4.1. Therapeutic indications

Headache including migraine and tension headaches, toothache, backache, rheumatic and muscle pains, dysmenorrhoea, sore throat, and for relieving the fever, aches and pains of colds and flu. Also recommended for the symptomatic relief of pain due to non-serious arthritis.

4.2. Posology and method of administration

Adults, the elderly, and children aged 16 years and over:

One or two tablets every 4-6 hours , if you need to. Do not take more than 8 tablets in any 24 hours.

Children:

Aged 10 - 15 years:

One tablet every 4-6 hours, if you need to. Do not take more than 4 tablets in any 24 hours.

Do not give children under 10 years of age.

Children should not be given Paracetmol 500mg tablets for more than 3 days without consulting a doctor.

These doses should not be repeated more frequently than every four hours nor should more than four doses be given in any 24 hour period.

Oral administration only.

4.3. Contraindications

Hypersensitivity to paracetamol or any of the constituents.

4.4. Special warnings and precautions for use

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 or 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.

Caution should be exercised in asthma patients who are sensitive to acetylsalicylic acid, since mild reactions of bronchospasm have been reported with paracetamol (cross-reaction).

In patients with glutathione-depleted conditions such as sepsis, the use of paracetamol may increase the risk of metabolic acidosis.

Caution in liver disease. Do not combine with other analgesic drugs containing paracetamol (eg combination medicine). Higher doses than recommended may result in very severe liver damage. Clinical signs of liver injury usually start after a couple of days and usually culminate in 4-6 days. Antidote should be given as early as possible. See also section 4.9 Overdose. In case of high fever, signs of secondary infection or if the symptoms last longer than 3 days, treatment should be reassessed.

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

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)

Studies have shown that the effect of warfarin may be enhanced during treatment with paracetamol. The effect appears to increase with the dose of paracetamol but may occur at doses of 1.5-2.0 g of paracetamol per day for at least 5-7 days. Single doses of paracetamol in normal dosage are considered to have no effect.

Pharmacokinetic interactions

Enzyme-inducing drugs, such as certain antiepileptics (phenytoin, phenobarbital, carbamazepine) have been shown to decrease to approximately 60% of plasma AUC of paracetamol in pharmacokinetic studies. Other substances with enzyme inducing properties, eg rifampicin and St. John's Wort (Hypericum) are also suspected of lowering paracetamol concentrations. In addition, the risk may be greater for liver injury when treated with the maximum recommended dose of paracetamol in patients on enzyme inducing drugs.

Probenecid almost halves the clearance of paracetamol by inhibiting its conjugation with glucuronic acid. This would mean that the dose of paracetamol may be halved when co-administered with probenecid.

The absorption rate of paracetamol may be increased by metoclopramide, but the substances can be given in combination. The absorption of paracetamol is reduced by cholestyramine. Colestyramine should not be given within one hour if maximum analgesic effect is to be achieved.

Paracetamol may affect the pharmacokinetics of chloramphenicol. Therefore, plasma-based chloramphenicol is recommended for combination therapy.

4.6. Fertility, pregnancy and lactation

Pregnancy: No known risks during use during pregnancy. A large amount of data from pregnant women indicates neither malformations, fetal toxicity nor neonatal toxicity. Paracetamol may be used during pregnancy if clinically motivated, but it should be used with the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Lactation: Paracetamol passes into breast milk but the risk of affecting the child seems unlikely with therapeutic doses.

4.7. Effects on ability to drive and use machines

Paracetamol has no or negligible effect on the ability to drive and use machines.

4.8. Undesirable effects

Adverse effects of paracetamol are rare. Very rare cases of serious skin reactions have been reported. There have been reports of blood dyscrasias including thrombocytopenia purpura, methaemoglobenaemia and agranulocytosis, but these were not necessarily causality related to paracetamol.

Blood and lymphatic system disorders

Very rare (<1/10 000)

Thrombocytopenia

Agranulocytosis

Immune system disorders

Very rare (<1/10 000)

Anaphylaxis

Respiratory, thoracic and mediastinal disorders

Very rare (<1/10 000)

Bronchospasm

Kidney and urinary tract

Very rare (<1/10 000)

renal effects

Skin and subcutaneous tissue

Rare (> 1/10 000 to <1/1 000)

Very rare (<1/10 000)

Exanthem, urticaria, angioedema

Allergic dermatitis

Hepatobiliary disorders

Rare (> 1/10 000 to <1/1 000)

Very rare (<1/10 000)

Hepatic dysfunction

Liver damage

Metabolism and nutrition disorders

Not known (cannot be estimated from the available data)

High anion gap metabolic acidosis*

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.

*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.

4.9. Overdose

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.

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 hours from ingestion should be discussed with the NPIS or a liver unit.