Robinul Injection

Glycopyrronium Bromide 200 micrograms in 1ml Solution for Injection.

Each 1ml of injection contains 200 micrograms (0.2mg) of glycopyrronium bromide (glycopyrrolate).

Solution for injection.

Clear, colourless, sterile solution.

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Robinul Injection is for intravenous or intramuscular injection.

Premedication: Adults and older patients: 200 to 400 micrograms (0.2mg 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 profound and prolonged antisialagogue effect which may be unpleasant for the patient.

Children: 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 profound and prolonged antisialagogue effect which may be unpleasant for the patient.

Intra-operative use: Adults and older patients: 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 to 0.005mg/kg) up to a maximum of 400 micrograms (0.4mg) may be used. This dose may be repeated if necessary.

Children: A single dose of 200 micrograms (0.2mg) by intravenous injection should be used. Alternatively, a single dose of 4 to 8 micrograms/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 residual non-depolarising neuromuscular block:

Adults and older patients: 200 micrograms (0.2mg) intravenously per 1000 micrograms (1mg) neostigmine or the equivalent dose of pyridostigmine. Alternatively, a dose of 10 to 15 micrograms/kg (0.01 to 0.015mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) neostigmine or equivalent dose of pyridostigmine. Robinul may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.

Children: 10 micrograms/kg (0.01mg/kg) intravenously with 50 micrograms/kg (0.05mg/kg) neostigmine or the equivalent dose of pyridostigmine. Robinul may be administered simultaneously from the same syringe with the anticholinesterase; greater cardiovascular stability results from this method of administration.

Hypersensitivity to glycopyrrolate, and any of the excipients.

Because Glycopyrrolate causes tachycardia, extreme caution is advised in patients with thyrotoxicosis, coronary artery disease, cardiac dysarythmias, hypertension, congestive heart failure and cardiac insufficiency. As glycopyrrolate inhibits sweating, patients with increased temperature (especially children) should be observed closely.

In common with other antimuscarinic drugs caution is advised in patients with prostatic hypertrophy, paralytic ileus, pyloric stenosis and closed angle glaucoma.

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

Quaternary ammonium compounds in large doses have been shown to block end plate nicotinic receptors. This should be considered before using glycopyrrolate in patients with myasthenia gravis.

Unlike atropine, glycopyrrolate is a quaternary ammonium compound and does not cross the blood-brain barrier. It is therefore less likely to cause postoperative confusion which is a particular concern in the elderly patients. Compared to atropine, glycopyrrolate has reduced cardiovascular and ocular effects.

There is increased risk of antimuscarinic side effects in patients taking drugs with antimuscarinic effects such as MAOIs, amantadine, clozapine, tricyclic antidepressants and nefopam.

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.

Lactation:

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

Do not operate or drive heavy machinery unless the drug has been shown not to interfere with mental or physical ability.

Robinul may produce the following effects which are extensions of its fundamental pharmacological actions: dry mouth, difficulty in micturition, inhibition of sweating. Side-effects of antimuscarinics include constipation, transient bradycardia (followed by tachycardia, palpitation and arrhythmias), reduced bronchial secretions, urinary urgency and retention, dilatation of the pupils with loss of accommodation, photophobia, flushing, and dryness of the skin.

Side-effects that occur occasionally include confusion (particularly in the elderly), nausea, vomiting, and giddiness; very rarely, angle-closure glaucoma may occur.

Since glycopyrrolate is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature. To combat peripheral anticholinergic effects, a quaternary ammonium anticholinesterase such as neostigmine methylsulphate 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.

Glycopyrrolate is a quaternary ammonium antimuscarinic agent and like other anticholinergic agents, it inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands and to a limited degree in the autonomic ganglia. Thus it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal and bronchial secretions. Glycopyrrolate antagonizes muscarinic symptoms (e.g. bronchorrhea, bronchospasm, bradycardia and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.

The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulphate and scopolamine hydrobromide, which are non-polar tertiary amines which penetrate lipid barriers easily.

Robinul Injection has been used successfully as an adjunct to reversal by neostigmine when atropine has been used as the preoperative anticholinergic. The use of Robinul Injection as an adjunct to reversal by neostigmine of non-depolarising muscle relaxants is associated with less initial tachycardia and better protection against the cholinergic effects of neostigmine compared to reversal with a mixture of neostigmine and atropine.

Glycopyrrolate is rapidly diminished and/or excreted after intravenous administration. The terminal elimination phase is relatively slow with quantifiable levels remaining up to 8 hours after administration. Peak effects occur approximately 30 to 45 minutes after intramuscular administration. The vagal blocking effects persist for 2 to 3 hours and the antisialagogue effects persist up to 7 hours, periods longer than for atropine. With intravenous injection, the onset of action is generally evident within one minute.

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.

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

Sodium Chloride

Dilute Hydrochloric Acid

Water for Injections

Robinul Injection 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.

Robinul Injection has been shown to be physically incompatible with the following agents commonly used in anaesthetic practice: Diazepam, Dimenhydrinate, Methohexitone Sodium, Pentazocine, Pentobarbitone Sodium, Thiopentone Sodium.

5 years.

Do not store above 25°C.

Robinul Injection 1ml and 3ml is presented in clear One point cut (OPC) glass ampoules, packed in cardboard cartons to contain 10 x 1ml; 10 x 3ml and 3 x 3ml ampoules.

Keep out of reach and sight of children.

If only part of an ampoule is used, discard the remaining solution.

Anpharm Ltd.

Roscrea

County Tipperary

Ireland.

PL 15372/0004

1 July 1997

02 .02. 2012