Mylan Oxybutynin

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in adult patients with unstable bladder.

The patch should be applied to dry, intact skin on the abdomen, hip, or buttock immediately after removal from the protective sachet. A new application site should be selected with each new patch to avoid reapplication to the same site within 7 days.

The recommended dose is one 3.9 mg transdermal patch applied twice weekly (every 3 to 4 days).

There is no experience in children

Hypersensitivity to the active substance or to any of the excipients.

Mylan Oxybutynin is contraindicated in patients with urinary retention, severe gastro-intestinal condition, myasthenia gravis or narrow-angle glaucoma and in patients who are at risk for these conditions.

Mylan Oxybutynin should be used with caution in patients with hepatic or renal impairment. The use of Mylan Oxybutynin in patients with hepatic impairment should be carefully monitored. Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Mylan Oxybutynin. If urinary tract infection is present, an appropriate antibacterial therapy should be started.

Urinary retention: Anticholinergic products should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

Mylan Oxybutynin should be used with caution in elderly patients, who may be more sensitive to the effects of centrally acting anticholinergics and exhibit differences in pharmacokinetics.

Oral administration of oxybutynin may warrant the following cautionary statements, but these events were not observed during clinical trials with Mylan Oxybutynin:

Gastrointestinal disorders: Anticholinergic medicinal products may decrease gastrointestinal motility and should be used with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Also in conditions such as ulcerative colitis, and intestinal atony. Anticholinergic medicinal products should be used with caution in patients who have hiatus hernia/gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as bisphosphonates) that can cause or exacerbate oesophagitis.

Anticholinergic medicinal products should be used with caution in patients who have autonomic neuropathy, cognitive impairment or Parkinson's disease

Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutynin are used in a hot environment.

Oxybutynin may exacerbate the symptoms of hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, tachycardia, hypertension and prostatic hypertrophy

Oxybutynin may lead to suppressed salivary secretions which could result in dental caries, parodontosis or oral candidiasis.

No studies on the effects on the ability to drive and use machines have been performed.

Because Mylan Oxybutynin may produce drowsiness, somnolence, or blurred vision, patients should be advised to exercise caution when driving or using machinery.

The most commonly reported adverse drug reactions were application site reactions, occurring in 23.1% of patients. Other commonly occurring adverse drug reactions reported were dry mouth (8.6%), constipation (3.9%), diarrhoea (3.2%), headache (3.0%), dizziness (2.3%) and blurred vision (2.3%).

Adverse reactions known to be associated with anticholinergic therapy, but not observed with Mylan Oxybutynin during clinical studies are anorexia, vomiting, reflux oesophagitis, decreased sweating, heat stroke, decreased lacrimation, mydriasis, tachycardia, arrhythmia, disorientation, poor ability to concentrate, fatigue, nightmares, restlessness, convulsion, intraocular hypertension and induction of glaucoma, confusion, anxiety, paranoia, hallucinations, photosensitivity, erectile dysfunction.

The adverse reactions reported below are classified according to frequency of occurrence as follows:

- Very common (> 1/10)

- Common (> 1/100 to < 1/10)

- Uncommon (> 1/1,000 to < 1/100)

Plasma concentration of oxybutynin declines within 1 to 2 hours after removal of transdermal system(s). Patients should be monitored until symptoms resolve. Overdosage with oxybutynin has been associated with anticholinergic effects including central nervous system (CNS) excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Ingestion of 100 mg oral oxybutynin chloride in association with alcohol has been reported in a 13 year old boy who experienced memory loss, and in a 34 year old woman who developed stupor, followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients recovered fully with symptomatic treatment.

No cases of overdose have been reported with Mylan Oxybutynin.

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, characterised 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 the 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.

Clinical efficacy:

A total of 957 patients with urge urinary incontinence were evaluated in three controlled studies comparing Mylan Oxybutynin to either placebo, oral oxybutynin and/or tolterodine long acting capsules. Reductions in weekly incontinence episodes, urinary frequency, and urinary void volume were evaluated. Mylan Oxybutynin led to consistent improvements in overactive bladder symptoms compared with placebo.

Absorption

Mylan Oxybutynin has a concentration of oxybutynin sufficient to maintain continuous transport over the 3 to 4 day dosing interval. Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Following the application of Mylan Oxybutynin, oxybutynin plasma concentration increases for approximately 24 to 48 hours, reaching average maximum concentrations of 3 to 4 ng/ml. Steady-state conditions are reached during the second application of the transdermal patch. Thereafter, steady concentrations are maintained for up to 96 hours. The difference in AUC and C_max of oxybutynin and the active metabolite N-desethyloxybutynin following transdermal administration of Mylan Oxybutynin on either the abdomen, buttocks or hip is not clinically relevant.

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.

Metabolism

Oxybutynin administered orally is metabolised primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. Metabolites include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and N-desethyloxybutynin, which is pharmacologically active. Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite.

Excretion

Oxybutynin is extensively metabolised by the liver, see above with less than 0.1% of the administered dose excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as the metabolite N-desethyloxybutynin.

Pre-clinical data reveal no special hazard for humans based on studies for acute toxicology, repeat dose toxicity, genotoxicity, carcinogenic potential and local toxicity. At a concentration of 0.4 mg/kg/day oxybutynin administered subcutaneously, the occurrence of organ anomalies is significantly increased, but is observed only in the presence of maternal toxicity. Mylan Oxybutynin delivers approximately 0.08 mg/kg/day. However, in the absence of understanding the association between maternal toxicity and developmental effect, the relevance to human safety cannot be addressed. In the subcutaneous fertility study in rats, while no effects were reported in males, in females, fertility was impaired and a NOAEL (no observed adverse effect level) of 5 mg/kg was identified.

Not applicable.

Apply immediately upon removal from the protective sachet. After use the patch still contains substantial quantities of active ingredients. Remaining active ingredients of the patch may have harmful effects if reaching the aquatic environment. Hence, after removal, the used patch should be folded in half, adhesive side inwards so that the release membrane is not exposed, placed in the original sachet and then discarded safely out of reach of children. Any used or unused patches should be discarded according to local requirements or returned to the pharmacy. Used patches should not be flushed down the toilet nor placed in liquid waste disposal systems.

Activities that may lead to excessive sweating, or exposure to water or extreme temperature may contribute to adhesion problems. Do not expose the patch to the sun.