KENTERA 90.7 MG / G (4 MG / 24H) GEL - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Kentera 90.7mg/g (4mg/24h) Gel

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose of 1 gram of gel contains 90.7 mg of oxybutynin (as 100 mg oxybutynin hydrochloride) resulting in a nominal delivery of approximately 4 mg/day.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Gel.

Rapid drying, clear, smooth, odourless, and colourless hydroalcoholic gel.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

The recommended dose is one metered dose from the multidose container with metering pump applied once daily which corresponds to a delivery dose of approximately 4 mg.

Elderly population

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 the effects of centrally acting anticholinergics and exhibit differences in pharmacokinetics (see section 4.4).

Renal impairment

There is no experience with the use of Kentera in patients with renal impairment.

Hepatic impairment

There is no experience with the use of Kentera in patients with hepatic impairment.

Paediatric population

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

Method of administration

Kentera should be applied to dry, intact skin on the abdomen, upper arms/shoulders, or thighs. Application sites should be rotated. Application should not be made to the same site on consecutive days.

Avoid bathing, swimming, showering, exercising or immersing the application site in water for one hour after application (see section 4.4).

It is recommended to cover the application site with clothing once the gel has dried.

4.3 Contraindications

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

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

4.4 Special warnings and precautions for use

As the stratum corneum is the rate-limiting step in transdermal delivery, any breach would provide direct access to the epidermis, potentially increasing penetration and facilitating the migration of the medicinal product to the blood stream. Kentera should therefore not be applied to a recently shaved or damaged skin surface.

Avoid bathing, swimming, showering, exercising or immersing the application site in water for one hour after application.

It is recommended to cover the application site with clothing once Kentera has dried.

The effect of fever, exposition to external heat sources, sun bathing and sauna on the absorption characteristics of Kentera have not been investigated.

Impaired metabolism

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

Urinary retention

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

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

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, and 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.

Kentera 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.

In total 496 patients were exposed to Kentera in the randomised, double-blind, placebo-controlled 12-week and the 14-week safety extension studies. Of these 188 patients (38%) were 65 years of age and 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 considered necessary.

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 elderly patients. Caution should be exercised when oxybutynin is administrated concomitantly with other anticholinergic medicines (see also section 4.5). If a patient experiences such events, drug discontinuation should be considered.

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

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.

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant use of oxybutynin with other anticholinergic medicinal products or with other active substances that compete for CYP3A4 enzyme metabolism may increase the frequency or severity of dry mouth, constipation, and drowsiness. As oxybutynin is metabolised by the cytochrome P 450 isoenzyme CYP 3A4, interactions with medicinal products that inhibit this isoenzyme, or known inducers of CYP 3A4, cannot be ruled out. This should be borne in mind when administering azole antifungals (e.g. ketoconazole) or macrolide antibiotics (e.g. erythromycin) concurrently with oxybutynin. Consumption of grapefruit juice may also influence metabolism of oxybutynin.

Anticholinergic medicinal products may potentially alter the absorption of some concomitantly administered medicinal products due to anticholinergic effects on gastrointestinal motility.

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, tricyclic antidepressants, atropine and related compounds like atropinic antispasmodics, and dipyridamole.

Oxybutynin may cause drowsiness or blurred vision. Drowsiness may be increased by consumption of alcohol. Because Kentera may cause drowsiness, somnolence, or blurred vision, patients should be advised to exercise caution when driving or using machinery (see section 4.7).

Oxybutynin may antagonise prokinetic therapies, such as cisapride and metocloparamide, and should be avoided in the presence of reduced gastrointestinal motility conditions.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Con­traception in males and females

Women of childbearing age should be tested for pregnancy before beginning therapy, and during therapy utilise some form of pregnancy contraceptive.

Pregnancy

There are no adequate data on the use of oxybutynin topical gel in pregnant women. Studies in animals have shown minor reproductive toxicity (see

section 5.3). Kentera should not to be used during pregnancy unless clearly necessary.

Breast-feeding

Available information shows that oxybutynin is excreted in milk of rats, but is not known whether oxybutynin is excreted in human milk. Use of oxybutynin is not recommended during breast-feeding.

Fertility

Data on possible effects of the use of oxybutynin on human male and female fertility are not available. Fertility studies in rats suggest a 6-fold margin of safety in both male and female breeding adults when Kentera is administered as prescribed. (see section 5.3)

Patients on Kentera therapy should keep application sites covered with clothing when coming into contact with breast-feeding or pregnant women or breast-fed infants.

4.7 Effects on ability to drive and use machines

Kentera has minor influence on the ability to drive and use machines. Because Kentera may cause drowsiness, somnolence, or blurred vision, patients should be advised to exercise caution when driving or using machinery (see section 4.5).

4.8 Undesirable effects

Summary of the safety profile

The safety of Kentera was evaluated in patients with urge urinary incontinence in a randomised, double-blind, placebo-controlled, parallel group Phase 3 study that included 789 patients (with 389 patients receiving Kentera and 400 patients receiving placebo).

The most commonly reported adverse reaction was dry mouth (Kentera 6.9%, placebo 2.8%). Other adverse reactions reported were application site pruritus (Kentera 2.1%, placebo 0.8%), application site dermatitis (Kentera 1.8%, placebo 0.3%), dizziness (Kentera 1.5%, placebo 0.5%), headache (Kentera 1.5%, placebo 2.8%), constipation (Kentera 1.3%, placebo 1.0%), and pruritus (Kentera 1.3%, placebo 1.3%).

Tabulated list of adverse reactions

Adverse reactions from phase 3 and 4 clinical studies are listed below by system organ class and frequency 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 each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Postmarketing adverse reactions not seen in clinical trials are also included.

# post-marketing adverse reactions from post-marketing reports only (not seen in clinical trials), with the frequency category estimated from clinical trial safety data, and reported in association with oxybutynin topical use (anticholinergic class effects).

Adverse reactions considered associated with anticholinergic therapy in general or observed with oral administration 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 and induction of glaucoma, paranoia, photosensitivity, erectile dysfunction.

Paediatric population

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

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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Overdose with oxybutynin has been associated with anticholinergic effects including CNS excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Patients should be monitored until symptoms resolve. Plasma concentrations of oxybutynin begin to decline 24 hours after Kentera application. Ingestion of 100 mg oral oxybutynin 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals, urinary antispasmodics, 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

The efficacy and safety of Kentera were evaluated in patients with urge urinary incontinence in a single Phase 3 study.

The Phase 3 study was a randomised, double-blind, placebo-controlled, parallel group study that included 789 patients. The 12-week double-blind treatment included daily applications of Kentera or matching placebo gel. A 14-week, open-label treatment was available for a subset of patients who completed the double-blind period. The majority of patients were Caucasian (86.3%) and female (89.2%), with a mean age of 59.4 years (range: 18 to 88 years). Approximately 75% of patients had no prior pharmacological treatment for incontinence.

Patients treated with Kentera experienced a highly statistically significant decrease in the number of urinary incontinence episodes per day from baseline to endpoint (the primary efficacy endpoint) compared with placebo (p<0.0001), as well as for the secondary endpoints: a decrease in the average daily urinary frequency (p=0.0017), and an increase in the average urine volume per void (p=0.0018). Significant improvements in the quality of life evaluations measured during the study were also observed with Kentera.

Mean and median change from baseline in daily incontinence episodes (primary endpoint), urinary frequency, and urinary void volume between placebo and active treatment groups are summarised in the table below.

Mean and median change from baseline for incontinence episodes, urinary frequency, and urinary void volume at Week 12 (LOCF)

During the double-blind treatment a significant positive effect on quality of life was seen with Kentera based on the Incontinence Impact Questionnaire (IIQ). These results were evident after the first month of treatment and were maintained throughout double-blind treatment as shown in the table below.

Mean (SD) change from baseline for IIQ total score and subscales at Week 12 (LOCF)

Significant positive effects were also noted for each subscale domain of the IIQ and for six of ten quality of life domains, including the incontinence impact domain, of the King’s Health Questionnaire (KHQ) as shown in the table below.

Mean (SD) change from baseline in KHQ Domain Scores at Week 12 (LOCF)

5.2 Pharmacokinetic properties

Absorption

Kentera is formulated for daily application and is capable of maintaining therapeutic blood levels of oxybutynin. Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Following the application of Kentera, oxybutynin plasma concentration increases for approximately 7 days, reaching average maximum concentrations of 4 to 5 ng/ml. Steady-state conditions are reached after the seventh day of administration. The difference in AUC and Cmax of oxybutynin and the active metabolite N-desethyloxybutynin following transdermal administration of Kentera on either the abdomen, upper arms/shoulders and thighs 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.

Biotransformation

Oxybutynin administered orally is metabolised primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. The expression of CYP3A and CYP3A4 may vary by as much as 40 fold due to genetic polymorphism. 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.

Person-to-person transference

The potential for dermal transfer of oxybutynin from a treated person to an untreated person was evaluated in a single-dose study where subjects dosed with Kentera engaged in vigorous contact with an untreated partner for 15 minutes, either with (N=14 couples) or without (N=12 couples) clothing covering the application area. The untreated partners not protected by clothing demonstrated detectable plasma concentrations of oxybutynin (mean Cmax = 0.94 ng/ml). Two of the 14 untreated subjects participating in the clothing-to-skin contact regimen had measurable oxybutynin plasma concentrations (Cmax < 0.1 ng/ml) during the 48 hours following contact with treated subjects; oxybutynin was not detectable with the remaining 12 untreated subjects.

Effects of showering

The effect of showering on the absorption of oxybutynin was evaluated in a randomised, steady-state crossover study under conditions of no shower, or showering 1, 2 or 6 hours after Kentera application (N=20). The results of the study indicate that showering after one hour does not affect the overall systemic exposure to oxybutynin.

Use with sunscreen

The effect of sunscreen on the absorption of oxybutynin when applied 30 minutes before or 30 minutes after Kentera application was evaluated in a single-dose randomised crossover study (N=16). Concomitant application of sunscreen, either before or after Kentera application, had no effect on the systemic exposure of oxybutynin.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on studies for acute toxicity, repeat dose toxicity, genotoxicity, carcinogenicity and local toxicity. Adverse reactions were observed in embryotoxicity studies in the rabbit. 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. 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.

Environmental Risk Assessment

The active substance oxybutynin is persistent in the environment.

6.1

Ethanol (96 per cent)

Glycerol

Hydroxypropyl­cellulose

Sodium hydroxide (for pH-adjustment) Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not refrigerate or freeze.

Kentera contains alcohol and is considered flammable and should not come in contact with an open flame.

6.5 Nature and contents of container

The multidose container is comprised of an outer polypropylene bottle with a Low Density Polyethylene (LDPE) pouch liner, a polypropylene metering pump, with ethylene propylene diene monomer (EPDM) gaskets, and a polypropylene cap.

Each multidose container contains at least 30 grams of Kentera and dispenses 30 metered 1 gram doses.

Kentera is packaged in a carton containing 1 multidose container with metering pump.

6.6 Special precautions for disposal

Before using the pump for the first time the multidose container should be primed. To prime the pump, fully depress the pump mechanism repeatedly until gel is observed, then depress the pump one more time, and discard this portion of the medicinal product to assure precise dose delivery. The pump is now primed and ready for use. After the priming step is complete, 30 full doses will remain in the pump. The metered dose should be applied immediately.

Always place the small protective cap back firmly on the tip of the pump nozzle and the large pump cover over the top of the pump after each use. If prime is lost during the use (no gel is dispensed after depressing the pump), repeat as instructed above to re-prime the pump.

After applying the gel, hands should immediately be washed thoroughly with soap and water. It is recommended to cover the application site with clothing once the gel has dried. Avoid bathing, swimming, showering, exercising or immersing the application site in water for one hour after application.

Empty multidose container must be discarded in accordance with local requirements.

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS