Leaflet SIALANAR 320mcg / ml oral solution

Sialanar 320 micrograms/ml oral solution

Each ml contains 400 micrograms of glycopyrronium bromide equivalent to 320 micrograms ofglycopyrronium.

Each ml contains 2.3 mg sodium benzoate (E211).

For the full list of excipients, see section 6.1

Oral solution

Clear, colourless solution.

Symptomatic treatment of severe sialorrhoea (chronic pathological drooling) in children andadolescents aged 3 years and older with chronic neurological disorders.

Sialanar should be prescribed by physicians experienced in the treatment of paediatric patients withneurological disorders.

Due to the lack of long term safety data, Sialanar is recommended for short -term intermittent use (seesection 4.4).

Paediatric population - children and adolescents aged 3 years and older

The dosing schedule for glycopyrronium is based on the weight of the child, starting withapproximately 12.8 micrograms/kg per dose (equivalent to 16 micrograms/kg per doseglycopyrronium bromide), three times per day and increasing by the doses shown in Table 1 below,every 7 days. Dose titration should be continued until efficacy is balanced with undesirable effects andamended up or down as appropriate, to a maximum individual dose of 64 micrograms/kg body weightglycopyrronium or 6 ml (1.9 mg glycopyrronium, equivalent to 2.4 mg glycopyrronium bromide) threetimes a day, whichever is less. Dose titrations should be conducted in discussion with the carer toassess both efficacy and undesirable effects until an acceptable maintenance dose is achieved.

Undesirable effects may be minimised by using the lowest effective dose necessary to controlsymptoms. It is important that the carer checks the dose volume in the syringe before administration.

The maximum volume of the highest dose is 6 ml. In the event of a known anticholinergic adversereaction occurring when the dose is increased, the dose should be reduced to the previous lower doseand the event monitored (see section 4.4). If the event does not resolve treatment should bediscontinued. In the event of constipation, urinary retention or pneumonia (see section 4.8), treatmentshould be stopped and the prescribing physician contacted.

Younger children may be more susceptible to adverse reactions and this should be borne in mind whenany dose adjustments are carried out.

Following the dose titration period, the child’s sialorrhoea should be monitored, in conjunction withthe carer at no longer than 3 monthly intervals, to assess changes in efficacy and/or tolerability overtime, and the dose adjusted accordingly.

The Table 1 shows the dose in ml of solution to be given for each weight range at each dosingincrease.

Table 1. Dosing table for children and adolescents with normal renal function

Weight Dose level 1 Dose level 2 Dose level 3 Dose level 4 Dose level 5

Kg (~12.8µg/kg) 1 (~25.6µg/kg) 1 (~38.4µg/kg) 1 (~51.2µg/kg) 1 (~64µg/kg) 1ml ml ml ml ml13-17 0.6 1.2 1.8 2.4 3*18-22 0.8 1.6 2.4 3.2 4*23-27 1 2 3 4 5*28-32 1.2 2.4 3.6 4.8 6*33-37 1.4 2.8 4.2 5.6 6*38-42 1.6 3.2 4.8 6* 643-47 1.8 3.6 5.4 6* 6≥48 2 4 6* 6 61 refers to µg/kg glycopyrronium

*Maximum individual dose in this weight range

Paediatric population (children aged < 3 years)

The safety and efficacy of glycopyrronium bromide in children aged from birth to < 3 years has notbeen established. No data are available.

Adult population

Sialanar is indicated for the paediatric population only. There is limited clinical trial evidence on theuse of glycopyrronium in the adult population with pathological drooling.

Sialanar is indicated for the paediatric population only. The elderly have a longer elimination half-lifeand reduced medicinal product clearance as well as limited data to support efficacy in short-term use.

As such Sialanar should not be used in patients over the age of 65 years.

Clinical studies have not been conducted in patients with hepatic impairment. Glycopyrronium iscleared predominantly from the systemic circulation by renal excretion and hepatic impairment is notthought to result in a clinically relevant increase in systemic exposure of glycopyrronium.

Doses should be reduced by 30% in patients with mild to moderate renal impairment (eGFR <90 -≥30 ml/min/1.73m2) (see Table 2). This medicinal product is contraindicated in patients with severerenal impairment (eGFR <30 ml/min/1.73m2), including those with end-stage renal disease requiringdialysis (see section 4.3).

Table 2. Dosing table for children and adolescents with mild to moderate renal impairment

Weight Dose level 1 Dose level 2 Dose level 3 Dose level 4 Dose level 5

Kg (~8.8µg/kg) 1 (~17.6µg/kg) 1 (~27.2µg/kg) 1 (~36µg/kg) 1 (~44.8µg/kg) 1ml ml ml ml ml13-17 0.4 0.8 1.2 1.7 2.1*18-22 0.6 1.1 1.7 2.2 2.8*23-27 0.7 1.4 2.1 2.8 3.5*28-32 0.8 1.7 2.5 3.4 4.2*33-37 1 2 2.9 3.9 4.2*38-42 1.1 2.2 3.4 4.2* 4.243-47 1.2 2.5 3.8 4.2* 4.2≥48 1.4 2.8 4.2* 4.2 4.21 refers to µg/kg glycopyrronium

*Maximum individual dose in this weight range

For oral use only.

Co-administration with food results in a marked decrease in systemic medicinal product exposure (seesection 5.2). Dosing should be at least one hour before or at least two hours after meals or at consistenttimes with respect to food intake. High fat food should be avoided. Where the child’s specific needsdetermine that co-administration with food is required, dosing of the medicinal product should beconsistently performed during food intake.

Insert the syringe adaptor into the neck of the bottle. Insert the end of the oral syringe into the syringeadaptor and ensure it is secure. Turn the bottle upside down. Gently pull down the plunger to thecorrect level (see Tables 1 and 2 for the correct dose). Turn the bottle upright. Remove the oralsyringe. Place the oral syringe inside the child’s mouth and press the plunger slowly to gently releasethe medicinal product. If the child is given the medicinal product through a feeding tube, flush the tubewith 10 ml of water after you have given the medicinal product.

The oral syringe should be gently washed with warm water and allowed to dry after each use (i.e. threetimes per day). Do not use a dishwasher.

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

Glaucoma.

Urinary retention.

Severe renal impairment (eGFR <30 ml/min/1.73m2), including those with end-stage renal diseaserequiring dialysis.

History of intestinal obstruction, ulcerative colitis, paralytic ileus, pyloric stenosis and myastheniagravis.

Concomitant treatment with potassium chloride solid oral dose and anticholinergics (see section 4.5).

Anticholinergic effects

Anticholinergic effects such as urinary retention, constipation and overheating due to inhibition ofsweating may be dose dependent and difficult to assess in a disabled child. Monitoring by physiciansand caregivers is required with adherence to the management instructions below:

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 thisshould continue at a lower dose (see section 4.2).

Lack of long-term safety data

Published safety data are not available beyond 24 weeks treatment duration. Given the limited long-term safety data available and the uncertainties around the potential risk for carcinogenicity, totaltreatment duration should be kept as short as possible. If continuous treatment is needed (e.g. in apalliative setting) or the treatment is repeated intermittently (e.g. in the non palliative setting treatingchronic disease) benefits and risks should be carefully considered on a case by case basis andtreatment should be closely monitored.

Mild to moderate sialorrhoea

Due to the low likelihood of benefit and the known adverse effect profile, Sialanar should not be givento children with mild to moderate sialorrhoea.

Glycopyrronium should be used with caution in patients with acute myocardial infarction,hypertension, coronary artery disease, cardiac arrhythmias and conditions characterised by tachycardia(including thyrotoxicosis, cardiac insufficiency, cardiac surgery) due to the potential increase in heartrate, blood pressure and rhythm disorders produced by its administration (see section 4.8). The carershould be advised to measure the pulse rate if the child seems unwell and report very fast or very slowheart rate.

Gastro-intestinal disorders

Antimuscarinics such as glycopyrronium should be used with caution in patients with gastro-oesophageal reflux disease, pre-existing constipation and diarrhoea.

Dental disorders

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

Glycopyrronium can cause thickening of secretions, which may increase the risk of respiratoryinfection and pneumonia (see section 4.8). Glycopyrronium should be discontinued if pneumonia ispresent.

Central nervous system (CNS) adverse reactions

Increased CNS effects have been reported in clinical trials including: irritability, drowsiness,restlessness, overactivity, short attention span, frustration, mood changes, temper outbursts orexplosive behaviour, excessive sensitivity, seriousness or sadness, frequent crying episodes andfearfulness (see section 4.8). Behavioural changes should be monitored.

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

Children below the age of 3 years

Sialanar is not recommended in children below the age of 3 years since there is very limited data onthe efficacy and safety of glycopyrronium in this age group

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum dose, that is to sayessentially ‘sodium free’.

This medicinal product contains 2.3 mg sodium benzoate (E211) in each ml.

No interaction studies have been performed.

There are limited data available relating to interactions with other medicinal products in the paediatricage group.

The following medicinal product interaction information is relevant to glycopyrronium.

Contraindications of concomitant use (see section 4.3)

Potassium chloride solid oral dose

Glycopyrronium may potentiate the risk of upper gastrointestinal injury associated with oral solidformulations of potassium chloride due to increased gastrointestinal transit time creating a highlocalized concentration of potassium ions. An association with upper gastrointestinal bleeding andsmall bowel ulceration, stenosis, perforation, and obstruction has been observed.

Anticholinergics

Concomitant use of anticholinergics may increase the risk of anticholinergic side effects.

Anticholinergics may delay the gastrointestinal absorption of other anticholinergics administeredorally and also increase the risk of anticholinergic side effects.

Concomitant use to be considered with caution

Antispasmodics

Glycopyrronium may antagonize the pharmacologic effects of gastrointestinal prokinetic activesubstances such as domperidone and metoclopramide.

Topiramate

Glycopyrronium may potentiate the effects of oligohidrosis and hyperthermia associated with the useof topiramate, particularly in pediatric patients.

Sedating antihistamines

Sedating antihistamines may have additive anticholinergic effects. A reduction in anticholinergicand/or antihistamine dose 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 systemicanticholinergic effects.

Tricyclic antidepressants and MAOIs

Tricyclic antidepressants and MAOIs may have additive anticholinergic effects. A reduction inanticholinergic and/or tricyclic antidepressants and MAOIs dose may be necessary.

Opioids

Active substances such as pethidine and codeine may result in additive central nervous system andgastrointestinal adverse effects, and increase the risk of severe constipation or paralytic ileus and CNSdepression. If concomitant use cannot be avoided, patients should be monitored for potentiallyexcessive or prolonged CNS depression and constipation.

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

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

Effective contraception should be considered prior to treating women of childbearing age, whereappropriate.

There are no data on the use of Sialanar in pregnant women. The assessment of reproductive endpointsfor glycopyrronium is limited (see section 5.3). Glycopyrronium is contraindicated during pregnancy(see section 4.3).

Safety in breast-feeding has not been established. Use while breast-feeding is contraindicated (seesection 4.3).

There are no data on the effects of Sialanar on male or female fertility. Reproductive performance inrats given glycopyrronium shows a decrease in the rate of conception and in survival rate at weaning.

There are insufficient data in the public domain to adequately assess effects on the reproductivesystem in young adults (see section 5.3).

Sialanar has moderate influence on the ability to drive and use machines. The anticholinergic effectsof glycopyrronium may cause blurred vision, dizziness and other effects that may impair a patient'sability to perform skilled tasks such as driving, riding a bicycle and using machines. The undesirableeffects are increased with increasing dose.

Adverse reactions are common with glycopyrronium due to its known pharmacodynamicanticholinergic effects. The most common adverse reactions are dry mouth (11%), constipation (20%),diarrhoea (18%), vomiting (18%), urinary retention (15%), flushing (11%) and nasal congestion(11%).

Adverse reactions are more common with higher doses and prolonged use.

Adverse reactions reported in the literature for trials using glycopyrronium for sialorrhoea in thepaediatric population (including 2 placebo controlled trials, an uncontrolled safety study usingglycopyrronium for a 6 month period, and 3 supportive studies with adverse reaction data in the targetpopulation) are listed by MedDRA system organ class (Table 3). Within each system organ class, theadverse reactions are ranked by frequency, with the most frequent reactions first. Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, thecorresponding frequency category for each adverse reaction is based on the following convention:very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 3. List of adverse reactions

Adverse reactions Frequency category

Upper respiratory tract infection Common

Pneumonia Common

Urinary tract infection Common

Irritability Very common

Agitation Common

Drowsiness Common

Restlessness Not known

Overactivity Not known

Short attention span Not known

Frustration Not known

Mood variable Not known

Adverse reactions Frequency category

Temper tantrum Not known

Intermittent explosive disorder Not known

Sensitivity, shyness, and social withdrawal disorder Not knownspecific to childhood or adolescence

Feeling sad Not known

Crying Not known

Fear Not known

Headache Uncommon

Insomnia Not known

Mydriasis Uncommon

Nystagmus Uncommon

Angle-closure glaucoma Not known

Photophobia Not known

Dry eyes Not known

Flushing Very common

Transient bradycardia Not known

Nasal congestion Very common

Epistaxis Common

Reduced bronchial secretions Very common

Sinusitis Not known

Dry mouth Very common

Constipation Very common

Diarrhoea Very common

Vomiting Very common

Halitosis Uncommon

Oesophageal candidiasis Uncommon

Gastrointestinal motility disorder Uncommon

Pseudo-obstruction Uncommon

Nausea Not known

Rash Common

Dryness of the skin Not known

Inhibition of sweating Not known

Urinary retention Very common

Urinary urgency Not known

Pyrexia Common

Dehydration Uncommon

Thirst in hot weather Uncommon

Angioedema Not known

Allergic reaction Not known

Urinary retention

Urinary retention is a known adverse reaction associated with anticholinergic medicinal products(15%). Glycopyrronium treatment should be stopped until the urinary retention resolves.

Pneumonia is a known adverse reaction associated with anticholinergic medicinal products (7.9%).

Glycopyrronium treatment should be stopped until the pneumonia resolves.

Constipation is a known adverse reaction associated with anticholinergic medicinal products (30%).

Glycopyrronium treatment should be stopped until the constipation resolves.

Central nervous system

Although glycopyrronium has limited ability to cross the blood brain barrier, increased central nervoussystem effects have been reported in clinical trials (23%). Such effects should be discussed with thecarer during treatment reviews and a dose reduction considered (see section 4.4).

Glycopyrronium is known to have an effect on heart rate and blood pressure at doses used duringanaesthesia although clinical trials in children with chronic drooling have not shown this effect. Aneffect on the cardiovascular system should be considered when assessing tolerability (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose of glycopyrronium can result in anticholinergic syndrome, produced by the inhibition ofcholinergic neurotransmission at muscarinic receptor sites. Clinical manifestations are caused by CNSeffects, peripheral nervous system effects, or both. Common manifestations include flushing, dry skinand mucous membranes, mydriasis with loss of accommodation, altered mental status and fever.

Additional manifestations include sinus tachycardia, decreased bowel sounds, functional ileus, urinaryretention, hypertension, tremulousness and myoclonic jerking.

Patients presenting with anticholinergic toxicity should be transported to the nearest emergencyfacility with advanced life support capabilities. Pre-hospital gastrointestinal decontamination withactivated charcoal is not recommended because of the potential for somnolence and seizures and theresulting risk of pulmonary aspiration. At hospital, activated charcoal can be administered if thepatient’s airways can be adequately protected. Physostigmine salicylate is recommended whentachydysrhythmia with subsequent hemodynamic compromise, intractable seizure, severe agitation orpsychosis is present.

Patients and/or parents/caregivers should be counselled to ensure an acurate dose is given each time, inorder to prevent the harmful consequences of anticholinergic reactions of glycopyrronium seen withdosing errors or overdose.

Pharmacotherapeutic group: Medicinal products for functional gastrointestinal disorders, syntheticanticholinergics, quaternary ammonium compounds, ATC code: A03AB02.

Glycopyrronium is a quaternary ammonium antimuscarinic with peripheral effects similar to those ofatropine.

Antimuscarinics are competitive inhibitors of the actions of acetylcholine at the muscarinic receptorsof autonomic effector sites innervated by parasympathetic (cholinergic postganglionic) nerves. Theyalso inhibit the action of acetylcholine where smooth muscle lacks cholinergic innervation.

Salivation is primarily mediated by parasympathetic innervation of the salivary glands.

Glycopyrronium competitively inhibits cholinergic muscarinic receptors in salivary glands and otherperipheral tissues, thus indirectly reducing the rate of salivation. Glycopyrronium has little effect oncholinergic stimuli at nicotinic acetylcholine receptors, on structures innervated by postganglioniccholinergic neurons, and on smooth muscles that respond to acetylcholine but have no cholinergicinnervation.

Peripheral antimuscarinic effects that are produced as the dose increases are: decreased production ofsecretions from the salivary, bronchial and sweat glands; dilatation of the pupils (mydriasis) andparalysis of accommodation (cyclopegia); increased heart rate; inhibition of micturition and reductionin gastrointestinal tone; inhibition of gastric acid secretion.

Placebo controlled efficacy data includes patients with a treatment duration of 8 weeks. There is noplacebo or comparator controlled data beyond 8 weeks.

Zeller et al 2012a evaluated the efficacy of glycopyrronium bromide oral solution (1 mg/5 mL) inmanaging problem drooling associated with cerebral palsy and other neurologic conditions. Thirty-eight patients aged 3-23 years weighing at least 27 lb (12.2 kg) with severe drooling (clothing damp5-7 days/week) were randomised to eight-weeks treatment with glycopyrronium (n = 20),20-100 μg/kg (not exceeding 3 mg in total) three times a day, or matching placebo (n = 18). The firstfour weeks were an individual titration period in fixed steps depending on response followed by4-weeks maintenance treatment. Primary efficacy endpoint was responder rate, defined as percentageshowing ≥3-point improvement on the modified Teacher’s Drooling Scale (mTDS). The primaryanalysis population was revised to only comprise patients with an age of 3 -16 years which rendered19 patients in the glycopyrrolate oral solution group and 17 in the placebo group. Responder rate wasdefined as at least a 3-point improvement in modified Teacher’s Drooling Scale (mTDS).

Responder rate at week 8 At least a 3-point Mean improvements in mTDSimprovement in mTDS

Glycopyrronium 14 of 19 patients (73.7%) 3.94 points(SD: 1.95; 95%; CI: 2.97-4.91)

Placebo 3 of 17 patients (17.6%) 0.71 points(SD: 2.14; 95% CI: -0.43-1.84)p value p = 0.0011 p <0.0001

In addition, 84% of physicians and 100% of parents/caregivers regarded glycopyrrolate as worthwhilecompared with 41% and 56%, respectively, for placebo (p≤0.014). Most frequently reportedtreatment-emergent adverse events (glycopyrrolate vs placebo) were dry mouth, constipation,vomiting and nasal congestion.

The safety and efficacy of glycopyrronium have been studied in an open labelled study with no controlgroup over a 24-week period in children aged 3 to 18 years. At the week 24/exit visit, 52.3% (95%confidence interval 43.7-60.9) of patients (n=130) had an at least three-point decrease in mTDS frombaseline and were classified as responders to treatment with oral glycopyrrolate solution. The safetyprofile was consistent with the one seen with anticholinergics (see sections 4.4 and 4.8).

Mean absolute oral bioavailability of glycopyrronium comparing a single 50 µg/kg oral dose and asingle 5 µg/kg intravenous dose was low at approximately 3% (range 1.3-13.3%) in children aged7-14 years undergoing intraocular surgery (n = 6) due to the medicinal product’s low lipid solubility.

Data from sparse PK sampling in children suggests dose proportional PK.

The bioavailability of oral glycopyrronium in children was between that of adults under fed and fastedconditions.

In adults, distribution of glycopyrronium was rapid following a single 6 µg/kg intravenous dose;distribution half-life was 2.2 ± 1.3 minutes. Following administration of 3H-labelled glycopyrroniummore than 90% of the radiolabel disappeared from the plasma in 5 minutes, and almost 100% within30 minutes, reflecting rapid distribution. Analyses of population pharmacokinetic data from healthyadults and children with cerebral palsy-associated chronic moderate to severe drooling who receivedglycopyrronium (route of administration and doses not specified) did not demonstrate linearpharmacokinetics of the medicinal product.

The volume of distribution, 0.64 ± 0.29 L/kg in adults is similar to that of total body water. Volume ofdistribution is somewhat higher in the paediatric population(s), in the range 1.31 to 1.83 L/kg.

The PK of glycopyrronium has been shown to be essentially independent of age in children in the agerange 0.19 - 14 years administered a 5 µg/kg intravenous single-dose. In most paediatric subjects,plasma glycopyrronium vs. time plots are reported to show a triexponential curve; adults generallyshow a biexponential curve. Modest changes in volume of distribution (Vss) and clearance (Cl) havebeen observed in children between 1 and 3 years of age, leading to a statistically significant shorterelimination half-life (t½, z) than that observed in younger (<1 year of age; p = 0.037) or older (>3 yearsof age; p = 0.042) groups.

In a study in healthy adults, a 2000 µg single dose of glycopyrronium bromide resulted in an AUC of2.39 µg.h/L (fasted). An AUC0-6 h of 8.64 µg.h/L was observed after 6 µg/kg intravenousglycopyrronium.

Based upon theoretical physicochemical considerations, the quaternary ammonium compoundglycopyrronium would be expected to have low central bioavailability; no glycopyrronium wasdetectable in the CSF of anaesthetised surgical patients or patients undergoing caesarean sectionfollowing a 6 - 8 µg/kg intravenous dose. In the paediatric population 5 µg/kg intravenousglycopyrronium has low central bioavailability, except in the case where the blood brain barrier hasbeen compromised (e.g. a shunt infection).

The primary route of elimination of glycopyrronium is via renal excretion, mainly as unchangedmedicinal product. Approximately 65% of an intravenous dose is renally excreted within the first24 hours. A small proportion (~5%) is eliminated in the bile.

The elimination half-life of glycopyrronium appears to be dependent on route of administration being0.83 ± 0.27 hours after intravenous administration, 75 minutes after intramuscular administration andin the region of 2.5 - 4 h after oral (solution) administration, though again this was highly variable.

That the latter two half-lives, and especially that for oral administration, are longer than forintravenous administration probably reflects the complex absorption and distribution ofglycopyrronium by each route. It is possible that prolonged absorption after oral administrationtranslates into elimination being faster than absorption (known as flip-flop kinetics, characterized by

Ka < Ke).

The total body clearance of the medicinal product following an intravenous dose is relatively high atbetween 0.54 ± 0.14 L/h/kg and 1.14 ± 0.31 L/h/kg. As this exceeds the glomerular filtration rate andit appears that more than 50% of the dose is excreted unchanged in the urine, it is probable that therenal elimination of glycopyrronium involves both glomerular filtration and proximal tubular secretionby the base secretory mechanism.

A mean increase in total systemic exposure (AUClast) of up to 1.4 fold was seen in adult subjects withmild and moderate renal impairment (GFR ≥30mL/min/1.73m2) and up to 2.2 fold in subjects withsevere renal impairment or end stage renal disease (estimated GFR <30 mL/min/1.73m2). A 30% dosereduction (see Table 2) is required for patients with mild to moderate renal impairment.

Glycopyrronium is contraindicated in patients with severe renal impairment.

Baseline characteristics

Baseline characteristics (age, weight, gender and race) do not affect the pharmacokinetics ofglycopyrronium.

Impaired hepatic function is not expected to affect the pharmacokinetics of glycopyrronium since themajority of the medicinal product is eliminated through the kidneys.

Co-administration with food results in a marked decrease in systemic glycopyrronium exposure (seesection 4.2).

Non-clinical data, including genotoxicity or carcinogenicity studies have not been performed for

Sialanar.

Limited non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology or repeated dose toxicity.

The single dose toxicity of glycopyrronium has been tested in a range of investigations, although onlylimited experimental details are available. Upon oral administration, high LD50 values of 550 mg/kg inmice and above 1,000 mg/kg in rats were reported. In rats at higher doses (1500-2000 mg/kg) tremors,clonic and tonic convulsions and laboured breathing were observed prior to death, resulting fromrespiratory failure.

Chronic oral administration of glycopyrronium at doses of 4, 16 and 64 mg/kg for up to 27 weeks indogs produced mydriasis, cycloplegia, xerostomia, emesis, occasional lacrimation, injection of scleraand rhinorrhoea.

Extrapolation of safety margins to the paediatric population is not possible, as no exposure data areavailable from repeated dose toxicology studies and no studies in juvenile animals have beenperformed with glycopyrronium.

Data on reproductive endpoints for glycopyrronium are very limited. A reduction in corpora lutea wasobserved in female rats administered glycopyrronium. No effects on fertility were observed in malerats. Reproductive performance in rats given glycopyrronium shows a decrease in the rate ofconception and in survival rate at weaning. The significance of the non-clinical findings for humans isnot clear, and the lack of human data on the medicinal product leads to glycopyrronium beingcontraindicated in pregnant women. There are insufficient data in the public domain to adequatelyassess effects on the reproductive system in young adults, and safety in human pregnancy has not beenestablished.

Sodium benzoate (E211)

Raspberry flavouring (containing propylene glycol E1520)

Sucralose (E955)

Citric acid (E330)

Purified water

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

2 months after first opening.

Do not store above 25°C.

Amber coloured glass bottle with a high density polyethylene tamper evident child resistant closurewith expanded low density polyethylene liner. The bottle contains 60 ml or 250 ml of oral solution.

Pack size of one bottle, one 8 ml low density polyethylene oral syringe (0.1 ml graduations) and onesyringe adaptor.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Proveca Pharma Limited2 Dublin Landings

North Wall Quay

Dublin 1

Ireland

EU/1/16/1135/001 (250 ml bottle)

EU/1/16/1135/002 (60 ml bottle)

Date of first authorisation: 15 September 2016

Date of latest renewal: 17 June 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu