Oxybutynin Hydrochloride 2.5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Oxybutynin hydrochloride 2.5 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Oxybutynin hydrochloride 2.5 mg per tablet.
Excipient with known effect:
Each tablet contains 72.7 mg of lactose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
Blue, biconvex, uncoated capsule shaped tablets, marked OB scoreline 2.5 on one side and G on the reverse. The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4.1 Therapeutic indications
Urinary incontinence, urgency and frequency in unstable bladder conditions. This may be due to idiopathic detrusor instability (motor urge incontinence) or due to neurogenic bladder disorders (detrusor hyperreflexia) in conditions such as multiple sclerosis and spina bifida.
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.
4.2 Posology and method of administration
Posology
Adult patients
The initial dose is 2.5 mg three times daily which if necessary may be titrated to the lowest effective dosage to obtain a satisfactory clinical response. 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 patients
In the elderly the elimination half life may be increased, hence an initial dose is 2.5 mg twice daily may be adequate, particularly if the patient is frail. This dose may be titrated upwards to 5 mg twice a day to obtain a clinical response provided the side effects are well tolerated.
Paediatric population
Children (older than 5 years of age)
Neurogenic bladder instability: 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 well tolerated. Nocturnal enuresis: 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 tolerated. The last dose should be given before bedtime.
Children (under 5 years of age)
Use is not recommended. Method of administration
Oxybutynin hydrochloride Tablets are for oral use and may be taken with a glass of water on an empty stomach. The tablets may also be taken during meals or with some milk if gastric irritation occurs.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with bladder outflow obstruction where urinary retention may be precipitated.
Patients with gastrointestinal obstructive disorders, intestinal atony or paralytic ileus.
Patients with toxic megacolon, severe ulcerative colitis, myasthenia gravis, narrow-angle glaucoma or shallow anterior chamber, tachyarrhythmia and cerebral sclerosis.
Patients with urinary frequency problems or nocturia due to cardiac or renal insufficiency.
4.4 Special warnings and precautions for use
Treatment with Oxybutynin hydrochloride Tablets should be reviewed after a period of 4 - 6 weeks as a normal bladder habit may be re-established in some patients.
Oxybutynin hydrochloride Tablets should not be used to treat stress or effort urinary incontinence.
Oxybutynin 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 (such as those with Parkinson’s disease), severe gastro-intestinal motility disorders and hepatic or renal impairment (see section 4.3).
Anticholinergics should be used with caution in elderly patients due to the risk of cognitive impairment.
Gastrointestinal disorders: Anticholinergic medicinal products may decrease gastrointestinal motility and should be used with caution in patients with gastrointestinal obstructive disorders, intestinal atony and ulcerative colitis.
Oxybutynin may aggravate tachycardia (and thus hyperthyroidism, congestive heart failure, cardiac arrhythmia, coronary heart disease, hypertension), cognitive disorders and symptoms of prostatic hypertrophy.
Anticholinergic CNS effects (e.g. hallucinations, agitation, confusion, somnolence) have been reported; monitoring recommended especially in first few months after initiating therapy or increasing the dose; consider discontinuing therapy or reducing the dose if anticholinergic CNS effects develop.
If urinary tract infection is present, an appropriate antibacterial therapy should be started.
Oxybutynin may reduce salivary secretions which could result in dental caries, parodontosis or oral candidiasis.
Since oxybutynin can cause narrow-angle glaucoma, patients should be advised to contact a physician immediately if they are aware of a sudden loss of visual acuity or ocular pain.
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.
When oxybutynin is used in high environmental temperatures, this can cause heat prostration due to decreased sweating.
Paediatric population
Oxybutynin hydrochloride Tablets 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 should be used with caution as they may be more sensitive to the effects of the product, particularly the CNS and psychiatric adverse reactions.
Excipients
Oxybutynin hydrochloride Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Care should be taken if other anticholinergic agents are administered together with oxybutynin as potentiation of anticholinergic effects could occur.
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, digitalis, tricyclic antidepressants, atropine and related compounds like atropinic antispasmodics and dipyridamole.
Concomitant use can also lead to confusion in the elderly.
Oxybutynin may antagonise prokinetic therapies such as the gastrointestinal effects of metoclopramide and domperidone.
Sublingual nitrates may fail to dissolve under the tongue owing to dry mouth, resulting in reduced therapeutic effect.
By reducing gastric motility, oxybutynin may affect the absorption of other drugs.
Oxybutynin is metabolised by cytochrome P 450 isoenzyme CYP 3A4. Concomitant administration with a CYP3A4 inhibtor can inhibit oxybutynin metabolism and increase oxybutynin exposure.
Concomitant use with cholinesterase inhibitors may result in reduced cholinesterase inhibitor efficacy.
Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin (see section 4.7).
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of oxybutynin in pregnant women.
Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential risk for humans is unknown.
Oxybutynin should not be used during pregnancy unless clearly necessary.
Breast-feeding
When oxybutynin is used during lactation, a small amount is excreted in mother's milk.
Use of oxybutynin during breast-feeding is therefore not recommended.
4.7 Effects on ability to drive and use machines
Oxybutynin may cause drowsiness or blurred vision. Patients should be cautioned regarding activities requiring mental alertness such as driving, operating machinery or performing hazardous work while taking this drug.
4.8 Undesirable effects
Classification of expected frequencies:
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).
• Infections and infestations
Not known: urinary tract infection
• Immune system disorders Not known: hypersensitivity
• Metabolism and nutrition disorders Uncommon: decreased appetite, anorexia
• Psychiatric disorders Common: confusional state
Not known: agitation, anxiety, hallucinations, nightmares, paranoia, restlessness, cognitive disorders in elderly, symptoms of depression, dependence (in patients with history of drug or substance abuse)
• Nervous system disorders
Very common: dizziness, headache, somnolence Not known: cognitive disorders, convulsions
• Eye disorders Common: dry eyes
Not known: angle closure glaucoma, mydriasis, ocular hypertension, vision blurred
• Cardiac disorders
Not known: tachycardia, arrhythmia
• Vascular disorders
Common: flushing (more marked in children than in adults)
• Gastrointestinal disorders
Very common: constipation, nausea, dry mouth
Common: diarrhoea, vomiting
Uncommon: abdominal discomfort, dysphagia
Not known: gastroesophageal reflux disease, pseudo-obstruction in patients at risk (elderly or patients with constipation and treated with other medicinal products that decrease intestinal motility)
• Skin and subcutaneous tissue disorders Very common: dry skin
Not known: angioedema, rash, urticaria, hypohidrosis, photosensitivity
• Renal and urinary disorders Common: urinary retention
Not known: problems with micturition
• Reproductive system and breast disorders Not known: impotence
• Injury, poisoning and procedural complications Not known: heat stroke
Dose reduction may reduce the incidence of some of the side effects.
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 the internet at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms
The symptoms of overdosage with oxybutynin progress from an intensification of the usual adverse effects of CNS disturbances (from restlessness and excitement to psychotic behaviour), circulatory changes (flushing, fall in blood pressure, circulatory failure etc.), respiratory failure, paralysis and coma.
Management Measures to be taken are:
1) immediate gastric lavage
2) physostigmine by slow intravenous injection:
Adults: 0.5 to 2.0 mg i.v. slowly, repeated if necessary, up to a maximum of 5 mg.
Children: 30 pg/kg i.v. slowly, repeated if necessary, up to a maximum of 2 mg.
Fever should be treated symptomatically.
In pronounced restlessness or excitation, diazepam 10 mg may be given by intravenous injection.
Tachycardia may be treated with intravenous propranolol and urinary retention managed by bladder catheterisation.
In the event of progression of curare-like effects to paralysis of the respiratory muscles, mechanical ventilation will be required.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Urologicals, Drugs for urinary frequency and incontinence, ATC code: G04BD04
Mechanism of action
Oxybutynin has a direct antispasmodic effect on the smooth muscle of the bladder detrusor.
Oxybutynin also inhibits the effects of acetylcholine on smooth muscle by blocking muscarinic receptors. Pharmacological models have established differences in affinity for subtypes of muscarinic receptors.
Pharmacodynamic effects
The pharmacodynamic properties of oxybutynin result in relaxation of the bladder detrusor muscle. Patients with unstable bladder experience increased bladder volume and a decreased incidence of spontaneous contractions of the detrusor muscle.
5.2 Pharmacokinetic properties
Absorption
Following oral administration oxybutynin is rapidly absorbed from the gastrointestinal tract (tmax 0.5 to 1.4 hours).
Studies have established a Cmax after a 5-10 mg dose in young healthy patients of 812 ng/ml. Large inter-individual variations in plasma concentrations are seen.
Distribution
Oxybutynin is 83-85% plasma albumin bound. Mean elimination half life is 2 hours.
The elimination half life may be increased in the elderly, particularly if they are frail. Biotransformation
Oxybutynin is subject to extensive first pass metabolism, resulting in an absolute systemic availability of 6.2%.
The major metabolite, desethyloxybutynin, is pharmacologically active. Several other metabolites are produced, including phenylcyclohexyglycolic acid, but are inactive.
Elimination
Urinary excretion has been established as less than 0.02% of an administered dose. Oxybutynin is eliminated biexponentially.
Repeated administration results in little accumulation.
5.3. Pre-clinical Safety Data
Oxybutynin hydrochloride has been shown to have low acute toxicity.
Chronic toxicity was associated with decreases in food consumption and body weight gain, tremors and nervousness and minor pathological changes in the liver and kidneys did occur in one species.
Preclinical studies did not suggest mutagenicity, carcinogenicity, or adverse effects on fertility or reproductive performance. No adverse effects on gestation or on the birth and development of offspring up to weaning were observed
Teratogenicity was not seen at oral-dose levels (rats - 20 mg/kg/day, rabbits -48 mg/kg/day) which did not cause significant maternal toxicity; but at maternally toxic doses of oxybutynin (100mg/kg/day), increased incidence of extra thoracolumbar ribs in rat foetuses and mortality of neonates was observed.
Pre-clinical data reveal no special hazard for humans based on conventional studies of general toxicity, genotoxicity and carcinogenicity beyond the information included in other sections of the SPC
Embryofetal studies in pregnant rats showed malformed hearts. Higher dosages additionally were associated with extra thoracolumbar ribs and increased neonatal mortality. Reproductive toxicity occurred only with concurrent general maternal toxicity. In the absence of exposure data, the relevance of these observations cannot be assessed.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Cellulose, microcrystalline Calcium stearate
Indigo carmine (aluminium lake) E132 6.2. Incompatibilities
Not applicable
6.3. Shelf-Life
3 years.
6.4 Special precautions for storage
Do not store above 25 °C.
Blisters: Store in the original package in order to protect from light.
Bottles: Keep the container tightly closed in order to protect from light.
6.5. Nature and Content of Container
Polypropylene tablet container with tamper-evident polyethylene cap. Polyvinylchloride (PVC)/aluminium foil blister packs.
Not all pack sizes may be marketed.
Pack sizes : 20, 30, 50, 56, 60, 84, 90, 100, 250 and 500 - polypropylene Pack sizes : 20, 30, 50, 56, 60, 84, 90 and 100 - blisters
6.6 Special precautions for disposal and other handling
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0339
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 18th June 1997 Date of last renewal: 18th June 2007
10 DATE OF REVISION OF THE TEXT
05/06/2015