KENTERA 3.9mg / 24h transdermic patch medication leaflet

Kentera 3.9 mg/24 hours transdermal patch

Each transdermal patch contains 36 mg of oxybutynin. The area of the patch is 39 cm2, releasing anominal 3.9 mg of oxybutynin per 24 hours.

For the full list of excipients, see section 6.1.

Transdermal patch

The patch is a clear plastic with an adhesive backing, protected by a release liner that is to be removedprior to application.

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

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

Based on clinical trial experience no dose adjustment is considered necessary in this population.

Nonetheless Kentera should be used with caution in elderly patients, who may be more sensitive to theeffects of centrally acting anticholinergics and exhibit differences in pharmacokinetics (see section4.4).

The safety and efficacy of Kentera in the paediatric population has not been established. Kentera is notrecommended for use in the paediatric population. Currently available data are described in section 4.8but no recommendation on a posology can be made.

The patch should be applied to dry, intact skin on the abdomen, hip, or buttock immediately afterremoval from the protective sachet. A new application site should be selected with each new patch toavoid reapplication to the same site within 7 days. The patch must not be divided or cut into pieces.

Patches that are damaged should not be used.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Kentera 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.

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

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

Kentera should be used with caution in elderly patients, who may be more sensitive to the effects ofcentrally acting anticholinergics and exhibit differences in pharmacokinetics.

In total 496 patients were exposed to Kentera in the randomised, double-blind, placebo-controlled12-week and the 14-week safety extension studies. Of these 188 patients (38%) were 65 years of ageand older and exhibited no overall differences in safety or effectiveness compared to younger patients.

Thus based on current clinical evidence no need for dose adjustment in elderly patients is considerednecessary.

Psychiatric and central nervous system (CNS) anticholinergic events like sleep disorders (e.g.insomnia) and cognitive disorders have been associated with oxybutynin use, especially in elderlypatients. Caution should be exercised when oxybutynin is administrated concomitantly with otheranticholinergic medicinal products (see also section 4.5). If a patient experiences such events, drugdiscontinuation should be considered.

Other psychiatric events implying an anticholinergic mechanism have been reported during post-marketing use (see section 4.8).

Oral administration of oxybutynin may warrant the following cautionary statements, but these eventswere not observed during clinical trials with Kentera:

Gastrointestinal disorders: Anticholinergic medicinal products may decrease gastrointestinal motilityand should be used with caution in patients with gastrointestinal obstructive disorders because of therisk 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 hiatushernia/gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such asbisphosphonates) that can cause or exacerbate oesophagitis.

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

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

Oxybutynin may exacerbate the symptoms of hyperthyroidism, coronary heart disease, congestiveheart 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.

The concomitant use of oxybutynin with other anticholinergic medicinal products or with other agentsthat compete for CYP3A4 enzyme metabolism may increase the frequency or severity of dry mouth,constipation, and drowsiness.

Anticholinergic agents may potentially alter the absorption of some concomitantly administeredmedicinal products due to anticholinergic effects on gastrointestinal motility. As oxybutynin ismetabolised by cytochrome P 450 isoenzyme CYP3A4, interactions with medicinal products thatinhibit this isoenzyme cannot be ruled out. This should be borne in mind when using azole antifungals(e.g. ketoconazole) or macrolide antibiotics (e.g. erythromycin) concurrently with oxybutynin.

The anticholinergic activity of oxybutynin is increased by concurrent use of other anticholinergics ormedicinal products with anticholinergic activity, such as amantadine and other anticholinergicantiparkinsonian medicinal products (e.g. biperiden, levodopa), antihistamines, antipsychotics (e.g.phenothiazines, butyrophenones, clozapine), quinidine, tricyclic antidepressants, atropine and relatedcompounds like atropinic antispasmodics, dipyridamole.

Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agentssuch as oxybutynin (see section 4.7).

Oxybutynin may antagonize prokinetic therapies.

There are no adequate data on the use of oxybutynin transdermal patch in pregnant women.

Studies in animals have shown minor reproductive toxicity (see section 5.3). Kentera should not beused during pregnancy unless clearly necessary.

When oxybutynin is used during breast-feeding, a small amount is excreted in the mother’s milk. Useof oxybutynin while breast-feeding is therefore not recommended.

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

Because Kentera may produce drowsiness, somnolence, or blurred vision, patients should be advisedto exercise caution when driving or using machinery (see section 4.5).

The most commonly reported adverse drug reactions were application site reactions, occurring in23.1% 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 from phase 3 and 4 clinical studies are listed below by system organ class andfrequency grouping. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10);uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness. Post-marketing adverse reactions not seen in clinical trials are also included.

System Organ Class Frequency Adverse reaction(MedDRA)

Infections and Common Urinary tract infectioninfestations Uncommon Upper respiratory tract infection, fungalinfection

Psychiatric disorders Uncommon Anxiety, confusion, nervousness, agitation,insomnia

Rare Panic reaction#, delirium#, hallucinations#,disorientation#

Nervous system Common Headache, somnolencedisorders Rare Memory impairment#, amnesia#, lethargy#,disturbance in attention#

Eye disorders Common Blurred vision

Ear and labyrinth Common Dizzinessdisorders

Cardiac disorders Uncommon Palpitations

Vascular disorders Uncommon Urticaria, hot flushes

Respiratory, thoracic Uncommon Rhinitisand mediastinaldisorders

Gastrointestinal Common Dry mouth, constipation, diarrhoea, nausea,disorders abdominal pain

Uncommon Abdominal discomfort, dyspepsia

Musculoskeletal and Uncommon Back painconnective tissuedisorders

Renal and urinary Uncommon Urinary retention, dysuriadisorders

General disorders and Very common Application site pruritisadministration site Common Application site erythema, application siteconditions reaction, application site rash

Injury, poisoning and Uncommon Inflicted injuryproceduralcomplications# post-marketing adverse reactions from post-marketing reports only (not seen in clinical trials), withthe frequency category estimated from clinical trial safety data, and reported in association withoxybutynin topical use (anticholinergic class effects).

Adverse reactions considered associated with anticholinergic therapy, in general or observed with oraladministration of oxybutynin, but as of yet not with Kentera in clinical trials or post-marketing, are:anorexia, vomiting, reflux oesophagitis, decreased sweating, heat stroke, decreased lacrimation,mydriasis, tachycardia, arrhythmia, nightmares, restlessness, convulsion, intraocular hypertension andinduction of glaucoma, paranoia, photosensitivity, erectile dysfunction.

During post-marketing use in this age group, cases of hallucinations (associated with anxietymanifestations) and sleep disorders correlated with oxybutynin have been reported. Children may bemore sensitive to the effects of the product, particularly the CNS and psychiatric adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Plasma concentration of oxybutynin declines within 1 to 2 hours after removal of transdermalsystem(s). Patients should be monitored until symptoms resolve. Overdosage with oxybutynin hasbeen associated with anticholinergic effects including CNS excitation, flushing, fever, dehydration,cardiac arrhythmia, vomiting, and urinary retention. Ingestion of 100 mg oral oxybutynin chloride inassociation with alcohol has been reported in a 13 year old boy who experienced memory loss, and ina 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 withsymptomatic treatment.

No cases of overdose have been reported with Kentera.

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

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, characterised by detrusor muscle instability or hyperreflexia,cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacityand increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency andthe frequency of both incontinence episodes and voluntary urination.

Oxybutynin is a racemic (50:50) mixture of R- and S-isomers. Antimuscarinic activity residespredominantly 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, haspharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in vitrostudies, but has a greater binding affinity for parotid tissue than oxybutynin. The free base form ofoxybutynin is pharmacologically equivalent to oxybutynin hydrochloride.

A total of 957 patients with urge urinary incontinence were evaluated in three controlled studiescomparing Kentera to either placebo, oral oxybutynin and/or tolterodine long acting capsules.

Reductions in weekly incontinence episodes, urinary frequency, and urinary void volume wereevaluated. Kentera led to consistent improvements in overactive bladder symptoms compared withplacebo.

Kentera has a concentration of oxybutynin sufficient to maintain continuous transport over the 3 to4 day dosing interval. Oxybutynin is transported across intact skin and into the systemic circulation bypassive diffusion across the stratum corneum. Following the application of Kentera, oxybutyninplasma concentration increases for approximately 24 to 48 hours, reaching average maximumconcentrations of 3 to 4 ng/ml. Steady-state conditions are reached during the second application ofthe transdermal patch. Thereafter, steady concentrations are maintained for up to 96 hours. Thedifference in AUC and Cmax of oxybutynin and the active metabolite N-desethyloxybutynin followingtransdermal administration of Kentera on either the abdomen, buttocks or hip is not clinically relevant.

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume ofdistribution was estimated to be 193 l after intravenous administration of 5 mg oxybutyninhydrochloride.

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

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

Pre-clinical data reveal no special hazard for humans based on studies for acute toxicology, repeatdose toxicity, genotoxicity, carcinogenic potential and local toxicity. At a concentration of0.4 mg/kg/day oxybutynin administered subcutaneously, the occurrence of organ anomalies issignificantly increased, but is observed only in the presence of maternal toxicity. Kentera deliversapproximately 0.08 mg/kg/day. However, in the absence of understanding the association betweenmaternal toxicity and developmental effect, the relevance to human safety cannot be addressed. In thesubcutaneous fertility study in rats, while no effects were reported in males, in females, fertility wasimpaired and a NOAEL (no observed adverse effect level) of 5 mg/kg was identified.

The active substance oxybutynin is persistent in the environment.

Backing film

Clear polyester/ethylene-vinyl acetate (PET/EVA)

Middle layer

Triacetin

Acrylic copolymer adhesive solution containing 2-ethylhexyl acrylate N-vinyl pyrrolidone andhexamethyleneglycol dimethacrylate polymer domains

Release Liner

Siliconised polyester

Not applicable.

3 years.

Do not refrigerate or freeze.

The transdermal patches are individually contained inpolyamide/polyethylene/aluminium/polyethylene terephthalate/paper laminate sachets and supplied inpatient calendar boxes of 2, 8 or 24 patches.

Not all pack sizes may be marketed.

Apply immediately upon removal from the protective sachet. After use the patch still containssubstantial quantities of active ingredients. Remaining active ingredients of the patch may haveharmful effects if reaching the aquatic environment. Hence, after removal, the used patch should befolded in half, adhesive side inwards so that the release membrane is not exposed, placed in theoriginal sachet and then discarded safely out of reach of children. Any used or unused patches shouldbe disposed of according with local requirements or returned to the pharmacy. Used patches shouldnot 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 maycontribute to adhesion problems. Do not expose the patch to the sun.

Teva B.V.

Swensweg 52031 GA Haarlem

The Netherlands

EU/1/03/270/001 8 transdermal patches

EU/1/03/270/002 24 transdermal patches

EU/1/03/270/003 2 transdermal patches

Date of first authorisation: 15 June 2004

Date of latest renewal: 30 April 2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMA) https://www.ema.europa.eu