4.1. Therapeutic indications

Adults

Lyrinel XL is indicated in adults for the symptomatic treatment of urge incontinence and/or increased urinary frequency associated with urgency as may occur in patients with unstable bladder.

Paediatric population

Oxybutynin hydrochloride is indicated in children over 5 years of age for:

- Urinary incontinence, urgency and frequency in unstable bladder conditions due to idiopathic overactive bladder or neurogenic bladder disorders (detrusor overactivity).

- Nocturnal enuresis associated with detrusor overactivity, in conjunction with nondrug therapy, when other treatment has failed.

4.2. Posology and method of administration

Posology

Lyrinel XL may be administered with or without food (see section 5.2).

Adults

Starting dose: the recommended starting dose is one 5 mg tablet once daily.

Maintenance dose/dose adjustment: In order to achieve a maintenance dose giving an optimal balance of efficacy and tolerability, after at least one week on 5 mg daily, the dose may be increased to 10 mg once daily, with subsequent incremental increases or decreases of 5 mg/day. There should be an interval of at least one week between dose changes.

Maximum dose: in patients requiring a higher dose, the total daily dose should not exceed 20 mg.

For patients currently taking oxybutynin immediate release, clinical judgement should be exercised in selecting the appropriate dose of Lyrinel XL. The dosage should be adjusted to the minimum dose that achieves an optimal balance of efficacy and tolerability, taking into account the current immediate-release dose.

In case of a missed dose, the patient should wait and take the next dose at the regular time.

Elderly

No dosage adjustment is necessary in elderly patients.

Paediatric population

Children over the age of 5 years

Initial dose of 5 mg once a day increased in 5mg increments up to a maximum of 15 mg once a day.

Lyrinel XL should not be used in children below age of 5 years, because safety and efficacy have not been established (see sections 5.1 and 5.2).

Method of administration

Lyrinel XL must be swallowed whole with the aid of liquid, and must not be chewed, divided, or crushed because the tablet is formulated to provide prolonged release.

Patients should be advised that the tablet membrane may pass through the gastrointestinal tract unchanged. This has no bearing on the efficacy of the product.

4.3. Contraindications

- Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

- Narrow-angle glaucoma or shallow anterior chamber

- Myasthenia gravis

- Urinary retention

- Gastrointestinal obstructive disorder, paralytic ileus or intestinal atony

- Severe ulcerative colitis

- Toxic megacolon

- Urinary frequency and nocturia due to heart or renal failure

- Porphyria

4.4. Special warnings and precautions for use

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects (see section 4.8). Anticholinergic CNS effects (e g , hallucinations, agitation, confusion, somnolence) have been reported; monitoring recommended especially in first few months after initiating therapy or increasing the dose; consider discontinuing therapy or reducing the dose if anticholinergic CNS effects develop.

Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling has the potential to become life-threatening. If involvement of tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

Oxybutynin should be given with caution in patients with the following conditions:

- hepatic or renal impairment

- clinically significant bladder outflow obstruction since anticholinergic drugs may aggravate bladder outflow and cause retention (see section 4.3)

- autonomic neuropathy

- Parkinson's disease

- gastrointestinal disorders: Anticholinergic medicinal products may decrease gastrointestinal motility and should be used with caution in patients with gastrointestinal obstructive disorders, intestinal atony and ulcerative colitis (see section 4.3)

- anticholinergic medicinal products should be used with caution in patients who have hiatal hernia/gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as bisphosphonates) that can cause or exacerbate oesophagitis.

- pre-existing dementia treated with cholinesterase inhibitors due to risk of aggravation of symptoms.

Oxybutynin should be used with caution in the frail elderly who may be more sensitive to the effects of oxybutynin. Anticholinergics should be used with caution in elderly patients due to the risk of cognitive impairment.

If urinary tract infection is present, an appropriate antibacterial therapy should be started.

Oxybutynin may aggravate tachycardia (and thus the symptoms of hyperthyroidism, congestive heart failure, cardiac arrhythmia, coronary heart disease, hypertension), cognitive disorders and symptoms of prostatic hypertrophy.

When oxybutynin is used in patients with fever or in high environmental temperatures, this can cause heat prostration, or heat stroke, due to decreased sweating.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Oxybutynin may reduce salivary secretions, which could result in dental caries, parodontotsis, or oral candidiasis.

As oxybutynin can cause angle-closure glaucoma, visual acuity and intraocular pressure should be monitored periodically during therapy. Patients should be advised to contact a physician immediately if they are aware of a sudden loss of visual acuity or ocular pain.

Paediatric population

Oxybutynin hydrochloride is not recommended for use in children below age 5 years due to insufficient data on safety and efficacy.

There is limited evidence supporting the use of Oxybutynin in children with monosymptomatic nocturnal enuresis (not related to detrusor overactivity).

In children over 5 years of age, Oxybutynin hydrochloride should be used with caution as they may be more sensitive to the effects of the product, particularly the CNS and psychiatric adverse reactions.

4.5. Interaction with other medicinal products and other forms of interaction

The anticholinergic activity of oxybutynin is increased by concurrent use of other anticholinergics or medicinal products with anticholinergic activity, such as amantadine and other anticholinergic antiparkinsonian medicinal products (e.g. biperiden, levodopa), antihistamines, antipsychotics (e.g. phenothiazines, butyrophenones, clozapine), quinidine, digitalis, tricyclic antidepressants, atropine and related compounds like atropinic antispasmodics and dipyridamole. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. They may also antagonize the gastrointestinal prokinetic effects of metoclopramide and domperidone.

Sublingual nitrates may fail to dissolve under the tongue owing to dry mouth, resulting in reduced therapeutic effect.

Oxybutynin is metabolised by cytochrome P450 isoenzyme CYP3A4. Concomitant administration with a CYP3A4 inhibitor can inhibit oxybutynin metabolism and increase oxybutynin exposure. Mean oxybutynin chloride concentrations were approximately 2 fold higher when Lyrinel XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g. itraconazole and fluconazole) or macrolide antibiotics (e.g. erythromycin), may increase oxybutynin exposure. The clinical relevance of such potential interaction is not known. Caution should be used when such drugs are co-administered.

Concomitant use with cholinesterase inhibitors may result in reduced cholinesterase inhibitor efficacy.

Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin.

Paediatric population

Interaction studies have only been performed in adults. It is not known whether the extent of interactions in the paediatric population is similar to that in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of oxybutynin in pregnant women. Studies in animals have shown minor reproductive toxicity (see section 5.3). Lyrinel XL is not recommended during pregnancy.

Breastfeeding

When oxybutynin is used during breastfeeding, a small amount is excreted in the mother's milk. The effect on newborns/infants is unknown. Use of Lyrinel XL during breastfeeding is therefore not recommended.

Fertility

Reproduction studies with oral oxybutynin in the mouse, rat, hamster, and rabbit showed no evidence of impaired fertility.

4.7. Effects on ability to drive and use machines

Oxybutynin has minor influence on the ability to drive and use machines. Oxybutynin may produce drowsiness or blurred vision, therefore, patients should be cautioned regarding activities requiring mental alertness such as driving, operating machinery or performing hazardous work while taking this drug

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions reported during clinical trials by > 5% of patients were dry mouth, constipation, diarrhoea, headache, somnolence and dizziness.

Serious adverse reactions associated with oxybutynin include anticholinergic central nervous system effects (see section 4.4).

List of adverse reactions

The safety of Lyrinel XL was evaluated in five double-blind, controlled (i.e., placebo or active comparator) clinical trials for the management of overactive bladder, in which 759 adult subjects received doses ranging from 5 to 20 mg/day. Additionally, safety was evaluated in one open-label (i.e., active comparator) clinical trial, in which 60 paediatric subjects received doses of 10 or 15 mg/day, Table 1 below reflects the adverse drug reactions reported with Lyrinel XL in clinical trials in adults and from postmarketing experience. Adverse drug reactions reported in the paediatric clinical trial are shown in Table 2.

Table 1: Adverse drug reactions reported in clinical trials in adults and from postmarketing experience

Very Common

≥1/10

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Rare

≥1/10,000 to <1/1000

Not Known*

Infections and infestations

Urinary tract infection

Immune System Disorders

Hypersensitivity

Anaphylactic reaction

Metabolism and nutrition disorders

Anorexia, Fluid retention, Decreased appetite

Psychiatric disorders

Insomnia

Hallucinations, Confusional state, Agitation, Memory impairment

Psychotic disorder, Anxiety, Nightmares, and Paranoia, symptoms of depression, dependence (in patients with history of drug or substance abuse)

Nervous system disorders

Somnolence, Dizziness, Headache, Dysgeusia

Convulsions

Cognitive disorders

Eye disorders

Vision blurred, Dry eye

Angle closure glaucoma

Mydriasis, Ocular hypertension

Cardiac disorders

Palpitations

Arrhythmia, Tachycardia

Vascular disorders

Hypertension, Flushing

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain, Cough, Nasal dryness, Dry throat

Dysphonia, Nasal congestion, Throat irritation

Gastrointestinal disorders

Dry mouth

Gastroesophageal reflux disease, Abdominal pain, Dyspepsia, Constipation, Diarrhoea, Nausea, Flatulence

Dysphagia, Abdominal discomfort, Frequent bowel movements, Vomiting

pseudo-obstruction in patients at risk (elderly or patients with constipation and treated with other medicinal products that decrease intestinal motility)

Skin and subcutaneous tissue disorders

Dry skin, Pruritus

Urticaria, Rash

Angioedema, Hypohidrosis

Renal and urinary disorders

Dysuria, Urinary hesitation

Urinary retention, Residual urine

Impotence

General disorders and administration site conditions

Fatigue

Chest discomfort, Mucosal dryness, Thirst

Investigations

Residual urine volume+

Injury, poisoning and procedural complications

Fall

Heat stroke

*Cannot be estimated from the available clinical data.

+The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased.

Description of selected adverse reactions

The following postmarketing adverse reactions listed in Table 1 are from postmarketing reports only (not seen in clinical trials), with the frequency category estimated from clinical trial safety data comprising 759 patients: hallucinations, agitation, memory impairment, and convulsions. These estimates represent the upper limit of the 95% CI.

As with other oxybutynin formulations, dry mouth was the most frequently reported adverse drug reaction. However, in clinical studies, dry mouth has been less frequently reported with Lyrinel XL than with oxybutynin immediate release formulations. For patients who required final doses of 5 or 10 mg of Lyrinel XL, the relative incidence of dry mouth that occurred at any dose level was 1.8 times lower compared with patients who required final doses > 10 mg.

Paediatric population

The safety of Lyrinel XL was evaluated in 60 paediatric subjects (age range 5 to 15 years; dose range 10-15 mg/day) who participated in an open-label, active control, three-arm clinical trial. Adverse drug reactions reported by Lyrinel XL-treated paediatric subjects in this clinical trial are shown in Table 2.

Table 2: Adverse drug reactions reported in clinical trials with paediatric subjects

Very Common

≥1/10

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Rare

≥1/10,000 to <1/1000

Metabolism and nutrition disorders

Anorexia

Psychiatric disorders

Insomnia

Nervous system disorders

Headache

Vascular disorders

Flushing

Gastrointestinal disorders

Constipation

Diarrhoea

Skin and subcutaneous tissue disorders

Rash,

Pruritus

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The symptoms of overdose with oxybutynin progress from an intensification of the usual CNS disturbances (from restlessness and excitement to psychotic behaviour), circulatory changes (flushing, fall in blood pressure, circulatory failure etc.), respiratory failure, paralysis and coma.

Measures to be taken include administration of physostigmine by slow intravenous injection.

Fever should be treated symptomatically with tepid sponging or ice packs.

In pronounced restlessness or excitation, diazepam may be given by intravenous injection. Tachycardia may be treated with intravenous propranolol and urinary retention managed by bladder catheterisation.

In the event of progression of curare-like effects to paralysis of the respiratory muscles, mechanical ventilation will be required.

The continuous release of oxybutynin from Lyrinel XL should be considered in the treatment of overdose. Patients should be monitored for at least 24 hours.