UCB Pharma Limited

Parvolex 200 mg/ml concentrate for Solution for Infusion.

Each ml contains 200 mg Aceylcysteine.

Each 10 ml contains 3.22.6 mg sodium.

For a full list of excipients, see section 6.1.

Concentrate for 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.) A ceiling weight of 110 kg is recommended when calculating the dosage for obese patients.

Children:

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.

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.

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).

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

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.

Concurrent use of carbamazapine with acetylcysteine may result in increased clearance of carbamazapine and its metabolites increasing the risk for seizure activity.

The safety of acetylcysteine in pregnancy has not been investigated in formal prospective clinical trials. However, clinical experience indicates that use of acetylcysteine in pregnancy for the treatment of paracetamol overdose is effective. Prior to use in pregnancy, the potential risks should be balanced against the potential benefits.

There are no known effects on ability to drive and use machines.

'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, abnormal thinking, extravasation, arthropathy, arthralgia, gait disturbance, 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.

There is a theoretical risk of hepatic encephalopathy. Overdosage of acetylcysteine has been reported to be associated with effects similar to the 'anaphylactoid' reactions noted in section 4.8 (Undesirable Effects), but they may be more severe. General supportive measures should be carried out. Such reactions are managed with antihistamines and steroids in the usual way. There is no specific antidote.

Acetylcysteine is considered to reduce the hepatic toxicity of NAPQI (n-acetyl-p-benzo-quinoneimine), the highly reactive intermediate metabolite following ingestion of a high dose of paracetamol, by at least two mechanisms. First, acetylcysteine acts as a precursor for the synthesis of glutathione and, therefore, maintains cellular glutathione at a level sufficient to inactivate NAPQI. This is thought to be the main mechanism by which acetylcysteine acts in the early stages of paracetamol toxicity.

Acetylcysteine has been shown to still be effective when infusion is started at up to 12 hours after paracetamol ingestion, when most of the analgesic will have been metabolised to its reactive metabolite. At this stage, acetylcysteine is thought to act by reducing oxidised thiol groups in key enzymes.

When acetylcysteine treatment is begun more than 8 to 10 hours after paracetamol overdose, its efficacy in preventing hepatotoxicity (based on serum indicators) declines progressively with further lengthening of the overdose-treatment interval (the time between paracetamol overdose and start of treatment). However, there is now evidence that it can still be beneficial when given up to 24 hours after overdose. At this late stage of paracetamol hepatotoxicity, acetylcysteine's beneficial effects may be due to its ability to improve systematic haemodynamics and oxygen transport, although the mechanism by which this may occur has yet to be determined.

Following intravenous administration of acetylcysteine using the standard 20-hour intravenous regimen, plasma levels of 300 to 900mg/l have been reported to occur shortly after the start of the infusion, falling to 11 to 90mg/l at the end of the infusion period. Elimination half-lives of 2 to 6 hours have been reported after intravenous dosing, with 20 to 30% of the administered dose being recovered unchanged in the urine.

Metabolism appears to be rapid and extensive. There is no information on whether acetylcysteine crosses the blood-brain barrier or the placenta, or whether it is excreted in breast milk.

None stated.

Disodium Edetate

Sodium Hydroxide

Water for Injections

Acetylcysteine is not compatible with rubber or metals, particularly iron, copper and nickel. Silicone rubber and plastic are satisfactory for use with Parvolex^®.

3 years.

Once opened, use immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Discard after use.

Store below 25°C.

For storage conditions of the diluted product, please see section 6.3.

Clear, Type I glass, 10ml snap ring ampoules. 10 x 10ml ampoules are packed in cartons. Not all pack sizes may be marketed.

Acetylcysteine to be diluted for intravenous infusion using either 5% dextrose, 0.9% sodium chloride, 0.3% potassium chloride with 5% glucose, or 0.3% potassium chloride with 0.9% sodium chloride. The volumes to be used are as directed in section 4.2.

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

UK

PA 365/48/1

7^th July 1993

Date of last renewal 7 July 2003

December 2010