4.1. Therapeutic indications

This medicine is a mild analgesic and antipyretic, and is recommended for the treatment of most painful and febrile conditions, for example headache including migraine and tension headaches, toothache, rheumatic and muscle pains, lower back pain, dysmenorrhea, sore throat, and for relieving the fever, aches and pains of flu and colds. Also recommended for the symptomatic relief of pain due to non-serious arthritis.

4.2. Posology and method of administration

This medicine is suitable for adults and children aged 10 years and older.

Children should not be given this medicine, for more than 3 days without consulting a doctor.

Posology

For adults and children aged 16 years and older, the usual dosage is 1 to 2 capsules (500-1000 mg) at a time, up to four times daily as required, with a maximum of 8 capsules (4000 mg) every 24 hours.

Paediatric population

A suitable dosage form should be used. See the table below for doses for children.

Age (years)

Number of capsules at a time

Frequency of dosing

Maximum number of capsules per day

Maximum daily dosage (mg)

10-15

1

up to four times daily as required

4 whole capsules

2000

≥16

1-2

up to four times daily as required

8 whole capsules

4000

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.

Instructions for use:

• The treatment should be kept as short as possible.

• The administration interval must be at least 4 hours.

• Do not exceed the recommended daily dose on account of the risk of severe hepatic damage (see section 4.4 and 4.9).

• Do not use in combination with other paracetamol-containing products.

• Depending on the recurrence of symptoms (fever and pain), repeated administration is allowed.

• If pain lasts for longer than 5 days or fever lasts for longer than 3 days or these symptoms become worse or if other symptoms occur, the treatment must be stopped, and a doctor must be consulted.

Method of administration:

Capsule

The capsules should be swallowed with enough water. The intake of paracetamol with food or drink doesn't influence the efficacy of the medicine.

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

4.4. Special warnings and precautions for use

• The recommended dose should not be exceeded.

• Long-term or frequent use is not advised.

• Patients must be advised not to use any other paracetamol-containing products at the same time.

• In the case of a high fever, symptoms of secondary infection or the persistence of symptoms, it will be necessary to reconsider the treatment.

• The taking of several daily doses at once can cause severe damage to the liver. In such cases, a loss of consciousness will not occur. However, immediate medical help must be sought even if the patient feels well because of the risk of irreversible damage to the liver (see section 4.9). Long-term use can be harmful except under medical supervision.

• Caution is required when administering paracetamol to patients with moderate to severe renal insufficiency, mild to moderate hepatic insufficiency (incl. Gilbert's syndrome), severe hepatic insufficiency (Child-Pugh > 9), acute hepatitis, the concomitant administration of medicinal products which have an influence on hepatic function, glucose-6-phosphate dehydrogenase deficiency, haemolytic anaemia, alcohol abuse, dehydration and chronic malnutrition.

• The risk of an overdose is greater in patients with non-cirrhotic alcoholic liver conditions. Caution is required in the case of chronic alcoholism. The daily dose may not exceed 2 grams in this case. No alcohol may be used during treatment with paracetamol.

• Caution is required in the case of asthmatic patients who are sensitive to acetylsalicylic acid as mild bronchospasms have been reported as a cross-reaction after the use of paracetamol.

• For children a treatment of 60 mg/kg/day of paracetamol combined with another antipyretic is not allowed, unless due to a lack of efficacy.

• After the long-term use (> 3 months) of analgesics with intake every other day or more frequently, headache can occur or become worse. Headache which is caused by the excessive use of analgesics (drug-dependent headache) must not be treated by increasing the dose. In these cases, the use of analgesics must be stopped in consultation with a doctor.

• Patients should be advised to consult a doctor if they suffer from non-serious arthritis and need to take painkillers every day.

• Caution should be exercised in patients with glutathione depleted states, as the use of paracetamol may increase the risk of metabolic acidosis (refer also to section 4.9). Use with caution in patients with glutathione depletion due to metabolic deficiencies.

• This medicine contains 20 mg propylene glycol in each soft capsule.

• This medicine contains 108 mg sorbitol liquid in each soft capsule. Sorbitol is a source of fructose. If your doctor has told you that you (or your child) have an intolerance to some sugars or if you have been diagnosed with hereditary fructose intolerance (HFI), a rare genetic disorder in which a person cannot break down fructose, talk to your doctor before you (or your child) take or receive this medicine.

• 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 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.

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

• The rate of absorption of paracetamol can be increased by metoclopramide or domperidone.

• Absorption can be reduced by cholestyramine. Therefore, ingestion of cholestyramine should not occur within one hour of the ingestion of paracetamol.

• The anticoagulatory effect of warfarin and other coumarins can increase during the long-term, regular use of paracetamol with an increase in the risk of bleeding as a result. There is no significant effect with the occasional taking of a dose.

• 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)

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Breastfeeding

Paracetamol is excreted into breast milk. No undesirable effects on nursing infants have been reported. Paracetamol 500 mg capsules, soft may be used in therapeutic dosages in breast-feeding women.

4.7. Effects on ability to drive and use machines

This medicine has no influence on the ability to drive and use machines.

4.8. Undesirable effects

At therapeutic doses few undesirable effects occur. Adverse events of paracetamol from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system class and frequency.

The frequency of undesirable effects is classified as follows: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000) and not known frequency (cannot be estimated from the available data).

System organ class

Undesirable effect

Frequency

Blood and lymphatic system disorders

Thrombocytopenia

Agranulocytosis

Very rare

Immune system disorders

Anaphylaxis

Cutaneous hypersensitivity reactions including, among others, skin rashes and angiodema. Very rare cases of serious skin reactions have been reported.

Very rare

Respiratory, thoracic and mediastinal disorders

Bronchospasm*

Very rare

Hepatobiliary disorders

Hepatic dysfunction

Very rare

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

*There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

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

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:

- 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:

The first symptoms of paracetamol overdose are pallor, nausea, vomiting, anorexia and abdominal pain and these symptoms usually appear within 24 hours after intake. 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.

Immediate treatment:

immediate hospitalization is essential for 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 24h from ingestion should be discussed with the NPIS or a liver unit.