Solpadol Capsules

1. Name Of The Medicinal Product

Solpadol Capsules

2. Qualitative And Quantitative Composition

Active Constituents
Paracetamol	500.0mg
Codeine Phosphate Hemihydrate	30.0mg

For excipients see 6.1.

3. Pharmaceutical Form

Capsules.

Solpadol Capsules are grey and purple with SOLPADOL printed on them in black ink.

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of severe pain.

4.2 Posology And Method Of Administration

Adults:	Two capsules not more frequently than every 4 hours, up to a maximum of 8 capsules in any 24 hour period.
Elderly:	As for adults, however a reduced dose may be required. See warnings.
Children:	Not recommended for children under 12 years of age.

Solpadol capsules are for oral administration.

4.3 Contraindications

Hypersensitivity to paracetamol or codeine which is rare.

Hypersensitivity to any of the other constituents.

Conditions where morphine and opioids are contraindicated e.g:

• Acute asthma

• Respiratory depression

• Acute alcoholism

• Head injuries

• Raised intra-cranial pressure

• Following biliary tract surgery

Monoamine oxidase inhibitor therapy, concurrent or within 14 days.

4.4 Special Warnings And Precautions For Use

Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the caucasian population may be ultra-rapid metabolisers.

The leaflet will state in the “pregnancy and breast-feeding” subsection of the section 2 “Before taking your medicine”:

Usually it is safe to take Solpadol while breast feeding as the levels of the active ingredients of this medicine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk of developing side effects at any dose may have higher levels in their breast milk. If any of the following side effects develop in you or your baby, stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing.

Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated.

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with alcoholic liver disease.

Patients should be advised not to exceed the recommended dose and not take other paracetamol containing products concurrently.

Patients should be advised to consult a doctor should symptoms persist and to keep the product out of the reach and sight of children.

The risk-benefit of continued use should be assessed regularly by the prescriber.

The leaflet will state in a prominent position in the 'before taking' section:

Do not take for longer than directed by your prescriber.

Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets.

Taking a pain killer for headaches too often or for too long can make them worse.

The label will state (To be displayed prominently on outer pack (not boxed) :

Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

The effects of CNS depressants (including alcohol) may be potentiated by codeine.

4.6 Pregnancy And Lactation

There is inadequate evidence of the safety of codeine in human pregnancy. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage. Both substances have been used for many years without apparent ill consequences and animal studies have not shown any hazard. Nonetheless careful consideration should be given before prescribing the products for pregnant patients. Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers.

Paracetamol is excreted in breast milk but not in a clinically significant amount.

At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant.

However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

4.8 Undesirable Effects

Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, confusion, drowsiness and urinary retention. The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

• Regular prolonged use of codeine/DHC is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped.

• Prolonged use of a painkiller for headaches can make them worse.

Adverse effects of paracetamol are rare:

Immune system disorders

- Hypersensitivity including skin rash may occur.

- Not known: Anaphylactic shock, angioedema.

There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Very rare occurrence of pancreatitis.

4.9 Overdose

Codeine

The effects of Codeine overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Symptoms

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.

Management

Management should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg.

Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken.

Paracetamol

Patients in whom oxidative liver enzymes have been induced, including alcoholics and those receiving barbiturates and patients who are chronically malnourished, may be particularly sensitive to the toxic effects of paracetamol in overdose.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is likely in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anilides, Paracetamol combinations

ATC Code: NO2B E51

Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors which evoke pain. Although it is a prostaglandin synthetase inhibitor, the synthetase system in the CNS rather than the periphery appears to be more sensitive to it. This may explain paracetamol's lack of appreciable anti-inflammatory activity. Paracetamol also exhibits antipyretic activity.

Codeine is a centrally acting analgesic which produces its effect by its action at opioid-binding sites (μ-receptors) within the CNS. It is a full agonist.

5.2 Pharmacokinetic Properties

Following oral administration of two capsules (ie, a dose of paracetamol 1000mg and codeine phosphate 60mg) the mean maximum plasma concentrations of paracetamol and codeine phosphate were 17.5 μg/ml and 327ng/ml respectively. The mean times to maximum plasma concentrations were 1.03 hours for paracetamol and 1.10 hours for codeine phosphate.

The mean AUC_(0-10) following administration was 48.0μg/ml per hour for paracetamol and 1301ng/ml per hour for codeine.

The bioavailabilities of paracetamol and codeine when given as the combination are similar to those when they are given separately.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Magnesium stearate

Talc

Indigotine E132

Azorubine E122

Titanium dioxide E171

Gelatin

Black iron oxide E172

Shellac

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

White, opaque PVC (250μm)/aluminium foil (20μm)/ PVC (15μm) blister packs or White, opaque PVC (250μm)/ 35gsm Glassine (Pergamin) paper/9µm soft temper Aluminium foil contained in cardboard cartons.

Pack sizes of 100 capsules.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 04425/0635

9. Date Of First Authorisation/Renewal Of The Authorisation

4^th December 2008

10. Date Of Revision Of The Text

2 November 2011

LEGAL STATUS

POM

Solpadol Caplets

SOLPADOL 30mg/500mg CAPLETS

Codeine Phosphate and Paracetamol

Is this leaflet hard to see or read?

Phone 01483 505515 for help

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 further questions, please ask your doctor or pharmacist



• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours



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

In this leaflet:

• 1. What Solpadol is and what it is used for



• 2. Before you take Solpadol



• 3. How to take Solpadol



• 4. Possible side effects



• 5. How to store Solpadol



• 6. Further information

What Solpadol is and what it is used for

The name of your medicine is Solpadol 30mg/500mg Caplets (called Solpadol throughout this leaflet). Solpadol contains two different medicines called codeine phosphate and paracetamol.

It belongs to a group of medicines called analgesics (painkillers) and is used to treat severe pain.

Before you take Solpadol

Important things you should know about Solpadol

• Do not take for longer than your doctor tells you to



• Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the caplets



• Taking a painkiller for headaches too often or for too long can make them worse

Do not take Solpadol and tell your doctor if:

• You are allergic (hypersensitive) to codeine, paracetamol or any of the other ingredients in your medicine (listed in Section 6: Further information). Signs of an allergic reaction include a rash and breathing problems. There can also be swelling of the legs, arms, face, throat or tongue



• You have severe asthma attacks or severe breathing problems



• You have recently had a head injury



• You have been told by your doctor that you have increased pressure in your head. Signs of this include: headaches, being sick (vomiting) and blurred eyesight



• You have recently had an operation on your liver, gallbladder or bile duct (biliary tract)



• You are taking medicine to treat depression called MAOIs (monoamine oxidase inhibitors) or have taken them in the last 2 weeks. MAOIs are medicines such as moclobemide, phenelzine or tranylcypramine (see ‘Taking other medicines’)



• You are an alcoholic



• The person going to take the caplets is under 12 years of age.

Do not take Solpadol if any of the above apply to you.

Take special care and check with your doctor before taking Solpadol if:

• You have severe kidney or liver problems



• You have problems passing water or prostate problems



• You have a bowel problem such as colitis or Crohn’s disease or a blockage of your bowel



• You are elderly

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

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is because Solpadol can affect the way some other medicines work. Also, some other medicines can affect the way Solpadol works.

While taking Solpadol you should not take any other medicines which contain paracetamol.

This includes some painkillers, cough and cold remedies. It also includes a wide range of other medicines available from your doctor and more widely in shops.

Do not take this medicine, and tell your doctor, if you are taking

• Medicines to treat depression called MAOIs (monoamine oxidase inhibitors) or have taken them in the last 2 weeks. MAOIs are medicines such as moclobemide, phenelzine, tranylcypramine

Tell your doctor if you are taking any of the following medicines:

• Medicines which make you drowsy or sleepy (CNS depressants)



• Medicines used to thin the blood such as warfarin



• Chloramphenicol - an antibiotic used for infections



• Metoclopramide or domperidone - used to stop you feeling sick (nausea) or being sick (vomiting)



• Colestyramine - for lowering blood cholesterol levels



• The oral contraceptive pill

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

Taking Solpadol with food and drink

You should not drink alcohol while you are taking these caplets. This is because Solpadol can change the way alcohol affects you.

Pregnancy and breast-feeding

Talk to your doctor before taking these caplets if:

• You are pregnant, think you may be pregnant or plan to get pregnant



• You are breast-feeding or planning to breast-feed

Driving and using machines

You may feel dizzy or sleepy while taking Solpadol. If this happens, do not drive or use any tools or machines.

Changing or stopping treatment

Long term usage of Solpadol may lead to tolerance and dependence. If you have taken regular daily doses of Solpadol for a long time, do not increase the dose or suddenly stop treatment without discussing this with your doctor.

How to take Solpadol

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

• Do not take more than the recommended dose



• Do not take for longer than your doctor tells you to

Adults and children over 12

• Take this medicine by mouth



• Swallow the caplets whole with a drink of water



• The usual dose of Solpadol is 2 caplets, taken together



• Wait at least 4 hours before taking another dose



• Do not take more than 8 caplets in any 24-hour period



• Elderly people may be prescribed a lower dose

Children

Solpadol should not be given to children under 12 years of age.

If you take more Solpadol than you should

• Tell your doctor or go to your nearest hospital casualty department straight away - even if you feel well. This is because of the risk of delayed, serious liver damage



• Remember to take any remaining caplets and the pack with you. This is so the doctor knows what you have taken

If you have forgotten to take Solpadol

If you forget to take a dose at the right time, take it as soon as you remember. However, if it is almost time for your
next dose, skip the missed dose. Do not take two doses at or near the same time. Remember to leave at least 4 hours between doses.

Solpadol Caplets Side Effects

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

Important side-effects you should know about Solpadol

• Taking a painkiller for headaches too often or for too long can make them worse.



• Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the caplets

Stop taking Solpadol and see a doctor or go to a hospital straight away if:

• You get swelling of the hands, feet, ankles, face, lips or throat which may cause difficulty in swallowing or breathing. You could also notice an itchy, lumpy rash (hives) or nettle rash (urticaria)

This may mean you are having an allergic reaction to Solpadol

Talk to your doctor straight away if you notice the following serious side effect:

• Severe stomach pain, which may reach through to your back. This could be a sign of inflammation of the pancreas
  (pancreatitis). This is a very rare side effect

Tell your doctor or pharmacist if any of the following side effects gets serious or lasts longer than a few days:

• Constipation



• Feeling sick (nausea), being sick (vomiting)



• Dizziness, light-headedness, drowsiness, confusion



• Difficulty in passing water (urine)



• Becoming dependent on codeine



• You get infections or bruise more easily than usual. This could be because of a blood problem (such as agranulocytosis, neutropenia or thrombocytopenia)

If any of the side effects gets serious, lasts longer than a few days or you notice any side effects not listed in this
leaflet, please tell your doctor or pharmacist.

How to store Solpadol

Keep this medicine in a safe place out of the reach and sight of children.

Do not use this medicine after the expiry date shown on the pack.

Store your medicine in the original packaging in order to protect from moisture.

Do not store above 25°C.

Ask your pharmacist how to dispose of medicines no longer required. Do not dispose of medicines by flushing down a toilet or sink or by throwing out with your normal household rubbish. This will help protect the environment.

Further information

What Solpadol 30mg/500mg Caplets contain

• The active substances of Solpadol 30mg/500mg Caplets are codeine phosphate and paracetamol. Each caplet contains 30mg of codeine phosphate and 500mg of paracetamol



• The other ingredients are pregelatinised starch, maize starch, potassium sorbate, microcrystalline cellulose, stearic acid, talc, magnesium stearate, povidone and croscarmellose sodium (type A)

What Solpadol 30mg/500mg Caplets look like and contents of pack

Solpadol 30mg/500mg Caplets are white, capsule shaped tablets (caplets), marked with the word ‘SOLPADOL’ on one face.

They come in cartons of 4, 10, 24, 30, 60 and 100 caplets. Not all pack sizes may be sold.

The Marketing Authorisation Holder is

Sanofi-Aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Tel:01483 505515

Fax:01483 535432

email:uk-medicalinformation@sanofi-aventis.com

The Manufacturer is

Fawdon Manufacturing Centre

Edgefield Avenue

Fawdon

Newcastle upon Tyne

NE3 3TT

UK

This leaflet was last updated in July 2007

© Sanofi-aventis 1989-2007

31962201

Synacthen Ampoules 250mcg

Synacthen Ampoules 250 micrograms

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 Ampoules is and what it is used for



• 2. Check before you receive Synacthen Ampoules



• 3. How Synacthen Ampoules is given to you



• 4. Possible side effects



• 5. How to store Synacthen Ampoules



• 6. Further information

What Synacthen Ampoules is and what it is used for

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

Check before you receive Synacthen Ampoules

You should not be given Synacthen Ampoules if:

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



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



• you suffer from asthma



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

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 Ampoules.

Taking other medicines

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

Pregnancy and breast-feeding

You should not receive Synacthen Ampoules 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 Ampoules, do not drive or operate machinery until these effects have worn off.

Important information about some of the ingredients of Synacthen Ampoules

Synacthen Ampoules is essentially ‘sodium-free’ - it contains less than 1 mmol sodium (9 mg) per 1mg.

How Synacthen Ampoules is given to you

Your treatment with Synacthen Ampoules 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 Ampoules.

You will be given one injection followed by a blood test. The liquid will be drawn up into a syringe and injected into a muscle by your doctor or nurse.

Adults including elderly patients will be given 250 micrograms (one ampoule).

Children will be given a lower dose based on their age and weight.

What to do if you think you have received more Synacthen Ampoules 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 Ampoules

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.

Possible side effects

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

Very rarely, Synacthen Ampoules can cause an allergic reaction with skin irritation and swelling, faintness, wheezing, flushing, feeling or being sick. For this reason, you should be monitored carefully for 30 minutes after the injection. Once you have had an allergic reaction like this, you should never be treated with Synacthen Ampoules or similar medicines again.

As Synacthen Ampoules is a single injection you are unlikely to experience any other side effects. However, if you have any side effects which you feel may have been caused by Synacthen Ampoules contact your doctor or pharmacist.

How to store Synacthen Ampoules

Synacthen Ampoules will be stored in the hospital pharmacy.

Keep out of the reach and sight of children.

Do not use Synacthen Ampoules 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 Ampoules?

The active ingredient in this medicine is tetracosactide acetate.

The other ingredients are acetic acid, sodium acetate, sodium chloride and water.

What Synacthen Ampoules looks like and contents of the pack

Synacthen Ampoules comes in packs of 5 ampoules.

Marketing Authorisation Holder and Manufacturer

The product licence holder is:

Alliance Pharmaceuticals Ltd

Avonbridge House

Chippenham

Wiltshire

SN15 2BB

UK

Synacthen Ampoules is manufactured by

Nycomed Austria GmbH

St-Peter-Strasse 25

A-4020 Linz

Austria

The information in this leaflet applies only to Synacthen Ampoules. 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 v2

Syndol Caplets

1. Name Of The Medicinal Product

Syndol Caplets.

2. Qualitative And Quantitative Composition

Paracetamol BP 450.0mg, Codeine Phosphate BP 10.0mg, Doxylamine Succinate NF 5.0mg, Caffeine BP 30.0mg.

3. Pharmaceutical Form

Tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of mild to moderate pain and as an antipyretic. Syndol Caplets are recommended for the symptomatic relief of headache, including muscle contraction or tension headache, migraine, neuralgia, toothache, sore throat, dysmenorrhoea, muscular and rheumatic aches and pains and for post-operative analgesia following surgical or dental procedures.

4.2 Posology And Method Of Administration

For oral administration. Adults and children over 12 years: 1 or 2 tablets every four to six hours as needed for relief. Total dosage over a 24 hour period should not normally exceed 8 tablets. Do not take for more than three days continuously without medical review.

Codeine should be used with caution in the elderly and debilitated patients, as they may be more susceptible to the respiratory depressant effects.

4.3 Contraindications

Hypersensitivity to paracetamol, codeine or other opioid analgesics, or any of the other constituents.

4.4 Special Warnings And Precautions For Use

Do not exceed the stated dose. Do not take concurrently with any other paracetamol or codeine containing compounds. Keep out of the reach of children. Care is advised in the administration of this preparation to patients with impaired kidney or liver function and in those with hypertension, hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock, obstructive bowel disorders, acute abdominal conditions, recent gastrointestinal surgery, gallstones, myasthenia gravis, a history of cardiac arrhythmias or convulsions and in patients with a history of drug abuse or emotional instability.

Codeine may induce faecal impaction, producing incontinence, spurious diarrhoea, abdominal pain and rarely colonic obstruction. Elderly patients may metabolise or eliminate opioid analgesics more slowly than younger adults.

The leaflet will state in a prominent position in the before taking section:

If you need to use this medicine for more than three days at a time, see your doctor, pharmacist or healthcare professional. Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop taking the tablets. Taking a painkiller for headaches too often or for too long can make them worse.

The label will state (to be displayed prominently on outer pack, not boxed):

If you need to use this medicine for more than three days at a time, see your doctor or pharmacist. Taking codeine regularly for a long time can lead to addiction. Taking a painkiller for headaches too often or for too long can make them worse.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

The depressant effects of codeine are enhanced by depressants of the central nervous system such as alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines. The hypotensive actions of diuretics and anti hypertensive agents may be potentiated when used concurrently with opioid analgesics. Concurrent use of hydroxyzine with codeine may result in increased analgesia as well as increased CNS depressant and hypotensive effects. Concurrent use of codeine with antidiarrhoeal and antiperistaltic agents such as loperamide and kaolin may increase the risk of severe constipation. Concomitant use of antimuscarinics or medications with antimuscarinic action may result in an increased risk of severe constipation that may lead to paralytic ileus and/or urinary retention. The respiratory depressant effect caused by neuromuscular blocking agents may be additive to the central respiratory depressant effects of opioid analgesics. CNS depression or excitation may occur if codeine is given to patients receiving monoamine oxidase inhibitors, or within two weeks of stopping treatment with them. Quinidine can inhibit the analgesic effect of codeine. Codeine may delay the absorption of mexiletine and thus reduce the antiarrhythmic effect of the latter. Codeine may antagonise the gastrointestinal effects of metoclopramide, cisapride and domperidone. Cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma concentrations. Naloxone antagonises the analgesic, CNS and respiratory depressant effects of opioid analgesics. Naltrexone also blocks the therapeutic effect of opioids.

Incompatibilities: Codeine has been reported to be incompatible with phenobarbitone sodium forming a codeine-phenobarbitone complex, and with potassium iodide, forming crystals of codeine periodide. Acetylation of codeine phosphate by aspirin has occurred in solid dosage forms containing the two drugs, even at low moisture levels.

Interference with laboratory tests: Opioid analgesics interfere with a number of laboratory tests including plasma amylase, lipase, bilirubin, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase and aspartate aminotransferase. Opioids may also interfere with gastric emptying studies as they delay gastric emptying and with hepatobiliary imaging-using technetium Tc 99m disofenin as opioid treatment may cause constriction of the sphincter of Oddi and increase biliary tract pressure.

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Codeine crosses the placenta. There is no adequate evidence of safety in human pregnancy and a possible association with respiratory and cardiac malformations has been reported. Regular use during pregnancy may cause physical dependence in the foetus leading to withdrawal symptoms in the neonate. Use during pregnancy should be avoided if possible.

Use of opioid analgesia during labour may cause respiratory depression in the neonate, especially the premature neonate. These agents should not be given during the delivery of a premature baby.

Codeine passes into breast milk in very small amounts that are considered to be compatible with breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Doxylamine succinate may cause drowsiness or dizziness in some patients.

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causally related to paracetamol.

The most frequent undesirable effects of codeine are constipation and drowsiness. Less frequent effects are nausea, vomiting, sweating, facial flushing, dry mouth, blurred or double vision, dizziness, orthostatic hypotension, malaise, tiredness, headache, anorexia, vertigo, bradycardia, palpitations, respiratory depression, dyspnoea, allergic reactions (itch, skin rash, facial oedema) and difficulties in micturition (dysuria, increased frequency, decrease in amount). Side effects that occur rarely include convulsions, hallucinations, nightmares, uncontrolled muscle movements, muscle rigidity, mental depression and stomach cramps.

Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is stopped. Prolonged use of a painkiller for headaches can make them worse.

4.9 Overdose

Symptoms of overdose in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Liver damage is possible in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested) become irreversibly bound to liver tissue. Immediate treatment is essential in the management of a paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

While the dose of codeine phosphate in this preparation is relatively small and therefore less likely to prove a problem, symptoms of overdose include cold clammy skin, confusion, convulsions, dizziness, drowsiness, nervousness or restlessness, miosis, bradycardia, dyspnoea, unconsciousness and weakness. Codeine in large doses may produce respiratory depression, hypotension, circulatory failure and deepening coma. Death may occur from respiratory failure.

Initial treatment includes emptying the stomach by aspiration and lavage. Intensive support therapy may be required to correct respiratory failure and shock. In addition the specific narcotic antagonist, naloxone hydrochloride, may be used rapidly to counteract the severe respiratory depression and coma. A dose of 0.4-2 mg is given intravenously or intramuscularly to adults, this is repeated at intervals of 2-3 minutes; if necessary up to 10mg of naloxone may be given. In children doses of 5-10µg/kg body weight may be given intravenously or intramuscularly. Codeine is not dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol - antipyretic, analgesic; codeine phosphate - analgesic; doxylamine succinate - antihistamine; caffeine - mild stimulant.

5.2 Pharmacokinetic Properties

The pharmacokinetics of paracetamol, codeine phosphate and caffeine are widely published (see Goodman & Gilman's The Pharmacological Basis of Therapeutics, Seventh Edition, pp 693, 505 and 596 respectively). Doxylamine succinate is readily absorbed from the gastrointestinal tract. Following oral administration, the effects start within 15 to 30 minutes and peak within one hour. In humans, 60-80% of doxylamine given has been recovered in urine at 24 hours post-dose.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet Core: Povidone; Croscarmellose Sodium; Corn Starch; Magnesium Stearate; Talc; Purified water.

Coating: Opadry II Yellow (Lactose Monohydrate; Hydroxypropyl Methyl Cellulose (Methocel E15); Polyethylene Glycol 4000; Quinoline Yellow Aluminium Lake (E104); Sunset Yellow Aluminium Lake (E110); Titanium Dioxide)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None stated.

6.5 Nature And Contents Of Container

Blister strips: 250 micron PVC and aluminium foil 20 micron coated with a 15 micron PVC layer.

Blister strips are presented in cardboard cartons.

Pack sizes are 10,20 or 30 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Seton Products Limited, Tubiton House, Oldham, OL1 3HS

8. Marketing Authorisation Number(S)

PL 11314/0122.

9. Date Of First Authorisation/Renewal Of The Authorisation

16^th January 1999.

10. Date Of Revision Of The Text

October 2006

Synphase Tablets

1. Name Of The Medicinal Product

Synphase.

2. Qualitative And Quantitative Composition

Synphase consists of 7 blue tablets containing norethisterone 500 micrograms and ethinylestradiol 35 micrograms, marked 'BX' on one side and 'SEARLE' on the other; 9 white tablets containing norethisterone 1.0 milligram and ethinylestradiol 35 micrograms inscribed 'SEARLE' on one face and 'BX' on the other; 5 blue tablets containing norethisterone 500 micrograms and ethinylestradiol 35 micrograms, marked 'BX' on one side and 'SEARLE' on the other.

3. Pharmaceutical Form

Tablets for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Synphase is indicated for oral contraception, with the benefit of a low intake of oestrogen.

4.2 Posology And Method Of Administration

Oral Administration: The dosage of Synphase for the initial cycle of therapy is 1 tablet taken at the same time each day from the first day of the menstrual cycle. For subsequent cycles, no tablets are taken for 7 days, then a new course is started of 1 tablet daily for the next 21 days. This sequence of 21 days on treatment, seven days off treatment is repeated for as long as contraception is required.

Patients unable to start taking Synphase tablets on the first day of the menstrual cycle may start treatment on any day up to and including the 5th day of the menstrual cycle.

Patients starting on day 1 of their period will be protected at once. Those patients delaying therapy up to day 5 may not be protected immediately and it is recommended that another method of contraception is used for the first 7 days of tablet-taking. Suitable methods are condoms, caps plus spermicides and intra-uterine devices.

The rhythm, temperature and cervical-mucus methods should not be relied upon.

Tablet omissions

Tablets must be taken daily in order to maintain adequate hormone levels and contraceptive efficacy.

If a tablet is missed within 12 hours of the correct dosage time then the missed tablet should be taken as soon as possible, even if this means taking 2 tablets on the same day, this will ensure that contraceptive protection is maintained. If one or more tablets are missed for more than 12 hours from the correct dosage time it is recommended that the patient takes the last missed tablet as soon as possible and then continues to take the rest of the tablets in the normal manner. In addition, it is recommended that extra contraceptive protection, such as a condom, is used for the next 7 days.

Patients who have missed one or more of the last 7 tablets in a pack should be advised to start the next pack of tablets as soon as the present one has finished (i.e. without the normal seven day gap between treatments). This reduces the risk of contraceptive failure resulting from tablets being missed close to a 7 day tablet free period.

Changing from another oral contraceptive

In order to ensure that contraception is maintained it is advised that the first dose of Synphase tablets is taken on the day immediately after the patient has finished the previous pack of tablets.

Use after childbirth, miscarriage or abortion

Providing the patient is not breast feeding the first dose of Synphase tablets should be taken on the 21st day after childbirth. This will ensure the patient is protected immediately. If there is any delay in taking the first dose, contraception may not be established until 7 days after the first tablet has been taken. In these circumstances patients should be advised that extra contraceptive methods will be necessary.

After a miscarriage or abortion patients can take the first dose of Synphase tablets on the next day; in this way they will be protected immediately.

4.3 Contraindications

As with all combined progestogen/oestrogen oral contraceptives, the following conditions should be regarded as contra-indications:

i. History of confirmed venous thromboembolic disease (VTE), family history of idiopathic VTE and other known risk factors of VTE

ii. Thrombophlebitis, cerebrovascular disorders, coronary artery disease, myocardial infarction, angina, hyperlipidaemia or a history of these conditions.

iii. Acute or severe chronic liver disease, including liver tumours, Dubin-Johnson or Rotor syndrome.

iv. History during pregnancy of idiopathic jaundice, severe pruritus or pemphigoid gestationis.

v. Known or suspected breast or genital cancer.

vi. Known or suspected oestrogen-dependent neoplasia.

vii. Undiagnosed abnormal vaginal bleeding.

viii. A history of migraines classified as classical, focal or crescendo.

ix. Pregnancy.

4.4 Special Warnings And Precautions For Use

Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.

Women taking oral contraceptives require careful observation if they have or have had any of the following conditions: breast nodules; fibrocystic disease of the breast or an abnormal mammogram; uterine fibroids; a history of severe depressive states; varicose veins; sickle-cell anaemia; diabetes; hypertension; cardiovascular disease; migraine; epilepsy; asthma; otosclerosis; multiple sclerosis; porphyria; tetany; disturbed liver functions; gallstones; kidney disease; chloasma; any condition that is likely to worsen during pregnancy. The worsening or first appearance of any of these conditions may indicate that the oral contraceptive should be stopped. Discontinue treatment if there is a gradual or sudden, partial or complete loss of vision or any evidence of ocular changes, onset or aggravation of migraine or development of headache of a new kind which is recurrent, persistent or severe.

Gastro-intestinal upsets, such as vomiting and diarrhoea, may interfere with the absorption of the tablets leading to a reduction in contraceptive efficacy. Patients should continue to take Synphase, but they should also be encouraged to use another contraceptive method during the period of gastro-intestinal upset and for the next 7 days.

Progestogen oestrogen preparations should be used with caution in patients with a history of hepatic dysfunction or hypertension.

An increased risk of venous thromboembolic disease (VTE) associated with the use of oral contraceptives is well established but is smaller than that associated with pregnancy, which has been estimated at 60 cases per 100,000 pregnancies. Some epidemiological studies have reported a greater risk of VTE for women using combined oral contraceptives containing desogestrel or gestodene (the so-called 'third generation' pills) than for women using pills containing levonorgestrel or norethisterone (the so-called 'second generation' pills)

The spontaneous incidence of VTE in healthy non-pregnant women (not taking any oral contraceptive) is about 5 cases per 100,000 per year. The incidence in users of second generation pills is about 15 per 100,000 women per year of use. The incidence in users of third generation pills is about 25 cases per 100,000 women per year of use; this excess incidence has not been satisfactorily explained by bias or confounding. The level of all of these risks of VTE increases with age and is likely to be further increased in women with other known risk factors for VTE such as obesity. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive.

Patients receiving oral contraceptives should be kept under regular surveillance, in view of the possibility of development of conditions such as thromboembolism.

The risk of coronary artery disease in women taking oral contraceptives is increased by the presence of other predisposing factors such as cigarette smoking, hypercholesterolaemia, obesity, diabetes, history of pre-eclamptic toxaemia and increasing age. After the age of thirty-five years, the patient and physician should carefully re-assess the risk/benefit ratio of using combined oral contraceptives as opposed to alternative methods of contraception.

Synphase should be discontinued at least four weeks before, and for two weeks following, elective operations and during immobilisation. Patients undergoing injection treatment for varicose veins should not resume taking Synphase until 3 months after the last injection.

Benign and malignant liver tumours have been associated with oral contraceptive use. The relationship between occurrence of liver tumours and use of female sex hormones is not known at present. These tumours may rupture causing intra-abdominal bleeding. If the patient presents with a mass or tenderness in the right upper quadrant or an acute abdomen, the possible presence of a tumour should be considered.

An increased risk of congenital abnormalities, including heart defects and limb defects, has been reported following the use of sex hormones, including oral contraceptives, in pregnancy. If the patient does not adhere to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and further use of oral contraceptives should be withheld until pregnancy has been ruled out. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen. If pregnancy is confirmed the patient should be advised of the potential risks to the foetus and the advisability of continuing the pregnancy should be discussed in the light of these risks. It is advisable to discontinue Synphase three months before a planned pregnancy.

The risk of arterial thrombosis associated with combined oral contraceptives increases with age, and this risk is aggravated by cigarette smoking. The use of combined oral contraceptives by women in the older age group, especially those who are cigarette smokers, should therefore be discouraged and alternative methods advised.

The use of this product in patients suffering from epilepsy, migraine, asthma or cardiac dysfunction may result in exacerbation of these disorders because of fluid retention. Caution should also be observed in patients who wear contact lenses.

Decreased glucose tolerance may occur in diabetic patients on this treatment, and their control must be carefully supervised.

The use of oral contraceptives has also been associated with a possible increased incidence of gall bladder disease.

Women with a history of oligomenorrhoea or secondary amenorrhoea or young women without regular cycles may have a tendency to remain anovulatory or to become amenorrhoeic after discontinuation of oral contraceptives. Women with these pre-existing problems should be advised of this possibility and encouraged to use other contraceptive methods.

Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer.

An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.

Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer (see bar chart).

The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.

The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

	Estimated cumulative numbers of breast cancers per 10,000 women diagnosed in 5 years of use and up to 10 years after stopping COCs, compared with numbers of breast cancers diagnosed in 10,000 women who had never used COCs.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The herbal remedy St John's wort (Hypericum perforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect.

Some drugs may modify the metabolism of Synphase reducing its effectiveness; these include certain sedatives, antibiotics, anti-epileptic and anti-arthritic drugs. During the time such agents are used concurrently, it is advised that mechanical contraceptives also be used.

The results of a large number of laboratory tests have been shown to be influenced by the use of oestrogen containing oral contraceptives, which may limit their diagnostic value. Among these are: biochemical markers of thyroid and liver function; plasma levels of carrier proteins, triglycerides, coagulation and fibrinolysis factors.

4.6 Pregnancy And Lactation

Contra-indicated in pregnancy.

Patients who are fully breast-feeding should not take Synphase tablets since, in common with other combined oral contraceptives, the oestrogen component may reduce the amount of milk produced. In addition, active ingredients or their metabolites have been detected in the milk of mothers taking oral contraceptives. The effect of Synphase on breast-fed infants has not been determined.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

As with all oral contraceptives, there may be slight nausea at first, weight gain or breast discomfort, which soon disappear.

Other side-effects known or suspected to occur with oral contraceptives include gastro-intestinal symptoms, changes in libido and appetite, headache, exacerbation of existing uterine fibroid disease, depression, and changes in carbohydrate, lipid and vitamin metabolism.

Spotting or bleeding may occur during the first few cycles. Usually menstrual bleeding becomes light and occasionally there may be no bleeding during the tablet-free days.

Hypertension, which is usually reversible on discontinuing treatment, has occurred in a small percentage of women taking oral contraceptives.

4.9 Overdose

Overdosage may be manifested by nausea, vomiting, breast enlargement and vaginal bleeding. There is no specific antidote and treatment should be symptomatic. Gastric lavage may be employed if the overdose is large and the patient is seen sufficiently early (within four hours).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The mode of action of Synphase is similar to that of other progestogen/oestrogen oral contraceptives and includes the inhibition of ovulation, the thickening of cervical mucus so as to constitute a barrier to sperm and the rendering of the endometrium unreceptive to implantation. Such activity is exerted through a combined effect on one or more of the following: hypothalamus, anterior pituitary, ovary, endometrium and cervical mucus.

5.2 Pharmacokinetic Properties

Norethisterone is rapidly and completely absorbed after oral administration, peak plasma concentrations occurring in the majority of subjects between 1 and 3 hours. Due to first-pass metabolism, blood levels after oral administration are 60% of those after i.v. administration. The half life of elimination varies from 5 to 12 hours, with a mean of 7.6 hours. Norethisterone is metabolised mainly in the liver. Approximately 60% of the administered dose is excreted as metabolites in urine and faeces.

Ethinylestradiol is rapidly and well absorbed from the gastro-intestinal tract but is subject to some first-pass metabolism in the gut-wall. Compared to many other oestrogens it is only slowly metabolised in the liver. Excretion is via the kidneys with some appearing also in the faeces.

5.3 Preclinical Safety Data

The toxicity of norethisterone is very low. Reports of teratogenic effects in animals are uncommon. No carcinogenic effects have been found even in long-term studies.

Long-term continuous administration of oestrogens in some animals increases the frequency of carcinoma of the breast, cervix, vagina and liver.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Synphase tablets contain:

Maize starch, polyvidone, magnesium stearate and lactose. The blue tablets also contain E132.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

The shelf life of Synphase tablets is 5 years.

6.4 Special Precautions For Storage

Store in a dry place below 25^oC away from direct sunlight.

6.5 Nature And Contents Of Container

Synphase tablets are supplied in pvc/foil blister packs of 21 and 63 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9JN

8. Marketing Authorisation Number(S)

PL 0032/0422

9. Date Of First Authorisation/Renewal Of The Authorisation

May 10th 1996 / 25/02/2009

10. Date Of Revision Of The Text

February 2009

Company Ref: SY3_0

Synflorix suspension for injection in pre-filled syringe

1. Name Of The Medicinal Product

Synflorix

Pneumococcal polysaccharide conjugate vaccine (adsorbed)

2. Qualitative And Quantitative Composition

1 dose (0.5 ml) contains:

Pneumococcal polysaccharide serotype 11,2	1 microgram
Pneumococcal polysaccharide serotype 41,2	3 micrograms
Pneumococcal polysaccharide serotype 51,2	1 microgram
Pneumococcal polysaccharide serotype 6B1,2	1 microgram
Pneumococcal polysaccharide serotype 7F1,2	1 microgram
Pneumococcal polysaccharide serotype 9V1,2	1 microgram
Pneumococcal polysaccharide serotype 141,2	1 microgram
Pneumococcal polysaccharide serotype 18C1,3	3 micrograms
Pneumococcal polysaccharide serotype 19F1,4	3 micrograms
Pneumococcal polysaccharide serotype 23F1,2	1 microgram
1 adsorbed on aluminium phosphate	0.5 milligram Al3+
2 conjugated to protein D (derived from non-typeable Haemophilus influenzae) carrier protein	9-16 micrograms
3 conjugated to tetanus toxoid carrier protein	5-10 micrograms
4 conjugated to diphtheria toxoid carrier protein	3-6 micrograms

For the full list of excipients, see section 6.1.

3. Pharmaceutical Form

Suspension for injection (injection).

The vaccine is a turbid white suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Active immunisation against invasive disease and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks up to 5 years of age. See sections 4.4 and 5.1 for information on protection against specific pneumococcal serotypes.

The use of Synflorix should be determined on the basis of official recommendations taking into consideration the impact of invasive disease in different age groups as well as the variability of serotype epidemiology in different geographical areas.

4.2 Posology And Method Of Administration

Posology

The immunisation schedules for Synflorix should be based on official recommendations.

Infants from 6 weeks to 6 months of age

Three-dose primary series

The recommended immunisation series to ensure optimal protection consists of four doses, each of 0.5 ml. The primary infant series consists of three doses with the first dose usually given at 2 months of age and with an interval of at least 1 month between doses. The first dose may be given as early as six weeks of age. A booster dose is recommended at least 6 months after the last priming dose and preferably between 12 and 15 months of age. (see sections 4.4 and 5.1)

Two-dose primary series

Alternatively, when Synflorix is given as part of a routine infant immunisation programme, a series consisting of three doses, each of 0.5 ml may be given. The first dose may be administered from the age of 2 months, with a second dose 2 months later. A booster dose is recommended at least 6 months after the last primary dose (see section 5.1).

Infants born between 27-36 weeks gestation

In preterm infants born after at least 27 weeks of gestational age, the recommended immunisation series consists of four doses, each of 0.5ml. The primary infant series consists of three doses with the first dose given at 2 months of age and with an interval of at least 1 month between doses. A booster dose is recommended at least 6 months after the last primary dose (see sections 4.4 and 5.1).

Previously unvaccinated older infants and children

- infants aged 7-11 months: The vaccination schedule consists of two doses of 0.5 ml with an interval of at least 1 month between doses. A third dose is recommended in the second year of life with an interval of at least 2 months between doses.

- children aged 12-23 months: The vaccination schedule consists of two doses of 0.5 ml with an interval of at least 2 months between doses. The need for a booster dose after this immunisation schedule has not been established. (see section 4.4)

- children aged 2– 5 years: The vaccination schedule consists of two doses of 0.5 ml with an interval of at least 2 months between doses.

It is recommended that subjects who receive a first dose of Synflorix complete the full vaccination course with Synflorix.

Paediatric population

The safety and efficacy of Synflorix in children over 5 years of age have not been established.

Method of administration

The vaccine should be given by intramuscular injection. The preferred sites are anterolateral aspect of the thigh in infants or the deltoid muscle of the upper arm in young children.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to any of the carrier proteins.

As with other vaccines, the administration of Synflorix should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic reaction following the administration of the vaccine.

The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunisation series to very premature infants (born

Synflorix should under no circumstances be administered intravascularly or intradermally. No data are available on subcutaneous administration of Synflorix.

As for other vaccines administered intramuscularly, Synflorix should be given with caution to individuals with thrombocytopenia or any coagulation disorder since bleeding may occur following an intramuscular administration to these subjects.

Official recommendations for the immunisation against diphtheria, tetanus and Haemophilus influenzae type b should also be followed.

There is insufficient evidence that Synflorix provides protection against pneumococcal serotypes not contained in the vaccine or against non-typeable Haemophilus influenzae. Synflorix does not provide protection against other micro-organisms.

As with any vaccine, Synflorix may not protect all vaccinated individuals against invasive pneumococcal disease or otitis media caused by the serotypes in the vaccine. Protection against otitis media caused by pneumococcal serotypes in the vaccine is expected to be substantially lower than protection against invasive disease. In addition, as otitis media is caused by many micro-organisms other than the Streptococcus pneumoniae serotypes represented in the vaccine, the overall protection against otitis media is expected to be limited (see section 5.1)

In clinical trials Synflorix elicited an immune response to all ten serotypes included in the vaccine, but the magnitude of the responses varied between serotypes. The functional immune response to serotypes 1 and 5 was lower in magnitude than the response against all other vaccine serotypes. It is not known whether this lower functional immune response against serotypes 1 and 5 will result in lower protective efficacy against invasive disease or otitis media caused by these serotypes (see section 5.1).

Synflorix is indicated for use in children aged from 6 weeks up to 5 years. Children should receive the dose regimen of Synflorix that is appropriate to their age at the time of commencing the vaccination series (see section 4.2). Safety and immunogenicity data are not yet available in children above 5 years of age.

Children with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced antibody response to vaccination.

Safety and immunogenicity data in children with increased risk for pneumococcal infections (e.g. sickle cell disease, congenital and acquired splenic dysfunction, HIV-infected, malignancy, nephrotic syndrome) are not yet available for Synflorix. Vaccination in high-risk groups should be considered on an individual basis (see section 4.2).

The immune response elicited after two doses of Synflorix in children 12-23 months of age is comparable to the response elicited after three doses in infants (see section 5.1). The immune response to a booster dose after two doses in children aged 12-23 months has not been evaluated, but a booster dose may be needed to ensure optimal individual protection.

However, a 2-dose schedule in children aged 12-23 months with high risk of pneumococcal disease (such as children with sickle-cell disease, asplenia, HIV infection, chronic illness or who are immunocompromised) may not be sufficient to provide optimal protection. In these children, a 23-valent pneumococcal polysaccharide vaccine should be given

Prophylactic administration of antipyretics before or immediately after vaccine administration can reduce the incidence and intensity of post-vaccination febrile reactions. However, data suggest that the prophylactic use of paracetamol might reduce the immune response to Synflorix. The clinical relevance of this observation, as well as the impact of antipyretics other than paracetamol on the immune response to Synflorix remains unknown.

The use of prophylactic antipyretic medicinal products is recommended:

- for all children receiving Synflorix simultaneously with vaccines containing whole cell pertussis because of higher rate of febrile reactions (see section 4.8).

- for children with seizure disorders or with a prior history of febrile seizures.

Antipyretic treatment should be initiated according to local treatment guidelines.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Use with other vaccines

Synflorix can be given concomitantly with any of the following monovalent or combination vaccines [including DTPa-HBV-IPV/Hib and DTPw-HBV/Hib]: diphtheria-tetanus-acellular pertussis vaccine (DTPa), hepatitis B vaccine (HBV), inactivated polio vaccine (IPV), Haemophilus influenzae type b vaccine (Hib), diphtheria-tetanus-whole cell pertussis vaccine (DTPw), measles-mumps-rubella vaccine (MMR), varicella vaccine (V), meningococcal serogroup C conjugate vaccine (CRM₁₉₇ and TT conjugates), oral polio vaccine (OPV) and oral rotavirus vaccine. Different injectable vaccines should always be given at different injection sites.

Clinical studies demonstrated that the immune responses and the safety profiles of the co-administered vaccines were unaffected, with the exception of the inactivated poliovirus type 2 response, for which inconsistent results were observed across studies (seroprotection ranging from 78% to 100%). The clinical relevance of this observation is not known. No negative interference was observed with meningococcal conjugate vaccines irrespective of the carrier protein (CRM₁₉₇ and TT conjugates). Enhancement of antibody response to Hib-TT conjugate, diphtheria and tetanus antigens was observed.

Use with systemic immunosuppressive medicinal products

As with other vaccines, it may be expected that in patients receiving immunosuppressive treatment an adequate response may not be elicited.

Use with prophylactic administration of antipyretics

See section 4.4.

4.6 Pregnancy And Lactation

Synflorix is not intended for use in adults. Human data on the use during pregnancy or lactation and animal reproduction studies are not available.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Summary of safety profile

Clinical trials involved the administration of 12,879 doses of Synflorix to 4,595 healthy children and 137 preterm infants as primary vaccination. Furthermore, 3,870 children and 116 preterm infants received a booster dose of Synflorix in the second year of life.

Safety was also assessed in 212 previously unvaccinated children from 2 to 5 years old of which 62 subjects received 2 doses of Synflorix.

In all trials, Synflorix was administered concurrently with the recommended childhood vaccines.

In infants, the most common adverse reactions observed after primary vaccination were redness at the injection site and irritability which occurred after 38.3% and 52.3% of all doses respectively. Following booster vaccination, these adverse reactions occurred at 52.6% and 55.4% respectively. The majority of these reactions were of mild to moderate severity and were not long lasting.

No increase in the incidence or severity of the adverse reactions was seen with subsequent doses of the primary vaccination series.

Reactogenicity was similar in infants < 12 months of age and in children > 12 months of age except for injection site pain for which the incidence increased with increasing age: pain was reported by more than 31% of the infants < 12 months of age and by more than 60% of the children > 12 months of age.

Reactogenicity was higher in children receiving whole cell pertussis vaccines concomitantly. In a clinical study children received either Synflorix (N=603) or 7-valent Prevenar (N=203) concomitantly with a DTPw containing vaccine. After the primary vaccination course, fever

In comparative clinical studies, the incidence of local and general adverse events reported within 4 days after each vaccination dose was within the same range as after vaccination with 7-valent Prevenar.

List of adverse reactions

Adverse reactions (for all age groups) considered as being at least possibly related to vaccination have been categorised by frequency.

Frequencies are reported as:

Very common:	(
Common:	(
Uncommon:	(
Rare:	(

Clinical trial data

Immune system disorders

Rare: allergic reactions (such as allergic dermatitis, atopic dermatitis, eczema)

Metabolism and nutrition disorders

Very common: appetite lost

Psychiatric disorders

Very common: irritability

Uncommon: crying abnormal

Nervous system disorders

Very common: drowsiness

Rare: febrile and non-febrile convulsions

Respiratory, thoracic and mediastinal disorders

Uncommon: apnoea in very premature infants (

Gastrointestinal disorders

Uncommon: diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Rare: rash, urticaria

General disorders and administration site conditions

Very common: pain, redness, swelling at the injection site, fever

Common: injection site induration, fever >39°C rectally (age<2 years), fever

Uncommon: injection site haematoma, haemorrhage and nodule, fever >40°C rectally* (age<2 years), fever >39°C (age 2 to 5 years)

*reported following booster vaccination of primary series

Post-marketing data

Nervous system disorders:

Rare: hypotonic-hyporesponsive episode

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: pneumococcal vaccines, ATC code: J07AL52

Epidemiological data

The 10 pneumococcal serotypes included in this vaccine represent the major disease-causing serotypes in Europe covering approximately 56% to 90% of invasive pneumococcal disease (IPD) in children <5 years of age. In this age group, serotypes 1, 5 and 7F account for 3.3% to 24.1% of IPD depending on the country and time period studied.

Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can be responsible for 60-70% of clinical episodes of AOM. Streptococcus pneumoniae and Non-Typeable Haemophilus influenzae (NTHi) are the most common causes of bacterial AOM worldwide.

1. Invasive pneumococcal disease (which includes sepsis, meningitis, bacteraemic pneumonia and bacteraemia)

The protective efficacy of Synflorix against IPD has not been studied. As recommended by WHO, the assessment of potential efficacy against IPD has been based on a comparison of immune responses to the seven serotypes shared between Synflorix and another pneumococcal conjugate vaccine for which protective efficacy was evaluated previously (i.e. 7-valent Prevenar). Immune responses to the extra three serotypes in Synflorix have also been measured.

In a head-to-head comparative trial with 7-valent Prevenar, non inferiority of the immune response to Synflorix measured by ELISA was demonstrated for all serotypes, except for 6B and 23F (upper limit of the 96.5% CI around the difference between groups >10%) (Table 1). For serotypes 6B and 23F, respectively, 65.9% and 81.4% of infants vaccinated at 2, 3 and 4 months reached the antibody threshold (i.e. 0.20 µg/ml) one month after the third dose of Synflorix versus 79.0% and 94.1% respectively, after three doses of 7-valent Prevenar. The clinical relevance of these differences is not known.

The percentage of vaccinees reaching the threshold for the three additional serotypes in Synflorix (1, 5 and 7F) was respectively 97.3%, 99.0% and 99.5% and was at least as good as the aggregate 7-valent Prevenar response against the 7 common serotypes (95.8%).

Table 1: Comparative analysis between 7-valent Prevenar and Synflorix in percentage of subjects with antibody concentrations > 0.20 µg/ml one month post-dose 3

Antibody	SYNFLORIX	7-valent Prevenar	Difference in %
N	%	N	%	%	96.5%CI
Anti-4	1106	97.1	373	100	2.89	1.71	4.16
Anti-6B	1100	65.9	372	79.0	13.12	7.53	18.28
Anti-9V	1103	98.1	374	99.5	1.37	-0.28	2.56
Anti-14	1100	99.5	374	99.5	-0.08	-1.66	0.71
Anti-18C	1102	96.0	374	98.9	2.92	0.88	4.57
Anti-19F	1104	95.4	375	99.2	3.83	1.87	5.50
Anti-23F	1102	81.4	374	94.1	12.72	8.89	16.13

Post-primary antibody geometric mean concentrations (GMCs) elicited by Synflorix against the seven serotypes in common were lower than those elicited by 7-valent Prevenar. Pre-booster GMCs (8 to 12 months after the last primary dose) were generally similar for the two vaccines. After the booster dose the GMCs elicited by Synflorix were lower for most serotypes in common with 7-valent Prevenar.

In the same study, Synflorix was shown to elicit functional antibodies to all vaccine serotypes. For each of the seven serotypes in common, 87.7% to 100% of Synflorix vaccinees and 92.1% to 100% of 7-valent Prevenar vaccinees reached an OPA titre

For serotypes 1, 5 and 7F, the percentages of Synflorix vaccinees reaching an OPA titre

The administration of a fourth dose (booster dose) in the second year of life elicited an anamnestic antibody response as measured by ELISA and OPA for the 10 serotypes included in the vaccine demonstrating the induction of immune memory after the three-dose primary course.

2. Acute Otitis Media (AOM)

In a large randomised double-blind Pneumococcal Otitis Media Efficacy Trial (POET) conducted in the Czech Republic and in Slovakia, 4,968 infants received an 11-valent investigational vaccine (11Pn-PD) containing the 10 serotypes of Synflorix (along with serotype 3 for which efficacy was not demonstrated) or a control vaccine (hepatitis A vaccine) according to a 3, 4, 5 and 12-15 months vaccination schedule.

Efficacy of the 11 Pn-PD vaccine against the first occurrence of vaccine-serotype AOM episode was 52.6% (95% CI: 35.0;65.5). Serotype specific efficacy against the first AOM episode was demonstrated for serotypes 6B (86.5%, 95%CI: 54.9;96.0), 14 (94.8%, 95% CI: 61.0;99.3), 19F (43.3%, 95% CI:6.3;65.4) and 23F (70.8%, 95% CI: 20.8;89.2). For other vaccine serotypes, the number of AOM cases was too limited to allow any efficacy conclusion to be drawn. Efficacy against any AOM episode due to any pneumococcal serotype was 51.5% (95% CI: 36.8;62.9). No increase in the incidence of AOM due to other bacterial pathogens or non-vaccine serotypes was observed in this study. The estimated vaccine efficacy against any clinical episodes of otitis media regardless of aetiology was 33.6% (95% CI: 20.8; 44.3).

Based on immunological bridging of the functional vaccine response (OPA) of Synflorix with the 11-valent formulation used within POET, it is expected that Synflorix provides similar protective efficacy against pneumococcal AOM.

3. Additional immunogenicity data

Infants from 6 weeks to 6 months of age

3-dose primary schedule

In total eight studies, conducted in various countries across Europe, in Chile and in the Philippines, have evaluated the immunogenicity of Synflorix after a three-dose primary series (N=3,089) according to different vaccination schedules (6-10-14 weeks, 2-3-4, 3-4-5 or 2-4-6 months of age). A fourth (booster) dose was given in six clinical studies to 1,976 subjects. In general, comparable vaccine responses were observed for the different schedules, although somewhat higher immune responses were noted for the 2-4-6 month schedule.

2-dose primary schedule

The immunogenicity of Synflorix following a 2-dose primary vaccination schedule in subjects less than 6 months of age was evaluated in two clinical studies.

In the first study, in a post-hoc analysis, the immunogenicity two months after the second dose of Synflorix was compared with 7-valent Prevenar and the percentages of subjects with ELISA antibody concentration

In the second study, the immunogenicity after two or three doses of Synflorix was compared. Although there was no significant difference between the two groups in the percentages of subjects with antibody concentration

Table 2: Percentage of 2-dose primed subjects with antibody concentrations

Antibody
Post-primary	Post-booster
%	95% CI	%	95%CI
Anti-1	97.4	93.4	99.3	99.4	96.5	100
Anti-4	98.0	94.4	99.6	100	97.6	100
Anti-5	96.1	91.6	98.5	100	97.6	100
Anti-6B	55.7	47.3	63.8	88.5	82.4	93.0
Anti-7F	96.7	92.5	98.9	100	97.7	100
Anti-9V	93.4	88.2	96.8	99.4	96.5	100
Anti-14	96.1	91.6	98.5	99.4	96.5	100
Anti-18C	96.1	91.6	98.5	100	97.7	100
Anti-19F	92.8	87.4	96.3	96.2	91.8	98.6
Anti-23F	69.3	61.3	76.5	96.1	91.7	98.6

Table 3: Percentage of 3-dose primed subjects with antibody concentrations

Antibody
Post-primary	Post-booster
%	95% CI	%	95%CI
Anti-1	98.7	95.3	99.8	100	97.5	100
Anti-4	99.3	96.4	100	100	97.5	100
Anti-5	100	97.6	100	100	97.5	100
Anti-6B	63.1	54.8	70.8	96.6	92.2	98.9
Anti-7F	99.3	96.4	100	100	97.5	100
Anti-9V	99.3	96.4	100	100	97.5	100
Anti-14	100	97.6	100	98.6	95.2	99.8
Anti-18C	99.3	96.4	100	99.3	96.3	100
Anti-19F	96.1	91.6	98.5	98.0	94.2	99.6
Anti-23F	77.6	70.2	84.0	95.9	91.3	98.5

In the follow-up of the second study, the persistence of antibodies at 36-46 months of age was demonstrated in subjects that had received a 2-dose primary series followed by a booster dose with at least 83.7% of subjects remaining seropositive for vaccine serotypes. In subjects that had received a 3-dose primary series followed by a booster dose, at least 96.5% of the subjects remained seropositive for vaccine serotypes. A single dose of Synflorix, administered during the 4th year of life, as a challenge dose, elicited similar ELISA antibody GMCs when measured 7-10 days after challenge in 2-dose primed subjects and 3-dose primed subjects. These levels were higher than those seen after challenge of unprimed subjects. The fold increase in ELISA antibody GMCs and OPA GMTs, pre to post vaccination, was also similar in 2-dose primed subjects to that in 3-dose primed subjects. These results are indicative of immunological memory in primed subjects for all vaccine serotypes.

The clinical consequences of the lower post-primary and post-booster immune responses observed after the two-dose primary schedule are not known.

Previously unvaccinated older infants and children

The immune responses in previously unvaccinated older children were evaluated in two clinical studies.