FDA Accepts Supplemental Biologics License Application (sBLA) for BOTOX® (onabotulinumtoxinA) for the Treatment of Pediatric Patients with Neurogenic Detrusor Overactivity

NORTH CHICAGO, Ill., June 22, 2020 /PRNewswire/ -- Allergan, an AbbVie (NYSE: ABBV) company, today announced that the U.S. Food and Drug Administration (FDA) has accepted the company's supplemental biologics license application (sBLA) to expand the BOTOX^® prescribing information for the treatment of signs and symptoms of detrusor (bladder muscle) overactivity associated with an underlying neurologic condition (e.g., spina bifida, spinal cord injuries) in pediatric patients (5 -17 years of age) who have an inadequate response to, or are intolerant of, or for any reason unwilling to continue anticholinergic medication.

The sBLA is based on data from a randomized, double-blind Phase 3 study evaluating the safety and efficacy of BOTOX^® in more than 100 pediatric patients with neurogenic detrusor overactivity and a long-term extension study. The Prescription Drug User Fee Act date is expected to be in the first quarter of 2021 following a standard 10-month review.

"The FDA acceptance of this application underscores our ongoing commitment to pursuing the full potential of BOTOX^® to serve patients across a wide spectrum of diseases and clinical needs," said Mitchell F. Brin, M.D., Senior Vice President, Chief Scientific Officer, BOTOX^® & Neurotoxins, AbbVie. "Children living with neurogenic detrusor overactivity currently have limited options when they fail anticholinergic medications and prior to surgical intervention. If approved, BOTOX^® will be the first neurotoxin treatment approved for use in treating detrusor overactivity in pediatric patients with an underlying neurologic condition who are not adequately managed by anticholinergic medications."

Neurogenic detrusor overactivity results from the inability of the spinal cord and bladder to communicate effectively. As a result, the bladder muscle (detrusor) involuntarily contracts, increasing the pressure in the bladder and reducing the bladder capacity, which can cause the individual to leak urine frequently and unexpectedly. If not adequately managed with clean intermittent catheterization and anticholinergic drugs, this condition may require augmentation cystoplasty (an extensive surgical procedure in which the bladder is enlarged using a section of the patient's intestine) to prevent renal damage.

There are a number of causes of neurogenic detrusor overactivity in children, such as transverse myelitis, spinal cord injury, and spina bifida, which is the most common and affects 1,500-2,000 of the more than 4 million babies born in the United States each year.¹ More than 90% of those living with spina bifida experience urinary symptoms.^2,3,4,5 

"Over time, many pediatric patients with underlying neurologic conditions experience bladder and kidney damage, and treatment is critical," said Paul F. Austin, M.D., FAAP, Chief of Pediatric Urology at Texas Children's Hospital and Professor of Urology at Baylor College of Medicine. "Current treatment options often include anticholinergic medications, where long-term use needs to be considered carefully, in addition to surgery. The favorable BOTOX^® clinical results for the treatment of pediatric patients with neurogenic detrusor activity are promising as we look to address unmet and ongoing needs in children and adolescents."

BOTOX^® is the first and only neurotoxin approved for the treatment of leakage of urine (incontinence) due to overactive bladder caused by a neurologic condition in adults who still have leakage or cannot tolerate the side effects after trying an anticholinergic medication. BOTOX^® temporarily reduces muscle contractions by blocking the transmission of nerve impulses to the muscle, in this case, the bladder muscle, by selectively preventing the release of the neurotransmitter acetylcholine at the neuromuscular junction.

About BOTOX^®
BOTOX^® is one of the most widely researched medications in the world, with a proven history as a therapeutic agent.⁶ First approved by the FDA in 1989 for two rare eye muscle disorders ? blepharospasm and strabismus in adults, BOTOX^® was the world's first approved botulinum toxin type A treatment. Today, BOTOX^® is FDA-approved for 11 therapeutic indications, including Chronic Migraine, overactive bladder, leakage of urine (incontinence) due to overactive bladder caused by a neurologic condition, cervical dystonia, spasticity, and severe underarm sweating (axillary hyperhidrosis). Backed by strong science and continuous innovation, BOTOX^® proudly embraces its past while boldly looking to the future.

BOTOX^® (onabotulinumtoxinA) Important Information

Indications
BOTOX^® is a prescription medicine that is injected into muscles and used:

• To treat overactive bladder symptoms such as a strong need to urinate with leaking or wetting accidents (urge urinary incontinence), a strong need to urinate right away (urgency), and urinating often (frequency) in adults 18 years and older when another type of medicine (anticholinergic) does not work well enough or cannot be taken
• To treat leakage of urine (incontinence) in adults 18 years and older with overactive bladder caused by a neurologic disease who still have leakage or cannot tolerate the side effects after trying an anticholinergic medication
• To prevent headaches in adults with Chronic Migraine who have 15 or more days each month with headache lasting 4 or more hours each day in people 18 years or older
• To treat increased muscle stiffness in elbow, wrist, finger, and thumb muscles in people 18 years and older with upper limb spasticity
• To treat increased muscle stiffness in ankle and toe muscles in people 18 years and older with lower limb spasticity
• To treat increased muscle stiffness in children 2 to 17 years of age with upper limb spasticity
• To treat increased muscle stiffness in children 2 to 17 years of age with lower limb spasticity, excluding spasticity caused by cerebral palsy
• To treat the abnormal head position and neck pain that happens with Cervical Dystonia (CD) in people 16 years and older
• To treat certain types of eye muscle problems (Strabismus) or abnormal spasm of the eyelids (Blepharospasm) in people 12 years and older

BOTOX^® is also injected into the skin to treat the symptoms of severe underarm sweating (severe primary axillary hyperhidrosis) when medicines used on the skin (topical) do not work well enough in people 18 years and older.

It is not known whether BOTOX^® is safe or effective to prevent headaches in patients with migraine who have 14 or fewer headache days each month (episodic migraine).

It is not known whether BOTOX^® is safe or effective to treat increased stiffness in upper limb muscles other than those in the elbow, wrist, fingers, and thumb, or in lower limb muscles other than those in the ankle and toes in people 18 years and older. BOTOX^® has not been shown to help people perform task-specific functions with their upper limbs or increase movement in joints that are permanently fixed in position by stiff muscles.

It is not known whether BOTOX^® is safe or effective for other types of muscle spasms or for severe sweating anywhere other than your armpits.

IMPORTANT SAFETY INFORMATION

BOTOX^® may cause serious side effects that can be life threatening. Get medical help right away if you have any of these problems any time (hours to weeks) after injection of BOTOX^®:

• Problems swallowing, speaking, or breathing, due to weakening of associated muscles, can be severe and result in loss of life. You are at the highest risk if these problems are pre-existing before injection. Swallowing problems may last for several months
   
• Spread of toxin effects. The effect of botulinum toxin may affect areas away from the injection site and cause serious symptoms including: loss of strength and all-over muscle weakness, double vision, blurred vision and drooping eyelids, hoarseness or change or loss of voice, trouble saying words clearly, loss of bladder control, trouble breathing, and trouble swallowing

There has not been a confirmed serious case of spread of toxin effect away from the injection site when BOTOX^® has been used at the recommended dose to treat Chronic Migraine, severe underarm sweating, Blepharospasm, or Strabismus.

BOTOX^® may cause loss of strength or general muscle weakness, vision problems, or dizziness within hours to weeks of taking BOTOX^®. If this happens, do not drive a car, operate machinery, or do other dangerous activities.

Do not receive BOTOX^® if you: are allergic to any of the ingredients in BOTOX^® (see Medication Guide for ingredients); had an allergic reaction to any other botulinum toxin product such as Myobloc^® (rimabotulinumtoxinB), Dysport^® (abobotulinumtoxinA), or Xeomin^® (incobotulinumtoxinA); have a skin infection at the planned injection site.

Do not receive BOTOX^® for the treatment of urinary incontinence if you: have a urinary tract infection (UTI) or cannot empty your bladder on your own and are not routinely catheterizing. Due to the risk of urinary retention (not being able to empty the bladder), only patients who are willing and able to initiate catheterization post treatment, if required, should be considered for treatment.

Patients treated for overactive bladder:
In clinical trials, 36 of the 552 patients had to self-catheterize for urinary retention following treatment with BOTOX^® compared to 2 of the 542 treated with placebo. The median duration of postinjection catheterization for these patients treated with BOTOX^® 100 Units (n = 36) was 63 days (minimum 1 day to maximum 214 days) as compared to a median duration of 11 days (minimum 3 days to maximum 18 days) for patients receiving placebo (n = 2). Patients with diabetes mellitus treated with BOTOX^® were more likely to develop urinary retention than nondiabetics.

Patients treated for overactive bladder due to neurologic disease:
In clinical trials, 30.6% of patients (33/108) who were not using clean intermittent catheterization (CIC) prior to injection, required catheterization for urinary retention following treatment with BOTOX^® 200 Units as compared to 6.7% of patients (7/104) treated with placebo. The median duration of postinjection catheterization for these patients treated with BOTOX^® 200 Units (n = 33) was 289 days (minimum 1 day to maximum 530 days) as compared to a median duration of 358 days (minimum 2 days to maximum 379 days) for patients receiving placebo (n = 7). Among patients not using CIC at baseline, those with MS were more likely to require CIC post injection than those with SCI.

The dose of BOTOX^® is not the same as, or comparable to, another botulinum toxin product.

Serious and/or immediate allergic reactions have been reported including itching, rash, red itchy welts, wheezing, asthma symptoms, or dizziness or feeling faint. Get medical help right away if you experience symptoms; further injection of BOTOX^® should be discontinued.

Tell your doctor about all your muscle or nerve conditions such as ALS or Lou Gehrig's disease, myasthenia gravis, or Lambert-Eaton syndrome, as you may be at increased risk of serious side effects including difficulty swallowing and difficulty breathing from typical doses of BOTOX^®.

Tell your doctor if you have any breathing-related problems. Your doctor may monitor you for breathing problems during your treatment with BOTOX^® for spasticity or for detrusor overactivity associated with a neurologic condition. The risk of developing lung disease in patients with reduced lung function is increased in patients receiving BOTOX^®.

Cornea problems have been reported. Cornea (surface of the eye) problems have been reported in some people receiving BOTOX^® for their Blepharospasm, especially in people with certain nerve disorders. BOTOX^® may cause the eyelids to blink less, which could lead to the surface of the eye being exposed to air more than is usual. Tell your doctor if you experience any problems with your eyes while receiving BOTOX^®. Your doctor may treat your eyes with drops, ointments, contact lenses, or with an eye patch.

Bleeding behind the eye has been reported. Bleeding behind the eyeball has been reported in some people receiving BOTOX^® for their Strabismus. Tell your doctor if you notice any new visual problems while receiving BOTOX^®.

Bronchitis and upper respiratory tract infections (common colds) have been reported. Bronchitis was reported more frequently in adults receiving BOTOX^® for upper limb spasticity. Upper respiratory infections were also reported more frequently in adults with prior breathing related problems with spasticity. In pediatric patients treated with BOTOX^® for upper limb spasticity, upper respiratory tract infections were reported more frequently. In pediatric patients treated with BOTOX^® for lower limb spasticity, upper respiratory tract infections were not reported more frequently than placebo.

Autonomic dysreflexia in patients treated for overactive bladder due to neurologic disease. Autonomic dysreflexia associated with intradetrusor injections of BOTOX^® could occur in patients treated for detrusor overactivity associated with a neurologic condition and may require prompt medical therapy. In clinical trials, the incidence of autonomic dysreflexia was greater in patients treated with BOTOX^® 200 Units compared with placebo (1.5% versus 0.4%, respectively).

Tell your doctor about all your medical conditions, including if you: have or have had bleeding problems; have plans to have surgery; had surgery on your face; weakness of forehead muscles; trouble raising your eyebrows; drooping eyelids; any other abnormal facial change; have symptoms of a urinary tract infection (UTI) and are being treated for urinary incontinence (symptoms of a urinary tract infection may include pain or burning with urination, frequent urination, or fever); have problems emptying your bladder on your own and are being treated for urinary incontinence; are pregnant or plan to become pregnant (it is not known if BOTOX^® can harm your unborn baby); are breastfeeding or plan to (it is not known if BOTOX^® passes into breast milk).

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using BOTOX^® with certain other medicines may cause serious side effects. Do not start any new medicines until you have told your doctor that you have received BOTOX^® in the past.

Tell your doctor if you received any other botulinum toxin product in the last 4 months; have received injections of botulinum toxin such as Myobloc^®, Dysport^®, or Xeomin^® in the past (tell your doctor exactly which product you received); have recently received an antibiotic by injection; take muscle relaxants; take an allergy or cold medicine; take a sleep medicine; take aspirin-like products or blood thinners.

Other side effects of BOTOX^® include: dry mouth, discomfort or pain at the injection site, tiredness, headache, neck pain, eye problems: double vision, blurred vision, decreased eyesight, drooping eyelids, swelling of your eyelids, dry eyes; drooping eyebrows; and upper respiratory tract infection. In people being treated for urinary incontinence other side effects include: urinary tract infection, painful urination, and/or inability to empty your bladder on your own. If you have difficulty fully emptying your bladder after receiving BOTOX^®, you may need to use disposable self-catheters to empty your bladder up to a few times each day until your bladder is able to start emptying again. 

For more information refer to the Medication Guide or talk with your doctor.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see BOTOX^® full Product Information, including Boxed Warning and Medication Guide.

About AbbVie

AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across its Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statements

Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2019 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

References:

1. National Institute of Neurological Disorders and Stroke. Spina Bifida Fact Sheet. Accessed online 5/6/2020 and available from: https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/spina-bifida-fact-sheet.
2. Hascoet J, Manunta A, Brochard C, Arnaud A, Damphousse M, Menard H, et al. Outcomes of intra-detrusor injections of botulinum toxin in patients with spina bifida: A systematic review. Neurourology and Urodynamics. 2017;36(3):557-564.
3. Pannek J, Blok B, Castro-Diaz D, Del Popolo G, Kramer G, Radziszewski P, et. al. Guidelines on neurogenic lower urinary tract dysfunction. European Association of Urology, 2013. Available from: https://uroweb.org/wp-content/uploads/20_Neurogenic-LUTD_LR.pdf.
4. Shin M, Besser LM, Siffel C, Kucik JE, Shaw GM, Lu C, Correa A; Congenital Anomaly Multistate Prevalence and Survival Collaborative. Prevalence of spina bifida among children and adolescents in 10 regions in the United States. Pediatrics. 2010;126(2):274-279.
5. Ouyang L, Grosse SD, Armour BS, Waitzman NJ. Health care expenditures of children and adults with spina bifida in a privately insured U.S. population. Birth Defects Research Part A, Clinical and Molecular Teratology. 2007;79(7):552-558.
6. Data on file, Allergan; BOTOX^® Worldwide Marketing Authorization Status; BOTOX^® Prescribing Information.

SOURCE AbbVie