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 24h from ingestion should be discussed with the NPIS or a liver unit.
High doses of sodium bicarbonate may be expected to induce gastrointestinal symptoms including belching and nausea. In addition, high doses of sodium bicarbonate may cause hypernatraemia; electrolytes should be monitored and patients managed accordingly.
None known.
Preclinical safety data on paracetamol in the literature have not revealed any findings which are of relevance to the recommended dosage and use of the product and which have not been mentioned in other sections of the SmPC.
ATC Code N02B E01
Paracetamol has analgesic and antipyretic actions. The mechanism of action is based on the inhibition of prostaglandin biosynthesis.
Paracetamol is poorly absorbed in the stomach but well absorbed in the small intestine due to the greater surface area and hence adsorptive capacity.
Sodium bicarbonate is an excipient in the formulation which has a role in increasing the rates of gastric emptying and of paracetamol dissolution and hence the speed of absorption of paracetamol to provide faster onset of relief.
The amount of sodium bicarbonate contained in 2 tablets of Paracetamol Actavis ActiFast are required per dose to have such effects. Sodium bicarbonate influences the rate of gastric emptying in a concentration dependant manner with the maximal effect achieved at near isotonic concentrations (150 mmol/litre)(i.e. 150 millimolar) - equivalent to 2 Paracetamol Actavis ActiFast tablets in 100 ml water.
Hypertonic solutions (500-1,000 mmol/litre)(i.e. 500 to 1,000 millimolar - equivalent to the amount of sodium bicarbonate in 6-12 Paracetamol Actavis ActiFast tablets given with 100 ml water) appear to inhibit gastric emptying. The therapeutic application of enhanced gastric emptying has previously been demonstrated with significantly faster rate of absorption of paracetamol and significantly faster onset of pain relief from soluble tablets containing sodium bicarbonate compared to conventional tablets. Paracetamol Actavis ActiFast has been formulated with 630 mg sodium bicarbonate per tablet that results in near isotonicity at a 2-tablet dose in gastric fluid.
The role of the dissolution rate of Paracetamol Actavis ActiFast Tablets in vivo at gastric pH is unknown. Therefore the role of tablet dissolution in the speed of action of Paracetamol Actavis ActiFast Tablets is unclear.
It is likely that no single mode of action is responsible for the pharmacokinetic profile observed with Paracetamol Actavis ActiFast. The relative contributions of the different factors will vary depending on the circumstances under which the product is taken.
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. It is metabolised in the liver and excreted in the urine as the glucuronide and sulphate conjugates, - less than 5% is excreted unchanged in the urine as unmodified paracetamol. Binding to plasma proteins is minimal.
The mean elimination half-life of paracetamol following administration of Paracetamol Actavis ActiFast is 2 to 3 hours and is similar to that achieved following administration of standard paracetamol tablets in fasted and fed states.
Following administration of Paracetamol Actavis ActiFast, paracetamol has a median time to peak plasma concentrations (tmax) of 25 minutes in fasted subjects and 45 minutes in the fed subjects. Maximum plasma concentrations were reached at least twice as fast for Paracetamol Actavis ActiFast as for standard paracetamol tablets in both the fed and fasted state (p= 0.0002). Following administration of Paracetamol Actavis ActiFast, paracetamol is generally measurable in plasma within 10 minutes in both the fed and fasted state.
Two tablets of Paracetamol Actavis ActiFast are required to be taken with 100 ml of water to obtain this fast rate of absorption of paracetamol. The maximum rate of absorption is obtained on an empty stomach. When one tablet is taken the rate of absorption of paracetamol for Paracetamol Actavis ActiFast is the same as for standard paracetamol tablets. This is thought to be due to insufficient sodium bicarbonate present in the single tablet dose to increase the rate of paracetamol absorption. In addition, tablets taken with insufficient (<100 mls) water are unlikely to have increased speed of action. (See 5.1 Pharmacodynamic properties).
The extent of absorption of paracetamol from Paracetamol Actavis ActiFast tablets is equivalent to that of standard paracetamol tablets as shown by AUC in both fed and fasted states.
Not applicable.
