Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Umsebe Healthcare, 506 Sunclare Building, 21 Dreyer Street, Claremont, Cape Town, 7708, South Africa Name of Manufacturer: Sintetica SA
Administer with caution to patients with asthma, bronchospasm or severe bradycardia, as the neostigmine may aggravate the pathology.
Administration of anticholinesterase agents to patients with intestinal anastomoses may produce rupture of the anastomosis or leakage of intestinal contents.
Cholstyq should be used with caution in patients with coronary artery disease, congestive heart failure, cardiac dysrhythmias, hypertension, hyperthyroidism or thyrotoxicosis and cardiac insufficiency.
Use with caution in patients with epilepsy or Parkinson’s disease.
Cholstyq should be used cautiously in pyrexical patients (especially children) due to inhibition of sweating.
In common with other antimuscarinic medicines caution is advised in patients with prostatic hypertrophy, paralytic ileus, pyloric stenosis and closed angle glaucoma.
Cholstyq should be used with caution in patients with hypotension, peptic ulceration or vagotonia.
Anticholinergic medicines can cause ventricular dysrhythmias when administered during inhalation anaesthesia especially in association with the halogenated hydrocarbons.
Quaternary ammonium compounds (like glycopyrronium) in large doses have been shown to block the nicotinic muscle end plate receptors. This must be evaluated prior to its administration in patients with myasthenia gravis. Cholstyq should be used with caution in patients with myasthenia gravis to avoid provoking a cholinergic crisis with increased muscular weakness.
Glycopyrronium 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. Glycopyrronium bromide glycopyrrolate has reduced cardiovascular and ocular effects.
Neostigmine metilsulfate: glycopyrronium given before or with neostigmine, prevents bradycardia, excessive salivation, and other muscarinic effects of neostigmine.
Cholstyq should be used with caution in elderly patients.
As neostigmine metilsulfate is excreted mainly by the kidneys, caution is advised in cases of impaired renal function.
Cholstyq contains less than 1 mmol sodium (23 mg) per ampoule, that is to say essentially ‘sodium free’.
Neostigmine metilsulfate should not be administered with suxamethonium (see section 4.3).
There is increased risk of antimuscarinic side effects in patients taking medicines with antimuscarinic effects such as MAOIs (Monoamine oxidase inhibitors), amantadine, clozapine, tricyclic antidepressants and nefopam.
Aminoglycosides, clindamycin, colistin and the halogenated inhalation anaesthetics possess neuromuscular blocking activity and may antagonise the effects of neostigmine metilsulfate. These agents must be used with care in conjunction with Cholstyq.
Hypotension and prolonged bradycardia have occurred in patients receiving beta-adrenoceptor blocking agents following administration of neostigmine metilsulfate.
Some antidysrhythmic medicines such as quinidine may antagonize neostigmine metilsulfate action by interfering with neuromuscular transmission.
Administration of methylprednisone to patients receiving neostigmine metilsulfate has exacerbated symptoms and produced profound weakness often necessitating assisted ventilation.
There are no data from the use of glycopyrronium bromide or neostigmine metilsulfate in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Anticholinesterase medicines, including neostigmine may cause uterine irritability and induce premature labour when administered to pregnant women near term. Neostigmine metilsulfate should be given to a pregnant woman with caution.
It is unknown whether glycopyrronium bromide is excreted in human milk. The amount of neostigmine metilsulfate distributed into breastmilk is very small, but breastfed infants need to be monitored. Glycopyrronium bromide (including its metabolites) was excreted in the milk of lactating rats (see section 5.3). The amount of Cholstyq excreted in breastmilk following a standard single dose is not expected to have any influence on the baby.
Reproduction studies and other data in animals do not indicate a concern regarding fertility in either males or females (see section 5.3). In a fertility and early embryonic development study in rats, male rats were treated for 28 days prior to mating and female rats were treated for 14 days prior to mating with intravenous neostigmine metilsulfate (human equivalent doses of 1,6, 4 and 8,1 mcg/kg/day, based on body surface area). No adverse effects were reported at any dose.
Cholstyq may cause the eyesight to become weak, which could interfere with the ability to drive or operate machinery safely.
Adverse events which have been associated with glycopyrronium bromide – neostigmine metilsulfate injection are given below, listed by system organ class and frequency.
Undesirable effects are especially likely to occur at treatment onset or at dose increase.
Tabulated list of adverse reactions for glycopyrronium bromide component of Cholstyq:
| System organ class (MedDRA) | Adverse event | Frequency |
|---|---|---|
| Immune system disorders | Hypersensitivity, severe allergic reaction or pharmacologic idiosyncrasies including anaphylaxis, angioedema | Not known |
| Nervous system disorders | Confusion and/or excitement**, dizziness, headache, nervousness, drowsiness, weakness, insomnia | Not known |
| Eye disorders | Blurred vision as a result of dilatation of the pupils, increased ocular tension, photophobia, angle closure glaucoma | Not known |
| Cardiac disorders | Transient bradycardia* | Not known |
| Respiratory, thoracic and mediastinal disorders | Bronchial secretion reduced | Not known |
| Gastrointestinal disorders | Dry mouth, constipation, nausea, vomiting, loss of taste, bloated feeling | Not known |
| Skin and subcutaneous tissue disorders | Flushing, dry skin, sweating decreased, urticaria and other dermal manifestations | Not known |
| Renal and urinary disorders | Micturition urgency, urinary hesitance and retention | Not known |
| Reproductive system and breast disorders | Impotence, suppression of lactation | Not known |
* Followed by tachycardia, palpitation and dysrhythmias
** Particularly in elderly
Tabulated list of adverse reactions for Neostigmine metilsulfate component of Cholstyq:
| System organ class (MedDRA) | Adverse event | Frequency |
|---|---|---|
| Cardiac disorders | Bradycardia, cardiac dysrhythmias | Not known |
| Respiratory, thoracic and mediastinal disorders | Increased oropharyngeal secretions | Not known |
| Gastrointestinal disorders | Increased gastrointestinal activity, nausea, vomiting, diarrhoea, abdominal cramps, anorexia | Not known |
| Musculoskeletal and connective tissue disorders | Muscle cramps, fasciculation, weakness | Not known |
| General disorders and administration site conditions | Salivation | Not known |
The glycopyrronium – neostigmine component of injection can give rise to hypersensitivity, angioedema and anaphylactic reaction.
If severe neostigmine-induced muscarinic side effects occur (bradycardia, increased oropharyngeal secretions, decreased cardiac conduction rate, bronchospasm or increased gastrointestinal activity etc.), these may be treated by the intravenous administration of glycopyrronium bromide injection 200-600 micrograms (0,2-0,6 mg) or atropine 400-1200 micrograms (0,4-1,2 mg).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
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