OXYSPAS Tablets

Oxybutynin chloride

Prescribing information

Composition

OXYSPAS-2.5 Tablets
Each uncoated tablet contains
Oxybutynin chloride ............... 2.5 mg

OXYSPAS-5 Tablets
Each uncoated tablet contains
Oxybutynin chloride ............... 5 mg

Mechanism of Action
Oxybutynin has both direct antispasmodic action on the smooth muscle of the bladder detrusor muscle as well as an anticholinergic action in blocking the muscarinic effects of acetylcholine on smooth muscle. These properties cause relaxation of the detrusor muscle of the bladder in patients with an unstable bladder. Oxybutynin increases bladder capacity and reduces the incidence of spontaneous contractions of the detrusor muscle.

Pharmacokinetics

Absorption
Oxybutynin is poorly absorbed from the gastrointestinal tract.

Distribution
It is highly bound to plasma proteins; the peak plasma level is reached between 0.5 to 1 hour after administration.

Metabolism & Excretion
The half life is biexponential, the first phase being about 40 minutes and the second about 2-3 hours. The elimination half life may be increased in the elderly, particularly if they are frail. Oxybutynin and its metabolites are excreted in the feces and urine. There is no evidence of accumulation.

Pharmacokinetics In Special Populations

Pediatric
The pharmacokinetics of oxybutynin chloride was evaluated in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of oxybutynin chloride in these pediatric patients were consistent with those reported for adults.

Gender
There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of oxybutynin chloride.

Race
Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of oxybutynin chloride.

Indications

OXYSPAS is indicated for urinary incontinence, urgency and frequency in the unstable bladder, whether due to neurogenic bladder disorders (detrusor hyperreflexia) in conditions such as multiple sclerosis and spina bifida, or to idiopathic detrusor instability (motor urge incontinence).

PAEDIATRIC POPULATION

Oxybutynin hydrochloride is indicated in children over 5 years of age for:

Urinary incontinence, urgency and frequency in unstable bladder conditions due to idiopathic overactive bladder or neurogenic bladder disorders (detrusor overactivity).
Nocturnal enuresis associated with detrusor overactivity, in conjunction with non-drug therapy, when other treatment has failed.

Dosage and Administration

Adults

The usual dose is 5 mg two or three times a day. This may be increased to a maximum of 5 mg four times a day to obtain a clinical response provided that the side effects are tolerated.

Elderly (Including Frail Elderly)

The elimination half-life is increased in the elderly. Therefore, a dose of 2.5 mg twice a day, particularly if the patient is frail, is likely to be adequate. This dose may be titrated upwards to 5 mg two times a day to obtain a clinical response provided the side effects are well tolerated.

Children (Under 5 Years of Age)

Not recommended.

Children (Over 5 Years of Age)

Neurogenic bladder instability: the usual dose is 2.5 mg twice a day. This dose may be titrated upwards to 5 mg two or three times a day to obtain a clinical response provided the side effects are well tolerated. Nocturnal enuresis: the usual dose is 2.5 mg twice a day. This dose may be titrated upwards to 5mg two or three times a day to obtain a clinical response provided the side effects are tolerated. The last dose should be given before bedtime.

Contraindications

Hypersensitivity to oxybutynin or any component
Myasthenia gravis
Narrow-angle glaucoma or shallow anterior chamber
Gastrointestinal obstruction including paralytic ileus, intestinal atony
Patients with toxic megacolon, severe ulcerative colitis
Patients with bladder outflow obstruction where urinary retention may be precipitated

Warnings and Precautions

General

OXYSPAS should be used with caution in the frail elderly and children who may be more sensitive to the effects of the product and in patients with autonomic neuropathy, hepatic or renal impairment and severe gastro-intestinal motility disorders.

OXYSPAS may aggravate the symptoms of hyperthyroidism, congestive heart failure, coronary heart disease, cardiac arrhythmias, tachycardia, hypertension and prostatic hypertrophy.

OXYSPAS can cause decreased sweating; in high environmental temperatures this can lead to heat prostration.

Special care should be taken in patients with hiatus hernia associated with reflux oesophagitis, as anticholinergic drugs can aggravate this condition.

Drug Interactions

Care should be taken if other anticholinergic agents are administered together with OXYSPAS, as potentiation of anticholinergic effects could occur.

Occasional cases of interaction between anticholinergics and clozapine, phenothiazines, amantidine, butyrophenones, L-dopa, digitalis and tricyclic antidepressants have been reported and care should be taken if OXYSPAS is administered concurrently with such drugs.

By reducing gastric motility, oxybutynin may affect the absorption of other drugs.

Angioedema

Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

Central Nervous System Effects

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including hallucinations, agitation, confusion and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how oxybutynin chloride affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

OXYSPAS should be used with caution in patients with preexisting dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms.

Worsening of Symptoms of Myasthenia Gravis

OXYSPAS should be used with caution in patients with myasthenia gravis due to the risk of symptom aggravation.

Urinary Retention

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

Gastrointestinal Adverse Reactions

OXYSPAS should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention.

OXYSPAS, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis and intestinal atony.

OXYSPAS should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

As with any other nondeformable material, caution should be used when administering OXYSPAS to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations.

Effects On Ability To Drive And Use Machines

As oxybutynin hydrochloride may produce drowsiness or blurred vision, the patient should be cautioned regarding activities requiring mental alertness such as driving, operating machinery or performing hazardous work while taking this drug.

Renal Impairment

There are no studies conducted with oxybutynin chloride. Use with caution in patients with renal impairment.

Hepatic Impairment

There are no studies conducted with oxybutynin chloride. Use with caution in patients with hepatic impairment.

Pregnancy

There is no evidence as to the safety of OXYSPAS in human pregnancy nor is there evidence from animal work that it is totally free from hazard. Avoid in pregnancy unless there is no safer alternative.

Lactation

Small amounts of oxybutynin have been found in mother's milk of lactating animals. Breast feeding while using oxybutynin is therefore not recommended.

Paediatric Use

Oxybutynin hydrochloride is not recommended for use in children below age 5 years due to insufficient data on safety and efficacy.

There is limited evidence supporting the use of oxybutynin in children with monosymptomatic nocturnal enuresis (not related to detrusor overactivity).

In children over 5 years of age, oxybutynin hydrochloride should be used with caution as they may be more sensitive to the effects of the product, particularly the CNS and psychiatric adverse reactions.

Geriatric Use

The rate and severity of anticholinergic effects reported by patients less than 65 years old and those 65 years and older were similar. The pharmacokinetics of oxybutynin chloride was similar in all patients studied (up to 78 years of age).

Information For Patients

Patients should be informed that oxybutynin may produce angioedema that could result in life threatening airway obstruction. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience swelling of the tongue, edema of the laryngopharynx, or difficulty breathing.
Patients should be informed that anticholinergic (antimuscarinic) agents such as OXYSPAS, may produce clinically significant adverse reactions related to anticholinergic activity including:
- Urinary retention and constipation
- Heat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature.
Patients should be informed that anticholinergic medicines such as OXYSPAS may produce drowsiness (somnolence), dizziness or blurred vision. Patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until OXYSPAS effects have been determined.
Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as OXYSPAS.
Patients should be informed that OXYSPAS should be swallowed whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
OXYSPAS should be taken at approximately the same time each day.

Undesirable Effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety and efficacy of oxybutynin chloride XL (5 to 30 mg/day) was evaluated in 774 adult subjects who participated in five double-blind, controlled clinical trials. In four of the five studies, oxybutynin chloride IR (5 to 20 mg/day in 199 subjects) was an active comparator. Adverse reactions reported by ≥ 1% of subjects are shown in Table 1.

Table 1: Adverse Drug Reactions Reported by ? 1% of Oxybutynin Chloride Treated Adult Subjects in Five Double-blind, Controlled Clinical Trials of Oxybutynin Chloride

System/Organ Class Preferred Term	Oxybutynin Chloride XL 5 to 30 mg/day n = 774 %	Oxybutynin Chloride IR* 5 to 20 mg/day n = 199 %

Psychiatric Disorders
Insomnia	3.0	5.5
Nervous System Disorders
Headache	7.5	8.0
Somnolence	5.6	14.1
Dizziness	5.0	16.6
Dysgeusia	1.6	1.5
Eye Disorders
Vision blurred	4.3	9.6
Dry eye	3.1	2.5
Respiratory, Thoracic and Mediastinal Disorders
Cough	1.9	3.0
Oropharyngeal pain	1.9	1.5
Dry throat	1.7	2.5
Nasal dryness	1.7	4.5
Gastrointestinal Disorders

Dry mouth	34.9	72.4
Constipation	8.7	15.1
Diarrhea	7.9	6.5
Dyspepsia	4.5	6.0
Nausea	4.5	11.6
Abdominal pain	1.6	2.0
Vomiting	1.3	1.5
Flatulence	1.2	2.5
Gastro-esophageal reflux disease	1.0	0.5
Skin and Subcutaneous Tissue Disorders
Dry skin	1.8	2.5
Pruritus	1.3	1.5
Renal and Urinary Disorders
Dysuria	1.9	2.0
Urinary hesitation	1.9	8.5
Urinary retention	1.2	3.0
General Disorders and Administration Site Conditions
Fatigue	2.6	3.0
Investigations
Residual urine volume†	2.3	2.3

*IR = immediate release

???he bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased.

The discontinuation rate due to adverse reactions was 4.4% with oxybutynin chloride XL compared to 0% with oxybutynin chloride IR. The most frequent adverse reaction causing discontinuation of study medication was dry mouth (0.7%).

The following adverse reactions were reported by Metabolism and Nutrition Disorders: anorexia, fluid retention; Vascular disorders: hot flush; Respiratory, thoracic and mediastinal disorders: dysphonia; Gastrointestinal Disorders: dysphagia, frequent bowel movements; General disorders and administration site conditions: chest discomfort, thirst.

Postmarketing Experience

The following additional adverse reactions have been reported from worldwide postmarketing experience with oxybutynin chloride XL. Because postmarketing reactions 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.

Psychiatric Disorders: psychotic disorder, agitation, hallucinations, memory impairment; Nervous System Disorders: convulsions; Eye Disorders: glaucoma; Cardiac Disorders: arrhythmia, tachycardia, QT interval prolongation; Vascular Disorders: flushing; Skin and Subcutaneous Tissue Disorders: rash; Renal and Urinary Disorders: impotence; General Disorders and Administration Site Conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; anaphylactic reactions requiring hospitalization for emergency treatment; Injury, poisoning and procedural complications: fall.
Additional adverse events reported with some other oxybutynin chloride formulations include: cycloplegia, mydriasis, and suppression of lactation.

Overdosage

The symptoms of overdose with oxybutynin progress from an intensification of the usual side effects of CNS disturbances (from restlessness and excitement to psychotic behaviour), circulation changes (flushing, fall in blood pressure, circulatory failure etc), respiratory failure, paralysis and coma.

Measures to be taken are:

Immediate gastric lavage
Physostigmine by slow intravenous injection

Adults: 0.5 to 2.0 mg of physostigmine by slow intravenous administration. Repeat after 5 minutes, if necessary up to a maximum total dose of 5 mg.

Children: 30 micrograms/kg of physostigmine by slow intravenous administration.
Repeat after 5 minutes, if necessary up to a maximum total dose of 2 mg.

Fever should be treated symptomatically with tepid sponging or ice packs.

In pronounced restlessness or excitation, diazepam 10 mg may be given by intravenous injection, tachycardia may be treated by intravenous injection of propranolol and urinary retention can be managed by catheterisation.

In the event of progression of the curare- like effect to the paralysis of the respiratory muscles, mechanical ventilation will be required.

Storage And Handling Information

Store below 30°C.

Packaging Information

OXYSPAS-2.5 ............... Blister pack of 10 tablets
OXYSPAS-5 ............... Blister pack of 10 tablets

Last updated: December 2013
Last reviewed: December 2013