Proposal to make Aquiette 2.5mg Tablets (oxybutynin hydrochloride) available from pharmacies

Question 1

1.  Background on deciding where medicines are available

Accepted Answer

The role of MHRA

MHRA regulates medicines and medical devices in the UK, on behalf of the UK Licensing Authority. This means that MHRA decides whether medicines are available:

on prescription only - ‘prescription only medicine’ (POM)
bought from pharmacies - ‘pharmacy medicine’ (P)
bought from other shops - ‘general sales list medicine’ (GSL)

What is re-classification of a medicine?

Making a change on where a medicine is available is called ‘reclassification’. This is sometimes referred to as ‘switching’. To decide on this change, MHRA may:

take advice from its committees of external experts
take advice from a group (‘stakeholder group’) of health professionals and representatives of people affected by the classification change
run a public consultation

When a medicine is reclassified, it is usual for reclassification from POM to P to occur in the first instance, and once some experience is gained with the product in the pharmacy (P) setting, further reclassification from P to GSL may occur. In some cases, a medicine may be reclassified directly from POM to GSL, where it meets the necessary requirements and it is safe to do so. To be reclassified directly from POM to GSL, a medicine must meet both the requirements of POM to P and P to GSL reclassification.

To be reclassified from POM to P a medicine must:

be unlikely to be a direct or indirect danger to human health when used without the supervision of a doctor, even if used correctly
be generally used correctly (ie not frequently or to a wide extent used incorrectly)
not contain substances or preparations of substances where the activity of the product or its side effects require further investigation
not normally be prescribed by a doctor for injection (parenteral administration).

To be reclassified from P to GSL, it must be demonstrated that the medicine may be supplied with reasonable safety in outlets other than in pharmacies. ‘Reasonable safety’ is defined as ‘Where the hazard to health, risk of misuse and need for special precautions in handling of the medicine are small, and where the wider sale would be a convenience to the purchaser’.

What evidence is needed?

A company or organisation can ask MHRA for a medicine to be available as a pharmacy medicine or a general sale medicine. To do this, they need to get together evidence to show that the medicine

a) is likely to be used appropriately, and

b) with relatively little danger to the public.

This evidence needs to focus on the risk to the public. This includes evidence on the possible abuse or misuse of the medicine. The evidence may include:

clinical studies
evidence showing acceptable level of side effects
advice of experts
views of relevant health professionals and their professional bodies
views of relevant public associations and individuals with an interest in the medicine under consideration.

Who makes the final decision?

The final decision on whether to approve a change is made by the MHRA, on behalf of the UK Licensing Authority.

Question 2

2.  About Aquiette

Accepted Answer

This consultation relates specifically to the proposal to reclassify Aquiette from prescription only to a pharmacy medicine.

What is in Aquiette?

Aquiette contains 2.5mg of oxybutynin hydrochloride in each tablet. Oxybutynin hydrochloride belongs to a group of medicines known as anticholinergics and works to control overactive bladder symptoms by causing relaxation of the detrusor^{[footnote 1]} muscle of the bladder, thereby increasing capacity of the bladder to hold urine and reducing the incidence of spontaneous contraction of the bladder.

What is Aquiette used for?

Aquiette 2.5mg Tablets are for treatment of long-standing (present for over 1 month) symptoms of overactive bladder (OAB) (e.g. urgent need to urinate, frequent urination without pain, sometimes leading to accidental leaks), which are not adequately controlled by bladder training alone, in women 18 to 65 years of age.

Aquiette tablets are for treatment of OAB at the milder end of the spectrum of this condition in suitable women.

Symptoms of this include having to urinate at least 8 times in the day, more than once during the night, sometimes leading to accidental leaks. A key symptom of OAB is urgency (urgent need to urinate).

Aquiette is not suitable for treating symptoms of stress incontinence alone (accidental leakage of urine during exercise, when coughing or when sneezing).

Aquiette may be initiated in suitable women who have tried at least 6 weeks of bladder training and lifestyle measures alone to control their OAB and in whom symptoms are not adequately controlled.

After 6 weeks of bladder training, an initial course of 6 weeks of Aquiette in combination with bladder training and lifestyle measures may be tried. If symptoms are adequately controlled, treatment may be continued together with bladder training and lifestyle measures for a further 6 weeks (12 weeks in total). After 12 weeks treatment, Aquiette should be stopped and bladder training and lifestyle measures continued alone to control symptoms.

If an initial 6 weeks of treatment with Aquiette does not adequately control symptoms or if they worsen at any time, Aquiette should be stopped and the woman referred to her doctor.

After 12 weeks treatment, if OAB symptoms return, the woman should be referred to her doctor as alternative/longer term treatment may be more appropriate for her condition.

If approved this will be the first time a medicine for the treatment of symptoms of overactive bladder (OAB) in suitable women, will be available as a Pharmacy (P) medicine. The Commission on Human Medicines (CHM) has advised that the application could be granted. This consultation outlines the background to this decision. Please tell us your views by using the link at the end of this document. The deadline for comments is 13 May 2022.

The patient information leaflet (PIL), label and summary of product characteristics (SmPC) are provided in Annex 1, 2 and 3.

Question 3

3.  Proposal to make Aquiette available as a Pharmacy (P) medicine

Accepted Answer

Who has made the proposal?

The applicant proposing to make Aquiette available from pharmacies is Maxwellia Ltd.

What is the view of the Commission on Human Medicines?

The Commission on Human Medicines has advised that Aquiette could be made available as a Pharmacy medicine. Views on the use of this medicine for treatment of long-standing OAB symptoms in women 18 to 65 years of age were also sought at a meeting of the Medicines for Women’s Health Expert Advisory Group (MWH EAG). The views of the MWH EAG were summarised and provided for CHM when they considered the reclassification application. CHM also considered the views of a stakeholder group on the suitability of oxybutynin as a P medicine.

Proposed terms of reclassification

What are the details of this change?

The application proposes to make Aquiette available from pharmacies as follows:

For oral use
Strength: 2.5mg oxybutynin hydrochloride
For treatment of long-standing (˃ 1 month) overactive bladder symptoms (ie. urinary urgency and frequency without dysuria, which may occasionally lead to incontinence), which are not adequately controlled by bladder training alone*, in women 18 to 65 years of age.
Dose: One 2.5mg tablet two or three times daily depending on symptom response. Doses should be separated by at least 6 hours. Lowest effective dose should be used.
Maximum dose: 2.5mg (1 tablet)
Maximum daily dose: 7.5mg (3 tablets)
Maximum duration of treatment: 12 weeks**
Maximum pack size: 30 tablets

*at least 6 weeks of bladder training alone
**6 weeks initially, alongside bladder training + further 6 weeks alongside bladder training if symptoms respond (maximum treatment of 12 weeks)

Question 4

4.  How was the proposal assessed for Aquiette being available as a Pharmacy medicine?

Accepted Answer

A medicine will be non-prescription unless it fulfils the criteria for prescription control (POM criteria) as set out below. Prescription-only medicine status is required if any of the following apply:

A direct or indirect danger exists to human health, even when used correctly, if used without medical supervision
There is frequently incorrect use which could lead to direct or indirect danger to human health
Further investigation of activity and/or side-effects is required
The product is normally prescribed for parenteral administration (by injection)

In the UK, these criteria are laid down in the Human Medicines Regulations 2012, regulation 62(3)^{[footnote 2]}.

The MHRA, advised by the Commission on Human Medicines, considered the application against the criteria for prescription control to assess the suitability for pharmacy availability. It was concluded that none of the criteria apply to Aquiette as all risks can be managed through the product information and pharmacist training.

The company has produced pharmacy training materials consisting of a Pharmacist Training Guide and a Pharmacist’s Quick Reference Guide. The Pharmacist’s Quick Reference Guide is intended to act as an aide memoire for the pharmacist during consultation with the patient in determining if Aquiette is suitable for supply. The company has also produced a Bladder Training Plan which outlines lifestyle measures and how to train the bladder (and keep track of progress) to improve symptoms of OAB. This is for the pharmacist to give to the patient presenting with OAB symptoms/requesting Aquiette. The Bladder Training Plan includes a checklist on reverse side for the patient to fill in prior to consultation with the pharmacist, identifying conditions the patient may have, for which Aquiette may not be suitable and referral to a doctor is required. The patient will also have the patient information leaflet and packaging to refer to, which contain the key safety messages for use of the product. The assessment of the application against each POM criteria is provided below.

4.1 POM Criterion 1 – The product is likely to present a direct or indirect danger to human health, even when used correctly, if used without medical supervision

The main criterion that must be considered in the reclassification of Aquiette to pharmacy status is that it does not present a direct or indirect danger to human health if used, even correctly, without the supervision of a doctor. A direct danger may be present if the product causes adverse reactions that are important because of their seriousness, severity, or frequency. A danger may also be present if the reaction is one for which there is no suitable preventative action such as being able to identify the group of patients who are at risk if they use the product without medical supervision so that they can be excluded from using the pharmacy product. Direct danger may arise from drug interactions with commonly used medicines. For the product to be suitable for pharmacy status the drug interactions would need to be preventable.

4.1.1 Direct danger to human health

Adverse reactions

Oxybutynin has been available as a prescription only medicine (POM) in the UK since 1991 with multiple generic forms available since the mid-1990s. Patient exposure to oxybutynin has been extensive since originally authorised as POM. It is a well-established product for which the safety profile is well known.

Post-marketing reports of adverse events with oxybutynin are in keeping with those listed in the Summary of Product Characteristics (SmPC). The SmPC is a legal document that is the basis of information for healthcare professionals on how to use a medicine.

Many adverse events reported for oxybutynin reflect the method of action of this medicine and are common to all drugs known as anticholinergics. Adverse events listed as ‘very common’ (seen in ˃ 10% of patients) include: dry mouth, headache, feeling dizzy or sleepy, constipation, nausea and dry skin. ‘Common’ events (seen in > 1% of patients) include diarrhoea, vomiting, confusional state, dry eyes, urinary retention and flushing.

Adverse events associated with anticholinergic medicines, including oxybutynin and groups of patients at risk:

Provoking urinary retention in patients with bladder outflow obstruction (blockage of urine flow from the bladder) The risk of this is primarily relevant to men, in whom symptoms of OAB may co-exist with bladder outflow obstruction associated with benign prostatic hyperplasia (enlargement of the prostate gland). Aquiette is not intended for use in men.

Risk of constipation and use in patients with gastro-intestinal obstructive disorders, intestinal atony, paralytic ileus and toxic megacolon

Anticholinergic medicines such as oxybutynin may decrease gastrointestinal motility, which can worsen conditions associated with gastrointestinal obstruction (obstruction of the digestive tract).

The dose of oxybutynin proposed for Aquiette as a pharmacy medicine is at the lower end of the prescription dosage range for this medicine which will minimise risk of constipation.

Aquiette is not intended for use in women with a history of gastro-intestinal obstructive disorders, intestinal atony (lack of tone in the intestine), paralytic ileus (impairment of motility of the intestine) and toxic megacolon (inflammatory enlargement of the colon).

Use in patients with severe ulcerative colitis

In patients with severe ulcerative colitis, use of anticholinergic medicines such as oxybutynin may decrease gastrointestinal motility and can increase the risk of complications such as toxic megacolon. Aquiette is not intended for use in women with a history of ulcerative colitis.

Use in patients with myasthenia gravis

Myasthenia gravis is a rare chronic autoimmune disease which causes muscle weakness. Anticholinergic medicines such as oxybutynin can exacerbate this condition.

Aquiette is not intended for use in women with a history of myasthenia gravis.

Narrow-angle Glaucoma

Drugs that cause pupillary dilatation (widening of the pupil in the eye), including anticholinergics such as oxybutynin, can cause blurred vision. They may also reduce the drainage of fluid from the eye in patients with narrow angle glaucoma, which in theory could cause episodes of high intraocular pressure (acute glaucoma). Aquiette is not intended for use in women with a history of narrow-angle glaucoma or a shallow anterior chamber (liquid-filled part of the eye between the iris (coloured part) and the cornea (front of the eye)). In addition, a warning is included in the SmPC section 4.4 as follows:

Women should contact their doctor immediately if they develop a sudden loss of visual acuity or ocular pain, halos around lights, headaches, dilated pupils, red eye or nausea and vomiting since oxybutynin can cause narrow-angle glaucoma. This information is clearly conveyed to the patient in section 2 of the PIL under sub-heading: ‘Talk to your pharmacist or doctor immediately if:’.

Section 4.3 of the SmPC for Aquiette states contraindications to use of the product in the above patient groups. This information is included in the training materials for pharmacists. The contraindications to use of Aquiette are conveyed to the patient in the patient information leaflet (PIL) and on the packaging (outer carton).

Important potential risks for anticholinergic medicines including oxybutynin:

Use in patients with autonomic neuropathy

Patients with damaged autonomic nerves may be particularly sensitive to anticholinergic drugs since these could interfere with cholinergic nerve transmission in the autonomic nervous system.

Section 4.4 of the SmPC includes a warning that oxybutynin should only be used under medical supervision in patients with autonomic neuropathy. A corresponding warning is included in the PIL in section 2 (Warnings and precautions) under sub-heading ‘you currently have one or more of the following signs, which could be related to a different condition:’

you have a nerve problem called ‘autonomic neuropathy’.

Aggravation of tachycardia (fast heart rate) with unmasking of hyperthyroidism, congestive heart failure, cardiac arrhythmia, coronary heart disease and hypertension

In common with other anticholinergic drugs, including those available OTC, oxybutynin may cause tachycardia through effects on autonomic nerve transmission.

The SmPC states that oxybutynin should only be used under medical supervision in women who have hyperthyroidism, congestive heart failure, cardiac arrhythmia (irregular heartbeat), coronary heart disease or hypertension (high blood pressure). Aquiette is also contraindicated in women with heart disease. Information for the patient is included in the PIL and on the label (outer carton).

Cognitive disorders and cognitive impairment

In common with other anticholinergic drugs, including those available without prescription, oxybutynin may have CNS (central nervous system) effects including cognitive impairment (trouble remembering, learning new things, concentrating). Use of anticholinergic medicines in elderly patients is associated with an increased risk of cognitive impairment.

For Aquiette, use is contraindicated in women aged >65 years of age, maximum daily dosage is low and duration of use is limited to maximum of 12 weeks, all of which minimise risk of cognitive impairment occurring in women using the product.

Risk of dental caries, parodontosis (gum disease) or oral candidiasis (fungal infections in the mouth) due to reduction in salivary secretions

In common with other anticholinergic drugs, including those available OTC, oxybutynin can cause dry mouth and therefore increase the risk of some infective conditions in the mouth. A warning regarding this is included in section 4.4 of the SmPC with corresponding information and advice (importance of good oral hygiene) for the patient in section 2 of the PIL.

Exacerbation of oesophagitis in patients with hiatus hernia/gastro-oesophageal reflux In common with other anticholinergic drugs, including those available OTC, oxybutynin can interfere with gastrointestinal motility which can impair removal of stomach acid from the oesophagus (gullet), resulting in worsening of symptoms of acid reflux.

The SmPC for Aquiette includes a warning that oxybutynin should be used only under medical supervision in women who have hiatus hernia/gastro-oesophageal reflux

Heat stroke due to decreased sweating in high environmental temperatures

In common with other anticholinergic drugs, including those available OTC, oxybutynin can reduce sweating and this can interfere with heat regulation in extremes of temperature.

A warning is included in section 4.4 of the SmPC regarding risk of heat exhaustion when using this medicine in high temperatures. Information in the PIL advises the woman to talk to her pharmacist or doctor before using Aquiette if she will be taking it in a hot climate.

Use during pregnancy or lactation

The SmPC contraindicates use of Aquiette in pregnant women, women who are suspected of being pregnant and women who are breast-feeding. This is conveyed to the patient on the label (outer carton) and in the PIL.

Use in patients with hepatic (liver) or renal (kidney) impairment

Oxybutynin undergoes metabolism in the liver and is excreted by the kidneys. Patients with liver or kidney problems may be exposed to greater levels of the drug in the bloodstream with greater potential for adverse reactions. The SmPC states that oxybutynin should only be used under medical supervision in patients with hepatic or renal impairment. This PIL advises the patient to speak to their pharmacist or doctor before using Aquiette if they have liver or kidney problems.

Depression and other ‘psychiatric’ adverse effects

The SmPC states ‘symptoms of depression’ as a side-effect of Aquiette. Other psychiatric adverse effects listed in the SmPC include agitation, anxiety, hallucinations, nightmares and paranoia.

A warning is included in the SmPC that Oxybutynin should be used only under medical supervision in women:

with a history of anxiety, depression or other psychiatric illness requiring treatment.

The PIL includes corresponding information for the patient to talk to their pharmacist or doctor before taking Aquiette if they have or have a history of feeling depressed or anxious, or any other psychiatric illness where they have needed treatment.

Conclusion: adverse reactions and risk minimisation

Adverse events associated with Aquiette as a pharmacy medicine can be managed through the product information (SmPC, PIL and label) and the pharmacy training materials.

The product information and the pharmacy training materials provide comprehensive information about all adverse events with Aquiette, groups of patients at risk and how women should be screened and counselled.

The low dose (2.5mg) and maximum daily dose (7.5mg), exclusion to use in at risk patient groups (e.g. those over 65 years of age) and maximum recommended duration of continuous use before seeking medical advice (12 weeks) reduce the potential for adverse events with Aquiette.

Drug interactions

The classes of medicines which have potential to interact with oxybutynin are stated in the SmPC for Aquiette. Corresponding detailed information is provided for the patient in the PIL and the label (outer carton) advises the patient to speak to the pharmacist if they are taking any other medicines. The pharmacy training materials provide comprehensive information concerning drug interactions with oxybutynin.

Other anticholinergic medicines

Women taking other anticholinergic medicines should not take Aquiette as enhancement of anticholinergic effects, including adverse events may occur. There are many medicines which have anticholinergic effect including the following:

amantadine and other antiparkinsonian medicines (e.g. procyclidine, levodopa)
antipsychotics (e.g. phenothiazines such as chlorpromazine)
butyrophenones (e.g. haloperidol, clozapine)
tricyclic antidepressants (e.g. amitriptyline, nortriptyline, clomipramine)
atropine and related medicines
antihistamines (e.g. diphenhydramine hydrochloride)
antispasmodics (e.g. hyoscine butylbromide) which are available in non-prescription cough/cold products/products for irritable bowel syndrome also have anticholinergic properties

Pharmacists are aware of the classes of drugs that share anticholinergic properties and are well placed to advise patients concerning potential interaction of these medicines with Aquiette and refer the patients using such medicines to their doctor. The low dose (2.5mg) and maximum daily dose (7.5mg) of Aquiette also reduces the potential for interactions in women who inadvertently use Aquiette despite warnings in the PIL and review of medicines a woman is taking by the pharmacist.

Medicines metabolised by the same/similar route to oxybutynin

Oxybutynin is metabolised (broken down by the body) by an enzyme in the liver known as CYP 3A4. Taking medicines that inhibit the activity of this enzyme at the same time as oxybutynin can increase the exposure to, and therefore effects of oxybutynin. Medicines in this class which are strong inhibitors of CYP 3A4 include antifungals (e.g. itraconazole) and some antibiotics of a type known as macrolides (e.g. erythromycin).

Pharmacists are aware of the potential for such drug interactions and well placed to advise patients taking such medicines and refer them to their doctor.

The effect of medicines known as cholinesterase inhibitors used in the treatment of Alzheimer’s disease (e.g. donepezil, rivastigmine, galantamine) may be reduced when oxybutynin is taken at the same time. Women over the age of 65 years seeking to treat symptoms of OAB are excluded from supply in the pharmacy, so this interaction is unlikely to present in the pharmacy. Regardless of this, pharmacists are aware of such interactions and are well equipped to advise patients taking cholinesterase inhibitors and refer them to their doctor.

Other medicines

Oxybutynin may antagonise the action of so-called prokinetic medicines (medicines which help control acid reflux) such as metoclopramide and domperidone.

Alcohol may enhance the drowsiness caused by anticholinergic medicines such as oxybutynin. The PIL and label (outer carton) have clear warning regarding this and advice for the patient.

Conclusion: drug interactions and risk minimisation

All drug interactions with Aquiette can be managed through the product information [SmPC, patient information leaflet (PIL) and labelling] and pharmacy training materials. In particular, the PIL provides detailed information for the patient on drug interactions; the product outer carton includes in bold text the statement ‘If you are taking any other medicines, speak to your pharmacist’.

Pharmacists will be familiar with these interactions; the pharmacy training materials are detailed in this respect, making it clear that all medication (including over the counter and herbal products) a woman is taking should be checked for interactions with Aquiette. Where clinically relevant interactions are identified, the woman should be referred to a doctor for discussion of alternative treatment of OAB symptoms.

Minimising direct risks associated with use of Aquiette as a pharmacy (P) medicine

The risk from adverse drug reactions and interactions can be adequately managed through the product information and pharmacy training materials. Pharmacists are skilled professionals already practised in medicines management including advising on adverse events and interactions. The product information and pharmacy training materials ensure they have all relevant information on the important adverse events and interactions for oxybutynin. This will allow pharmacists to identify women suitable for supply and be able to counsel those women appropriately.

The MHRA considers that the direct risks can be minimised to an acceptable level for pharmacy supply of Aquiette.

4.1.2 Indirect danger to human health

The potential for indirect danger occurring from non-prescription use of a medicine arises mainly from the use of the medicine without medical supervision in groups of patients that are not suitable. In these circumstances, danger can arise from mistaken diagnosis, or exclusions that are deliberately or inadvertently not heeded. The following potential indirect dangers have been identified for pharmacy supply of Aquiette:

Intentional misuse – risk of non-prescription ‘off-label’ use (use outside the terms of the marketing authorisation) It is possible that some excluded categories of people with OAB may try to purchase Aquiette in the pharmacy.

This reflects the fact that some categories of patients (including men and some ages of children) are not excluded from the use of oxybutynin on prescription.

Aquiette is not intended for use in men. Although men can present with symptoms of OAB, diagnosis is complicated by the potential for symptoms to be related to benign prostatic hyperplasia (BPH/enlargement of the prostrate) and this affects the range of treatment options that should be considered. It is unlikely that men will identify their symptoms as OAB rather than BPH without professional assistance. One possible concern of treating such patients with an anticholinergic drug such as oxybutynin is the possible precipitation of acute urinary retention (AUR). However, studies show that anticholinergics are not, in fact, associated with a substantial increase in risk of AUR. Therefore, even if a man with OAB symptoms and BPH were to self-treat with low dose oxybutynin it is unlikely that significant harm will result. Pharmacy staff can readily intercept the purchase of Aquiette by men, should this be attempted and refer men to their GP for assessment of their symptoms.

Females <18 and >65 years of age are excluded from use of Aquiette.

The label (outer carton) clearly identifies these categories of patients and reminds patients and pharmacists that Aquiette is not suitable for use as a pharmacy medicine in these individuals. The pharmacy training materials clearly highlight the exclusions to supply of Aquiette, the rationale for such exclusions and need to refer such patients to their doctor. It is considered that the product information (SmPC, PIL and label) and pharmacist training will be adequate to minimise the risk of usage by men or women <18 and >65 years of age.

Indirect Danger resulting from missed underlying conditions

Self-assessment of symptoms

The symptoms of OAB are considered suitable for self-assessment by women, supplemented by advice from a pharmacist.

The symptoms of OAB in women (e.g. urgent need to urinate and frequent urination without pain, sometimes leading to accidental leaks) when they occur alone, do not overlap with a typical presentation for other serious disorders. Consequently, there is low potential for treatment of the typical OAB symptoms in women to mask other serious underlying conditions. If symptoms of OAB exist alongside additional urinary symptoms, the possibility of other underlying conditions being present is greater. For this reason, the label (outer carton) highlights ‘red flag’ symptoms that might indicate other important causes of urinary symptoms.

Women with other conditions presenting in pharmacy with urinary frequency or incontinence may have a worsened outcome if the underlying condition is not recognised, since other specific treatments may be available. Women with known diseases that may cause similar symptoms to OAB are excluded from use of Aquiette. These conditions are listed in the product information. If a woman has urinary frequency or nocturia (need to urinate during the night) this may be a feature of illnesses such as diabetes or heart failure. However, the pharmacy training materials, PIL and label (outer carton) stress that a key symptom of OAB is urgency (urgent need to urinate). Absence of urgency, and/or presence of other symptoms suggestive of systemic disease (e.g. thirst in diabetes and breathlessness in heart failure) would indicate an increased likelihood of another underlying cause for urinary symptoms and therefore need to refer the woman to her doctor. Furthermore, in these conditions, frequency and/or nocturia will not respond to Aquiette, which works by reducing overactive bladder contractions.

Urinary Tract Infection (UTI)

Frequent urination is a symptom of urinary tract infection. However, if other symptoms are present such as pain on urination, fever, cloudy urine or loin pain, then further assessment by a doctor is required. Women with a sudden onset of symptoms or with a history of recurrent cystitis are more likely to have a UTI and should be referred to their doctor, even in the absence of painful urination.

The indication for Aquiette excludes women with a history of bladder symptoms of less than 1 month. In addition, women with symptoms suggestive of a UTI, including painful urination, fever, cloudy urine or loin pain should not be supplied with Aquiette and be referred to their doctor.

It is possible that women may present with more chronic urinary symptoms resulting from a more longstanding ‘low grade’ urinary tract infection. Such women are unlikely to respond to oxybutynin. If Aquiette is suppled for an initial 6-week treatment course to such women, failure to respond at 6 weeks would result referral of the woman to their doctor.

Bladder cancer

Overactive bladder symptoms can sometimes be associated with bladder cancer. It is possible that in a small number of cases, if presenting to a doctor with such symptoms, a physical examination or finding of invisible traces of blood in a urine test might raise concerns that would lead to further investigation and identification of the cancer. However, with appropriate questioning by the pharmacist, aided by the quick reference guide, the risk of missing a bladder cancer which might otherwise have been detected by physical examination or urine analysis is considered very low, and not greater than the corresponding risk of undiagnosed malignancy accepted for other medicines available without prescription, such as those for indigestion or pain killers.

The presence of visible haematuria (blood in the urine), which might indicate the presence of a tumour in the bladder, kidneys or connecting tubes, would trigger referral of a woman to their doctor for review. This is covered by the pharmacist quick reference guide and the product information for Aquiette highlights this, including the label (outer carton) which clearly identifies symptoms suggestive of urinary obstruction or urinary tract malignancy such as dysuria (pain on urination) accompanied by poor urinary flow and haematuria (blood in the urine).

Ovarian mass

An ovarian mass may be a cyst or a tumour with similar symptoms seen for both conditions. The most common symptoms are feeling bloated, a swollen stomach, feeling discomfort in the pelvic region and needing to urinate more often or more urgently than normal. Ovarian cancer is most commonly seen in women over 50 years, with most cases seen after the menopause; a cyst can be seen in younger women. The SmPC includes a warning that women with symptoms suggestive of an ovarian malignancy (consistent bloating, swollen abdomen and discomfort in the pelvic region) should be referred to their doctor for investigation before treatment. The pharmacist training materials provide this information with emphasis that such women should be referred to their doctor. The PIL advises the patient not to take Aquiette and speak to their pharmacist/doctor if they have a feeling of being bloated all the time or have a discomfort in the stomach or pelvic region. As with bladder cancer, the risk of missing a diagnosis of ovarian cancer which might otherwise have been picked up via physical examination by a doctor is considered to be low.

Fibroids/womb malignancy

Evidence suggests that there may be the potential for a higher risk of some womb conditions in women with typical OAB symptoms. These conditions more commonly present with abnormal menstrual bleeding, particularly heavy bleeding (in the case of fibroids) and inter-menstrual bleeding (bleeding between periods) or postmenopausal bleeding (in the case of womb malignancy).

The SmPC for Aquiette includes the warning that women with symptoms suggestive of womb disease such as fibroids or malignancy (abnormal menstrual bleeding such as heavy periods, inter-menstrual bleeding or any postmenopausal bleeding) should be referred to their doctor. This information is also included in the pharmacist training materials and conveyed to the patient in the PIL and on the label (outer carton). Again, the risk of missing a diagnosis of womb cancer which might otherwise have been picked up via physical examination by a doctor is considered to be low.

In any case of malignancy, treatment with an anticholinergic such as oxybutynin is unlikely to improve symptoms. If Aquiette were to be supplied to such women, poor symptomatic response at six weeks would prompt the pharmacist to refer the woman to her doctor. This acts as a further safety net in the event that Aquiette were to be supplied inappropriately.

Diabetes

The Aquiette SmPC contraindicates use in women with diabetes and includes a warning that women with symptoms suggestive of diabetes (e.g. increased thirst, frequent urination, fatigue, unexplained weight loss, frequent infections) should be referred to their doctor.

Pharmacists are reminded in the training materials that urinary frequency might be due to undiagnosed systemic diseases, for instance diabetes, and that they should be alert to the need for screening through referral of the woman to her doctor, particularly when additional symptoms (such as thirst and weight loss) are present. The label (outer carton) advises the patient not to take Aquiette and speak to their pharmacist if they have urinary frequency which may be due to other illnesses including diabetes and heart failure.

Atrophic Vaginitis (thinning and drying of the vagina)

Women may experience atrophic vaginitis after menopause, as oestrogen levels fall. This condition is characterised mainly by vaginal dryness and frequently goes unreported. If the condition progresses (as it may do with advancing age) then it can be associated with lower urinary tract symptoms, particularly dysuria (painful urination) and frequency.

The SmPC contraindicates use of Aquiette in women over 65 years of age thereby excluding many older women with advanced atrophic vaginitis and associated urinary symptoms.

The SmPC also warns that women with symptoms suggestive of atrophic vaginitis (e.g. vaginal pain and dryness, with pain or burning on urination or frequent urination), should be referred to their doctor before treatment. The pharmacist training materials provide this information with emphasis that such women should be referred to their doctor. The PIL advises the patient not to take Aquiette and speak to their pharmacist/doctor if they have signs of vaginal pain or dryness, as well as pain or burning when urinating. The label (outer carton) advises the woman not to take Aquiette and speak to their pharmacist if they have vaginal problems including dryness or burning.

Vaginal Prolapse

The incidence of prolapse increases with advancing age, menopause and giving birth. Symptoms of vaginal prolapse include a description by women of ‘something coming down’. Women may also describe a lump or a feeling of pressure in the vagina. Urinary symptoms such as poor flow of urine, hesitancy, straining to void, incomplete emptying of the bladder, recurrent urinary tract infections and the need to strain or reduce the bulge using the fingers in order to void urine, may accompany symptomatic prolapse.

The SmPC includes a warning that women with symptoms suggestive of a prolapse (feeling a bulge/lump from the vagina, heaviness in the pelvic region with constipation and frequent urinary tract infections) should be referred to their doctor before treatment. The pharmacist training materials provide this information with emphasis that such women should be referred to their doctor. The PIL advises the patient not to take Aquiette and speak to their pharmacist/doctor if they have a feeling of a bulge or lump in the vagina. The label (outer carton) also advises the woman not to take Aquiette and speak to their pharmacist if they have such symptoms.

Duration of treatment

It is possible in certain situations that a woman may suffer a worsened outcome as a result of unsupervised use of non-prescription oxybutynin if she continues to use Aquiette in circumstances where alternative treatments might have been more suitable. These would include the need for continuous treatment every day for prolonged periods to control symptoms to a satisfactory degree, or cases where incontinence is the primary problem and is difficult to control.

The maximum duration of treatment with Aquiette is 12 weeks.

The pharmacy training materials detail the supply model for Aquiette in the pharmacy as defined in the product licence (SmPC) and corresponding PIL and label as follows:

Aquiette may be initiated in suitable women who have tried at least 6 weeks of bladder training and lifestyle measures alone to control their OAB and in whom symptoms are not adequately controlled.

Following 6 weeks of bladder training, an initial course of 6 weeks of Aquiette in combination with bladder training and lifestyle measures may be tried. If symptoms are adequately controlled, treatment may be continued together with bladder training and lifestyle measures for a further 6 weeks (12 weeks in total). After 12 weeks treatment, Aquiette should be stopped and bladder and lifestyle measures continued alone to control symptoms.

If an initial 6 weeks of treatment with Aquiette does not adequately control symptoms or if they worsen at any time, Aquiette should be stopped and the woman referred to her doctor.

After 12 weeks treatment, if OAB symptoms return, the woman should be referred to her doctor as alternative/longer term treatment may be more appropriate for her condition.

The headline section of the PIL prominently states:

You must stop taking Aquiette and talk to a pharmacist or doctor if your symptoms are not under control or get worse after taking Aquiette Tablets for 6 weeks.

Section 3 of the PIL provides the following advice under sub-heading ‘If Aquiette does not work for you’:

Aquiette may not be suitable for some people. Speak to your pharmacist or doctor if:

your symptoms do not get better or get worse after taking Aquiette
your symptoms do not get better or get worse within 6 weeks of starting Aquiette
after 12 weeks treatment, your symptoms are not improved or return after stopping Aquiette
this medicine has worked for you in the past but no longer controls your symptoms
in some people the bladder may become more overactive as they get older
you have any further questions on the use of this medicine

The label (outer carton) states:

After 6 weeks, if symptoms improve – take for another 6 weeks then stop taking Aquiette and continue with bladder training alone

See your doctor

If symptoms get worse or do not get better after 6 weeks
If you still need Aquiette after 12 weeks

Minimising indirect risks associated with use of Aquiette as a pharmacy (P) medicine

The indirect risks of using Aquiette in the absence of medical supervision are considered addressed through the product information (SmPC, PIL, label) and training materials for pharmacists.

The MHRA considers that the indirect risks can be minimised to an acceptable level for pharmacy supply of Aquiette.

Overall conclusion on POM Criterion 1 (The product is likely to present a direct or indirect danger to human health, even when used correctly, if used without medical supervision).

POM criterion 1 is not considered to be fulfilled for Aquiette. Lack of medical supervision is not anticipated to result in direct or indirect danger to human health, provided the advice in the product information and pharmacy training materials is followed.

4.2 POM Criterion 2 – The product is frequently and to a very wide extent used incorrectly, and as a result is likely to present a direct or indirect danger to human health

The ways that Aquiette could be used incorrectly are:

Misuse/abuse
Overdose

Risk of ‘off-label’ use (use outside the terms of the marketing authorisation) is discussed above.

Risk of misuse/abuse

The risk of abuse of anticholinergic medicines such as oxybutynin is considered low. This is particularly the case for Aquiette with the low strength of tablets (2.5mg) intended for use as a pharmacy medicine. The adverse event section of the SmPC for Aquiette states dependence (in patients with history of drug or substance abuse) with frequency not known (cannot be estimated from available data).

Safety in overdose

The risk of significant overdose with Aquiette is mitigated by the low strength (2.5 mg) tablets and maximum pack size of 30 tablets. An entire pack of 30 tablets represents 75 mg of oxybutynin.

The primary effects of oxybutynin in overdose are an exaggeration of the known adverse effects of the drug, based on the anticholinergic method of action. Other non-prescription medicines with anticholinergic action (e.g. hyoscine butylbromide for treatment of symptoms of irritable bowel syndrome (IBS) and diphenhydramine hydrochloride in cough/cold preparations) are available without prescription which would produce similar possible effects in overdose to oxybutynin. While a risk of overdose exists, this is not considered to be any greater than with the POM product.

The PIL and label for Aquiette warn against taking too much of the product, for example on the label ‘Use the lowest effective dose’ and ‘Do not take more medicine than the label tells you to’. In the PIL, clear advice is provided to the patient on what to do if they take too many tablets (tell a doctor or go to hospital casualty department straight away) along with a list of possible symptoms they may experience if too many tablets are taken (feeling restless or excited, flushing, feeling dizzy or light-headed, very fast, uneven or forceful heartbeat breathing problems, feeling numb).

Overall conclusion on POM criterion 2 (The product is frequently and to a very wide extent used incorrectly, and as a result is likely to present a direct or indirect danger to human health.)

The second POM criterion is not considered to be fulfilled for Aquiette because the risks of direct or indirect danger to human health from incorrect use, can be adequately managed through the product information and pharmacy training materials.

4.3 POM Criterion 3 – The product contains substances or preparations of substances of which the activity requires, or the side effects require, further investigation

Oxybutynin is a well-established product having been widely used as a prescription only medicine (POM) in the UK since 1991. Its efficacy and safety profile are well known, and there are no issues requiring further investigation.

Overall conclusion on POM criterion 3

The 3rd POM criterion is not considered to be fulfilled for Aquiette.

4.4 POM Criterion 4 – The product is normally prescribed by a doctor for parenteral administration (that is, by injection).

Aquiette is a tablet intended for oral administration only.

Overall conclusion on POM criterion 4

The 4th POM criterion is not considered to be fulfilled for Aquiette.

Question 5

5.  Further details on the application

Accepted Answer

5.1 Risk Management Plan

The application contained a risk management plan (RMP), which documents everything that is known and not known about the safety profile of a product, including any plans for further characterising risks and minimising risks.

Potential safety concerns for Aquiette as a pharmacy medicine, over and above the identified and potential safety concerns associated with oxybutynin as a POM include the following:

women may confuse their symptoms with urinary conditions other than OAB, or other underlying conditions causing urinary symptoms
women may be taking other medicines with anticholinergic properties or medicines with the potential to interact and increase the effect of Aquiette
some excluded categories of people with OAB may try to purchase the drug in the pharmacy
women with conditions presenting with symptoms of frequent urination or incontinence may have a worsened outcome if the underlying condition is not recognised

Monitoring of the safety concerns

The safety concerns associated with Aquiette can be monitored through the routine activities that pharmaceutical companies have to undertake legally to monitor their products (routine pharmacovigilance). No additional monitoring is considered necessary.

Further characterising the safety concerns (additional pharmacovigilance)

None of the safety concerns are considered to require further investigation or study, either because current knowledge is considered adequate, or because studies are unlikely to provide useful additional information.

Minimising the safety concerns

The risk of all safety concerns and adverse events for Aquiette are minimised through routine measures including the product information (SmPC, PIL & label).

The safety concerns for the supply of Aquiette in the pharmacy will be minimised further through an additional risk minimisation measure of pharmacist training materials. These will highlight the important potential risks of Aquiette and ensure that pharmacists know how to identify relevant conditions and advise and manage women appropriately, including decision to supply or when referral to a doctor is necessary.

5.2 Pharmacy support materials

Additional resources in the form of pharmacy training materials will be provided for pharmacists. These are optional for pharmacists to use and include a Pharmacist Training Guide and Pharmacist’s Quick Reference Guide. These are supplemented by a Bladder Training Plan for the patient.

The Pharmacist Training Guide provides details of the management of early stage overactive bladder (OAB) alongside bladder training, covering key aspects of treatment and supply of Aquiette in the pharmacy including:

description of OAB including symptoms, prevalence and impact of this condition on lives of some women
differentiating between bladder problems that can lead to incontinence and their causes (OAB verses other conditions with similar symptoms)
recommending appropriate self-help measures (bladder training and lifestyle) as the first-line approach in controlling symptoms of OAB, enabling women to control symptoms in the long-term
knowing when to recommend Aquiette and when to refer the woman to her doctor (contraindications, warnings, drug interactions)
providing advice and counselling to women supplied with Aquiette including how to take, duration of treatment alongside bladder training (initial 6 weeks + further 6 weeks at follow-up), side effects of oxybutynin, when to stop Aquiette and seek medical advice.

The Pharmacist’s Quick Reference Guide is intended to act as an aide memoire for the pharmacist during consultation with the woman in determining if Aquiette is suitable for supply.

The company has also produced a Bladder Training Plan which outlines lifestyle measures and how to train the bladder (and keep track of progress) to improve symptoms of OAB. This is for the pharmacist to give to the patient presenting with OAB symptoms/requesting Aquiette. The Bladder training Plan includes a checklist on reverse side for the patient to fill in prior to consultation with the pharmacist, identifying conditions the patient may have, for which Aquiette may not be suitable and referral to a doctor required.

5.3 Label and leaflet

The patient information leaflet and label are provided in Annex 1 and 2.

5.4 Summary of Product Characteristics

The Summary of Product Characteristics is provided in Annex 3. This document is a description of the properties of Aquiette and the conditions attached to its use. It is used as a reference by healthcare professionals.

Question 6

6.  Consultation with stakeholders

Accepted Answer

CHM considered the views of a stakeholder group that had been convened to consider the suitability of oxybutynin for the treatment of OAB in the P setting. The stakeholder group included representation from individual pharmacists, GPs and nurses, and professional bodies (Royal Pharmaceutical Society, Royal College of General Practitioners). Pharmacy stakeholders considered there was an unmet need for an appropriate product to be available as a pharmacy medicine. It would increase awareness that OAB is a treatable condition. Prescribing members highlighted the need to rule out underlying conditions that may present with the same or similar symptoms as OAB, such as diabetes, urinary tract infections and prolapsed womb, which would necessitate blood and urine testing, in some cases before treatment. The group highlighted the importance of bladder training and lifestyle advice, which could alleviate OAB symptoms without the need for medication and the importance of following clinical guidance on the treatment of OAB in the P setting. These views were taken into consideration by the CHM when considering the suitability of Aquiette for use without medical supervision and the conditions under which Aquiette could be classified as a P medicine.

MHRA separately discussed widening access of this medicine with health policy officials in the Department of Health and Social Care and the Devolved Administrations and this met with strong support.

Question 7

7.  What do you think?

Accepted Answer

Aquiette 2.5mg Tablets are a medicine for treatment of long-standing (present for over 1 month) symptoms of overactive bladder (OAB) (e.g. urgent need to urinate and frequent urination without pain, sometimes leading to accidental leaks) which are not adequately controlled by bladder training alone, in women 18 to 65 years of age.
Tablets containing oxybutynin, the active ingredient of Aquiette, are currently only available on prescription.
Aquiette tablets are for treatment of OAB at the milder end of the spectrum of this condition.
Aquiette is not suitable for treating symptoms of stress incontinence alone (accidental leakage of urine during exercise, when coughing or when sneezing).
Aquiette may be initiated in suitable women who have tried at least 6 weeks of bladder training and lifestyle measures alone to control their OAB and in whom symptoms are not adequately controlled.
Alongside bladder training and lifestyle measures, an initial course of 6 weeks treatment and up to a maximum of 12 weeks treatment may be tried.
After 12 weeks treatment, if OAB symptoms return, the woman should be referred to her doctor as alternative/longer term treatment may be more appropriate for her condition.
The Commission on Human Medicines has advised that this product could be made available as a Pharmacy (P) medicine.
We want to know what you think about this proposed change.

Please tell us your views using this form. The deadline for comments is 13 May 2022.

a muscle which forms a layer of the wall of the bladder. ↩
The Human Medicines Regulations 2012 http://www.legislation.gov.uk/uksi/2012/1916/contents/made ↩

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1. Background on deciding where medicines are available