Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK
Pharmacotherapeutic group: urinary antispasmodic
ATC code: G04BD04
Oxybutynin acts as a competitive antagonist of acetylcholine at post-ganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle.
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.
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.
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.
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.
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.
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
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.
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.
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