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.Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. They may also antagonize the gastrointestinal prokinetic effects of metoclopramide and domperidone.

Oxybutynin is metabolised by cytochrome P450 isoenzyme CYP3A4. Concomitant administration with a CYP3A4 inhibitor can inhibit oxybutynin metabolism and increase oxybutynin exposure. Mean oxybutynin chloride concentrations were approximately 2 fold higher when oral oxybutynin was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g. itraconazole and fluconazole) or macrolide antibiotics (e.g. erythromycin), may increase oxybutynin exposure. The clinical relevance of such potential interaction is not known. Caution should be used when such drugs are co-administered.

Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin.

Concomitant use with cholinesterase inhibitors may result in reduced cholinesterase inhibitor efficacy.

Oxybutynin should be given with caution in patients with pre-existing dementia treated with cholinesterase inhibitors due to risk of aggravation of symptoms.

Oxybutynin may aggravate tachycardia (and thus the symptoms of hyperthyroidism, congestive heart failure, cardiac arrhythmia, coronary heart disease, hypertension), cognitive disorders and symptoms of prostatic hypertrophy.

When oxybutynin is used in patients with fever or in high environmental temperatures, this can cause heat prostration, or heat stroke, due to decreased sweating.

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.

There are no adequate data on the use of oxybutynin transdermal patch in pregnant women. Studies in animals have shown minor reproductive toxicity. Oxybutynin should not be used during pregnancy unless clearly necessary.

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

Fertility

Reproduction studies with oral oxybutynin in the mouse, rat, hamster, and rabbit showed no evidence of impaired fertility.

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

Because oxybutynin may produce drowsiness, somnolence, or blurred vision, patients should be advised to exercise caution when driving or using machinery.

Oral administration

Summary of the safety profile

The most common adverse reactions reported during clinical trials by >5% of patients were dry mouth, constipation, diarrhoea, headache, somnolence and dizziness.

Serious adverse reactions associated with oxybutynin include anticholinergic central nervous system effects.

List of adverse reactions

The safety of oxybutynin was evaluated in five double-blind, controlled (i.e. placebo or active comparator) clinical trials for the management of overactive bladder, in which 759 adult subjects received doses ranging from 5 to 20 mg/day. Additionally, safety was evaluated in one open-label (i.e. active comparator) clinical trial, in which 60 paediatric subjects received doses of 10 or 15 mg/day. Table 1 below reflects the adverse drug reactions reported with oxybutynin in clinical trials in adults and from postmarketing experience. Adverse drug reactions reported in the paediatric clinical trial are shown in Table 2.

Table 1. Adverse drug reactions reported in clinical trials in adults and from postmarketing experience:

Infections and infestations

Common: Urinary tract infection

Immune System Disorders

Uncommon: Hypersensitivity

Not Known*: Anaphylactic reaction

Metabolism and nutrition disorders

Uncommon: Anorexia, Fluid retention, Decreased appetite

Psychiatric disorders

Common: Insomnia

Uncommon: Hallucinations, Confusional state, Agitation, Memory impairment

Not Known*: Psychotic disorder, Anxiety, Nightmares, and Paranoia, symptoms of depression, dependence (in patients with history of drug or substance abuse)

Nervous system disorders

Common: Somnolence, Dizziness, Headache, Dysgeusia

Uncommon: Convulsions

Not Known*: Cognitive disorders

Eye disorders

Common: Vision blurred, Dry eye

Uncommon: Angle closure glaucoma

Not Known*: Mydriasis, Ocular hypertension

Cardiac disorders

Common: Palpitations

Uncommon: Arrhythmia, Tachycardia

Vascular disorders

Uncommon: Hypertension, Flushing

Respiratory, thoracic and mediastinal disorders

Common: Oropharyngeal pain, Cough, Nasal dryness, Dry throat

Uncommon: Dysphonia, Nasal congestion, Throat irritation

Gastrointestinal disorders

Very Common: Dry mouth

Common: Gastroesophageal reflux disease, Abdominal pain, Dyspepsia, Constipation, Diarrhoea, Nausea, Flatulence

Uncommon: Dysphagia, Abdominal discomfort, Frequent bowel movements, Vomiting

Not Known*: 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

Common: Dry skin, Pruritus

Uncommon: Urticaria, Rash

Not Known*: Angioedema, Hypohidrosis

Renal and urinary disorders

Common: Dysuria, Urinary hesitation

Uncommon: Urinary retention, Residual urine

Not Known*: Impotence

General disorders and administration site conditions

Common: Fatigue

Uncommon: Chest discomfort, Mucosal dryness, Thirst

Investigations

Common: Residual urine volume+

Injury, poisoning and procedural complications

Uncommon: Fall

Not Known*: Heat stroke

* Cannot be estimated from the available clinical data.
⁺ The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased.

Description of selected adverse reactions

The following postmarketing adverse reactions listed in Table 1 are from postmarketing reports only (not seen in clinical trials), with the frequency category estimated from clinical trial safety data comprising 759 patients: hallucinations, agitation, memory impairment, and convulsions. These estimates represent the upper limit of the 95% CI.

As with other oxybutynin formulations, dry mouth was the most frequently reported adverse drug reaction. However, in clinical studies, dry mouth has been less frequently reported with oxybutynin than with oxybutynin immediate release formulations. For patients who required final doses of 5 or 10 mg of oxybutynin, the relative incidence of dry mouth that occurred at any dose level was 1.8 times lower compared with patients who required final doses >10 mg.

Paediatric population

The safety of oxybutynin was evaluated in 60 paediatric subjects (age range 5 to 15 years; dose range 10-15 mg/day) who participated in an open-label, active control, three-arm clinical trial. Adverse drug reactions reported by oxybutynin-treated paediatric subjects in this clinical trial are shown in Table 2.

Table 2. Adverse drug reactions reported in clinical trials with paediatric subjects:

Metabolism and nutrition disorders

Common: Anorexia

Psychiatric disorders

Common: Insomnia

Nervous system disorders

Common: Headache

Vascular disorders

Common: Flushing

Gastrointestinal disorders

Very Common: Constipation

Common: Diarrhoea

Skin and subcutaneous tissue disorders

Common: Rash, Pruritus

Transdermal use

The most commonly reported adverse drug reactions were application site reactions, occurring in 23.1% 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%).

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.

^# 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 oxybutynin 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.