SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Paracetamol, Codeine, Caffeine & Doxylamine Compound Tablets Boots Pharmacy Tension Headache Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Paracetamol 450 mg Codeine Phosphate 10.0 mg Doxylamine Succinate 5.0 mg Caffeine 30.0 mg

3    PHARMACEUTICAL FORM

Tablets

4.1    Therapeutic indications

This product (which contains codeine) is indicated in patients older than 12 years of age for the short term treatment of acute moderate pain which is not considered to be relieved by paracetamol, ibuprofen or aspirin alone. Boots Tension Headache Relief is recommended for the relief of headache, including muscle contraction or tension headache, migraine, neuralgia, toothache, dysmenorrhoea, muscular and rheumatic aches and pains, and post-operative analgesia following surgical or dental procedures.

Posology and method of administration

Route of administration: Oral

Adults:

One or two tablets every four to six hours as needed for relief. Total dosage over a 24 hour period should not normally exceed eight tablets.

Children aged 12 years to 18 years:

One or two tablets every four to six hours as needed for relief. Total dosage over a 24 hour period should not normally exceed eight tablets.

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).

Elderly:

Dosage as for Adults

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

The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.

4.3 Contraindications

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

Concomitant treatment with Monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment (see section 4.5).

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

Do not exceed the stated dose.

Do not take concurrently with any other paracetamol or codeine containing products.

Keep out of the reach and sight of children.

Care is advised in the administration of this product in patients with severe renal or hepatic impairment.

Paracetamol:

The hazards of overdose are greater in those with (non-cirrhotic) alcoholic liver disease.

Doxylamine:

Use with caution in patients with prostatic hypertrophy, urinary retention, and susceptibility to angle-closure. This product may cause drowsiness. This product should not be used to sedate a child.

Codeine:

CYP2D6 metabolism

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme anadequate analgesic effect will not be obtained. 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 commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimates 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%
Northern European	1%-2%

Post-operative use in children

There have been reports in the published literature that codeine given post-operatively 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 ultrarapid 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.

Care is advised in the administration of codeine to patients with hypotension, hypothyroidism, adrenocortical insufficiency, shock, obstructive bowel disorders, acute abdominal conditions (e.g. peptic ulcer), recent gastrointestinal surgery, gallstones, myasthenia gravis, a history of cardiac arrhythmias, a history of peptic ulcer or convulsions and also in patients with a history of drug abuse or emotional instability.

Codeine may induce paralytic ileus (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.

Prolonged regular use of codeine, 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 with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Immediate medical advice should be sought in the event of overdosage, even if you feel well because of the delayed risk of liver damage.

If you are pregnant or are being prescribed medicines by your doctor, seek this advice before taking this product.

The label will state:

Front of Pack

•    Can cause addiction

•    For three days use only

Back of Pack

•    For the short term treatment of acute moderate pain such as headache, tension headache, migraine, rheumatic and muscular aches and pains, period pain, neuralgia, toothache and pain after surgical procedures that is not relieved by aspirin, ibuprofen or paracetamol alone. Do not take less than four hours after taking other pain killers.

•    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 in children over 12 years of age for the short term treatment of acute moderate pain such as headache, tension headache, migraine, rheumatic and muscular aches and pains, period pain, neuralgia, toothache and pain relief after dental or surgical operations that is not relieved by aspirin, ibuprofen or paracetamol 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 them worse

Section 1: What the medicine is for

• This medicine can only be used for the short term treatment of acute moderate pain such as headache including those involving tense muscles or tension headache, migraine, rheumatic and muscular aches and pains, period pain, neuralgia, toothache and pain relief after dental and surgical operations that is not relieved by aspirin, ibuprofen or paracetamol alone

Section 2: Before taking • This medicine contains codeine which can cause addiction if you take it for more than 3 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 3 days it can make them worse

Section 3: Dosage

•    Do not take for more than 3 days. If you need to use 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.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard By reporting side effects, you can help provide more information on the safety of this medicine.

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 Interaction with other medicinal products and other forms of interaction

Paracetamol:

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.

Medicinal products which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdose.

Doxylamine:

CNS depressants: may enhance the sedative effects of CNS depressants including barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives, antipsychotics, and alcohol.

Antimuscarinic drugs: may have an additive muscarinic action with other drugs, such as atropine and some antidepressants.

MAOIs: not be used in patients taking MAOIs or within 14 days of stopping treatment as there is a risk of serotonin syndrome.

Codeine:

The depressant effects of codeine are enhanced by depressants of the central nervous system such as alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants or antipsychotics and phenothiazines.

The hypotensive actions of diuretics and anti hypertensive agents may be potentiated when used concurrently with opioid analgesics.

Concurrent use of hydroxyzine (anxiolytics) with codeine may result in increased analgesia as well as increased CNS depressant, sedative 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 muscarinic action, e.g. atropine and some antidepressants may result in an increased risk of severe constipation which 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.

Concomitant aadministration of pethidine and possibly other opioid analgesics to patients taking MAOIs has been associated with very severe and sometimes fatal reactions such as severe CNS excitation or depression, including hypertension or hypotension. Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

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.

Naxolone 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.

Caffeine undergoes extensive metabolism by hepatic microsomal cytochrome P450, factors known to alter the activity of this enzyme system may influence caffeine clearance. Thus, caffeine elimination is enhanced in cigarette smokers and inhibited by cimetidine, disulfiram and oral contraceptive steroids.

Alcoholic drink should be avoided

4.6 Fertility, pregnancy and lactation

The product should not be used during pregnancy unless considered essential by the physician.

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.

Lactation/Breastfeeding:

Codeine:

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

At normal therapeutic doses codeine and its active metabolite 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 metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.

If symptoms of opioid toxicity develop in either then 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.

Caffeine:

Caffeine is excreted in breast milk but at levels which are not thought to present a hazard, although irritability and a poor sleeping pattern have been reported.

4.7 Effects on ability to drive and use machines

Some side effects related to doxylamine succinate include drowsiness (usually diminishes within a few days), paradoxical stimulation, headaches, psychomotor impairment, hypotension, dizziness, confusion, tremor and convulsions.

Opioid analgesics can impair mental function and cause blurred vision and dizziness. Rare side effects may include convulsions, hallucinations, blurred or double vision, dizziness and orthostatic hypotension

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

See section 4.8 for more information on side effects.

4.8 Undesirable effects

Paracetamol:

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

Codeine:

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, which occur rarely, including 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.

Doxylamine succinate:

Common side-effects:

CNS effects: Doxylamine succinate may cause drowsiness (usually diminishes within a few days), paradoxical stimulation, headache, and psychomotor impairment.

Antimuscarinic effects:-urinary retention, dry mouth, blurred vision, gastrointestinal disturbances, thickened respiratory tract secretions.

Rare side-effects include: Hypotension, extrapyramidal effects, dizziness, confusion, depression, sleep disturbances, tremor, convulsions, palpitation, arrhythmia, hypersensitivity reactions, blood disorders and liver dysfunction.

Caffeine:

The most commonly reported adverse effects following dosing with caffeine are GI irritation and CNS stimulation. Adverse CNS effects include insomnia, restlessness, nervousness and mild delirium; adverse GI effects include nausea, vomiting and gastric irritation.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. 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

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

Or

b,    Regularly consumes ethanol in excess of recommended amounts.

Or

c,    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 to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, 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, see BNF overdose section.

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). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion.

The effectiveness of the antidote declines sharply after this time. 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. Management of patients who present with serious hepatic dysfunction beyond 24 h from ingestion should be discussed with the NPIS or a liver unit.

Codeine

Symptoms:

While the dose of Codeine Phosphate in this preparation is relatively small and therefore less likely to prove a problem, symptoms of overdosage 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.

Management:

Initial treatment includes emptying the stomach by aspiration and lavage. This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Intensive support therapy may be required to correct respiratory failure and shock. 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. In addition the specific narcotic antagonist, naloxone hydrochloride, may be used rapidly to counteract the severe respiratory depression and coma.

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 four hours after ingestion, or eight hours if a sustained release preparation has been taken. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

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 5-10pg/kg body weight may be given intravenously or intramuscularly. Codeine is not dialysable.

Doxylamine

Symptoms:

In evaluation of cases of intoxication with doxylamine, no correlation was found between the amount ingested or plasma concentration and the frequency or extent of symptoms. The most common symptom was impaired consciousness.

Psychotic behaviour, seizures, and antimuscarinic symptoms such as tachycardia and mydriasis were also seen. Rhabdomyolysis had been noted in cases of doxylamine overdosage, with an associated rise in plasma creatine kinase and myoglobinuria, and suggested that doxylamine has a direct toxic effect on striated muscle.

Management:

If clinical symptoms of doxylamine succinate overdose are suspected, consult a doctor or the NPIS immediately. Rhabdomyolysis and secondary acute renal failure are rare but potentially serious complications, making early recognition and treatment essential. Treatment of rhabdomyolysis induced by doxylamine overdose is by aggressive hydration and urine alkalisation.

Aggressive hydration with intravenous crystalloids such as 0.9% saline (NS) or lactated Ringer’s solution (LR) at a rate of 300 - 500 ml/h in an adult is essential. To date, it has been believed that there is no difference in effectiveness between NS and LR

Caffeine

The most commonly reported adverse events following dosing with caffeine are GI irritation and CNS stimulation. Adverse CNS effects include insomnia, restlessness, nervousness and mild delirium; adverse GI effects include nausea, vomiting and gastric irritation.

Fatal poisoning is rare. If symptoms become apparent or overdose is suspected, consult a doctor immediately.

5.1 Pharmacodynamic properties

Paracetamol: Anagesic, Antipyretic

Codeine Phosphate: Analgesic

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through p opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

Doxylamine Succinate: Antihistamine

Caffeine: Mild Stimulant

5.2 Pharmacokinetic properties

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

5.3 Preclinical safety data

No data held.

6.1    List of excipients

Maize starch

Povidone

Talc

Magnesium Stearate Croscarmellose

6.2    Incompatibilities

Not applicable

6.3    Shelf life

24 months

6.4    Special precautions for    storage

None stated.

6.5    Nature and contents of    container

Blister Strips: 250p PVC base material with an aluminium foil 20p coated with a 15p PVC layer.

Blister strips are presented in cardboard cartons Pack sizes are 4*, 10, 20, 24, 30, or 32 (*sample pack).

6.6    Special precautions for    handling and disposal

None applicable.

MARKETING AUTHORISATION HOLDER

SSL International plc,

103-105 Bath Road

Slough

Berkshire

SL13UH

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 17905/0065

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/06/1997

10    DATE OF REVISION OF THE TEXT

29/07/2014