In section 4.4, addition of warning regarding metabolic acidosis.
In section 4.8, addition of warning regarding serious skin reactions.
In section 10, revision date of text updated.

In section 4.2, the addition of:
The lowest dose necessary to achieve efficacy should be used.

In section 4.4, the addition of:
Contains paracetamol. Do not use with any other paracetamol-containing products. The concomitant use with other products containing paracetamol may lead to an overdose. Paracetamol overdose may cause liver failure which can lead to liver transplant or death.
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.

In section 4.4, the deletion of:
Patients should be advised not to take other paracetamol-containing products concurrently.

In section 4.9, the addition of:
Paracetamol overdose may cause liver failure which can lead to liver transplant or death.

There is a risk of poisoning with paracetamol particularly in elderly subjects, young children,  patients with liver disease, cases of chronic alcoholism and in patients with chronic malnutrition. Overdosing may be fatal in these cases.
Symptoms generally appear within the first 24 hours and may comprise: nausea, vomiting, anorexia, pallor, and abdominal pain, or patients may be asymptomatic.

Overdose of paracetamol in a single administration in adults or in children can cause liver cell necrosis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with increased prothrombin levels that may appear 12 to 48 hours after administration.
Liver damage is likely in adults who have taken more than the recommended amounts of paracetamol. It is considered that excess quantities of toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Some patients may be at increased risk of liver damage from paracetamol toxicity.

Risk Factors include: 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.
•    Regularly consumes ethanol in excess of recommended amounts
•    Is likely to be glutathione depleted e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia

Emergency Procedure:

Immediate transfer to hospital.

Blood sampling to determine initial paracetamol plasma concentration. In the case of a single acute overdose, paracetamol plasma concentration should be measured 4 hours post ingestion.

 Administration of activated charcoal should be considered if >150mg/kg paracetamol has been taken within 1 hour.

The antidote N-acetylcysteine, should be administered as soon as possible in accordance with National treatment guidelines

Symptomatic treatment should be implemented.

In section 4.9, the deletion of:
Immediate medical attention (in-hospital, if possible) is required in the event of overdose, even if there are no significant early symptoms.  There may be no early symptoms following a life-threatening overdose.  Ingestion of more than 12 g paracetamol (24 standard 500 mg tablets) or more than 150 mg paracetamol per kg bodyweight (9 g paracetamol in a 60 kg individual), whichever is the smaller, can cause severe liver damage.  Liver damage (as demonstrated by a rise in plasma transaminase levels) may be apparent between 8 and 36 hours following overdose.  Biochemical evidence of maximal damage, however, may not be attained until 72-96 hours after ingestion of the overdose.

Intravenous N-acetylcysteine (NAC) is effective when initiated within 8 hours of the overdose.  Efficacy declines progressively after this time, but NAC may provide some benefit up to and possibly beyond 24 hours.  Oral methionine is also effective provided that it is given within 10 to 12 hours of the overdose.  Activated charcoal should be considered if the dose of paracetamol ingested exceeds 12 g or 150 mg/kg, whichever is the smaller, and the procedure can be undertaken within 1 hour of the overdose. There is little evidence that undertaking gastric lavage will be of benefit to a patient in whom paracetamol is known to have been the only substance ingested.

Symptoms of paracetamol overdose in the first 24 hours may include pallor, nausea, vomiting, anorexia, and abdominal pain.  Abnormalities of glucose metabolism and metabolic acidosis may occur.  In severe poisoning, hepatic failure may progress to encephalopathy, coma and death.  Liver damage results when excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested) become irreversibly bound to liver tissue.  Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage.  Cardiac arrhythmias and pancreatitis have been reported.

In section 10, the deletion of:
July 2015

In section 10, the addition of:
March 2017

Section 7

Marketing Authorisation Holder address updated to:

12 Riverwalk,

Citywest Business Campus,

Dublin 24,

Ireland

Section 4.2

The following warning is added:

Maximum duration of continued use without medical advice: 3 days.

Section 4.8

Side effects updated and shown in table

Section 4.9

Last paragraph is added.