Lyrinel XL 5 mg prolonged release tablet

Lyrinel XL 10 mg prolonged release tablet

Each prolonged release tablet contains 5 mg of oxybutynin hydrochloride

Each prolonged release tablet contains 10 mg of oxybutynin hydrochloride

Excipient: Each Lyrinel XL prolonged release tablet contains 0.03 mg lactose.

For the full list of excipients, see Section 6.1.

Prolonged release tablet.

Lyrinel XL 5 mg prolonged release tablets: Round yellow coloured tablet, approximately 7.5 mm in diameter, printed with “5 XL" on one side in black ink.

Lyrinel XL 10 mg prolonged release tablets: Round pink coloured tablet, approximately 7.5 mm in diameter, printed with “10 XL" on one side in black ink.

Adults and Elderly

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.

Dosage

Adults and Elderly

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.

Children over the age of 5 years

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

Lyrinel XL is not recommended for use in children below age of 5 years, due to a lack of data on safety and efficacy (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.

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.

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

- Hypersensitivity to oxybutynin or any of the excipients

- 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

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects (see section 4.8 Undesirable Effects). Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

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)

- gastrointestinal motility disorders (see section 4.3)

- gastroesophageal reflux and/or who are currently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis

- 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.

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

Oxybutynin may aggravate the symptoms of hyperthyroidism, congestive heart failure, cardiac arrhythmia, tachycardia, hypertension and 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 lead to decreased salivary secretions, which could result in tooth caries, periodontitis, or oral candidiasis.

As oxybutynin may trigger angle-closure glaucoma, visual acuity and intraocular pressure should be monitored periodically during therapy. Patients should be advised to seek advice immediately if they are aware of a sudden loss of visual acuity.

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.

The concomitant use of oxybutynin with other anticholinergic medicinal products or drugs with anticholinergic activity, such as amantadine and other anticholinergic antiparkinsonian drugs (e.g. biperiden, levodopa), antihistamines, antipsychotics (e.g. phenothiazines, butyrophenones, clozapine), quinidine, tricyclic antidepressants, atropine and related compounds like atropinic antispasmodics, dipyridamole, may increase the frequency or severity of dry mouth, constipation and drowsiness.

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. However, the interaction between prokinetics and oxybutynin has not been established.

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. 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 alter oxybutynin pharmacokinetics. The clinical relevance of such potential interaction is not known. Caution should be used when such drugs are co-administered.

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 should only be used during pregnancy if the expected benefit outweighs the risk.

Lactation

When oxybutynin is used during lactation, a small amount is excreted in the mother's milk. Breast feeding while using oxybutynin is therefore not recommended.

As oxybutynin may produce drowsiness or blurred vision, patients should be cautioned regarding activities requiring mental alertness such as driving, operating machinery or performing hazardous work while taking this drug.

The table below reflects the data obtained with Lyrinel XL in clinical trials and from postmarketing experience. In clinical trials with Lyrinel XL (n=1006), adverse events were associated mainly with the anticholinergic actions of oxybutynin. Adverse events were generally dose related. As with other oxybutynin formulations, dry mouth was the most frequently reported adverse 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.

Undesirable effects noted with other oxybutynin hydrochloride formulations:

In addition, cyclopegia, mydriasis and suppression of lactation have been reported with the use of other oxybutynin hydrochloride formulations.

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 are:

1) administration of activated charcoal

2) physostigmine by slow intravenous injection:

Adults: 0.5 to 2.0 mg i.v. slowly, repeated after 5 minutes if necessary, up to a maximum of 5 mg.

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

In pronounced restlessness or excitation, diazepam 10 mg 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.

Pharmacotherapeutic group: urinary antispasmodic, ATC code: G04B D04.

Mechanism of action: oxybutynin acts as a competitive antagonist of acetylcholine at post-ganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle.

Pharmacodynamic effects: in patients with overactive bladder, characterized by detrusor muscle instability or hyperreflexia, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency and frequency of both incontinence episodes and voluntary urination.

Oxybutynin is a racemic (50:50) mixture of R- and S- isomers. Antimuscarinic activity resides predominantly in the R-isomer. The R-isomer of oxybutynin shows greater selectivity for the M₁ and M₃ muscarinic subtypes (predominant in bladder detrusor muscle and parotid gland) compared to the M₂ subtype (predominant in cardiac tissue). The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in vitro studies, but has a greater binding affinity for parotid tissue than oxybutynin. The free base form of oxybutynin is pharmacologically equivalent to oxybutynin hydrochloride.

Children over the age of 6 years: in children with detrusor hyperreflexia secondary to a neurogenic condition, oxybutynin, in combination with clean intermittent urinary catheterisation, has been shown in open uncontrolled studies to increase mean urine volume per catherisation, increase maximum cystometric capacity and decrease mean detrusor pressure at maximum cystometric capacity.

Following the first dose of Lyrinel XL, oxybutynin plasma concentrations rise for 4 to 6 hours; thereafter, concentrations are maintained for up to 24 hours, thus reducing the fluctuations between peak and trough concentrations associated with oxybutynin immediate release formulations.

The relative bioavailabilities of R-oxybutynin and S-oxybutynin from Lyrinel XL are 156% and 187% respectively, compared with oxybutynin immediate release. After a 10 mg single dose of Lyrinel XL, the peak plasma concentrations of R-oxybutynin and S-oxybutynin, achieved after 12.7±5.4 and 11.8±5.3 hours respectively, are 1.0±0.6 and 1.8±1.0 ng/ml, and the plasma concentration time profiles of both enantiomers are similar in shape. The elimination half-life is 13.2±10.3 hours for R-oxybutynin and 12.4±6.1 hours for S-oxybutynin.

Steady state oxybutynin plasma concentrations are achieved by Day 3 of repeated Lyrinel XL dosing, with no observed change in oxybutynin and desethyloxybutynin pharmacokinetic parameters over time.

Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (C_max and AUC) are dose proportional following administration of 5-20 mg of Lyrinel XL.

The pharmacokinetics of Lyrinel XL were similar in all patients studied, irrespective of gender or age and are unaffected by food intake.

Limited data suggest that the pharmacokinetics of Lyrinel XL is similar in adults and children aged 8 years and above. The pharmacokinetics of Lyrinel XL have not been investigated in patients with renal or hepatic insufficiency.

Oxybutynin is extensively metabolised by the liver, primarily by the cytochrome P450 enzyme system, particularly CYP3A4 found mostly in the liver and gut wall. Absolute bioavailability of immediate release oxybutynin has been estimated to be 2-11%. Following intravenous administration of 5 mg oxybutynin, clearance and volume of distribution were estimated to be 26 L/h and 193 L, respectively. Less than 0.1% of the administered dose is excreted unchanged in the urine. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active. Following Lyrinel XL administration, area under the plasma concentration profiles of R- and S-desethyloxybutynin are 73% and 92% respectively of those observed with oxybutynin immediate release formulations.

The binding of oxybutynin to plasma proteins is unknown.

Preclinical data reveal no special hazard for humans based on studies of acute toxicity, repeat dose toxicity, genotoxicity, carcinogenic potential and local toxicity. In a fertility study of subcutaneous oxybutynin injections in rats, female fertility was impaired while no effect was noted in male animals. In a rabbit embryotoxicity study, organ anomalies were observed in the presence of maternal toxicity at a dose of 0.4 mg/kg/day subcutaneously. The relevance to human safety is unknown.

5 mg

butylhydroxytoluene (E321), cellulose acetate 398-10,, hypromellose 5 cp, macrogol 3350, magnesium stearate, macrogol 200 000, macrogol 2 000 000, sodium chloride, black iron oxide (E172), ferric oxide yellow (E172) and lactose anhydrous.

Film coat: ferric oxide yellow (E172), hypromellose 3 cp and 6 cp, macrogol 400, polysorbate 80 and titanium dioxide (E171).

Printing Ink: black iron oxide (E172), hypromellose 6 cp and propylene glycol.

10 mg

butylhydroxytoluene (E321), cellulose acetate 398-10, hypromellose 5 cp, macrogol 3350, magnesium stearate, macrogol 200 000, macrogol 2 000 000, sodium chloride, black iron oxide (E172), ferric oxide red (E172) and lactose anhydrous.

Film coat: ferric oxide red (E172), hypromellose 3 cp and 6 cp, macrogol 400, polysorbate 80 and titanium dioxide (E171).

Printing Ink: black iron oxide (E172), hypromellose 6 cp and propylene glycol.

Not applicable.

Lyrinel XL 5mg: 2 years

Lyrinel XL 10mg: 18 months

Keep the container tightly closed in order to protect from moisture. Do not store above 25^oC.

High density polyethylene bottles with child resistant closure (polypropylene) and desiccant.

Pack sizes 3, 7, 10, 14, 30, 50, 60, 90 or 100 tablets.

Not all pack sizes may be marketed.

Do not remove or swallow the sachet of granules in the bottle. This contains desiccant, which keeps the tablets dry

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PL 0242/0385

PL 0242/0386

1 August 2002/14 June 2010

20 December 2011