RYBRILA Oral solution Ref.[50429] Active ingredients: Glycopyrronium

Anticholinergic effects

Anticholinergic effects such as urinary retention, constipation and overheating due to inhibition of sweating are dose dependent. Monitoring by physicians and caregivers is required with adherence to the management instructions below:

Management of important anticholinergic side effects

The carer should stop treatment and seek advice from the prescriber in the event of:

• constipation
• urinary retention
• pneumonia
• allergic reaction
• pyrexia
• very hot weather
• changes in behaviour

After evaluating the event, the prescriber will decide if treatment should remain stopped or if this should continue at a lower dose.

Rybrila should be used with caution in gastro-oesophageal reflux disease, ulcerative colitis, pre-existing constipation, acute myocardial infarction, hypertension, conditions characterised by tachycardia (including hyperthyroidism, cardiac insufficiency, cardiac surgery) because of the increase in heart rate produced by its administration, coronary artery disease and cardiac arrhythmias.

Due to the potential change to normal heart rhythm, Rybrila should be used with caution in patients receiving inhalation anaesthesia.

Diarrhoea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with this drug would be inappropriate and possibly harmful.

Because Rybrila inhibits sweating, patients with increased temperature should be observed closely. In the presence of a high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of this medicinal product.

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

Patients with rare hereditary problems of fructose intolerance should not take this medicine. This is due to the presence of sorbitol (E420) in this medicine.

Rybrila contains sodium propyl parahydroxybenzoate (E217) and sodium methyl parahydroxybenzoate (E219). These may cause allergic reactions (possibly delayed).

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum dose, i.e. essentially is ‘sodium free’.

Paediatric population – children younger than 3 years

Rybrila is not recommended for use in children younger than 3 years of age.

Lack of long-term safety data

Safety data are not available beyond 24 weeks treatment duration. Given the limited long-term safety data available and the uncertainties around the long term use of the product, the treatment duration should be kept as short as possible. If continuous treatment is needed (e.g. in a palliative setting) or the treatment is repeated intermittently (e.g. in the non palliative setting treating chronic disease) benefits and risks should be carefully considered on a case by case basis and treatment should be closely monitored.

Mild to moderate sialorrhoea

Due to the low potential benefit and the known adverse effect profile, Rybrila should not be given to children with mild to moderate sialorrhoea.

Dental

Since reduced salivation can increase the risk of oral cavities and periodontal diseases, it is important that patients receive adequate daily dental hygiene and regular dental health checks.

CNS adverse events

Increased central nervous system effects have been reported in clinical trials including: irritability; drowsiness; restlessness; overactivity; short attention span; frustration; mood changes; temper outbursts or explosive behaviour; excessive sensitivity; seriousness or sadness; frequent crying episodes; fearfulness. Behavioural changes should be monitored.

As a consequence of its quaternary charge glycopyrronium has limited ability to penetrate the blood brain barrier, although the extent of penetration is unknown. Caution should be exercised in children with compromised blood brain barrier e.g.: intraventricular shunt, brain tumour, encephalitis.

Growth and development

The effects of glycopyrronium on the reproductive system have not been investigated. Whilst clinical studies do not report any short or long-term effect of glycopyrronium on neurodevelopment or growth, no studies have been conducted to specifically address these issues.

No interaction studies have been performed.

Contraindication of concomitant use

Concomitant use of the following medicinal products is contraindicated (see section 4.3):

• Potassium chloride solid oral dose products: glycopyrronium may potentiate the risk of upper gastrointestinal injury associated with oral solid formulations of potassium chloride due to increased gastrointestinal transit time creating a high localized concentration of potassium ions. An association with upper GI bleeding and small bowel ulceration, stenosis, perforation, and obstruction has been observed.
• Anticholinergic medicines: concomitant use of anticholinergics may increase the risk of anticholinergic side effects. Anticholinergics may delay the gastrointestinal absorption of other anticholinergics administered orally and also increase the risk of anticholinergic side effects.

Concomitant use to be considered with caution including dose adjustment

Concomitant use of the following medicinal products should be considered with caution:

Antispasmodics: glycopyrronium may antagonize the pharmacologic effects of gastrointestinal prokinetic active substances such as domperidone and metoclopramide.

Sedating antihistamines: may have additive anticholinergic effects. A reduction in anticholinergic and/or antihistamine dosage may be necessary;

Neuroleptics/antipsychotics: the effects of active substances such as phenothiazines, clozapine and haloperidol may be potentiated. A reduction in anticholinergic and/or neuroleptic/antipsychotic dose may be necessary;

Skeletal muscle relaxants: Use of anticholinergics after administration of botulinum toxin may potentiate systemic anticholinergic effects;

Tricyclic antidepressants and MAOIs: may have additive anticholinergic effects. A reduction in anticholinergic and/or tricyclic antidepressants and MAOIs dosage may be necessary.

Opioids: active substances such as pethidine and codeine may result in additive central nervous system and gastrointestinal adverse effects, and increase the risk of severe constipation or paralytic ileus and CNS depression. If concomitant use cannot be avoided, patients should be monitored for potentially excessive or prolonged CNS depression and constipation;

Corticosteroids: Steroid-induced glaucoma may develop with topical, inhaled, oral or intravenous, steroid administration. Concomitant use may result in increased intraocular pressure via an open- or a closed-angle mechanism;

Topiramate: glycopyrronium may potentiate the effects of oligohidrosis and hyperthermia associated with the use of topiramate, particularly in pediatric patients.

Other

Medicinal products with anticholinergic properties (e.g. antihistamines, antidepressants) may cause cumulative parasympatholytic effects including dry mouth, urinary retention, constipation and confusion, and an increased risk of anticholinergic intoxication syndrome.

Pregnancy

There is limited amount of data (less than 300 pregnancy outcomes) from the use of glycopyrronium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of Rybrila during pregnancy.

Breastfeeding

Available toxicological data in animals have shown excretion of glycopyrronium and its metabolites in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue from Rybrilatherapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of Rybrila on male or female fertility. Animal data do not indicate an effect of glycopyrronium on male or female fertility at clinically relevant exposures.

Rybrila may influence the ability to drive and use machines because it may produce drowsiness or blurred vision. In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or performing hazardous work while taking this medicinal product.

Rybrila may produce the following effects, which are extensions of its fundamental pharmacological actions: dry mouth, diminished gastrointestinal motility, difficulty in micturition, increased body temperature and inhibition of sweating.

Side-effects of antimuscarinics include difficulty swallowing, difficulty talking, thirst, 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.

Other side-effects that occur less frequently include confusion (particularly in the elderly), nausea, vomiting, drowsiness, dizziness andangle-closure glaucoma.

Summary of the safety profile

The highest incidence of adverse reactions associated with glycopyrronium therapy is related to its anticholinergic properties 1 i.e. dry mouth (13%), constipation (16%), diarrhoea (9.4%), nasal congestion (8.4%), vomiting (11.4%), urinary retention (5.4%) etc.

Pulmonary undesirable effects including upper respiratory infection and pneumonia have been reported (See Section 4.4). There is no data on the long-term use of the product. (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions associated with glycopyrronium obtained from published studies1 are tabulated below according to the following convention: Very common (>1/10); Common (>1/100, <1/10); Uncommon (>1/1,000, <1/100); Unknown (cannot be estimated from the available data).

¹ Frequency categories are assigned from the pooled datafrom the following published studies: double blinded placebo controlled trials Mier et al. and Zeller et al. 2012a, one retrospective review Bachrach et al., and three one open –label studies Zeller et al 2012b, Stern and Blasco et al. with a total of 297 patients exposed to glycopyrronium.
² Behavioural changes include agitation, drowsiness, restlessness, overactivity, short attention span, frustration, irritability, mood changes, temper outbursts, explosive behaviour, excessive sensitivity, seriousness, sadness, frequent crying, fearfulness.

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 national reporting system: HPRA Pharmacovigilance Website: www.hpra.ie.

Not applicable.