also on body composition and metabolism. It interacts with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes and hematopoietic cells. Some, but not all of its effects are mediated through another class of hormones known as somatomedins (IGF-1 and IGF-2).

Depending on the dose, the administration of Saizen elicits a rise in IGF-1, IGFBP-3, non-esterified fatty acids and glycerol, a decrease in blood urea, and decreases in urinary nitrogen, sodium and potassium excretion. The duration of the increase in GH levels may play a role in determining the magnitude of the effects. A relative saturation of the effects of Saizen at high doses is probable. This is not the case for glycemia and urinary C-peptide excretion, which are significantly elevated only after high doses (20 mg).

In a randomized clinical trial, three years treatment of pre-pubertal short children born SGA with a dose of 0.067 mg/kg/day resulted in a mean gain of +1.8 height-SDS. In those children who did not receive treatment beyond 3 years, part of the treatment benefit was lost, but the patients retained a significant gain of +0.7 height-SDS at final height (p<0.01 compared to baseline). Patients who received a second treatment course after a variable period of observation experienced a total gain of +1.3 height-SDS (p=0.001 compared to baseline) at final height. (The mean cumulative treatment duration in the latter group was 6.1 years). The gain in height-SDS (+1.3±1.1) at final height in this group was significantly (p<0.05) different from the gain in height-SDS obtained in the first group (+0.7±0.8) that received only 3.0 years of treatment on average.

A second clinical trial investigated two different dose regimens over four years. One group was treated with 0.067 mg/kg/day for 2 years and then observed without treatment for 2 years. The second group received 0.067 mg/kg/day in the first and third year and no treatment in the second and fourth year. Either treatment regimen resulted in a cumulative administered dose of 0.033 mg/kg/day over the four-year study period. Both groups showed a comparable acceleration of growth and a significant improvement of +1.55 (p<0.0001) and + 1.43 (p<0.0001) height-SDS respectively at the end of the four year study period. Long-term safety data are still limited.

5.2 Pharmacokinetic Properties

The pharmacokinetics of Saizen are linear at least up to doses of 8 IU (2.67 mg). At higher doses (60 IU/20 mg) some degree of non-linearity cannot be ruled out, however with no clinical relevance.

Following IV administration in healthy volunteers the volume of distribution at steady-state is around 7 L, total metabolic clearance is around 15 L/h while the renal clearance is negligible, and the drug exhibits an elimination half-life of 20 to 35 min.

Following single-dose SC and IM administration of Saizen, the apparent terminal half-life is much longer, around 2 to 4 hours. This is due to a rate limiting absorption process.

Maximum serum growth hormone (GH) concentrations are reached after approximately 4 hours and serum GH levels return to baseline within 24 hours, indicating that no accumulation of GH will occur during repeated administrations.

The absolute bioavailability of both routes is 70-90 %.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Formal carcinogenicity bioassays were not performed. This is justified, given the proteinous nature of the drug substance and the negative outcome of the genotoxicity testing. The potential effects of r-hGH on the growth of pre-existing tumours have been evaluated through in vitro and in vivo experiments which have shown that r-hGH is not expected to cause or stimulate tumours in patients.

Reproductive toxicology studies do not indicate any adverse effect on fertility and reproduction, despite administration of doses sufficiently high to produce some pharmacological effects on growth.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder:

- Mannitol, Disodium phosphate dihydrate, Sodium dihydrogen phosphate monohydrate

Solvent:

- sodium chloride (0.9 % w/v) and benzyl alcohol (0.9 % w/v, as preservative) solution for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

2 years.

After reconstitution, the product may be stored for a maximum of 7 days in a refrigerator (2°C

6.4 Special Precautions For Storage

Store in a refrigerator (2°C

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

Store the reconstituted product in a refrigerator (2°C

Do not freeze.

6.5 Nature And Contents Of Container

The 10 ml vials containing 3.33 mg of powder and the 5 ml vials containing 5 ml of solvent are of neutral glass (Type I). The vials are closed by rubber stoppers.

Saizen 3.33 mg is available in the following pack sizes:

1 vial of Saizen 3.33 mg product and 1 vial of bacteriostatic solvent.

5 vials of Saizen 3.33 mg product and 5 vials of bacteriostatic solvent.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

To reconstitute Saizen, inject 1 ml of the bacteriostatic solvent into the vial of Saizen 3.33 mg aiming the liquid against the glass wall. Swirl the vial with a gentle rotary motion until the content is dissolved completely. Avoid vigorous shaking. Discard any unused solvent.

Benzyl alcohol as a preservative in bacteriostatic sodium chloride solution may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old and must not be given to premature babies or neonates. Saizen may be reconstituted with Sodium Chloride Injection BP or Sterile Water for Injections for immediate use when administering to children under 3 years of age.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Serono Ltd

Bedfont Cross

Stanwell Road

Feltham

Middlesex

TW14 8NX

8. Marketing Authorisation Number(S)

PL 03400/0034

9. Date Of First Authorisation/Renewal Of The Authorisation

23 April 2009

10. Date Of Revision Of The Text

04/2009