SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Autoject (ComboPen) Nerve Agent Antidote L4A1

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Constituents:

Each 2ml dose contains

Pralidoxime methane sulphonate (P2S) 500mg Avizafone    10mg

Atropine Sulphate USP    2mg

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Automatic injectors containing a sterile aqueous solution of P2S, avizafone and atropine sulphate in a form suitable for parenteral administration to human subjects.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For use by service and MOD sponsored civilian personnel as an antidote to exposure to nerve agent. The personnel will normally have received pyridostigmine bromide pre-treatment at a dosage of 30mg, 8 hourly for up to 4 weeks.

4.2. Posology and Method of Administration

a)    Adults: The contents of one ComboPen are administered on exposure to nerve agent. If nerve agent poisoning symptoms persist, repeat dose at 15 minute intervals with a maximum total dose of 3 injections.

Dosage is not applicable to children or the elderly.

b)    Administration.

By intramuscular injection into the thigh.

4.3. Contra-indications

No situation is envisaged in which exposure to nerve agents has occurred and treatment by this triple therapy is not given.

4.4 Special warnings and precautions for use

Limited information will appear on the injector issued to personnel. More detailed directions for use will be incorporated into training manuals. A training device will also be available to enable the directions for use to be followed under simulated conditions. The product has not been tested under the conditions proposed for its use.

4.5 Interaction with other medicinal products and other forms of interaction

Not applicable to this indication. No interaction has been reported between the pre-treatment and the triple therapy or between the triple therapy and other medicaments. It is likely that active service and MOD sponsored civilian personnel will be taking anti-malarials, antibiotics and have been injected with vaccines as well as receiving pre-treatment with pyridostigmine bromide. It is likely that service women will also be taking the contraceptive pill in addition to other medication stated.

4.6. Pregnancy and Lactation

The safety of the triple therapy has not been established during pregnancy and lactation. The administration of triple therapy in pregnancy and during breast feeding therefore is not advised unless there are compelling medical reasons.

4.7. Effects on Ability to Drive and Use Machines

Treatment may increase levels of incoordination, tiredness, drowsiness and sedation. Subjects should be warned of these adverse effects and that their ability to drive and use machines may be reduced.

Undesirable Effects

The main adverse effects observed in clinical studies are impairments of psychomotor function, drowsiness, conjunctival suffusion, difficulty in focusing, incoordination and unsteadiness on standing, feelings of disorientation and sedation.

Some personnel may use the ComboPen inappropriately, in the mistaken belief that they have been exposed to nerve agent. These individuals will initially show signs and symptoms of atropine overdose. Central symptoms such as anxiety, euphoria, restlessness and delirium, with coma in severe cases and peripheral effects such as dry mouth, hot dry skin, rapid pulse and urinary retention. Such personnel should be treated for atropine overdose.

4.9 Overdose

Personnel who have been exposed to nerve agent are classified as casualties, and are therefore unlikely to receive more than the recommended maximum total dose of 3 injections on any one occasion. Dosage is not applicable to children.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Atropine is the primary treatment following inhibition of acetylcholinesterase activity by organophosphorus agents. Atropine antagonises the effects of acetylcholine at muscarinic sites but has little effect at nicotinic sites. Pralidoxime is indicated in moderate or severe poisoning by organophosphorus compounds. Pralidoxime reactivates acetylcholinesterase by exerting a nucleophilic attack on the dialkylphosphate or dialkylphosphonate groups attached to a serine moiety of the esteratic site of the enzyme. Following poisoning with nerve agents the stability of the inhibiting group is enhanced by partial dealkylation (ageing), leaving a monoalkyl phosphate or phosphonate group. The rate at which this occurs is variable and depends on the nature of the alkyl groups. Pralidoxime will not reactivate aged enzyme.

Avizafone is rapidly hydrolysed in the blood and tissues to the benzodiazepine diazepam. Diazepam has a well established anxiolytic effect with sedation at higher dose levels. It has central depressant effects on spinal reflexes, affects seizure threshold and is an anticonvulsant. Benzodiazepines exert some of their actions via the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Pharmacokinetic Properties

Absorption

The three active constituents are water soluble and are rapidly absorbed and distributed to all tissues following intramuscular injection. Peak plasma levels of diazepam have been reported at 30 to 60 minutes after single and double i.m. treatments. Peak plasma levels of pralidoxime methane sulphonate have been reported at 10 to 20 minutes after single and double i.m. treatments. Peak plasma levels of atropine have been reported at 20 minutes after single and double i.m. treatments.

b) Elimination/Biotransformation

The half-life of diazepam is 20 to 24 hours following intramuscular injections. Maximum levels of desmethyldiazepam, the main metabolite of diazepam, occur at 24 hours after intramuscular injection. The mean elimination half-life for atropine sulphate is 2.2 hours. The elimination half-life of pralidoxime chloride is reported to range from 1 to 2.5 hours.

5.3. Preclinical Safety Data

Both atropine and pralidoxime have been extensively used for many years for clinical treatment following poisoning by anti-cholinesterase compounds. The reviews available in the literature are based almost entirely on the results of clinical experience.

The combination of avizafone with atropine sulphate and P2S have been shown to be a more effective treatment than atropine sulphate and P2S alone against nerve agents in guinea pig and rhesus monkey. The absorption, distribution and elimination of avizafone are generally similar to those of diazepam in animals. Doses of avizafone used in pre-clinical acute toxicity studies were far higher than the proposed clinical dose with ComboPen automatic injector.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Citric Acid Monohydrate Ph Eur, Water for Injections Ph Eur, Sodium Hydroxide BP/NF and Sulphuric Acid BP/NF.

6.2. Incompatibilities

None.

6.3. Shelf Life

5 years.

6.4. Special Precautions for Storage

To be stored between 2° and 8°C protected from light. The contents are not to be used if pack is removed from cold for more than six months.

6.5. Nature and Contents of Container

The sterile aqueous solution of atropine sulphate, P2S and avizafone is contained in a colourless glass tube and sealed with a rubber plunger and rubber diaphragm, the whole glass tube is within the automatic injector assembly.

6.6. Instructions for Use, Handling and Disposal

Pullout grey safety cap from end of automatic injector, place black end of the ComboPen on thigh and press hard until injector functions, count ten slowly and then withdraw. If nerve agent poisoning symptoms persist, repeat dose at 15 minute intervals. Maximum total dose of 3 injections.

7. MARKETING AUTHORISATION HOLDER

Secretary of State for Defence

Ministry of Defence

Main Building

Whitehall

London

SW1 2HB

UK

8. MARKETING AUTHORISATION NUMBER(S)

PL 04537/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12 June 1996

10 DATE OF REVISION OF THE TEXT

13/05/2005