Oxybutynin

1).

Posology Initial dose adjustment shall be done by a neuro-urologist under close urodynamic control. There are no fixed rules for the dose regimen as high interindividual differences in bladder pressure and doses required to improve neurogenic detrusor overactivity exist.

The dose regimen (doses and timings) must therefore be determined individually according to the patient´s need. Individual dosages will be applied to control uro-dynamic parameters sufficiently (maximum detrusor pressure < 40 cm H2O) aiming at complete inhibition of neurogenic detrusor overactivity.

In the course of intravesical oxybutynin therapy, urodynamic parameters shall be controlled in regular intervals as defined by the attending urologist. Paediatric population The safety and efficacy of oxybutynin hydrochloride in children aged 0 to 5 years of age have not yet been established.

Dose recommendations in the following age groups The dose recommendations have been calculated according to the body weight percentiles of the different age groups (table 1) Table 1: Dose recommendations in all age groups Age group Age [years] Recommended daily starting dose [mg] Recommended total daily dose [mg] Children 6 - 12 2 2 - 30 Adolescents 12 - 18 10 10 - 40 Adults 19 - 65 10 10 - 40 Elderly from 65 10 10 - 30 If higher doses than the starting dose are considered necessary, the dose should be increased using a step-wise approach until neurogenic detrusor overactivity is sufficiently controlled to allow close monitoring of both efficacy and safety.

The required daily maintenance doses may be divided into several applications (table 2 and 3). 4). Hepatic or renal impairment Velariq should be used with caution in patients with hepatic or renal impairment. The use of Velariq in those patients should be carefully monitored and dose reductions may be needed.

Method of administration Intravesical use. To ensure safe and effective treatment, patients must be familiar with the procedure of clean intermittent catheterisation (CIC). The patients and/or relative, carer shall be trained on CIC and the administration procedure by specialised health care professionals.

As soon as the environmental conditions are aseptic, a sterile disposable urethral catheter is inserted into the bladder. The bladder has to be drained completely before the instillation. The scaled prefilled syringe is taken from the bag and the cap is removed from the syringe.

A stepped tapered luer-lock adapter is screwed on the tip of the syringe. With the help of the stepped tapered luer-lock adapter, the syringe is connected to the catheter. The required amount of the oxybutynin solution is instilled into the bladder by constant pressing on the plunger of the syringe.

If the application of less than 10 ml (one syringe content) is required, the solution that is not used remains in the syringe which has to be brought to a pharmacy for disposal later. After the instillation the catheter is removed. The instilled solution remains in the bladder until the next catheterisation.

Any unused medicinal product, the urethral catheter and the stepped tapered luer-lock adapter have to be discarded. The duration of treatment depends on the symptoms, the underlying disease and / or the treatment goal and is determined by the treating physician.

Undesirable effects observed with oxybutynin hydrochloride such as dry mouth, somnolence, and constipation mainly reflect the typical anticholinergic properties of the active ingredient. Table 4 includes adverse reactions from clinical trials with intravesical use of oxybutynin hydrochloride.

The adverse reactions are classified by System Organ Class and frequency, using the following convention: 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), Not known (cannot be estimated from the available data).

3). Paediatric population Children may be more sensitive to the effects of the product, particularly the CNS and psychiatric adverse reactions. Adverse reactions known to be associated with anticholinergic therapy, but not observed with intravesical use of oxybutynin during clinical studies are vomiting, anorexia, decreased appetite, dysphagia, gastroesophageal reflux disease, pseudo-obstruction in patients at risk (elderly or patients with constipation and treated with other drugs that decrease intestinal motility), confusional state, agitation, anxiety, nightmares, paranoia, symptoms of depression, dependence to oxybutynin (in patients with history of drug or substance abuse), arrhythmia, heat stroke, angle closure glaucoma, ocular hypertension, dry skin, angioedema, urticaria, photosensitivity, hypersensitivity.

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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

1. - Severe gastro-intestinal condition (e. g. severe ulcerative colitis and toxic megacolon). - Myasthenia gravis. - Narrow angle glaucoma and in patients who are at risk for these conditions. - Concomitant oxygen therapy.

INDICATIONS AND USAGE

, urgency, frequency, urinary leakage, urge incontinence, dysuria).

DOSAGE AND ADMINISTRATION

Adults The usual dose is one 5-mg tablet two to three times a day. The maximum recommended dose is one 5-mg tablet four times a day. 5 mg two or three times a day is recommended for the frail elderly. Pediatric patients over 5 years of age The usual dose is one 5-mg tablet two times a day.

The maximum recommended dose is one 5-mg tablet three times a day.

ADVERSE REACTIONS

The safety and efficacy of oxybutynin chloride was evaluated in a total of 199 patients in three clinical trials. These participants were treated with oxybutynin chloride 5-20 mg/day for up to 6 weeks. Table 3 shows the incidence of adverse events judged by investigators to be at least possibly related to treatment and reported by at least 5% of patients.

Table 3 Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using oxybutynin chloride (5-20 mg/day) The most common adverse events reported by patients receiving oxybutynin chloride 5-20 mg/day were the expected side effects of anticholinergic agents.

The incidence of dry mouth was dose-related. In addition, the following adverse events were reported by 1 to < 5% of patients using oxybutynin chloride (5 to 20 mg/day) in all studies. Infections and Infestations: nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection; Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders: confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations, sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic andMediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat, sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders: diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper, dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria, pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased, blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural Complications: fall.

Postmarketing Surveillance Because postmarketing adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following additional adverse events have been reported from worldwide postmarketing experience with oral oxybutynin chloride: Psychiatric Disorders: psychotic disorder, agitation, hallucination, memory impairment; Nervous System Disorders: convulsions; Eye Disorders: cycloplegia, mydriasis, glaucoma; Cardiac Disorders: tachycardia, QT interval prolongation, chest discomfort; Gastrointestinal Disorders: decreased gastrointestinal motility, frequent bowel movements; Skin and Subcutaneous Tissue Disorders: rash, decreased sweating; Renal and Urinary Disorders: impotence; Reproductive System and Breast Disorders: suppression of lactation; General Disorders and Administration Site Conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; rare anaphylactic reactions requiring hospitalization for emergency treatment; Metabolism and Nutrition Disorders: anorexia; Respiratory, Thoracic and Mediastinal Disorders: dysphonia.

To report SUSPECTED ADVERSE REACTIONS, contact KVK-Tech, Inc. gov/medwatch. Table 3

CONTRAINDICATIONS

Oxybutynin chloride is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions.

Oxybutynin chloride is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.

AND CLINICAL USE ..................................................................................................... 3 CONTRAINDICATIONS ......................................................................................................................

4 WARNINGS AND PRECAUTIONS ....................................................................................................... 4 ADVERSE REACTIONS .......................................................................................................................

6 DRUG INTERACTIONS ...................................................................................................................... 9 DOSAGE AND ADMINISTRATION ....................................................................................................

9 OVERDOSAGE ................................................................................................................................. 10 ACTION AND CLINICAL PHARMACOLOGY ..................................................................................

11 STORAGE AND STABILITY ............................................................................................................... 12 DOSAGE FORMS, COMPOSITION AND PACKAGING .....................................................................

12 PART II: SCIENTIFIC INFORMATION................................................................................................... 14 PHARMACEUTICAL INFORMATION .................................................................................................

14 CLINICAL TRIALS .............................................................................................................................. 14 DETAILED PHARMACOLOGY ...........................................................................................................

16 TOXICOLOGY ................................................................................................................................... 17 REFERENCES ...................................................................................................................................

20 PART III: CONSUMER INFORMATION ................................................................................................. e. urgency, frequency, urinary leakage, urge incontinence, dysuria).

Geriatrics (> 65 years of age):

Clinical studies of oxybutynin chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between healthy elderly and younger patients.

Page 4 of 23 Pediatrics (< 5 years of age):

The safety and effectiveness of oxybutynin chloride in pediatric patients under 5 years of age have not been established. CONTRAINDICATIONS OXYBUTYNIN/OXYBUTYNIN SYRUP (oxybutynin chloride) is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma, and in patients who are at risk for these conditions.

OXYBUTYNIN/OXYBUTYNIN SYRUP is contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product. For a complete listing of the nonmedicinal ingredients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS General Anticholinergics, such as OXYBUTYNIN/OXYBUTYNIN SYRUP, can cause heat prostration (fever and heat stroke due to decreased sweating) when administered in the presence of high environmental temperature.

Because anticholinergic agents, such as OXYBUTYNIN/OXYBUTYNIN SYRUP may produce drowsiness or blurred vision, the patient should be cautioned regarding activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug.

Alcohol or other sedative drugs may enhance the drowsiness caused by anticholinergic agents such as OXYBUTYNIN/OXYBUTYNIN SYRUP. Pretreatment examinations should include cystometry and other appropriate diagnostic procedures. Cystometry should be repeated at appropriate intervals to evaluate response to therapy.

The appropriate antibiotic therapy should be instituted in the presence of infection.

Page 5 of 23 Carcinogenesis and Mutagenesis See Product Monograph Part II:

TOXICOLOGY, Carcinogenesis and Mutagenesis, for discussion on animal data. Cardiovascular The symptoms of coronary heart disease, congestive heart failure, cardiac arrhythmias, tachycardia and hypertension may be aggravated following administration of OXYBUTYNIN/OXYBUTYNIN SYRUP.

Endocrine and Metabolism The symptoms of hyperthyroidism and prostatic hypertrophy may be aggravated following administration of OXYBUTYNIN/OXYBUTYNIN SYRUP. Gastrointestinal OXYBUTYNIN/OXYBUTYNIN SYRUP should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS).

Administration of OXYBUTYNIN/OXYBUTYNIN SYRUP to patients with severe ulcerative colitis may precipitate toxic megacolon. […]

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

9 mg transdermal patch applied twice weekly (every 3 to 4 days). Elderly Based on clinical trial experience no dose adjustment is considered necessary in this population. 4). 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. 8 but no recommendation on a posology can be made. Method of administration 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 patch must not be divided or cut into pieces. Patches that are damaged should not be used.

1% of patients. 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. Post- marketing adverse reactions not seen in clinical trials are also included. System Organ Class (MedDRA) Frequency Adverse reaction Infections and infestations Common Urinary tract infection Uncommon Upper respiratory tract infection, fungal infection Psychiatric disorders Uncommon Anxiety, confusion, nervousness, agitation, insomnia 5 # 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 national reporting system listed in Appendix V.

1. 3 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.