- Approval Id
- 34015b5b83efb21b
- Drug Approval Emc Name
- Lyrinel XL 10 mg prolonged release tablet
- Drug Name
- Lyrinel XL 10 mg prolonged release tablet
- Company Name
- Janssen-Cilag Ltd (a Johnson & Johnson Company)
- Company Address
- 50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG
- Company Website
- https://innovativemedicine.jnj.com/uk/
- Company Telephone
- +44 (0)1494 567 567
- Company Medical Info Direct Line
- +44 (0)800 731 8450
- Company Medical Info Email
- medinfo@janssen-cilag.co.uk
- Company Customer Care Direct Line
- +44 (0)800 731 5550
- Company Medical Info Fax
- +44 (0) 1494 567 445
- Atc Code
- G04BD04
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Janssen-Cilag Ltd
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
UK
- Authorisation Number
- PL 00242/0386
- Authorisation Date
- 1 August 2002/14 June 2010
- Instruction Authorisation Holder
- Janssen-Cilag Ltd
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
UK
- Instruction Authorisation Number
- PL 00242/0386
- Instruction Authorisation Date
- 1 August 2002/14 June 2010
- Instruction Composition
- Each prolonged release tablet contains 10 mg of oxybutynin hydrochloride
For the full list of excipients, see Section 6.1.
Excipient(s) with known effect: Each LYRINEL XL prolonged release tablet contains 0.03 mg lactose.
Each LYRINEL XL prolonged release tablet contains less than 1 mmol sodium (23 mg), and is essentially 'sodium-free'.
- Instruction Dosage Form
- Prolonged release tablet.
Round pink coloured tablet approximately 7.5 mm in diameter printed with “10 XL" on one side in black ink.
- Instruction Clinical Particulars
- 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 5 mg 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
- Porphyria4.4 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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
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.
\*\*Paediatric population\*\*
An open-label study was conducted to evaluate the efficacy and safety of Lyrinel XL in children aged 6-15 years with detrusor hyperreflexia due to neurogenic conditions, all used clean intermittent catheterisation, and all were current users of 10 or 15 mg oxybutynin hydrochloride administered as Ditropan syrup, Ditropan tablets or Ditropan XL extended-release tablets.
The study results showed that there was an increase from baseline in mean urine volume per catheterisation, an increase from baseline in mean urine volume after morning awakening, from baseline in the mean percentage of catheterisations without a leaking episode, an increase from baseline in mean maximum cystometric capacity, a decrease from baseline in mean detrusor pressure at maximum cystometric pressure and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions as shown in the table below.
| | | | |
| --- | --- | --- | --- |
| Change in Baseline to Week 24 | | | |
| Parameter | n | Mean (SEM) | Range |
| Average volume per catheterisation (mL) | 109 | 25.5 (5.9) | -292 to 245 |
| Volume of 1st catheterisation after morning awakening (mL) | 109 | 33.0 (8.3) | -223 to 450 |
| Maximal bladder capacity (mL)\\* | 105 | 75.4 (9.8) | -150 to 420 |
| Detrusor pressure at maximal bladder capacity (cm H2O)\\* | 105 | -9.2 (2.3) | -102 to 64 |
| Intravesical pressure at maximal bladder capacity (cm H2O)\\* | 105 | -7.5 (2.5) | -108 to 76 |
| \\*Urodynamic studies | | | |
| At baseline, 66 of 116 (56.9%) patients had uninhibited detrusor contractions ≥ 15 cm H2O. At Week 24, 30 of 105 (28.6%) patients had uninhibited contractions ≥ 15 cm H2O. The percentage of catheterisations without a leaking accident increased from 36.0% at baseline to 55.5% at Week 24. | | | |5.2 Pharmacokinetic properties
\*\*Absorption\*\*
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. Absolute bioavailability of immediate release oxybutynin has been estimated to be 2-11%. 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 pharmacokinetics of Lyrinel XL are unaffected by food intake.
\*\*Distribution\*\*
Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 L after intravenous administration of 5 mg oxybutynin hydrochloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of desethyloxybutynin are also highly bound (>97%) to plasma proteins. The major binding protein is alpha-1 acid glycoprotein.
\*\*Biotransformation and Excretion\*\*
Oxybutynin is extensively metabolised by the liver, primarily by the cytochrome P450 enzyme system, particularly CYP3A4 found mostly in the liver and gut wall. 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. Following intravenous administration of 5 mg oxybutynin, clearance was estimated to be 26 L/h. Less than 0.1% of the administered dose is excreted unchanged in the urine. The elimination half-life is 13.2±10.3 hours for R-oxybutynin and 12.4±6.1 hours for S-oxybutynin.
\*\*Special Populations\*\*
\*\*\*Paediatric population\*\*\*
The steady-state pharmacokinetics of Lyrinel XL were evaluated in a limited number of children aged 6-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida) receiving 10 or 15 mg total daily doses of Lyrinel XL. The pharmacokinetics of Lyrinel XL in these paediatric patients were consistent with those reported for adults. The table below summarizes maximum and average plasma concentrations for each of the four analytes, R- and S-Oxybutynin and R- and S-Desethyloxybutynin, by age group and total daily dose.
| | | | | |
| --- | --- | --- | --- | --- |
| \*\*Mean (SD) Maximum and Average Concentrations (ng/mL) of R- and S-Oxybutynin and R- and S-Desethyloxybutynin in Children Following Administration of 10 and 15 mg Lyrinel XL Once Daily\*\* | | | | |
| | \*\*Age <10 yrsa\*\* | | \*\*Age >10 yrsb\*\* | |
| \*\*Dose/Analyte\*\* | \*\*Cmax\*\* | \*\*Cavg\*\* | \*\*Cmax\*\* | \*\*Cavg\*\* |
| \*\*10 mg Dose\*\* | | | | |
| R-Oxybutynin | 1.39 (0.1) | 0.91 (0.2) | 1.37 (0.9) | 1.06 (0.8) |
| S-Oxybutynin | 2.46 (0.5) | 1.58 (0.5) | 2.45 (1.7) | 2.00 (1.5) |
| R-Desethyloxybutynin | 15.4 (2.2) | 8.74 (2.8) | 13.2 (9.7) | 9.48 (6.8) |
| S-Desethyloxybutynin | 6.81 (0.9) | 4.38 (1.8) | 8.05 (6.7) | 6.70 (6.1) |
| \*\*15 mg Dose\*\* | | | | |
| R-Oxybutynin | 2.59 (1.4) | 1.78 (0.8) | 2.16 (2.0) | 1.86 (2.0) |
| S-Oxybutynin | 5.03 (3.2) | 3.67 (2.1) | 3.29 (2.7) | 2.80 (2.7) |
| R-Desethyloxybutynin | 23.0 (11.0) | 16.2 (6.0) | 27.8 (22) | 20.8 (22) |
| S-Desethyloxybutynin | 13.3 (7.9) | 10.3 (6.1) | 12.2 (6.8) | 9.13 (7.5) |
| a – 10 mg: n=3; 15 mg: n=6 b – 10 mg: n=5; 15 mg: n=2 | | | | |
\*\*Linearity/non-linearity\*\*
The pharmacokinetic parameters (Cmax and AUC) of oxybutynin and desethyloxybutynin are dose proportional following administration of 5-20 mg of Lyrinel XL. 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. These characteristics support linearity in the pharmacokinetics for oxybutynin.5.3 Preclinical safety data
Non-clinical 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.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
butylhydroxytoluene (E321), cellulose acetate 398-10, hypromellose 5 cp, polyethylene glycol 3350, magnesium stearate, polyethylene oxide 200K, polyethylene oxide 2000K, 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, polyethylene glycol 400, polysorbate 80 and titanium dioxide (E171)
Printing Ink: black iron oxide (E172), hypromellose 6 cp and propylene glycol.6.2 Incompatibilities
Not applicable.6.3 Shelf life
18 months6.4 Special precautions for storage
Keep the container tightly closed in order to protect from moisture. Do not store above 25°C.6.5 Nature and contents of container
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.6.6 Special precautions for disposal and other handling
Do not remove or swallow the sachet of granules in the bottle. This contains desiccant, which keeps the tablets dry
.
- Instruction Content
- ## Composition
Each prolonged release tablet contains 10 mg of oxybutynin hydrochloride
For the full list of excipients, see Section 6.1.
Excipient(s) with known effect: Each LYRINEL XL prolonged release tablet contains 0.03 mg lactose.
Each LYRINEL XL prolonged release tablet contains less than 1 mmol sodium (23 mg), and is essentially 'sodium-free'.
## Pharmaceutical Form
Prolonged release tablet.
Round pink coloured tablet approximately 7.5 mm in diameter printed with “10 XL" on one side in black ink.
## Clinical Particulars
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 5 mg 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
- Porphyria4.4 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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
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.
\*\*Paediatric population\*\*
An open-label study was conducted to evaluate the efficacy and safety of Lyrinel XL in children aged 6-15 years with detrusor hyperreflexia due to neurogenic conditions, all used clean intermittent catheterisation, and all were current users of 10 or 15 mg oxybutynin hydrochloride administered as Ditropan syrup, Ditropan tablets or Ditropan XL extended-release tablets.
The study results showed that there was an increase from baseline in mean urine volume per catheterisation, an increase from baseline in mean urine volume after morning awakening, from baseline in the mean percentage of catheterisations without a leaking episode, an increase from baseline in mean maximum cystometric capacity, a decrease from baseline in mean detrusor pressure at maximum cystometric pressure and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions as shown in the table below.
| | | | |
| --- | --- | --- | --- |
| Change in Baseline to Week 24 | | | |
| Parameter | n | Mean (SEM) | Range |
| Average volume per catheterisation (mL) | 109 | 25.5 (5.9) | -292 to 245 |
| Volume of 1st catheterisation after morning awakening (mL) | 109 | 33.0 (8.3) | -223 to 450 |
| Maximal bladder capacity (mL)\\* | 105 | 75.4 (9.8) | -150 to 420 |
| Detrusor pressure at maximal bladder capacity (cm H2O)\\* | 105 | -9.2 (2.3) | -102 to 64 |
| Intravesical pressure at maximal bladder capacity (cm H2O)\\* | 105 | -7.5 (2.5) | -108 to 76 |
| \\*Urodynamic studies | | | |
| At baseline, 66 of 116 (56.9%) patients had uninhibited detrusor contractions ≥ 15 cm H2O. At Week 24, 30 of 105 (28.6%) patients had uninhibited contractions ≥ 15 cm H2O. The percentage of catheterisations without a leaking accident increased from 36.0% at baseline to 55.5% at Week 24. | | | |5.2 Pharmacokinetic properties
\*\*Absorption\*\*
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. Absolute bioavailability of immediate release oxybutynin has been estimated to be 2-11%. 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 pharmacokinetics of Lyrinel XL are unaffected by food intake.
\*\*Distribution\*\*
Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 L after intravenous administration of 5 mg oxybutynin hydrochloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of desethyloxybutynin are also highly bound (>97%) to plasma proteins. The major binding protein is alpha-1 acid glycoprotein.
\*\*Biotransformation and Excretion\*\*
Oxybutynin is extensively metabolised by the liver, primarily by the cytochrome P450 enzyme system, particularly CYP3A4 found mostly in the liver and gut wall. 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. Following intravenous administration of 5 mg oxybutynin, clearance was estimated to be 26 L/h. Less than 0.1% of the administered dose is excreted unchanged in the urine. The elimination half-life is 13.2±10.3 hours for R-oxybutynin and 12.4±6.1 hours for S-oxybutynin.
\*\*Special Populations\*\*
\*\*\*Paediatric population\*\*\*
The steady-state pharmacokinetics of Lyrinel XL were evaluated in a limited number of children aged 6-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida) receiving 10 or 15 mg total daily doses of Lyrinel XL. The pharmacokinetics of Lyrinel XL in these paediatric patients were consistent with those reported for adults. The table below summarizes maximum and average plasma concentrations for each of the four analytes, R- and S-Oxybutynin and R- and S-Desethyloxybutynin, by age group and total daily dose.
| | | | | |
| --- | --- | --- | --- | --- |
| \*\*Mean (SD) Maximum and Average Concentrations (ng/mL) of R- and S-Oxybutynin and R- and S-Desethyloxybutynin in Children Following Administration of 10 and 15 mg Lyrinel XL Once Daily\*\* | | | | |
| | \*\*Age <10 yrsa\*\* | | \*\*Age >10 yrsb\*\* | |
| \*\*Dose/Analyte\*\* | \*\*Cmax\*\* | \*\*Cavg\*\* | \*\*Cmax\*\* | \*\*Cavg\*\* |
| \*\*10 mg Dose\*\* | | | | |
| R-Oxybutynin | 1.39 (0.1) | 0.91 (0.2) | 1.37 (0.9) | 1.06 (0.8) |
| S-Oxybutynin | 2.46 (0.5) | 1.58 (0.5) | 2.45 (1.7) | 2.00 (1.5) |
| R-Desethyloxybutynin | 15.4 (2.2) | 8.74 (2.8) | 13.2 (9.7) | 9.48 (6.8) |
| S-Desethyloxybutynin | 6.81 (0.9) | 4.38 (1.8) | 8.05 (6.7) | 6.70 (6.1) |
| \*\*15 mg Dose\*\* | | | | |
| R-Oxybutynin | 2.59 (1.4) | 1.78 (0.8) | 2.16 (2.0) | 1.86 (2.0) |
| S-Oxybutynin | 5.03 (3.2) | 3.67 (2.1) | 3.29 (2.7) | 2.80 (2.7) |
| R-Desethyloxybutynin | 23.0 (11.0) | 16.2 (6.0) | 27.8 (22) | 20.8 (22) |
| S-Desethyloxybutynin | 13.3 (7.9) | 10.3 (6.1) | 12.2 (6.8) | 9.13 (7.5) |
| a – 10 mg: n=3; 15 mg: n=6 b – 10 mg: n=5; 15 mg: n=2 | | | | |
\*\*Linearity/non-linearity\*\*
The pharmacokinetic parameters (Cmax and AUC) of oxybutynin and desethyloxybutynin are dose proportional following administration of 5-20 mg of Lyrinel XL. 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. These characteristics support linearity in the pharmacokinetics for oxybutynin.5.3 Preclinical safety data
Non-clinical 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.
## Pharmaceutical Particulars
6.1 List of excipients
butylhydroxytoluene (E321), cellulose acetate 398-10, hypromellose 5 cp, polyethylene glycol 3350, magnesium stearate, polyethylene oxide 200K, polyethylene oxide 2000K, 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, polyethylene glycol 400, polysorbate 80 and titanium dioxide (E171)
Printing Ink: black iron oxide (E172), hypromellose 6 cp and propylene glycol.6.2 Incompatibilities
Not applicable.6.3 Shelf life
18 months6.4 Special precautions for storage
Keep the container tightly closed in order to protect from moisture. Do not store above 25°C.6.5 Nature and contents of container
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.6.6 Special precautions for disposal and other handling
Do not remove or swallow the sachet of granules in the bottle. This contains desiccant, which keeps the tablets dry
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