Amino acids (paracetamol antidote).

Acetylcysteine

Each ml contains Acetylcysteine 200mg Each 10 ml contains 322.6 mg of sodium.

Solution for infusion. Clear colourless solution contained in a 10 ml clear colourless Type I glass ampoule.

For the treatment of paracetamol overdosage.

The injection is administered by intravenous infusion. The following infusion fluids may be used: 5% dextrose, 0.9% sodium chloride, 0.3% potassium chloride with 5% glucose, or 0.3% potassium chloride with 0.9% sodium chloride.

Adults:

An initial dose of 150mg/kg body weight of acetylcysteine is infused in 200ml of the recommended infusion fluid over 15 minutes, followed by 50mg/kg in 500ml infusion fluid over the next 4 hours, then 100mg/kg in 1 litre infusion fluid over the next 16 hours. (This gives a total dose of 300mg/kg in 20 hours.)

Critical times:

Acetylcysteine (Parvolex^®) is very effective in preventing paracetamol-induced hepatotoxicity when administered during the first 8 hours after a paracetamol overdose. When administered after the first 8 hours, the protective effect diminishes progressively as the overdose-treatment interval increases. However, clinical experience indicates that acetylcysteine can still be of benefit when administered up to 24 hours after paracetamol overdose, without any change in its safety profile. It may also be administered after 24 hours in patients at risk of severe liver damage. In general, for patients presenting later than 24 hours after a paracetamol overdose, guidance should be sought from a National Poisons Centre.

Treatment 'nomogram':

Plasma paracetamol concentration in relation to time after the overdose is commonly used to determine whether a patient is at risk of hepatotoxicity and should, therefore, receive treatment with an antidote such as acetylcysteine.

For the majority of otherwise healthy patients, a line joining points of 200mg/l at 4 hours and 30mg/l at 15 hours on a semilogarithmic plot is used. (Treatment line A - see graph.) This line can be extended to 24 hours after overdose, based on a paracetamol half-life of 4 hours. It is recommended that patients whose plasma paracetamol concentrations fall on or above this line receive acetylcysteine. If there is doubt about the timing of the overdose, consideration should be given to treatment with acetylcysteine.

Patients with induced hepatic microsomal oxidase enzymes (such as chronic alcoholics and patients taking anticonvulsant drugs) are susceptible to paracetamol-induced hepatotoxicity at lower plasma paracetamol concentrations (see section 4.4 - Special Warnings and Precautions for Use) and should be assessed against treatment line B (see graph).

In patients who have taken staggered overdoses, blood levels are meaningless in relation to the treatment graph. These patients should all be considered for treatment with acetylcysteine.

NB: Blood samples taken less than 4 hours after a paracetamol overdose give unreliable estimates of the serum paracetamol concentration.

Plasma paracetamol concentrations in relation to time after overdosage as a guide to prognosis.

From guidelines agreed by National Poisons Centres - June 1995.

Parvolex is indicated in patients with values on or above the appropriate treatment line.

Children should be treated with the same doses and regimen as adults; however, the quantity of intravenous fluid used should be modified to take into account age and weight, as fluid overload is a potential danger. The National Poisons Centres in the UK have provided the following guidance:

Children weighing 20kg or more:

150mg/kg intravenous infusion in 100ml infusion fluid over 15 minutes; then 50mg/kg in 250ml infusion fluid over 4 hours; then 100mg/kg in 500ml infusion fluid over 16 hours.

Children under 20kg:

Volumes for infusion of the above doses are the responsibility of the prescriber and should be based on the daily maintenance requirements of the child by weight.

Hypersensitivity to any ingredient in the preparation.

Precautions:

Administer with caution in patients with asthma or a history of bronchospasm.

Liver enzyme-inducing drugs; chronic alcohol abuse:

Patients taking drugs that induce liver enzymes, such as some anticonvulsant drugs (e.g. phenytoin, phenobarbitone, primidone and carbamazepam) and rifampicin, and patients who routinely consume alcohol above recommended levels are believed to be at risk of hepatotoxicity from paracetamol poisoning at lower plasma paracetamol concentrations than other patients. It is recommended that such patients whose plasma paracetamol concentrations fall on or above a treatment line joining 100mg/l at 4 hours after overdose and 15mg/l at 15 hours after overdose on a semilogarithmic plot (i.e. treatment line B - see graph), be given acetylcysteine.

Other patients predisposed to toxicity:

Patients suffering from malnutrition, for example, patients with anorexia or AIDS, may have depleted glutathione reserves. It has been recommended that paracetamol overdose in such patients be treated as for chronic alcohol consumers or patients taking anticonvulsant drugs (treatment line B - see graph).

Changes in haemostatic parameters have been observed in association with acetylcysteine treatment, some leading to decreased prothrombin time, but most leading to increased prothrombin time. Caution should be exercised in interpreting changes in haemostatic parameters as a sign of liver failure.

Use with caution in children, patients requiring fluid restriction or those who are <40 kg because of the risk of fluid overload which may result in hyponatraemia, seizures and death.

Each 10ml of Parvolex Solution for Infusion contains 322.6mg sodium. To be taken into consideration with patients on a controlled sodium diet.

There are no known interactions.

'Anaphylactoid' or 'hypersensitivity-like' reactions have been reported. They include nausea/vomiting, injection-site reactions, flushing, itching, rashes/urticaria, angioedema, bronchospasm/respiratory distress, hypotension, and rarely, tachycardia or hypertension. These have usually occurred between 15 and 60 minutes after the start of infusion. In many cases, symptoms have been relieved by stopping the infusion. Occasionally, an antihistamine drug may be necessary. Corticosteroids may occasionally be required. Once an anaphylactoid reaction is under control, the infusion can normally be restarted at the lowest infusion rate (100mg/kg in 1 litre over 16 hours).

In rare instances, the following side-effects have occurred: coughing, chest tightness or pain, puffy eyes, sweating, malaise, raised temperature, vasodilation, blurred vision, bradycardia, facial or eye pain, syncope, acidosis, thrombocytopenia, respiratory or cardiac arrest, stridor, anxiety, extravasation, arthropathy, arthralgia, deterioration of liver function, generalised seizure, cyanosis, lowered blood urea, prothrombin time abnormal. Rare instances of fatality have also occurred.

Hypokalaemia and ECG changes have been noted in patients with paracetamol poisoning irrespective of the treatment given. Monitoring of plasma potassium concentration is, therefore, recommended.

If any side-effects to Parvolex^® (acetylcysteine) develop, advice should be sought from a National Poisons Centre to ensure that the patients receives adequate treatment of the paracetamol overdose.

UCB Pharma Limited

(POM)

14 February 2012