4.1. Therapeutic indications

For the treatment of mild to moderate pain including headache, migraine, neuralgia, toothache, sore throat, period pains, symptomatic relief of sprains, strains, rheumatic pain, sciatica, lumbago, fibrositis, muscular aches and pains, joint swelling and stiffness, influenza, feverishness and feverish colds.

4.2. Posology and method of administration

Adults, the elderly and young persons aged 16 and over:

2 tablets every 4 hours to a maximum of 8 tablets in 24 hours.

Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki's disease).

For migraine indication: use of this medicine is not recommended for children and adolescents (under 18 years of age).

Elderly:

Should be used with caution in elderly patients who are more prone to adverse events (see Warnings and Precautions)

Renal Impairment:

Contraindicated in patients with renal failure (e.g., Glomerular Filtration Rate (GFR) <15 mL/min/1.73m2). Aspirin is known to cause sodium and water retention which may exacerbate hypertension, congestive heart failure and renal impairment (see Contraindications, Warnings and Precautions).

Hepatic Impairment:

Contraindicated in patients with hepatic failure (see Contraindications, Warnings and Precautions).

4.3. Contraindications

This combination is contraindicated in the following conditions:

- Hypersensitivity to the active ingredients or to any other excipients.

- Patients in whom asthma, bronchospasm, angioedema, urticaria, or acute rhinitis are precipitated by aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).

- Peptic ulceration and those with a history of peptic ulceration;

- History of upper gastrointestinal bleeding or perforation, related to previous NSAID therapy.

- History of hemophilia, hypothrombinemia or other clotting disorders

- Renal failure (GFR < 15mL/min/1.73m2).

- Hepatic failure.

- Third trimester of pregnancy

children under 16 years and when breast feeding because of possible risk of Reyes Syndrome.

4.4. Special warnings and precautions for use

Serious hypersensitivity reactions or anaphylaxis can occur, bronchospasm may be precipitated in patients suffering from or with a previous history of asthma, allergic disease or nasal polyps. Aspirin should be used with caution in patients with uncontrolled hypertension (in whom target blood pressure has not been achieved), impaired renal or hepatic function, or in patients who are dehydrated or suffering from diabetes mellitus. The overall benefit-risk should be considered in patients diagnosed with hepatic or renal impairment before use. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Contains paracetamol. Do not use with any other paracetamol containing products. The concomitant use with other products containing paracetamol may lead to an overdose.

Do not take if you have a stomach ulcer.

Do not take more medicine than the label tells you to. Paracetamol overdose may cause liver failure which may require liver transplant or lead to death. Talk to your doctor at once if you take too much of this medicine, even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

Underlying liver disease increases the risk of paracetamol- related liver damage. The overall benefit-risk should be considered in patients diagnosed with hepatic or renal impairment before use.

If you do not get better, talk to your doctor.

There is a possible association between aspirin and Reye's syndrome when given to children, especially during or immediately after a viral illness. Reye's syndrome is a very rare disease, which affects the brain and liver, and can be fatal. For this reason, aspirin should not be given to children under 16 years, particularly during or immediately after chickenpox, influenza, or other viral infections, unless prescribed by a physician or specifically indicated (e.g. Kawasaki's disease).

Aspirin decreases platelet adhesiveness and increases bleeding time. Haematological and haemorrhagic effects can occur and may be severe. Patients should report any unusual bleeding symptoms to their physician.

In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, aspirin may induce haemolysis or haemolytic anaemia. Factors that may increase the risk of haemolysis are high dosage, fever, or acute infections.

Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have been reported with all NSAIDs and may occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. These effects generally have more serious consequences in the elderly (see Interactions)

Cases of hepatic dysfunction/failure have been reported in patients with depleted glutathione levels, such as those who are severely malnourished, anorexic, have a low body mass index or are chronic heavy users of alcohol or have sepsis.

In patients with glutathione depleted states, the use of paracetamol may increase the risk of metabolic acidosis.

Keep out of sight and reach of children

Should be used with caution in elderly patients who are more prone to adverse events.

The concomitant use of aspirin with other systemic NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive undesirable effects (see Interactions).

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

Aspirin can reduce uric acid excretions and therefore should be used with care in patients with gout or a history of gout.

Excessive intake of caffeine (e.g., coffee, tea and some canned drinks) should be avoided while taking this product.

4.5. Interaction with other medicinal products and other forms of interaction

Aspirin, paracetamol and caffeine combination medicines should not be used together with other non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin and cyclo-oxygenase-2 specific inhibitors as these may increase the risk of adverse effects.

Aspirin, paracetamol and caffeine combination medicines should be used with caution when taken in combination with the following drugs as interactions have been reported:

Aspirin:

Other NSAIDS and corticosteroids: Do not use in combination with other NSAIDs as these may increase the risk of adverse effects.

Thrombolytics: There is an increased risk of bleeding. Particularly, treatment with aspirin should not be initiated within the first 24 hours after treatment with alteplase in acute stroke patients. Concomitant use is therefore not recommended. (see Warnings and Precautions).

Uricosurics (e.g. probenecid, sulfinpyrazone): Aspirin may reduce the activity of uricosurics (e.g. probenecid, sulfinpyrazone) due to inhibition of tubular resorption, leading to high plasma levels of aspirin.

Loop diuretics (e.g. furosemide), diuretics and antihypertensive agents: Aspirin may reduce the activity of loop diuretics (e.g., furosemide) due to competition and inhibition of urinary prostaglandins. NSAIDs can cause acute kidney failure, especially in dehydrated patients. If a diuretic is administered simultaneously with aspirin, it is necessary to ensure adequate hydration of the patient and to monitor the kidney function and blood pressure, particularly when starting diuretic treatment.

Like other NSAIDs, concomitant use of aspirin with diuretics or antihypertensive agents (e.g., beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect. Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors, due to the increased risk of nephrotoxicity. Concomitant treatment with potassium-sparing drugs may be associated with increased serum potassium levels, which should therefore be monitored frequently.

Anticoagulants: Aspirin may enhance the effects of oral anticoagulants, such as heparin and coumarins, and of platelet aggregation inhibitors, such as ticlopidine, clopidogrel, and cilostazol, as there is an increased risk of bleeding. Clinical and laboratory monitoring of the bleeding time and prothrombin time should be performed.

Metoclopramide: Metoclopramide increases the rate of absorption of aspirin. However, concurrent use need not be avoided.

Phenytoin : Aspirin increases phenytoin serum levels; serum phenytoin should be well monitored.

Valproate: Aspirin inhibits valproate metabolism and hence could increase its toxicity; valproate levels should be well monitored.

Methotrexate ≤ 15 mg/week: The toxicity of methotrexate may be enhanced by concomitant use of aspirin. In case of concomitant use with aspirin, renal function should be monitored.

Sulphonylureas: Aspirin increases the hypoglycaemic effect of sulphonylureas, thus some downward readjustment of the dosage of the antidiabetic may be appropriate if large doses of salicylates are used. Increased blood glucose controls are recommended.

Alcohol: Co-administration of alcohol and aspirin increases the risk of gastrointestinal haemorrhage.

Antacids: Antacids may increase the excretion of aspirin by alkalinization of the urine.

Selective Serotonin Re-Uptake Inhibitors (SSRIs): Concurrent use of aspirin and SSRIs can increase the risk of gastrointestinal bleeding.

Paracetamol:

Cholestyramine: The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, the cholestyramine should not be taken within one hour if maximal analgesia is required.

Metoclopramide and Domperidone : The speed of absorption of paracetamol is increased by metoclopramide and domperidone. However, concurrent use need not be avoided.

Warfarin: 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.

Flucloxacillin:

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4)

Caffeine:

Lithium: Caffeine can increase the elimination of lithium from the body. Concomitant use is therefore not recommended.

4.6. Fertility, pregnancy and lactation

Fertility

Aspirin

There is some evidence that medicinal products that inhibit cyclo-oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment. However, no accurate data are available on when the reversibility of fertility effects occur after the treatment is suspended. Caution should be exercised when used by women who are planning on becoming pregnant.

Pregnancy

Not recommended for use during pregnancy. This medicine is contraindicated during the third trimester of pregnancy (see Contraindications).

Aspirin

Aspirin should be avoided in the first two trimesters of pregnancy unless the potential benefit to the mother outweighs the risk to the foetus in the view of the treating physician. Aspirin is contraindicated during the third trimester of pregnancy as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension (see Contraindications) and a risk of foetal renal impairment with subsequent oligohydramnios. The onset of labour may be delayed and its duration increased with an increased risk of bleeding tendency in both the mother and child. If the expected benefit to the mother is greater than the possible risk to the foetus, the lowest effective dose and the shortest duration of treatment should be considered.

Paracetamol:

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Caffeine:

Caffeine is not recommended for use during pregnancy due to the possible increased risk of spontaneous abortion associated with caffeine consumption.

Lactation

Aspirin

Aspirin appears in breast milk, and regular high doses may affect neonatal clotting. Not recommended while breast-feeding due to possible risk of Reye's Syndrome as well as neonatal bleeding due to hypoprothrombinaemia.

Paracetamol

Paracetamol is excreted in breast milk but not in a significant amount. Available published data do not contraindicate breast feeding.

Caffeine

Caffeine appears in breast milk. Irritability and poor sleeping pattern in the infant have been reported.

4.7. Effects on ability to drive and use machines

None stated.

4.8. Undesirable effects

The following convention has been utilised for the classification of the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data).

Adverse reactions from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labeled dose and considered attributable are tabulated below by MedDRA System Organ Class. As these reactions are reported voluntarily from a population of uncertain size, the frequency of these reactions is not known but likely to be rare or very rare (<1/1000).

Adverse events are more likely to occur with increasing dose and duration of use.

MedDRA SOC

Adverse Reaction

Frequency

Aspirin

Blood and lymphatic system disorders

Prolonged bleeding time, thrombocytopenia, ecchymosis.

Not known

Immune system disorders

Hypersensitivity reactions (e.g. anaphylaxis, angioedema, bronchospasm, urticaria, skin reactions and rhinitis).

Not known

Respiratory, thoracic and mediastinal disorders

Aspirin-exacerbated respiratory disease

Very rare

Metabolism and Nutrition disorders

Sodium and fluid retention.

Not known

Ear and labyrinth disorders

Temporary hearing loss, tinnitus.

Not known

Gastrointestinal disorders

Gastrointestinal haemorrhage, gastrointestinal ulceration, vomiting, gastritis, nausea, and dyspepsia.

Not known

Hepatobiliary disorders

Reye's syndrome (see Warnings and Precautions).

Elevation in aminotransferase levels.

Not known

Renal and urinary disorders

Renal dysfunction, increased blood uric acid levels.

Not known

Paracetamol

Blood and lymphatic system disorders

Thrombocytopenia.

Very rare

Immune system disorders

Anaphylaxis

Cutaneous hypersensitivity reactions including, among others, skin rashes, angioedema, Stevens–Johnson syndrome and Toxic Epidermal Necrolysis.

Very rare

Metabolism and nutrition disorders

High anion gap metabolic acidosis (cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients).

Not known

Respiratory, thoracic and mediastinal disorders

Bronchospasm in patients sensitive to aspirin and other NSAIDs.

Very rare

Hepatobiliary disorders

Hepatic dysfunction.

Very rare

Caffeine

Central Nervous System

Dizziness, headache.

Not known

Cardiac disorders

Palpitation.

Not known

Psychiatric disorders

Insomnia, restlessness, anxiety and irritability, nervousness.

Not known

Gastrointestinal disorders

Gastrointestinal disturbances.

Not known

When the recommended aspirin-paracetamol-caffeine dosing regimen is combined with dietary caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeine-related adverse effects.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

This product contains both paracetamol and aspirin, and as such, any overdose events should be assessed using information available on both active substances.

Liver damage is possible in adults who have taken 10g or more of paracetamol. Adults who have consumed more than 5g of paracetamol, may experience liver damage if they have one of the following risk factors:

• long term treatment with either anti-infectives, anti-epileptics or St John's Wort, or any other drugs that induce liver enzymes

• regular consumption of ethanol in excess of recommended amounts

• likely to be glutathione deplete e.g. eating disorder, cystic fibrosis, HIV infection, starvation, cachexia.

Salicylate poisoning is usually associated with plasma concentrations >350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Symptoms

Common features exist for both active substances when taken in overdose, but these can be tabulated as follows:

Paracetamol

Aspirin

Caffeine

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain.

Liver damage is possible in adults who have taken 10g or more of paracetamol. Adults who have consumed more than 5g of paracetamol, may experience liver damage if they have one of the following risk factors:

•long term treatment with either anti-infectives, anti-epileptics or St John's Wort, or any other drugs that induce liver enzymes

•regular consumption of ethanol in excess of recommended amounts

•likely to be glutathione deplete e.g. eating disorder, cystic fibrosis, HIV infection, starvation, cachexia

Symptoms of paracetamol overdosage after 12-48 hours are:

•Liver damage

•Abnormalities of glucose metabolism and metabolic acidosis

•Severe poisoning: Hepatic failure may progress to Encephalopathy, Haemorrhage, Hypoglycaemia, cerebral oedema, and death.

•With or without severe liver damage: Acute renal failure with acute tubular necrosis strongly suggested by loin pain, haematuria and proteinuria.

Common:

Vomiting, Dehydration, Tinnitus

Vertigo, Deafness, Sweating

Warm extremities with bounding pulses Increased respiratory rate

Hyperventilation

Acid base disturbance

Mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) in adults and children aged over 4 years.

In children aged 4 years or less, a dominant metabolic acidosis with law arterial pH (raised hydrogen ion concentration) is common.

Acidosis can increase salicylate transfer across the blood brain barrier.

Uncommon:

Haematemesis

Hyperpyrexia

Hypoglycaemia

Hypokalaemia

Thrombocytopenia

Increased INR/PTR

Intravascular coagulation

Renal failure

Non-cardiac pulmonary oedema

Confusion, disorientation, coma and convulsions are more common in children than adults.

Other symptoms of overdosage, associated with the caffeine component, include:

CNS stimulation; agitation, anxiety, nervousness, restlessness, insomnia, excitement, muscle twitching, confusion, convulsions

Cardiac: tachycardia, cardiac arrhythmia

Gastric: Abdominal or stomach pains, vomiting

Other: diuresis, facial flushing

For clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related liver toxicity.

Management

Paracetamol:

Immediate treatment is essential in the management of overdose due to the paracetamol content of the product.

If overdose is confirmed or suspected, seek immediate advice from your Poison Centre and refer patient to nearest Emergency Medical Centre for management and expert treatment. This should happen even in patients without symptoms or signs of overdose due to the risk of delayed liver damage. Where a Poison Information Centre is not available, refer patient to the nearest Emergency Medical Centre for management and expert treatment.

There may be few or no initial symptoms, and these can 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 concentrations 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, or are under 10 years or over 70, beyond 24h from ingestion should be discussed with the National Poisons Information Service (NPIS) or a liver unit.

Salicylates:

Give activated charcoal if an adult presents within one hour of ingestion of more than 120 mg/kg

Plasma salicylate concentrations should be measured although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account.

Elimination of aspirin is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Metabolic acidosis should be corrected with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features.

Patients under 10 years or over 70 years of age may be at an increased risk of salicylate toxicity and may require dialysis at an earlier stage.

Caffeine:

Treatment of caffeine overdose is primarily symptomatic and supportive. Diuresis should be treated by maintaining fluid and electrolyte balance and CNS symptoms can be controlled by intravenous administration of diazepam