Glycopyrrolate 200 micrograms/ml Solution for Injection – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Glycopyrrolate 200 micrograms/ml Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml of solution contains 200 micrograms (0.2mg) of glycopyrrolate USP.

Each 3ml of solution contains 600 micrograms (0.6mg) of glycopyrrolate USP.

Excipient with known effect

Sodium Chloride: contains 9 mg per ml

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

(1) To protect against the peripheral muscarinic actions of anticholinesterases such as neostigmine and pyridostigmine used to reverse residual neuromuscular blockade produced by non-depolarising muscle relaxants.

(2) As a pre-operative antimuscarinic agent to reduce salivary, tracheobronchial and pharyngeal secretions, and to reduce the acidity and volume of the gastric contents.

(3) As a pre-operative or intra-operative antimuscarinic to attenuate or prevent intra-operative bradycardia associated with the use of suxamethonium, cardiac vagal reflexes or that associated with the use of the non-depolarising relaxants atracurium and vecuronium.

4.2 Posology and method of administration

Posology

A.) Premedication

Adults and the Elderly

200 to 400 micrograms (0.2 to 0.4mg) intravenously or intramuscularly before the induction of anaesthesia. Alternatively, a dose of 4 to 5 micrograms/kg (0.004 to 0.005mg/kg) up to a maximum of 400 micrograms (0.4mg) may be used. Larger doses may result in a marked and prolonged antisialogogue action which may be unpleasant for the patient.

Paediatric population

4 to 8 micrograms/kg (0.004 to 0.008mg/kg) up to a maximum of 200 micrograms (0.2mg) intravenously or intramuscularly before the induction of anaesthesia. Larger doses may result in a marked and prolonged antisialogogue action which may be unpleasant for the patient.

B.) Intra-operative Use

Adults and the Elderly

A single dose of 200 to 400 micrograms (0.2 to 0.4mg) by intravenous injection should be used. Alternatively, a single dose of 4 to 5 micrograms/kg (0.004 - 0.005mg/kg) up to a maximum of 400 micrograms (0.4mg) may be used. This dose may be repeated as necessary.

Paediatric population

When indicated, a single dose of 200 micrograms (0.2mg) by intravenous injection should be used. Alternatively, a single dose of 4 to 8 micrograms per kg (0.004 to 0.008mg/kg) up to a maximum of 200 micrograms (0.2mg) may be used. This dose may be repeated if necessary.

Reversal of non-depolarising neuromuscular block

Adults and the Elderly

200 micrograms (0.2mg) intravenously per 1000 micrograms (1mg) neostigmine or the equivalent dose of pyridostigmine. Alternatively, a dose of 10 - 15 micrograms/kg (0.01 to 0.015mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) of neostigmine or the equivalent dose of pyridostigmine.

Glycopyrrolate may be mixed with either neostigmine or pyridostigmine in the same syringe and administered simultaneously; greater cardiovascular stability results from this method of administration.

Paediatric population

10 micrograms/kg (0.01mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) neostigmine or equivalent doses of pyridostigmine. Glycopyrrolate may be mixed in the same syringe as neostigmine or pyridostigmine and administered simultaneously; greater cardiovascular stability results from this method of administration.

Method of administration

For intravenous or intramuscular use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrrolate should be avoided in patients with a prolonged QT interval.

4.4 Special warnings and precautions for use

Antimuscarinics should be used with caution (due to increased risk of side effects) in Down's syndrome, in children and in the elderly.

Extreme caution is advised in patients with gastro-oesophageal reflux disease, diarrhoea, ulcerative colitis, acute myocardial infarction, thyrotoxicosis, coronary artery disease, cardiac dysarythmias, hypertension, congestive heart failure, conditions characterised by tachycardia (including hyperthyroidism, cardiac insufficiency, cardiac surgery) because of the increase in heart rate produced by their administration, coronary artery disease and cardiac arrhythmias, pyrexia (due to inhibition of sweating), pregnancy and breast feeding. As glycopyrrolate inhibits sweating, patients with increased temperature (especially children) should be observed closely.

Because of prolongation of renal elimination, repeated or large doses of Glycopyrrolate should be avoided in patients with uraemia.

Anticholinergic drugs can cause ventricular arrhythmias when administered during inhalation anaesthesia especially in association with the halogenated hydrocarbons.

Unlike atropine,

C

effects.

This medicine contains less than 1 mmol sodium (23 mg) per 2ml, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

Many drugs have antimuscarinic effects; concomitant use of two or more of such drugs can increase side-effects such as dry mouth, urine retention and constipation. Concomitant use can also lead to confusion in the elderly. Anticholinergic agents may delay absorption of other medication given concomitantly.

Concurrent administration of anticholingergics and corticosteroids may result in increased intraocular pressure.

Concurrent use of antocholinergic agents with slow-dissolving tablets of digoxin may cause increased serum digoxin levels.

Ritodrine: tachycardia

There is increased risk of antimuscarinic side effects in patients taking drugs with antimuscarinic effects such as MAOIs, amantadine, clozapine, disopyramaide, tricyclic antidepressants, antihistamines, pethidine, phenothiazines (increased antimuscarinic side effects of phenothiazines but reduced plasma concentrations) and nefopam.

Domperidone/Metoclopramide: antagonism of effect on gastro-intestinal activity Ketoconazole: reduced absorption of ketoconazole

Levodopa: absorption of levodopa possibly reduced

Memantine: effects possibly enhanced by memantine

Nitrates: possibly reduced effect of sublingual nitrates (failure to dissolve under the tongue owing to dry mouth)

Parasympathomimetics: antagonism of effect

4.6 Fertility, pregnancy and lactation

Pregnancy

For use as indicated, animal studies (see section 5.3) are of very limited relevance. Use in human pregnancy has not been systematically evaluated. This product should only be used in pregnancy if considered essential.

Breast-feeding

May reach breast milk but in amounts probably too small to be harmful.

Caution is advised when considering administration to a nursing mother.

Fertility

There are no data on the effects of Glycopyrrolate on male or female fertility. For non-clinical studies please refer to section 5.3

4.7 Effects on ability to drive and use machines

Glycopyrrolate has moderate influence on the ability to drive and use machines. However, systemic administration of antimuscarinics may cause blurred vision, dizziness and other effects that may impair a patient's ability to perform skilled tasks such as driving. These activities should not be undertaken until any disturbance of visual accommodation or balance has resolved. Do not operate or drive heavy machinery unless the drug has been shown not to interfere with mental or physical ability.

4.8 Undesirable effects

Adverse reactions listed by System Organ Class. Frequencies are defined using the following convention: Very common: (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very rare (<1/10,000); not known: cannot be estimated from the available data.

Tabulated list of adverse reactions:

Other side effects of anti-muscarinics include-

* Particularly in elderly

** Followed by tachycardia, palpitation and arrhythmias

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.

4.9 Overdose

Symptoms

Because glycopyrrolate is a quaternary ammonium compound, symptoms of overdosage are peripheral rather than central in nature such as hyperthermia, hypertension, increased respiratory rate, nausea and vomiting may occur.

Management

To treat peripheral anticholinergic effects, a quaternary ammonium anticholinesterase such as neostigmine methyl sulphate may be given in a dose of 1000 micrograms (1.0mg) for each 1000 micrograms (1.0mg) of glycopyrrolate known to have been administered by the parenteral route.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Quaternary ammonium antimuscarinic, ATC Code: A03AB02

Mechanism of action

Glycopyrrolate has a specific effect on salivary and sweat gland activity with little effect on pupil size, visual accommodation or heart rate. At a dose of 0.2mg intramuscularly, sweat gland activity and salivation are markedly inhibited for over 6 hours.

Absorption from the intramuscular site of administration is almost complete and as rapid, as that following intravenous (IV) administration. As would be anticipated from a quaternary ammonium compound, oral absorption is poor and erratic.

Glycopyrrolate is a superior drug when compared with atropine. A dose of 0.4mg IM inhibits salivation by over 90% and produces only slight slowing of the heart rate. Atropine has been shown in doses of 2.0mg IM to inhibit salivation by approximately 80% but produces a rise in heart rate of greater than 80%.

5.2 Pharmacokinetic properties

Absorption

Approximately 10 - 20% is absorbed from the gastro-intestinal tract and is excreted in bile and urine as unchanged drug and metabolites.

Distribution

Like all quaternary ammonium compounds, it penetrates the blood brain barrier only poorly. Studies involving radio-labelled glycopyrrolate (200ug intravenously) show that the initial distribution phase is extremely rapid.

Elimination

Approximately 90% of the radio-activity disappeared from plasma within five minutes and being rapidly excreted in bile and urine.

5.3 Preclinical safety data

Safety Pharmacology

Acute toxicity of glycopyrrolate was studied in mice and rats. Following intraperitoneal administration, the LD₅₀ was estimated to be 107 mg/kg in mice and 196 mg/kg in rats. Following oral dosing, the LD₅₀ was estimated to be 1150 mg/kg in rats. Chronic oral administration doses of 4, 16, and 64 mg/kg for up to 27 weeks in dogs produced mydriasis, cycloplegia, xerostomia, emesis, occasional lacrimation, injection of sclera and rhinorrhea. There were no changes in organ weight and histopathology showed no drug-related changes.

Teratogenicity

Although reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate,

Toxicity to reproduction and development

Safety in human pregnancy and lactation has not been established. Diminished rates of conception and of survival at weaning were observed in rats, in a dose related manner. Studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate. The significance of this for man is not clear.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride BP

Dilute Hydrochloric Acid BP

Water for Injections BP

6.2 Incompatibilities

Glycopyrrolate has been shown to be physically compatible with the following agents commonly used in anaesthetic practice: butorphanol, lorazepam, droperidol and fentanyl citrate, levorphanol tartrate, pethidine hydrochloride, morphine sulphate, neostigmine, promethazine and pyridostigmine.

Glycopyrrolate is incompatible with alkalis, these include the following agents used in anaesthetic practice : diazepam, dimenhydrinate, methohexitone sodium, pentazocine, pentobarbitone sodium, propofol, thiopentone sodium.

6.3 Shelf life

20 months.

6.4 Special precautions for storage

Protect from light.

Do not store above 25°C.

6.5 Nature and contents of container

1ml and 3ml clear glass ampoules, glass type I, Ph. Eur. borosilicate glass packed in cardboard cartons to contain 10 x 1ml or 10 x 3ml ampoules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

For IM and IV Injection.

Keep this medicine out of the sight and reach of children.

If only part used, discard the remaining solution. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Mercury Pharmaceuticals Ltd,

Dashwood House, 69 Old Broad Street, London,

EC2M 1QS, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 12762/0577

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

18/09/2002

10 DATE OF REVISION OF THE TEXT

05/10/2023