Allergan has announced that Botox (botulinum toxin type A) has received a positive opinion from the Irish Medicines Board for the management of urinary incontinence in adults with Neurogenic Detrusor Overactivity (NDO) resulting from neurogenic bladder due to stable sub-cervical spinal cord injury, or multiple sclerosis. This is an important step towards securing national licences in the 14 European countries involved in the Mutual Recognition Procedure and marks a key milestone in bringing this innovative treatment to patients suffering from urinary incontinence due to NDO. The positive opinion is specific for Botox and is based on Allergan's successful global phase III programme.

Between 60-80 per cent of people with multiple sclerosis (MS) and 75-80 per cent of people with Spinal Cord Injury (SCI) will suffer from some degree of bladder dysfunction including urinary incontinence which can be distressing2-4. Urinary incontinence in patients with MS or SCI is frequently caused by a condition called NDO, which results in involuntary contractions of the bladder during the filling stage when the bladder should be relaxed. This overactivity can lead to urinary incontinence (uncontrolled urinary leaking). Targeted injections of Botox into the bladder muscle have been shown to reduce the involuntary contractions and increase bladder capacity. In turn, this reduces the number of urinary leaking episodes and may even stop leaking altogether in some patients.

In Europe, approximately 656,000 people live with MS and, on average, nearly 11,000 people are diagnosed with SCI per year. Many of these people face long-term mobility issues, yet remain professionally and socially active. Urinary incontinence can be a disabling and socially isolating condition10. It is also associated with significant quality of life and emotional well-being implications such as embarrassment, low self esteem, depression and loss of independence. Other health implications of urinary incontinence in people living with MS or spinal cord injury include skin irritation and ulcers, kidney failure and recurrent urinary tract infections, which may lead to serious health consequences, if the overactivity of the detrusor muscle is not treated.

“We are pleased that Botox has received a positive opinion following the Mutual Recognition Procedure for the treatment of urinary incontinence in people living with multiple sclerosis or spinal cord injury,” said Douglas Ingram, president of Allergan in Europe, Africa and the Middle East. “For many people with spinal cord injury or multiple sclerosis, gaining effective control over their bladder and staying dry can be a significant step towards improving daily functioning and overall quality of life. Our task now is to work closely with the national health authorities to secure the relevant national licences so that we can bring this valuable treatment option to patients, as quickly as possible.”

DIGNITY, the largest clinical trial programme in NDO. The DIGNITY programme (Double-blind InvestiGation of purified Neurotoxin complex In neurogenic deTrusor overactivitY) was Allergan's phase III clinical programme evaluating the safety and efficacy of Botox as a treatment in patients suffering from urinary incontinence due to NDO. The programme consisted of two pivotal trials involving nearly 700 patients with either spinal cord injury or multiple sclerosis who were not adequately managed with at least one anti-cholinergic therapy. Eligible patients needed to be willing to perform clean intermittent catheterisation (CIC) to remove urine from the body, if required.

Patients were randomised to receive a physician-administered single treatment of placebo, 200 or 300 Units of Botox injected as one procedure into the detrusor muscle using a rigid or flexible cystoscope. Treatment was shown to be effective within 2 weeks and lasted for approximately 8-10 months.

The results from the DIGNITY programme showed there was a significant reduction in frequency of urinary incontinence (leakage) reported in BOTOX treated patients compared to placebo.

Patients treated with 200 Units of Botox experienced a highly statistically significant and clinically relevant reduction in the episodes of the most bothersome symptom, urinary incontinence (leakage), at week 6 compared to placebo. In fact, patients treated with 200 Units of Botox experienced a reduction in the number of wetting episodes from 32.4 episodes/week at baseline to only 11.1 episodes / week by week 6 (a reduction of 21.3 episodes). In contrast, patients treated with placebo had an average of 31.5 episodes/week at baseline which was reduced to 21.0 episodes/week by week 6 (a reduction of only 10.5 episodes) (p<0.001). Nearly 40% of patients (37%) treated with 200 Units of BOTOX were completely dry throughout week 6 compared to just 9% of patients treated with placebo.

Patients in the Botox treatment groups experienced significant improvements in quality of life including less avoidance behaviour, less psychosocial impact and less embarrassment compared to those on the placebo treatment arm. Like all medicines, Botox can cause side effects, although not everybody gets them. In general, side effects occur within the first few days following injection. They usually last only for a short time, but they may last for several months and in rare cases, longer. Overall, Botox treatment was generally well-tolerated in the majority of patients in the phase III clinical trial programme.

The most common adverse reactions were mainly associated with the urinary tract and included urinary tract infections and the inability to empty the bladder (urinary retention) in patients who were not using a catheter to remove urine1. Other side effects included difficulty in sleeping (insomnia), constipation, muscle weakness, muscle spasm, blood in the urine after the injection, painful urination after the injection, bulge in the bladder wall (bladder diverticulum), tiredness, problems with walking (gait disturbance), possible uncontrolled reflex reaction of the body (e.g. profuse sweating, throbbing headache or increase in pulse rate) around the time of the injection (autonomic dysreflexia) or falls.

Many patients with neurogenic bladder do not actively talk to their doctors or other healthcare professionals about their urinary leakage, hence may remain undiagnosed and under treated. Current treatments are focussed primarily on oral anticholinergics as first line treatment and, if the condition cannot be managed with the anticholinergics, the last step for many patients is surgery. However, over 70% of patients with urinary incontinence stop taking oral anticholinergic treatments after just one year because of side effects or lack of efficacy and many are reluctant to have surgery, demonstrating the need for alternative minimally invasive treatments.

In addition to the Mutual Recognition Procedure in Europe, Allergan is working with other health regulatory agencies around the world to bring this valuable minimally invasive treatment option to people living with multiple sclerosis or spinal cord injury who have urinary incontinence due to NDO.

The detrusor muscle is the most important muscle of the bladder and contracts when urinating to squeeze out urine. Otherwise, it remains relaxed to allow the bladder to fill. Other muscles involved in urination include the urethral sphincter muscles which control the flow of urine. Detrusor overactivity is characterised by involuntary bladder contractions which can lead to urinary incontinence (wetting or leaking) as well as urgency to urinate or an increased need to urinate. It is commonly divided into two categories: Idiopathic Detrusor Overactivity (IDO) where the cause is unknown and NDO resulting from neurogenic bladder.

Neurogenic bladder occurs when the nerves controlling the detrusor muscle, predominantly in the spinal cord, are damaged — for example by lesions in the spine (such as plaques caused by MS) or an injury to the spinal cord (SCI). Given the nature of their underlying conditions, the nerve damage for most patients with neurogenic bladder cannot be repaired. Reducing the number of involuntary detrusor muscle contractions with Botox is one way to treat bladder issues in patients with NDO. Botulinum toxin is currently recommended in the 2011 European Association of Urology guidelines, with a grade A recommendation, as an effective minimally invasive treatment to reduce neurogenic detrusor overactivity.

Botox (botulinum toxin type A) from Allergan is a prescription-only medicine that contains tiny amounts of highly purified botulinum toxin protein refined from the bacterium, Clostridium botulinum.
In the UK, Botox is licensed in adults for the treatment of: blepharospasm (uncontrolled blinking of the eyelids), hemifacial spasm (a neuromuscular disorder characterised by unpredictable and involuntary twitching of facial muscles on one side of the face), cervical dystonia (a muscle condition affecting the neck making it difficult to hold the head up straight), severe axillary hyperhidrosis (excessive sweating) of the armpits, treatment of post stroke spasticity in the hand and wrist, prophylaxis of headaches in adults who have chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine).

In addition, Botox is also indicated to treat dynamic equinus foot deformity in children aged two years and older who have cerebral palsy. Allergan's botulinum toxin type A is licensed under the brand name of Vistabel for the treatment of glabellar lines (frown lines).

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