NAME OF THE MEDICINAL PRODUCT

Atropine Sulphate 600 micrograms/ml Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml of solution contains 600 micrograms of Atropine Sulphate B.P. For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Clear, colourless, sterile, aqueous solution intended for parenteral administration to human beings.

4 CLINICAL PARTICULARS

4.1. Therapeutic indications

1.    In anaesthesia, to reduce the risk of vagal inhibition of the heart and to reduce salivary and bronchial secretions.

2.    In the treatment of cholinergic crisis of myasthenia gravis.

3.    In conjunction with neostigmine used to reverse the effects of non-depolarising muscle relaxants.

4.    In the treatment of poisoning by certain cholinesterase inhibitors e.g. organo-phosphorous compounds.

5.    During cardiopulmonary resuscitation to counteract excessive vagal tone on the heart.

Posology

1)    Use in Anaesthesia

Adults (including older people): The usual dose is 0.3 to 0.6mg (300 micrograms to 600 micrograms).

Paediatric population :

Premature Infants : 65 micrograms

Full-term Infants : 100 micrograms

6 months - 1 year : 200 micrograms

Over one year : 10 - 20 micrograms/kg bodyweight

2)    Treatment of cholinergic crisis of myasthenia gravis

Adults : The usual dose is 0.4 to 2.0mg intravenously, which may be increased according to patients response.

3)    In conjunction with neostigmine used to reverse the effects of non-depolarising muscle relaxants

Adults : The usual dose is 0.6 to 1.2mg given by slow intravenous injection.

Atropine should be administered before neostigmine.

4)    Treatment of poisoning by certain cholinesterase inhibitors Adults : From 1.2mg, increased according to patients response.

5)    Use during Cardiopulmonary Resuscitation

Adults : A dose of 0.2 to 0.5mg may be given intravenously and repeated if necessary. Persistent bradycardia should be controlled by the insertion of a pacemaker as soon as possible.

4.3 Contraindications

Hypersensitivity to Atropine Sulphate or to any of the excipients listed in section 6.1

Myasthenia gravis (except when given with an anticholinesterase). No absolute contraindication to atropine in Advanced Cardiovascular Life Support (ACLS) or severe bradycardia.

Relative contraindications

Paralytic ileus, pyloric stenosis, toxic megacolon, severe ulcerative colitis, reflux oesophagitis, narrow-angle glaucoma, thyrotoxicosis, and prostatic hypertrophy. No absolute contraindication to atropine in Advanced Cardiovascular Life Support (ACLS) or severe bradycardia.

4.4 Special warnings and precautions for use

Atropine sulphate should be used with caution in children, older people and those with Down’s syndrome. It should be given with caution to patients with diarrhoea, urinary retention or fever.

Paradoxical atrioventricular block or sinus arrest has been reported following administration of atropine in a few patients after heart transplantation.

The use of atropine for therapeutic or diagnostic procedures in heart transplant patients should be undertaken with extreme caution, and ECG monitoring and equipment for immediate temporary pacing should be available.

Caution is required when atropine is administered systemically to patients with chronic obstructive pulmonary diseases, as a reduction in bronchial secretions may lead to the formation of bronchial plugs.

Antimuscarinics such as atropine may delay gastric emptying, decrease gastric motility and relax the oesophageal sphincter. They should be used with caution in patient whose condition may be aggravated by these effects. e.g. reflux oesophagitis.

Atropine should be used only with extreme caution in toxic pyrexial children, or in high ambient temperatures, because of the danger of hyperpyrexia.

Atropine should be used with caution in conditions characterised by tachycardia such as thyrotoxicosis, cardiac insufficiency or failure and in cardiac surgery.

When used to treat a cholinergic crisis in myasthenia gravis, all anti-cholinesterase medication should be withdrawn, if necessary for several days.

Doses of atropine up to 1mg are mildly stimulant to the central nervous system. Higher doses may induce mental disturbances and depression of the central nervous system. Children and older people are particularly susceptible.

Care is required when using atropine in the presence of acute myocardial ischaemia or infarction as the ischaemia or infarction may be worsened.

4.5. Interaction with other medicinal products and other forms of interaction

Drugs with anticholinergic effects including antihistamines, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, disopyramide, domperidone, phenothiazines, amantadine, butyrophenones, antispasmodics, anti-parkinsonian drugs, quinidine	Enhanced antimuscarinic effects of atropine.
Beta-blockers	Reduced cardioacceleratory effect of atropine.
Ketoconazole, chlorpromazine, olanzepine, clozapine, mexilitine	Antimuscarinic drugs may alter the absorption of orally administered drugs by slowing GIT motility.
Sublingual medication such as nitrates	May have reduced absorption due to dry mouth.
Gastrointestinal prokinetic drugs such as metoclopromide, neostigmine	Antimuscarinic drugs including atropine antagonise effects of metoclopromide on gastric motility.

4.6. Fertility, pregnancy and lactation

Pregnancy

Atropine sulphate crosses the placenta. Studies in humans have not been done and only limited information is available from animal studies. Studies in animals have shown a teratogenic effect of atropine in one species with very high doses.

Intravenous administration of atropine during pregnancy or at term may cause tachycardia in foetus. Atropine should only be administered to pregnant women if the benefits outweigh the risks to the foetus.

Breast-feeding

Trace amounts of atropine appear in the breast milk and may cause antimuscarinic effects in the infant; lactation may be inhibited.

Fertility

There are no preclinical fertility data with atropine, and no epidemiological data.

4.7 Effects on ability to drive and use machines

Atropine may cause blurred vision, drowsiness, confusion, hallucinations and other neuro-psychiatric effects (see sections 4.8 and 4.9). Patients should be advised that they should not drive, operate machinery or take part in any activities that could, if they are affected, put them or others at risk.

4.8 Undesirable effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: Very common: (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); Not known: cannot be estimated from the available data.

The most commonly reported adverse events are due to the action of atropine on muscarinic receptors and at high doses, nicotinic receptors. These effects are dose related and usually reversible when therapy is discontinued.

Immune system disorders Very rare: Anaphylaxis

Psychiatric disorders

Not known: confusion state, especially in the elderly. At higher doses hallucinations, restlessness, delirium (see 4.9 overdose).

Nervous system disorders Not known: Dizziness

Eye disorders

Not known: Dilatation of the pupils with loss of accommodation and photophobia, raised intraocular pressure.

Cardiac disorders

Not known: Transient bradycardia followed by tachycardia, palpitations, arrhythmias. Exacerbation of myocardial ischaemia or myocardial infarction.

Very rare: paradoxical atrioventricular block, especially after heart transplantation (see section

4.4 special warnings and precautions for use).

Vascular disorders Not know: Flushing

Respiratory, thoracic and mediastinal disorders

Not known: Reduced bronchial secretion may result in the formation of thick bronchial plugs which are difficult to eject from respiratory tract (see section 4.4 special warnings and precautions for use)

Gastrointestinal disorders

Not known: Dry mouth with difficulty in swallowing, constipation, nausea, vomiting, inhibition of gastric secretion, retrosternal pain due to gastric reflux.

Skin and subcutaneous tissue

Not known: Dry skin, urticaria, rashes, skin exfoliation.

Renal and urinary disorders

Not known: Urinary retention, difficulty with micturition.

General disorders and administration site conditions Not known: Thirst, fever.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Marked dryness of the mouth accompanied by a burning sensation, difficulty in swallowing, pronounced photophobia, flushing and dryness of the skin, raised body temperature, rash, tachycardia, hypertension, nausea, and vomiting. Restlessness, tremor, confusion, excitement, hallucinations and delirium may result from CNS stimulation; this is followed by increasing drowsiness, stupor and general central depression terminating in death from circulatory and respiratory failure.

Management:

In severe cases, physostigmine, 1 to 4 mg, should be administered intravenously, intramuscularly or subcutaneously, the dose may be repeated if necessary since it is rapidly eliminated from the body. Diazepam may be administered for sedation of the delirious patient but the risk of central depression occurring late in the course of atropine poisoning contraindicates large doses of sedative. An adequate airway should be maintained and respiratory failure may be treated with oxygen and carbon dioxide inhalation. Fever is reduced by the application of cold packs or sponging with tepid water. Adequate fluid intake is important. Urethral catheterisation may be necessary. If photophobia is present or likely, the patient should be nursed in a darkened room.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anticholinergic agents. ATC code: A03BA01.

Mechanism of action

Atropine is an antimuscarinic agent which competitively antagonizes acetylcholine at postganglionic nerve endings, thus affecting receptors of the exocrine glands, smooth muscle, cardiac muscle and the central nervous system.

Pharmacodynamic effects

Peripheral effects include tachycardia, decreased production of saliva, sweat, bronchial, nasal, lachrymal and gastric secretions, decreased intestinal motility and inhibition of micturition.

Atropine increases sinus rate and sinoatrial and AV conduction. Usually heart rate is increased but there may be an initial bradycardia.

Atropine inhibits secretions throughout the respiratory tract and relaxes bronchial smooth muscle producing bronchodilatation.

5.2 Pharmacokinetic properties

Absorption

Following intravenous administration, the peak increase in heart rate occurs within 2 to 4 minutes. Plasma levels after intramuscular and intravenous injection are comparable at one hour.

Distribution

Peak plasma concentrations of atropine after intramuscular administration are reached within 30 minutes, although peak effects on the heart, sweating and salivation may occur nearer one hour after intramuscular administration. Atropine is distributed widely throughout the body and crosses the blood brain barrier.

Biotransformation

Atropine is metabolised in the liver by oxidation and conjugation to give inactive metabolites.

Elimination

The elimination half life is about 2 to 5 hours. Up to 50% of the dose is protein bound. It disappears rapidly from the circulation.

About 50% of the dose is excreted within 4 hours and 90% in 24 hours in the urine, about 30 to 50% as unchanged drug.

5.3. Preclinical safety data

Not applicable since atropine has been used in clinical practice for many years and its effects in man are well known.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Dilute Sulphuric Acid BP Water for Injections BP (in bulk)

6.2. Incompatibilities

Atropine Sulphate Injection is incompatible with alkalis, tannic acid and mercury salts.

6.3 Shelf life

Unopened: 4 years*

After reconstitution: not applicable * If only part of an ampoule is used, the remainder should be discarded.

6.4. Special Precautions for Storage

Store below 25°C.

Protect from light.

6.5. Nature and Content of Container

6.6. Instruction for Use, Handling and Disposal

For S.C., I.M. or I.V. injection.

Use as directed by the physician.

Keep out of reach of children.

If only part used, discard the remaining solution.

Mercury Pharma International Ltd 4045, Kingswood Road,

City West Business Park,

Co Dublin, Ireland

8. MARKETING AUTHORISATION NUMBER

PL 02848/5912R.

26/2/91.

10 DATE OF REVISION OF THE TEXT

09/06/2015