1. NAME OF THE MEDICINAL PRODUCT

Co-Codamol Plus Caffeine Tablets Syndol Headache Relief Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

INGREDIENT	QTY	UNIT	DOSE
Paracetamol	500	mg	Per tablet
Caffeine	30	mg	Per tablet
Codeine Phosphate	8	mg	Per tablet

3    PHARMACEUTICAL FORM

Tablet

White, capsule-shaped with dimensions of 17.55 mm x 7.5 mm and debossed on one face to read PCC.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone.

Suitable for migraine, headache, rheumatic pain, period pain, toothache and neuralgia.

4.2.    Posology and method of administration

Adults, the elderly and children over 12 years of age:

2 tablets taken with water every 4 hours.

Do not give to children under 12 years of age.

Not more than 8 tablets in 24 hours.

Do not take for more than three days continuously without medical review. If no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.

Children aged less than 12 years:

Codeine should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4)

.3. Contra-indications

Hypersensitivity to paracetamol, caffeine, codeine or any of the other constituents. Conditions where morphine and opioids are contra-indicated, e.g. acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra-cranial pressure, paralytic ileus and following biliary tract surgery.

In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4)

In women during breastfeeding (see section 4.6)

In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.

4.4. Special Warnings and Precautions for Use

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

Care should be taken in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, in whom there is increased sensitivity to the central and gastro-intestinal effects, those on concurrent treatment with other CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders.

Debilitated patients should discuss their treatment prior to taking this medicine, as well as patients suffering from hypotension and hypothyroidism.

Patients should be advised not to exceed the recommended dose as taking a painkiller for headaches too often or for too long can make them worse.

Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped.

Patients should be advised that they should not take this product for more than 3 days continuously without consulting a doctor.

Patients should be advised not to take other paracetamol-containing products concurrently.

If symptoms persist, patients should consult a doctor.

Keep out of the reach and sight of children.

Codeine is partially metabolised by CYP2D6 into morphine, its active metabolite. 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 extensive or ultra-rapid metaboliser there is an increased risk of developing

side effects of opioid toxicity even at low doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels. General symptoms of opioid toxicity include confusion, shallow breathing, small pupils, nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimate of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Population	Prevalence %
African/ Ethiopian	29%
African American	3.4% to 6.5%
Asian	1.2% to 2%
Caucasian	3.6% to 6.5%
Greek	6.0%
Hungarian	1.9%
North European	1%-2%

Post-operative use in children

There have been reports in the published literature that codeine given postoperatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

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

Usually it is safe to take “brand name” 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.

The label will state:

Front of Pack:

• Can cause addiction

•    For three days use only Back of Pack

•    List of indications as agreed in 4.1 of the SmPC

•    If you need to take this medicine continuously for more than three days you should see your doctor or pharmacist

•    This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse

The leaflet will state:

Headlines section (to be prominently displayed)

•    This medicine can only be used for acute moderate pain, which is not relieved by paracetamol, ibuprofen or aspirin alone.

•    You should only take this product for a maximum of three days at a time. If you need to take it for longer than three days you should see your doctor or pharmacist for advice

•    This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it

•    If you take this medicine for headaches for more than three days it can make then worse

Section 1: What is this medicine for

•    Succinct description of the indications from 4.1 of the SmPC

Section 2: Before taking

•    This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it

•    If you take a painkiller for headaches for more than three days it can make them worse

3: Dosage

Do not take for more than 3 days. If you need to take this medicine for more than three days you must speak to your doctor or pharmacist This medicine contains codeine and can cause addiction if you take it continuously for more than three days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms

Section 4: Side effects

•    Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk; alternatively you can call

Freephone 0808 100 3352 (available between 10am-2pm Monday - Friday) or fill in a paper form available from your local pharmacy.

How do I know if I am addicted?

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:

•    You need to take the medicine for longer periods of time

•    You need to take more than the recommended dose

•    When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again

4.5. Interactions with other Medicaments and other forms of Interaction

Paracetamol may delay the elimination of chloramphenicol. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone, and absorption reduced by cholestyramine. Codeine may antagonise the gastrointestinal effects of metoclopramide and domperidone

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 use of drugs which induce hepatic microsomal enzymes, such as anticonvulsants, oral contraceptive steroids, alcohol and barbiturates, may increase the hepatotoxicity of paracetamol, particularly after overdosage by increasing the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate.

The metabolism of opioid analgesics is inhibited by cimetidine, which results in increased plasma concentrations.

Sedative effects are possibly increased when opioid analgesics are given with tricyclic antidepressants.

Mexiletine absorption may be delayed when taken concurrently with opioid analgesics and thus reduce the antiarrhythmic effect of the mexiletine.

The use of opioid analgesics should be given with care to patients receiving antipsychotic drugs, as enhanced hypotensive and sedative effects may be experienced.

CNS depression or excitation may occur if codeine is given to patients receiving mono-amine oxidase inhibitors, or within two weeks of stopping treatment with them, including moclobemide. The effects of CNS depression (including alcohol, anxioytics such as sodium oxybate) may be potentiated by codeine.

Concurrent use of codeine with antidiarrhoeal and antiperistaltic agents may increase the risk of severe constipation. Concomitant use of antimuscarinics or medications with antimucarinic action may result in an increased risk of severe constipation, which may lead to paralytic ileus and/or urinary retention.

Quinidine can inhibit the analgesic effect of codeine.

Naltrexone blocks the therapeutic effect of opioids.

Cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma concentration.

4.6. Fertility, pregnancy and Lactation

There is inadequate evidence on the use of codeine in human pregnancy. Codeine crosses the placenta and should be used with caution in pregnancy.

Epidemiological studies in human pregnancy, have shown no ill effects due to paracetamol and caffeine use in the recommended dosage, but patients should follow medical advice regarding its use.

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

Codeine should not be used during breastfeeding (see section 4.3).

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 and may be fatal.

4.7 Effects on Ability to Drive and Use Machines

Patients should not drive or operate machinery if affected by drowsiness.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When taking this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been taken to treat a medical or dental problem and

You have taken it according to the information provided with the medicine and o It was not affecting your ability to drive safely

4.8. Undesirable effects

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:

Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to<1/1000) and very rare (<1/10,000), not known (cannot be estimated from the available data)

Paracetamol

Blood and lymphatic system disorders

Not known: blood dyscrasias* (blood disorder), thrombocytopenia* (thrombocytopenia), agranulocytosis* (agranulocytosis)

Immune system disorders

Not known: hypersensitivity (hypersensitivity)

Skin and subcutaneous tissue disorders Not known: skin rash (rash)

Very rare cases of serious skin reactions have been reported.

*not necessarily causally related to paracetamol Caffeine

High doses of caffeine may produce

Psychiatric disorders

Not known: nervousness (nervousness)

Nervous system disorders

Not known: headache (headache), tremor (tremor)

General disorders and administration site conditions Not known: irritability

Codeine

Immune system disorders

Not known: allergic reactions (hypersensitivity)

Psychiatric disorders

Not known: dysphoria (dysphoria), hallucinations (hallucination), mood changes (mood altered), confusion (confusional state), decreased libido (libido decreased), nightmares (nightmare), restlessness (restlessness)

Nervous system disorders

Not known: dizziness (dizziness), light-headedness (dizziness), drowsiness (somnolence)

Eye disorders

Not known: miosis (miosis), blurred vision (vision blurred), double vision (diplopia)

Ear and labyrinth disorders Not known: vertigo (vertigo)

Cardiac disorders

Not known: bradycardia (bradycardia), palpitations (palpitations), tachycardia (tachycardia)

Vascular disorders

Not known:    postural    hypotension (orthostatic hypotension), hypotension

(hypotension), facial flushing (flushing)

Respiratory, thoracic and mediastinal disorders

Not known: respiratory depression (respiratory depression)

Gastrointestinal disorders

Not known: constipation (constipation), nausea (nausea), vomiting (vomiting), dry mouth (dry mouth), stomach cramps (abdominal pain upper)

Hepatobiliary disorders

Not known: biliary spasm (biliary spasm)

Skin and subcutaneous tissue disorders

Not known: pruritus (pruritus), sweating (hyperhidrosis), urticaria (urticaria), rash (rash)

Musculoskeletal and connective tissue disorders Not known: muscle rigidity (muscle rigidity)

Renal and urinary disorders

Not known: urinary retention (urinary retention), uretic (ureteral spasm), difficulties in micturition (dysuria), dysuria (dysuria), increased frequency (polyuria)

Reproductive system and breast disorders

Not known: decreased potency (erectile dysfunction)

General disorders and administration site conditions

Not known: hypothermia (hypothermia), facial oedema (face oedema)

Investigations

Not known: decrease in amount (urine output decreased)

The frequency and severity are determined by dosage, duration of treatment and individual sensitivity, and are unlikely at this dosage. Tolerance and dependency can occur, especially with prolonged high doses of codeine.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Paracetamol

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. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient:

§ Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

§ Regularly consumes ethanol in excess of recommended amounts.

Or

§ Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

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 in encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, coma and death. Acute renal failure with acute tubular necrosis strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

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 .Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) but results should not delay initiation of treatment beyond 8 hours after ingestion, as the effectiveness of the antidote declines sharply after this time. Activated charcoal should not be used if it is anticipated that oral methionine will be given to the patient. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Codeine

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

Codeine overdose associated with central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless sedative agents have been coingested, 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.

Symptoms of codeine overdose also include cold clammy skin, confusion, convulsions, dizziness, drowsiness, nervousness or restlessness, miosis, bradycardia, dyspnoea, unconsciousness and weakness.

Management of codeine overdose 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 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. A dose of 0.4-2mg is given intravenously or intramuscularly to adults, this is repeated at intervals of 2-3 minutes if necessary up to 10mg naloxone may be given. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken. Codeine is not dialysable.

Caffeine

Caffeine overdose may cause diuresis, tachycardia, irritability, nervousness, restlessness, gastrointestinal disturbance and CNS stimulation such as agitation, excitement, insomnia and tremors. Lethal doses of caffeine tend to be between 5 -10g. The management of caffeine toxicity is generally symptomatic and supportive (e.g. hydration). For acute ingestion gastric lavage is advised.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Paracetamol has analgesic, antipyretic and mild anti-inflammatory properties. It inhibits prostaglandin synthesis, especially in the Central Nervous System.

Paracetamol does not inhibit chronic inflammatory reactions.

Caffeine acts on the Central Nervous System, on muscle, including the cardiac muscle, and on the kidneys. Its action on the CNS is mainly on the higher centres and produces a condition of wakefulness and increased mental activity.

Codeine Phosphate is an opioid analgesic. It acts mostly on the Central Nervous System and on smooth muscle.

5.2 Pharmacokinetic properties

Paracetamol is rapidly absorbed from the upper gastrointestinal tract after oral administration with the small intestine being an important site of absorption. Paracetamol is satisfactorily absorbed from the rectum, but with greater variation than following oral administration.

Peak blood levels of 15-20 micrograms per ml after normal 1g doses of paracetamol occur within 30-60 minutes depending on dosage form. It is rapidly distributed throughout the body and is primarily metabolised in the liver with excretion via the kidney. Elimination half-life is about 2 hours after reaching a peak following a 1g oral dose.

Caffeine is absorbed readily after oral administration but absorption from the gastrointestinal tract may be erratic. There is little evidence of accumulation in any particular tissue.

Caffeine passes readily into the Central Nervous System and into saliva; concentrations have also been detected in breast milk.

Caffeine is metabolised almost completely and is excreted via the kidney.

Caffeine has a plasma half-life of approximately 3.5 hours and peak plasma concentrations may occur some 50 - 75 minutes after oral administration.

Codeine Phosphate is absorbed from the gastrointestinal tract. Ingestion of Codeine Phosphate produces peak plasma concentrations in approximately 1 hour. Codeine is metabolised in the liver, and the metabolites are excreted almost entirely by the kidney, largely as inactive forms.

The half-life of Codeine in plasma is 2-4 hours.

5.3 Preclinical safety data

Not applicable

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Maize Starch Methylcellulose Polyvidone Purified Water Talc

Calcium Stearate

Coating

Methylhydroxypropylcellulose (5) Methylhydroxypropylcellulose (15) Polyethylene Glycol 3350 NF

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

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

6.5. Nature and contents of container

Opaque white UPVC/Aluminium foil blisters inside a carton.

30 micron pyamidally embossed hard temper aluminium (with 250 micron PVC blisters).

OR

35gsm Glassine (Pergamin) paper/9 micron soft tamper aluminium foil/250 micron PVC.

8 tablets per blister, either 1, 2, 3 or 4 strips per carton. 10 tablets per blister, either 1 or 3 strips per carton. 12 tablets per blister strip, either 1 or 2 strips per carton.

6.6    Special precautions for disposal

None

7    MARKETING AUTHORISATION    HOLDER

Wrafton Laboratories Limited

Wrafton

Braunton

North Devon EX33 2DL United Kingdom

8    MARKETING AUTHORISATION    NUMBER(S)

PL 12063/0028

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/11/1999 / 04/03/2009

DATE OF REVISION OF THE TEXT

14/06/2016