Atropine sulfate 0.1 mg/ml, solution for injection in pre-filled syringe

Each ml of solution for injection contains 0.1 mg atropine sulfate monohydrate, equivalent to0.083 mg atropine.

Each 5 ml syringe contains 0.5 mg atropine sulfate monohydrate, equivalent to 0.415 mg atropine.

Each 10 ml syringe contains 1 mg atropine sulfate monohydrate, equivalent to 0.83 mg atropine.

Excipient with known effect: Sodium

Each ml of solution for injection contains 3.5 mg equivalent to 0.154 mmol of sodium.

Each 5 ml syringe contains 17.7 mg equivalent to 0.770 mmol of sodium.

Each 10 ml syringe contains 35.4 mg equivalent to 1.54 mmol of sodium.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled syringe.

Clear and colourless solution.

pH 3.0 - 4.0.

Atropine sulfate 0.1 mg/ml, solution for injection in pre-filled syringe is indicated in adults and in paediatric population from birth, but with a body weight superior to 3 kg (see section 4.2).

- As a pre-anaesthetic medication to prevent vagal reactions associated with tracheal intubation and surgical manipulation,

- To limit the muscarinic effects of neostigmine, when given postsurgically to counteract non depolarising muscle relaxants

- Treatment of hemodynamically compromising bradycardia and/ or atrioventricular block due to excessive vagal tone in emergency situation

- Cardiopulmonary resuscitation: to treat symptomatic bradycardia and AV block

- As antidote following overdosage or poisoning with acetylcholinesterase- inhibitors e.g. anticholinesterases, organophosphorus, carbamates and muscarinic mushrooms

Atropine sulfate 0.1 mg/ml, solution for injection in pre-filled syringe must be administered under medical supervision.

Posology

Pre-anaesthetic medication

Intravenous administration immediately before surgery; if necessary an intramuscular administration 30-60 minutes before surgery is possible.

Adults:

0.3 – 0.6 mg IV (3 – 6 ml)

Paediatric population:

The usual dose in children is between 0.01-0.02 mg/kg body weight (maximum 0.6 mg per dose), dosage should be adjusted according to the patient's response and tolerance.

In combination with neostigmine to limit its muscarinic effects:

Adults:

0.6-1.2 mg IV (6 to 12 ml)

Paediatric population

0.02 mg/kg IV

Treatment of hemodynamically compromising bradycardia, atrioventricular block, cardiopulmonary resuscitation:

Adults:

- Sinus bradycardia: 0.5 mg IV (5 ml), every 2-5 minutes until the desired heart rate is achieved.

- AV block: 0.5 mg IV (5 ml), every 3-5 minutes (maximum 3 mg)

Paediatric population

0.02 mg/kg IV in a single dose (maximum dose 0.6 mg).

As an antidote to organophosphates (pesticides, nerve gases), to cholinesterase inhibitors and in muscarinic mushroom poisoning:

Intravenous use.

Adults:

0.5 - 2 mg atropine sulfate (5 - 20 ml), can be repeated after 5 minutes and subsequently every 10-15 minutes as required, until signs and symptoms disappear (this dose may be exceeded many times).

Paediatric population:

0.02 mg atropine sulfate/kg body weight possibly repeated several times until signs and symptoms disappear.

Dose adjustments

In general, dosage should be adjusted according to patient's response and tolerance.

Dosage to a total maximum dose of 3 mg in adults and 0.6 mg in children is usually increased until adverse effects become intolerable; then a slight reduction in dosage generally yields the maximum dosage tolerated by the patient.

Paediatric Population

This medicinal product is not appropriate to deliver a dose of less than 0.5 ml and should therefore not be used in neonates for which the body weight is inferior to 3 kg (see section 4.1).

The dosage ranges for the paediatric weight groups as stated below are values for guidance. The usual dose in children is between 0.01-0.02 mg/kg body weight (maximum 0.6 mg per dose), dosage should be adjusted according to the patient's response and tolerance.

Special populations

Caution is advised for patients with renal or hepatic impairment and in elderly (see section 4.4).

Method of administration

Atropine is administered by intravenous injection or intramuscular injection. Other pharmaceutical forms/strengths may be more appropriate in the cases where a dose above 1 mg is required.

- Hypersensitivity to the active substance or to any of the excipients

- Closed-angle glaucoma

- Risk of urinary retention because of prostatic or urethral disease

- Achalasia of the esophagus, paralytic ileus, and toxic megacolon

All these contra-indications are however not relevant in life-threatening emergencies (such as bradyarrhythmia, poisoning).

Use with caution in case of:

- Prostatic enlargement

- Renal or hepatic insufficiency

- Cardiac insufficiency, arrhythmias, hyperthyroidism

- Chronic obstructive pulmonary disease, as a reduction in bronchial secretions may lead to the formation of bronchial plugs

- Intestinal atonia in elderly

- Pyloric stenosis

- Fever, or when ambient temperature is high

- In children and elderly, who may be more susceptible to its adverse effects

- In reflux oesophagitis, as atropine may delay gastric emptying, decrease gastric motility and relax oesophageal sphincter

Atropine should not be given to patients with myasthenia gravis unless given in conjunction with anticholinesterase.

Atropine administration should not delay implementation of external pacing for unstable patients, particularly those with high-degree (Mobitz type II second-degree or third-degree) block.

Antimuscarinics block vagal inhibition of the SA nodal pacemaker and should thus be used with caution in patients with tachyarrhythmias, congestive heart failure or coronary heart disease.

This medicinal product contains 17.7 mg sodium per 5 ml pre-filled syringe, equivalent to 0.885 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. The 10 ml syringe contains 35.4 mg sodium, equivalent to 1.77 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Combinations to be taken into account

Other drugs with anticholinergic activity, such as tricyclic antidepressants, some H1-antihistamines, antiparkinsonian drugs, disopyramide, mequitazine, phenothiazines, neuroleptic drugs, atropinic antispasmodics, clozapine and quinidine, because of the risk of potentialisation of atropinic adverse effects (urinary retention, constipation, dry mouth).

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse effects of atropine on pregnancy or on the health of the fetus/new-born child.

Animal studies did not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Studies of the pharmacokinetics of atropine in mother and fetus in late pregnancy indicated that atropine rapidly crosses the placental barrier. Intravenous administration of atropine during pregnancy or at term may cause tachycardia in the fetus and the mother.

Atropine should not be used during pregnancy unless clearly necessary.

Breast-feeding

Small amounts of atropine may pass into human breast milk. Infants have an increased sensitivity to the anticholinergic effects of atropine. Atropine may inhibit the production of milk, particularly upon repeated use. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from treatment taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. If it is decided during treatment to continue breastfeeding, the child should be monitored for anticholinergic effects.

Fertility

There are no data on effects of this atropine sulfate on fertility in humans. Atropine sulfate reduced fertility in male rats, presumably as a consequence of an inhibitory effect on the transport of sperm and semen during the process of emission.

Atropine may cause confusion or blurred vision and patients should be advised of it.

The pattern of adverse effects seen with atropine can mostly be related to their pharmacological actions at muscarinic and, at high doses, nicotinic receptors. Adverse effects are dose-related and usually reversible when therapy is discontinued. The most common effects occurring with relatively small doses are visual disturbances, reduced bronchial secretion, dry mouth, constipation, reflux, flushing, difficulty in micturition and dryness of the skin. Transient bradycardia may develop followed by tachycardia, with palpitations and arrhythmias.

The evaluation of adverse reactions is based on the following definition of frequency:

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

Paediatric population

Infants, children and children with spastic paralysis or brain damage may be more susceptible to antimuscarinic effects.

Special populations

Atropine may cause excitement, incoordination, confusion and/or hallucinations especially in the elderly. An epidemiological study similarly reported lower cognitive performance in elderly patients receiving antimuscarinics. Patients with Down syndrome may be more susceptible to antimuscarinic effects.

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 website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms:

Flushing and dryness of the skin, dilated pupils with photophobia, dry mouth and tongue accompanied by a burning sensation, difficulty in swallowing, tachycardia, rapid respiration, hyperpyrexia, nausea, vomiting, hypertension, rash and excitement. Symptoms of CNS stimulation include restlessness, confusion, hallucinations, paranoid and psychotic reactions, incoordination, delirium and occasionally convulsions. In severe overdose, drowsiness, stupor and CNS depression may occur with coma, circulatory and respiratory failure and death.

Treatment:

Treatment should be supportive. An adequate airway should be maintained. Diazepam may be administered to control excitement and convulsions but the risk of CNS depression should be considered.

Pharmacotherapeutic group: Belladonna alkaloids, tertiary amines.

ATC code: A03BA01.

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

Peripheral effects include decreased production of saliva, sweat, 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 bronchodilation.

Absorption

Following intravenous administration, the peak increase in heart rate occurs within 2 to 4 minutes. Peak plasma concentrations of atropine after intramuscular administration are reached within 30 minutes, although peak effects on the heart, sweating and salivation may occur 1 hour after intramuscular administration.

Distribution

Plasma levels after intramuscular and intravenous injection are comparable at 1 hour. Atropine is distributed widely throughout the body and crosses the blood brain barrier and the placenta barrier.

Biotransformation

Atropine is incompletely metabolised in the liver and is excreted in the urine as unchanged drug and metabolites. About 50 % of the dose is excreted within 4 hours and 90 % in 24 hours.

Elimination

The elimination half-life is about 2 to 5 hours. Up to 50 % of the dose is protein bound.

Paediatric Population

Children, particularly those younger than two years, may be more susceptible to the actions of atropine. The elimination half-life is more than doubled in children less than two years compared to adults.

Elderly

The elimination half-life of atropine is more than doubled in the elderly (>65 years old) compared to adults.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Atropine sulfate reduced fertility in male rats, presumably as a consequence of an inhibitory effect on the transport of sperm and semen during the process of emission.

Sodium chloride

Sulfuric acid (for pH adjustment)

Sodium Hydroxide (for pH adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products.

Unopened syringe: 2 years

This medicinal product does not require any special temperature storage conditions. Keep syringe in the outer box to protect from light.

5 ml clear glass (clear type I glass) pre-filled syringe with tip cap (luer tip and luer lock), plunger stopper (bromobutyl rubber) and plunger rod (polypropylene). Graduations of 0.5 mL, from 0 mL to 5 mL, are present on the barrel of the syringe.

10 ml clear glass (clear type I glass) pre-filled syringe with tip cap (luer tip and luer lock), plunger stopper (bromobutyl rubber) and plunger rod (polypropylene). Graduations of 1 mL, from 0 mL to 10 mL, are present on the barrel of the syringe.

The pre-filled syringe is supplied without needle, packaged in an outer box.

Pack sizes: 1 pre-filled syringe

The pre-filled syringe is for single patient only. Discard syringe after use. DO NOT REUSE.

The product should be inspected visually for particles and discoloration prior to administration. Only clear colourless solution free from particles or precipitates should be used.

The pre-filled syringe is packed in twist box (plastic material). For tamper evident sealing, twist box is sealed with self-adhesive plain paper base sticker label. The product should not be used if the tamper evident seal twist box (plain sticker label) is broken.

The needle gauge appropriate for use with the syringe are 23 to 20 gauge for IV administration and 23 to 21 gauge for IM administration.

Any unused product or waste material should be disposed of in accordance with local requirements.

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

PL 0142/1261

Date of first authorisation : 16/06/2020

16/06/2020