Botox Dubai – Botulinum Toxin Anti-Wrinkle Injections

Botox Dubai as a muscle relaxant has an excellent safety record and a long record of use in medicine. It has been used successfully in adults and children in variety medical conditions over the last 20 years. It has been used cosmetically to treat facial wrinkles for about 15 years and has become one of the most popular and frequently used cosmetic treatments.

Botox Treatment can be used for treating wrinkles in men and women, however men often need slightly higher doses than women. It should not be used in People with infection at the proposed injection site. People who have previously had an allergic reaction to Botulinum toxin type A injections. People with muscle problems or chronic diseases affecting the muscles, such as Myasthenia Gravis, Eaton Lambert syndrome. Children under the age of 18 years. Women who are pregnant or breast feeding. It should be used cautiously in (please let the doctor know if the following applies to you) People at risk of bleeding as there is an increased risk of bruising post procedure. These include people who have blood clotting disorders such as Haemophilia, those who are taking treatments with anticoagulant medicines such as Warfarin, Heparin, Aspirin and Anti-Inflammatory medicines. Certain herbal remedies such as Gingiko Bilboa, St John’s Wort and Vitamin E People with excessive weakness or wasting in the muscle to be injected, such as those patients with history of Strokes or Bell’s Palsy People with Chronic Breathing difficulties

Botox Dubai injections are relatively painless as the injections are performed using a very fine needle. Patients therefore and do not require any anaesthesia. The full treatment takes about 15-20 minutes to perform and you are able to drive and go to work the same day.

It can take about 2-14 days to see the full effects after the initial treatment. The cosmetic effects of Botox Dubai can last up to six months but typically range from three to four months. Eventually most people require re treatment as the wrinkles reappear. However in some treated areas (such as frown wrinkles), the wrinkles may return less severe after repeated treatments as the unconscious muscle contraction habit is broken. We offer all our patients a free two week follow up appointment to assess the effect of treatment and administer any top up treatments if necessary.

Most people find that the Botox Dubai injections cause only mild local pain and tenderness. Immediately after the injection there may be mild swelling at the injection site which usually subsides within 48 hours. Slight bruising is also possible. Side effects of these treatments are extremely rare. Occasionally, the treatment may relax nearby muscle groups causing temporary drooping of the eyebrow or eyelids. This may last for a few weeks but will resolve with time. As with any medicine an allergic reaction may occur, this is however quite rare. Conversely there may be some unintended benefits in some people such as easing of tension type headaches as the muscles in the forehead relax. Botox has been used for over 20 years and does not appear to cause any negative long-term effects. Once administered, Botox typically leaves the body within 3-4 days, although, as with any medical procedure, it is important to seek advice from a qualified professional beforehand.

BOTOX® Cosmetic is an iconic brand. It’s been approved for use in 95 countries. But find out the truth behind common misconceptions, and you’ll get to know BOTOX® Cosmetic even better. WHAT IS BOTOX® COSMETIC? BOTOX® Cosmetic is the #1 selling treatment of its kind*: It’s the first and only treatment FDA-approved to temporarily make moderate to severe frown lines, crow's feet, and forehead lines look better in adults Treatment requires minimal downtime. You can return to your daily routine immediately after you leave your specialist's office You may begin to notice results within 24 to 48 hours for moderate to severe frown lines. Full results in 30 days It delivers predictable, subtle results, so you look like you, only with less noticeable facial lines Join the millions of men and women who make BOTOX® Cosmetic part of what they do to care for their appearance. Ask for the first and only BOTOX® Cosmetic by name. HOW MUCH RESEARCH HAS GONE INTO BOTOX® COSMETIC? When you choose BOTOX® Cosmetic, you can trust in its established track record. Backed by over 16 years of published studies, BOTOX® Cosmetic is the most widely researched and studied treatment of its kind, approved for use in 95 countries. The safety and efficacy of BOTOX® Cosmetic have been described in more than 528 peer-reviewed articles in scientific and medical journals. Learn The Story of BOTOX Cosmetic HOW DOES BOTOX® COSMETIC WORK? BOTOX® Cosmetic targets one of the underlying causes of frown lines, crow’s feet and forehead lines — the repeated muscle contractions from frowning, squinting, smiling and raising the eyebrows over the years. Your specialist will inject these muscles with BOTOX® Cosmetic to temporarily reduce muscle activity. You will begin to notice a visible smoothing of the frown lines between your brows, your crow’s feet lines and your forehead lines. Learn How BOTOX Cosmetic Works IS THERE A SUBSTITUTE FOR BOTOX® COSMETIC? BOTOX® Cosmetic is a biologic product that cannot be interchanged – or substituted – for another product. In fact, the FDA has stated BOTOX® Cosmetic is “non-interchangeable,” which means that its safety and effectiveness cannot be claimed by any other product. The potency – or strength – of BOTOX® Cosmetic is measured in scientifically defined units that cannot be compared to any other product, due to our unique manufacturing process. There are no substitutes for our product. People who are prescribed a biologic product have a right to know exactly what they are receiving. Be sure to ask which product you are being prescribed and why. WILL MY FACE LOOK OVERDONE OR UNNATURAL? BOTOX® Cosmetic is a technique-sensitive treatment. You can trust BOTOX® Cosmetic to deliver subtle results when you are treated by someone who is licensed, trained, and a medical expert in facial anatomy. So you’ll look like yourself—only with less noticeable lines. No one should be able to tell you’ve had anything done. Compare the before and after pictures of real patients in our gallery, and see the difference for yourself. HOW CAN I SAVE ON BOTOX® COSMETIC? Be wary of discount products or “cheap” BOTOX® Cosmetic – if it sounds too good to be true, it probably is. Your cost of BOTOX® Cosmetic not only includes the price of the product, but more importantly, the skill and expertise of the specialist or healthcare professional who is administering your treatment. The best way to save money on your treatments is to enroll in AllēSM, the aesthetics loyalty program by the makers of BOTOX® Cosmetic. IS BOTOX® COSMETIC ONLY FOR WOMEN? Not at all! Many men make BOTOX® Cosmetic part of what they do to care for their appearance. The number of men choosing treatments like BOTOX® Cosmetic has risen fast – in the past three years alone, men have received over one million botulinum toxin treatments. When surveyed, the majority of men say they want to look good and they’re bothered by the changes they see in the mirror. 80% would choose to treat their crow’s feet first, while 74% would prioritize their forehead lines, and 60% would most like to treat their frown lines.† †Results from a survey of men to determine most likely treatment areas and top areas of concern for injectable-naive, aesthetically-oriented men aged 30 to 65 years (N=600). Proportion of respondents selecting that area as highest priority to treat using the Maximum Difference (MaxDiff) scaling system. DO I NEED TO BE OVER 40 TO START USING BOTOX® COSMETIC? It's not your age that determines when BOTOX® Cosmetic is right for you, it's the severity of your lines. In fact, 64% of plastic surgeons report seeing a rise in cosmetic surgery or injectable treatments for patients in their early 30’s. The truth is, everyone's lines form differently. The timing can be influenced by a combination of factors, from cellular changes that may occur over time, to reduction of collagen, to genetic factors, or damage caused by free radicals from the sun and the environment. Whenever your lines start to bother you, go speak with your doctor. They can help you determine if treatment is right for you. HOW MUCH TIME DOES BOTOX® COSMETIC TREATMENT TAKE? WILL IT HURT? Your specialist will discuss your treatment goals and perform a facial analysis to determine the appropriate treatment areas for you. Some patients report that being injected with BOTOX® Cosmetic feels like a pinch. Your specialist may use ice to numb the treatment area. Or, if you are concerned about discomfort, your specialist may apply a topical numbing cream before administering your treatment. Treatment requires minimal downtime. So you can return to your daily routine immediately after you leave your specialist’s office. WILL I SEE RESULTS QUICKLY? HOW LONG DOES BOTOX® COSMETIC LAST? You may begin to notice results within 24 to 48 hours, with full results in 30 days, with results lasting up to four months for moderate to severe frown lines. Remember that results vary from patient to patient though, so your physician will plan your next appointment based on your results and aesthetic goals. Start talking about your goals with a specialist today and find out what you could expect. Find a Specialist HOW LONG IS THE RECOVERY TIME AFTER TREATMENT? Treatment requires minimal downtime. So you can return to your daily routine immediately after you leave your specialist’s office. HOW MANY INJECTIONS WILL I RECEIVE? Treatment with BOTOX® Cosmetic is customized to your goals and needs. When you meet with your specialist, he or she will determine the appropriate treatment for any areas you wish to address, including moderate to severe frown lines, crow’s feet and forehead lines. Remember, only BOTOX® Cosmetic is approved to treat all three of these areas. For the crow’s feet area, your specialist will inject 3 areas of the muscle that frames the side of the eye. This will be repeated on the muscle that frames the other eye. For the frown lines area, your specialist will administer 5 injections into the muscles between your brows and in your forehead. For the forehead lines area, your specialist will administer 5 injections into a muscle in your forehead. WHAT WERE COMMON SIDE EFFECTS SEEN IN CLINICAL STUDIES? Three percent of patients experienced eyelid drooping in the frown lines studies, one percent of patients experienced eyelid swelling in the crow's feet studies, and one percent of patients experienced brow drooping in the forehead lines studies. Other possible side effects include: dry mouth; discomfort or pain at the injection site; tiredness; headache; neck pain; eye problems: double vision, blurred vision, decreased eyesight and dry eyes; and allergic reactions. These are not all of the possible serious side effects of BOTOX® Cosmetic. Please see the Important Safety Information including Boxed Warning and Medication Guide and talk to your specialist. IS THERE A “GENERIC” BOTOX® COSMETIC? There is no such thing as a “generic” form of BOTOX® Cosmetic. Be wary of discount products or “cheap” BOTOX® Cosmetic. Medical formulations, potency, and approved doses vary among products, so no one product can take the place of another. FDA labeling states that BOTOX® Cosmetic is not interchangeable with any other product. If it doesn’t say BOTOX® Cosmetic on the vial, then it isn’t BOTOX® Cosmetic. BOTOX® Cosmetic has a one-of-a-kind formulation. And BOTOX® Cosmetic is the most widely researched and studied treatment of its kind. Backed by more than 16 years of published studies, the safety and efficacy of BOTOX® Cosmetic have been described in 528 peer-reviewed articles in scientific and medical journals. Finally, Allergan, the maker of BOTOX® Cosmetic, owns the entire manufacturing and packaging process, which helps ensure the reliability and safety of each vial. For proven results, ask for BOTOX® Cosmetic.

Botox Dubai is a quick and safe procedure that has very little impact on usual activity on the day of injection. We deliver tiny injections to relax the action of the muscles that create excessive movement. These movements create ‘dynamic wrinkles’ over time. We recommend the following precautions to allow the anti-wrinkle injections to work optimally in the targeted muscles: No rubbing or massaging of the injected area for 4 hours after treatment, including facials. No strenuous exercise for 24 hours after treatment. Keep upright for 4 hours — no lying on your front. Minimise activities such as shoe shopping. Avoid headwear that is tightly fitted across the forehead. Reduce excessive alcohol consumption or medically necessary blood-thinning medication before the treatment to prevent bruising. 2. How soon after can I go back to my normal exercise regime? Patients can resume normal daily activities immediately following treatment. Light exercise can be performed after 4 hours but it is recommended that strenuous activities are avoided for 24 hours. After 4 hours you may perform light exercise such as: Walking Jogging Upright yoga (avoid any positions that leave you lying flat or upside down) Gardening It is recommended that you wait 24 hours before attempting any strenuous exercise, including: Weight training Cross-training Long-distance running Yoga (positions where the body is inverted) 3. Are there any possible side effects? In most cases, there will be no side effects to treatment of BOTOX®. However, because everybody’s physiology is different, people can be affected in different ways. A small minority of people reported the following side effects. Bruising — For the majority of patients, the area of injection will appear no different. For a small minority, some minor bruising may occur. Bumps — A few minutes after treatment small bumps may be visible on the skin. These will disappear very quickly. Headache — True BOTOX Dubai® allergies are exceedingly rare. Temporary headache is the most commonly reported symptom following anti-ageing injectables, though the numbers of patients who report headaches is very small compared with the number of treatments performed. Any headache can be treated with usual painkillers. 4. How soon can I drink alcohol after my muscle relaxant treatment? Some practitioners advise limiting alcohol in the first 24 hours and for the day prior to treatment. This is because alcohol can thin the blood much like an aspirin, and abstaining can help prevent bruising. 5. What are the symptoms of a reaction to BOTOX Dubai®? Generally, BOTOX® injections side effects are rare and recovery is swift. Your practitioner is available should you have any questions or concerns over minor side effects such as bruising and headache. 6. Am I allowed to touch my face after having anti-wrinkle injections? Yes. Your face will not feel overly sore or tender. Treatment will not prevent you from washing or continuing with your normal skincare regimen. However, you are advised to avoid rubbing or massaging your face for up to 4 hours after your last treatment. 7. Are BOTOX® injections long-lasting? Although some people experience longer-lasting results, scientific evidence shows that the effect of Botulinum Toxin injections usually last 12-16 weeks. 8. Can I keep having anti-wrinkle injections? Yes. BOTOX® does not ‘build up’ or accumulate in your system. We recommend scheduled treatments at about 12-16 weeks. Once the effects have worn off it is safe for you to top up treatments in the same area. It is also perfectly safe to have multiple treatments in different areas at the same time. See an amazing before and after result achieved for one of our lovely patients: Botox Dubai Muscle relaxant before and after 9. What happens when Botox® wears off? Once the treatment wears off, your muscles will function as they did before the injectables. This means that the wrinkles you smoothed or reduced will slowly begin to appear again. You will simply witness old wrinkles reappearing, and no new wrinkles should emerge. 10. Can I wear make-up after my treatment? Yes. Ideally, avoid make-up for an hour or so. However, mineral make-up can be applied immediately after BOTOX®. Again, it is recommended that you do not apply too much pressure during these activities in order to ensure that the injectable treatment does not disperse from the treated area. 11. What if my BOTOX® results are not what I expected? The results of Botulinum Toxin injections usually show through from 3–5 days to two weeks post-treatment. We review the technical and aesthetic results after this time in a follow-up session. If you would like to see results from real patients please take a look at our before and after anti-wrinkle injections gallery. 12. Can I fly directly after having BOTOX® injections? Yes. Patients will not experience any adverse effects from flying with anti-wrinkle injections. They not affected by changes in altitude or cabin pressure. 13. What should I do if I have any concerns after my anti-wrinkle injections treatment? Our practitioners are always available at the clinic if you have any concerns regarding the aesthetic outcome of your treatment. 14. Can I sleep after BOTOX®? Botulinum Toxin injections consist of a safe, naturally purified protein. A course of treatment has little impact on usual day-to-day activity and will not affect your sleeping patterns. To allow the BOTOX® injectables to settle, you should avoid putting pressure on the treated area or laying on your front for around four hours. 15. How soon after the treatment can I have a facial? We recommend that you do not rub the Botox treatment area for up to 4 hours post-treatment. This includes the gentle rubbing associated with a facial treatment. We advise not having a facial within 24 hours post-procedure.

Botox® is one of the most popular and well-established injectable substances that practitioners use to successfully reduce wrinkles in patients. While many patients fear the frozen and completely overdone Botox® jobs, there have been many more cases of natural-looking, amazing results. The key? Get a practitioner that knows what they’re doing. What is Botox Dubai®? First of all, Botox® is just the brand name of a certain neuromodulator, called “Botulinum Toxin Type A” but Botox® refers to an injectable cosmetic treatment used to effectively reduce fine lines and wrinkles on the face. Now, don’t let the word “toxin” scare you, it is completely safe to use (it has been FDA approved since 1989), but only by a licensed medical professional. There are also other well-known brand names for the same type of product, such as Dysport® or Xeomin®. Which wrinkles on my face can I treat with Botox®? Cosmetic Botox® is FDA approved for use on Crow’s feet around the eyes Horizontal lines on the forehead Wrinkles between the eyebrows Does it hurt? Any injection can hurt, but the needles used for Botox® injections are very small, so pain is usually minimal. At White Coat Aesthetics, we offer distractors from the pain such as a vibrating tool used on the skin near the injection site, ice packs, and even numbing cream, so you may not feel much pain, if anything at all! Will my face look unnatural? Receiving too much Botox® in the wrong places, can make your face look “frozen” or expressionless. We can assure you that our experienced Master Injector and Nurse Practitioner, Amanda Ralph, is skilled in making you look just like your normal self--just noticeably more youthful and refreshed! How much will I need? The amount of Botox Dubai® you’ll need depends entirely on a few contributing factors. These include: The type of wrinkles you’d like to treat Your unique aesthetic goals The degree of muscle movement in your face The number of times you've had Botox® in the past Your health history What's the difference between Botox Dubai® and fillers? People easily get these two types of injectables confused all the time, but here’s an easy way to distinguish between the two: Botox® is for limiting muscle movement, fillers are for building volume. Botox® reduces the activity of muscles in the face that cause wrinkles. Facial fillers, however, fill the trouble areas with a gel made up of hyaluronic acid, which helps to plump and lift the skin to replace volume loss. How does it work to prevent wrinkles? Explained simply, when injected directly into the muscle, Botox® blocks the muscle’s nerve signals and temporarily relaxes it. When the muscle is relaxed, dynamic wrinkles caused by muscle movement soften, dissipate, or disappear completely. Are there any side effects of Botox Dubai? Common side effects of any injectable include: Muscle weakness near the injection sites Slight bruising Bleeding Redness Swelling How long does it last? In general, Botox® injections are meant to last 3-4 months. To keep results going, you could need a follow-up treatment. After that, you should be able to expect your treatments to begin lasting longer. Consultations Are Always First If Botox Dubai is the right treatment, you’ll probably be asked to make all kinds of facial expressions so that Dr. Vigo can assess the size and movement of the muscles on your face and where/how deep the wrinkles form. From there, he can accurately create a treatment plan for you that is completely unique and customized to your own face. (As it should be!) HIGHLIGHTSOFPRESCRIBINGINFORMATION These highlights do not include all the information needed to use BOTOX safelyandeffectively.SeefullprescribinginformationforBOTOX. BOTOX® (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor, or intradermal use Initial U.S. Approval: 1989 ________________________________RECENT MAJOR CHANGES________________________________ Indications and Usage, Pediatric Detrusor Overactivity associated with a Neurologic Condition (1.2) 2/2021 Dosage and Administration, Pediatric Detrusor Overactivity associated with a Neurologic condition (2.4) 2/2021 Dosage and Administration, Adult Spasticity (2.6) 7/2021 _________________________________INDICATIONS AND USAGE_________________________________ BOTOX is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for:  Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication (1.1)  Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication (1.1)  Treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. (1.2)  Prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer) (1.3)  Treatment of spasticity in patients 2 years of age and older (1.4)  Treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain (1.5)  Treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients (1.6)  Treatment of blepharospasm associated with dystonia in patients 12 years of age and older (1.7)  Treatment of strabismus in patients 12 years of age and older (1.7) Limitations of Use Safety and effectiveness of BOTOX have not been established for:  Prophylaxis of episodic migraine (14 headache days or fewer per month) (1.3)  Treatment of hyperhidrosis in body areas other than axillary (1.6) ____________________________DOSAGE AND ADMINISTRATION____________________________  Follow indication-specific dosage and administration recommendations. In a 3 month interval, do not exceed a total dose of:  Adults: 400 Units  Pediatrics: the lesser of 10 Units/kg or 340 Units (2.1)  See Preparation and Dilution Technique for instructions on BOTOX reconstitution, storage, and preparation before injection (2.2)  Overactive Bladder: Recommended total dose 100 Units, as 0.5 mL (5 Units) injections across 20 sites into the detrusor (2.3)  Adult Detrusor Overactivity associated with a Neurologic Condition: Recommended total dose 200 Units, as 1 mL (~6.7 Units) injections across 30 sites into the detrusor (2.3)  Pediatric Detrusor Overactivity associated with a Neurologic Condition: 0.5 mL injections across 20 sites into the detrusor (2.4)  Greater than or equal to 34 kg: Recommended total dose is 200 Units  Less than 34 kg: Recommended total dose is 6 Units/kg  Chronic Migraine: Recommended total dose 155 Units, as 0.1 mL (5 Units) injections per each site divided across 7 head/neck muscles (2.5)  Adult Upper Limb Spasticity: Recommended total dose up to 400 Units divided among affected muscles (2.6)  AdultLowerLimbSpasticity:Recommendedtotaldose300Unitsto400Units divided across ankle and toe muscles (2.6)  PediatricUpperLimbSpasticity:Recommendedtotaldose3Units/kgto6 Units/kg (maximum 200 Units) divided among affected muscles (2.7)  PediatricLowerLimbSpasticity:Recommendedtotaldose4Units/kgto8 Units/kg (maximum 300 Units) divided among affected muscles (2.7)  CervicalDystonia:Basedosingonthepatient’sheadandneckposition, localization of pain, muscle hypertrophy, patient response, and adverse event history; use lower initial dose in botulinum toxin naïve patients (2.8)  Axillary Hyperhidrosis: 50 Units per axilla (2.9)  Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected eye (2.10)  Strabismus: The dose is based on prism diopter correction or previous response to treatment with BOTOX (2.11) _______________________DOSAGE FORMS AND STRENGTHS________________________ For Injection: 100 Units or 200 Units vacuum-dried powder in a single-dose vial (3) ________________________________CONTRAINDICATIONS_________________________________  Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation (4, 5.4, 6)  Infection at the proposed injection site (4)  Intradetrusor Injections: Urinary tract infection or urinary retention (4) __________________________WARNINGS AND PRECAUTIONS__________________________  Spread of toxin effects; swallowing and breathing difficulties can lead to death. Seek immediate medical attention if respiratory, speech or swallowing difficulties occur (5.1, 5.6)  Potency Units of BOTOX are not interchangeable with other preparations of botulinum toxin products (5.2, 11)  Potential serious adverse reactions after BOTOX injections for unapproved uses (5.3)  Concomitant neuromuscular disorder may exacerbate clinical effects of treatment (5.5)  Use with caution in patients with compromised respiratory function (5.6, 5.7, 5.10)  Corneal exposure and ulceration due to reduced blinking may occur with BOTOX treatment of blepharospasm (5.8)  Retrobulbar hemorrhages and compromised retinal circulation may occur with BOTOX treatment of strabismus (5.9)  Bronchitis and upper respiratory tract infections in patients treated for spasticity (5.10)  Urinary tract infections in patients treated for OAB (5.12)  Urinary retention: Post-void residual urine volume should be monitored in patients treated for OAB or adult detrusor overactivity associated with a neurologic condition who do not catheterize routinely, particularly patients with multiple sclerosis or diabetes mellitus. (5.13) _________________________________ADVERSE REACTIONS___________________________________ The most common adverse reactions (≥5% and >placebo, if applicable) are (6.1):  OAB: urinary tract infection, dysuria, urinary retention  Adult Detrusor Overactivity associated with a neurologic condition: urinary tract infection, urinary retention  Pediatric Detrusor Overactivity associated with a neurologic condition: urinary tract infection, leukocyturia, bacteriuria  Chronic Migraine: neck pain, headache  Adult Spasticity: pain in extremity  Pediatric Spasticity: upper respiratory tract infection  Cervical Dystonia: dysphagia, upper respiratory infection, neck pain, headache, increased cough, flu syndrome, back pain, rhinitis  Axillary Hyperhidrosis: injection site pain and hemorrhage, non-axillary sweating, pharyngitis, flu syndrome To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ________________________________DRUG INTERACTIONS____________________________________ Patients receiving concomitant treatment of BOTOX and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents), or muscle relaxants, should be observed closely because the effect of BOTOX may be potentiated (7.1, 7.4) __________________________USE IN SPECIFIC POPULATIONS___________________________  Pregnancy: Based on animal data, may cause fetal harm. (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. WARNING: DISTANT SPREAD OF TOXIN EFFECT See full prescribing information for complete boxed warning. The effects of BOTOX and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms. (5.1) Revised: 7/2021 * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION WARNING: DISTANT SPREAD OF TOXIN EFFECT Postmarketing reports indicate that the effects of BOTOX and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and spasticity and at lower doses [see Warnings and Precautions (5.1)]. INDICATIONS AND USAGE Adult Bladder Dysfunction Overactive Bladder BOTOX for injection is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication. Detrusor Overactivity associated with a Neurologic Condition BOTOX is indicated for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., SCI, MS) in adults who have an inadequate response to or are intolerant of an anticholinergic medication. Pediatric Detrusor Overactivity associated with a Neurologic Condition BOTOX is indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. Chronic Migraine BOTOX is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer). Limitations of Use Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in seven placebo-controlled studies. Spasticity BOTOX is indicated for the treatment of spasticity in patients 2 years of age and older. Limitations of Use BOTOX has not been shown to improve upper extremity functional abilities, or range of motion at a joint affected by a fixed contracture. Cervical Dystonia BOTOX is indicated for the treatment of adults with cervical dystonia, to reduce the severity of abnormal head position and neck pain associated with cervical dystonia. Primary Axillary Hyperhidrosis BOTOX is indicated for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents. Limitations of Use The safety and effectiveness of BOTOX for hyperhidrosis in other body areas have not been established. Weakness of hand muscles and blepharoptosis may occur in patients who receive BOTOX for palmar hyperhidrosis and facial hyperhidrosis, respectively. Patients should be evaluated for potential causes of secondary hyperhidrosis (e.g., hyperthyroidism) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease. Safety and effectiveness of BOTOX have not been established for the treatment of axillary hyperhidrosis in pediatric patients under age 18. Blepharospasm and Strabismus BOTOX is indicated for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and older. DOSAGE AND ADMINISTRATION Instructions for Safe Use The potency Units of BOTOX (onabotulinumtoxinA) for injection are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see Warnings and Precautions (5.2) and Description (11)]. Indication specific dosage and administration recommendations should be followed. When initiating treatment, the lowest recommended dose should be used. In treating adult patients for one or more indications, the maximum cumulative dose should not exceed 400 Units, in a 3-month interval. In pediatric patients, the total dose should not exceed the lower of 10 Units/kg body weight or 340 Units, in a 3-month interval [see Dosage and Administration (2.7)]. The safe and effective use of BOTOX depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. An understanding of standard electromyographic techniques is also required for treatment of strabismus, upper or lower limb spasticity, and may be useful for the treatment of cervical dystonia. Physicians administering BOTOX must understand the relevant neuromuscular and structural anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures and disease, especially when injecting near the lungs. Do not use BOTOX and contact Allergan (1-800-890-4345) if:  the carton labeling does not contain an intact seal with a translucent silver Allergan logo (on both ends of the carton) or the seal has a black circle with a diagonal line through it (i.e., prohibition sign),  the vial label does not contain a holographic film containing the name “Allergan” within rainbow colored horizontal lines, or  the U.S. License number 1145 is not present on the vial label and carton labeling [see How Supplied/Storage and Handling (16)]. Preparation and Dilution Technique Prior to injection, reconstitute each vacuum-dried vial of BOTOX with only sterile, preservative-free 0.9% Sodium Chloride Injection, USP. Draw up the proper amount of diluent in the appropriate size syringe (see Table 1, or for specific instructions for detrusor overactivity associated with a neurologic condition, see Section 2.3), and slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Gently mix BOTOX with the diluent by rotating the vial. Record the date and time of reconstitution on the space on the label. BOTOX should be administered within 24 hours after reconstitution. During this time period, unused reconstituted BOTOX should be stored in a refrigerator (2° to 8°C) for up to 24 hours until time of use. BOTOX vials are for single-dose only. Discard any unused portion. Table 1: Dilution Instructions for BOTOX Vials (100 Units and 200 Units)** Diluent* Added Resulting Dose Diluent* Added to Resulting Dose to 100 Unit Vial Units per 0.1 mL 200 Unit Vial Units per 0.1 mL *Preservative-free 0.9% Sodium Chloride Injection, USP Only **For Detrusor Overactivity associated with a Neurologic Condition Dilution, see Section 2.3 Note: These dilutions are calculated for an injection volume of 0.1 mL. A decrease or increase in the BOTOX dose is also possible by administering a smaller or larger injection volume - from 0.05 mL (50% decrease in dose) to 0.15 mL (50% increase in dose). 1 mL 2 mL 4 mL 8 mL 10 mL 10 Units 5 Units 2.5 Units 1.25 Units 1 Unit 1 mL 2 mL 4 mL 8 mL 10 mL 20 Units 10 Units 5 Units 2.5 Units 2 Units An injection of BOTOX is prepared by drawing into an appropriately sized sterile syringe an amount of the properly reconstituted toxin slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe is attached to an appropriate injection needle. Patency of the needle should be confirmed. A new, sterile needle and syringe should be used to enter the vial on each occasion for removal of BOTOX. Reconstituted BOTOX should be clear, colorless, and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit. Adult Bladder Dysfunction General Patients must not have a urinary tract infection (UTI) at the time of treatment. Prophylactic antibiotics, except aminoglycosides, [see Drug Interactions (7.1)] should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment to reduce the likelihood of procedure-related UTI. Patients should discontinue anti-platelet therapy at least 3 days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding. Appropriate caution should be exercised when performing a cystoscopy. Overactive Bladder An intravesical instillation of diluted local anesthetic with or without sedation may be used prior to injection, per local site practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection. The recommended dose is 100 Units of BOTOX, and is the maximum recommended dose. The recommended dilution is 100 Units/10 mL with preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1). Dispose of any unused saline. Reconstituted BOTOX (100 Units/10 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided. The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injections (depending on the needle length) to remove any air. The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart (see Figure 1). For the final injection, approximately 1 mL of sterile normal saline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, patients should demonstrate their ability to void prior to leaving the clinic. The patient should be observed for at least 30 minutes post-injection and until a spontaneous void has occurred. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median time until patients qualified for the second treatment of BOTOX in double-blind, placebo-controlled clinical studies was 169 days [~24 weeks]), but no sooner than 12 weeks from the prior bladder injection. Figure 1: Injection Pattern for Intradetrusor Injections for Treatment of Overactive Bladder and Detrusor Overactivity Associated with a Neurologic Condition Detrusor Overactivity associated with a Neurologic Condition An intravesical instillation of diluted local anesthetic with or without sedation, or general anesthesia may be used prior to injection, per local site practice. If a local anesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection. The recommended dose is 200 Units of BOTOX per treatment, and should not be exceeded. 200 Unit Vial of BOTOX  Reconstitute a 200 Unit vial of BOTOX with 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vial gently.  Draw 2 mL from the vial into each of three 10 mL syringes.  Complete the reconstitution by adding 8 mL of preservative-free 0.9% Sodium Chloride Injection, USP into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of reconstituted BOTOX.  Use immediately after reconstitution in the syringe. Dispose of any unused saline. 100 Unit Vial of BOTOX  Reconstitute two 100 Unit vials of BOTOX, each with 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vials gently.  Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe for a total of 4 mL in each syringe.  Complete the reconstitution by adding 6 mL of preservative-free 0.9% Sodium Chloride Injection, USP into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of reconstituted BOTOX.  Use immediately after reconstitution in the syringe. Dispose of any unused saline. Reconstituted BOTOX (200 Units/30 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided. The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injections (depending on the needle length) to remove any air. The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of 1 mL (~6.7 Units) each (total volume of 30 mL) should be spaced approximately 1 cm apart (see Figure 1). For the final injection, approximately 1 mL of sterile normal saline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 minutes post-injection. Patients should be considered for re-injection when the clinical effect of the previous injection diminishes (median time to qualification for re-treatment in the double-blind, placebo-controlled clinical studies was 295-337 days [42-48 weeks] for BOTOX 200 Units), but no sooner than 12 weeks from the prior bladder injection. Pediatric Detrusor Overactivity associated with a Neurologic Condition Patients must not have a urinary tract infection (UTI) at the time of treatment. Oral prophylactic antibiotics, except aminoglycosides, [see Drug Interactions (7.1)] should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment to reduce the likelihood of procedure-related UTI. Alternatively, for patients receiving general anesthesia (or conscious sedation) for the treatment of detrusor overactivity associated with a neurologic condition, one dose of IV prophylactic antibiotics, except aminoglycosides, [see Drug Interactions (7.1)] may be administered prior to treatment administration on the day of treatment. Patients should discontinue anti-platelet therapy at least 3 days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding. Appropriate caution should be exercised when performing a cystoscopy.  In patients 5 years to less than 12 years of age: Consider general anesthesia (or conscious sedation) prior to injection, per local site practice.  In patients 12 years of age or older: Consider an intravesical instillation of diluted local anesthetic with or without sedation, or general anesthesia prior to injection, per local site practice. At a minimum, consider a diluted instillation of local anesthetic for all age groups. If a local anesthetic instillation is performed, drain and irrigate the bladder with sterile saline before injection. If patient’s body weight is greater than or equal to 34 kg, the recommended dosage is 200 Units of BOTOX per treatment administered as an intradetrusor injection after dilution:  Reconstitute BOTOX to result in 20 Units BOTOX/mL in the vial(s): o BOTOX 200 Unit vial: add 10 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vial gently. o BOTOX 100 Unit vials: add 5 mL of preservative-free 0.9% Sodium Chloride Injection, USP to each of two 100 Unit vials of BOTOX and mix the vials gently.  Draw 10 mL from the vial(s) into one 10 mL dosing syringe.  Use immediately after reconstitution in the syringe. Dispose of any unused saline. If patient’s body weight is less than 34 kg, the recommended dosage is 6 Units/kg body weight administered as a bladder injection after dilution (refer to Table 2):  Reconstitute BOTOX to result in 20 Units BOTOX/mL in the vial(s): o BOTOX 200 Unit vial: add 10 mL of preservative-free 0.9% Sodium Chloride Injection, USP and mix the vial gently. o BOTOX 100 Unit vial(s): add 5 mL of preservative-free 0.9% Sodium Chloride Injection, USP to one 100 Unit vial of BOTOX (if final dose is less than or equal to100 U) or to each of two 100 Unit vials of BOTOX (if final dose is greater than 100 U) and mix the vial(s) gently.  Refer to Table 2 for dilution instructions (i.e., the amount of reconstituted BOTOX and additional diluent to draw into one 10 mL dosing syringe).  Use BOTOX immediately after reconstitution in the syringe. Dispose of any unused preservative-free 0.9% Sodium Chloride Injection, USP. Table 2: BOTOX Dilution Instructions and Final Dosing for Patients with Body Weight < 34 kg Body Weight Volume of reconstituted BOTOX and Diluent* (mL) to draw into dosing syringe to achieve a final volume of 10 mL Final dose of BOTOX in dosing syringe BOTOX Diluent* (mL) (mL) *Preservative-free 0.9% Sodium Chloride Injection, USP Only Reconstituted BOTOX is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualization for the injections, but over-distension should be avoided. The injection needle should be filled (primed) with approximately 1 mL of reconstituted BOTOX prior to the start of injections (depending on the needle length) to remove any air. The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart (see Figure 1). For the final injection, approximately 1 mL of sterile normal saline should be injected so that the remaining BOTOX in the needle is delivered to the bladder. After the injections are given, the saline used for bladder wall visualization should be drained. The patient should be observed for at least 30 minutes post-injection. Patients should be considered for re-injection when the clinical effect of the previous injection diminishes (median time to qualification for re-treatment in the double-blind, parallel group clinical study was 207 days [30 weeks] for BOTOX 200 Units), but no sooner than 12 weeks from the prior bladder injection. Chronic Migraine The recommended dilution is 200 Units/4 mL or 100 Units/2 mL, with a final concentration of 5 Units per 0.1 mL (see Table 1). The recommended dose for treating chronic migraine is 155 Units administered intramuscularly using a sterile 30-gauge, 0.5 inch needle as 0.1 mL (5 Units) injections per each site. Injections should be divided across 7 specific head/neck muscle areas as specified in the diagrams and Table 3 below. A one inch needle may be needed in the neck region for patients with thick neck muscles. With the exception of the procerus muscle, which should be injected at one site (midline), all muscles should be injected bilaterally with half the number of injection sites administered to the left, and half to the right side of the head and neck. The recommended re-treatment schedule is every 12 weeks. Diagrams 1-4: Recommended Injection Sites (A through G) for Chronic Migraine 1234 Table 3: BOTOX Dosing by Muscle for Chronic Migraine Head/Neck Area Frontalisb Corrugatorb Procerus Occipitalisb Temporalisb Trapeziusb Cervical Paraspinal Muscle Groupb Total Dose: Recommended Dose (Number of Sitesa) 20 Units divided in 4 10 Units divided in 2 5 Units in 1 site 30 Units divided in 6 40 Units divided in 8 30 Units divided in 6 20 Units divided in 4 sites sites sites sites sites sites 155 Units divided in 31 sites a Each IM injection site = 0.1 mL = 5 Units BOTOX b Dose distributed bilaterally Adult Spasticity General Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient’s response to previous treatment, or adverse event history with BOTOX. The recommended dilution is 200 Units/4 mL or 100 Units/2 mL with preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1). The lowest recommended starting dose should be used, and no more than 50 Units per site should generally be administered. An appropriately sized needle (e.g., 25-30 gauge) may be used for superficial muscles, and a longer 22 gauge needle may be used for deeper musculature. Localization of the involved muscles with techniques such as needle electromyographic guidance, nerve stimulation, or ultrasound is recommended. Repeat BOTOX treatment may be administered when the effect of a previous injection has diminished, but generally no sooner than 12 weeks after the previous injection. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of BOTOX and muscles to be injected. Adult Upper Limb Spasticity In clinical trials, doses ranging from 75 Units to 400 Units were divided among selected muscles (see Table 4 and Figure 2) at a given treatment session. Table 4: BOTOX Dosing by Muscle for Adult Upper Limb Spasticity Recommended Dose Muscle Biceps Brachii Brachioradialis Brachialis Pronator Teres Pronator Quadratus Flexor Carpi Radialis Flexor Carpi Ulnaris Flexor Digitorum Profundus Flexor Digitorum Sublimis Lumbricals/Interossei Adductor Pollicis Flexor Pollicis Longus Flexor pollicis brevis/ Opponens pollicis Total Dosage (Number of Sites) 60 Units to 200 Units divided in 2 to 4 sites 45 Units to 75 Units divided in 1 to 2 sites 30 Units to 50 Units divided in 1 to 2 sites 15 Units to 25 Units in 1 site 10 Units to 50 Units in 1 site 12.5 Units to 50 Units in 1 site 12.5 Units to 50 Units in 1 site 30 Units to 50 Units in 1 site 30 Units to 50 Units in 1 site 5 Units to 10 Units in 1 site 20 Units in 1 site 20 Units in 1 site 5 Units to 25 Units in 1 site Figure 2: Injection Sites for Adult Upper Limb Spasticity Adult Lower Limb Spasticity The recommended dose for treating adult lower limb spasticity is 300 Units to 400 Units divided among 5 muscles (gastrocnemius, soleus, tibialis posterior, flexor hallucis longus and flexor digitorum longus) (see Table 5 and Figure 3). Table 5: BOTOX Dosing by Muscle for Adult Lower Limb Spasticity Muscle Gastrocnemius medial head Gastrocnemius lateral head Soleus Tibialis Posterior Flexor hallucis longus Flexor digitorum longus Recommended Dose Total Dosage (Number of Sites) 75 Units divided in 3 sites 75 Units divided in 3 sites 75 Units divided in 3 sites 75 Units divided in 3 sites 50 Units divided in 2 sites 50 Units divided in 2 sites Figure 3: Injection Sites for Adult Lower Limb Spasticity Pediatric Spasticity General Localization of the involved muscles with techniques such as needle electromyographic guidance, nerve stimulation, or ultrasound is recommended. When treating both lower limbs or the upper and lower limbs in combination, the total dose should not exceed the lower of 10 Units/kg body weight or 340 Units, in a 3-month interval [see Boxed Warning and Warnings and Precautions (5.1, 5.6)]. Additional general adult spasticity dosing information is also applicable to pediatric spasticity patients [see Dosage and Administration (2.6)]. Pediatric Upper Limb Spasticity The recommended dose for treating pediatric upper limb spasticity is 3 Units/kg to 6 Units/kg divided among the affected muscles (see Table 6 and Figure 4). The total dose of BOTOX administered per treatment session in the upper limb should not exceed 6 Units/kg or 200 Units, whichever is lower. Table 6: BOTOX Dosing by Muscle for Pediatric Upper Limb Spasticity Muscle Biceps Brachii Brachialis Brachioradialis Flexor Carpi Radialis Flexor Carpi Ulnaris Flexor Digitorum Profundus Flexor Digitorum Sublimis Recommended Dose and Number of Sites 1.5 Units/kg to 3 Units/kg divided in 4 sites 1 Unit/kg to 2 Units/kg divided in 2 sites 0.5 Units/kg to 1 Unit/kg divided in 2 sites 1 Unit/kg to 2 Units/kg divided in 2 sites 1 Unit/kg to 2 Units/kg divided in 2 sites 0.5 Units/kg to 1 Unit/kg divided in 2 sites 0.5 Units/kg to 1 Unit/kg divided in 2 sites Figure 4: Injection Sites for Pediatric Upper Limb Spasticity Pediatric Lower Limb Spasticity The recommended dose for treating pediatric lower limb spasticity is 4 Units/kg to 8 Units/kg divided among the affected muscles (see Table 7 and Figure 5). The total dose of BOTOX administered per treatment session in the lower limb should not exceed 8 Units/kg or 300 Units, whichever is lower. Table 7: BOTOX Dosing by Muscle for Pediatric Lower Limb Spasticity Muscle Gastrocnemius medial head Gastrocnemius lateral head Soleus Tibialis Posterior Recommended Dose Total Dosage (Number of Sites) 1 Unit/kg to 2 Units/kg divided in 2 sites 1 Unit/kg to 2 Units/kg divided in 2 sites 1 Unit/kg to 2 Units/kg divided in 2 sites 1 Unit/kg to 2 Units/kg divided in 2 sites Figure 5: Injection Sites for Pediatric Lower Limb Spasticity Cervical Dystonia A double-blind, placebo-controlled study enrolled patients who had extended histories of receiving and tolerating BOTOX injections, with prior individualized adjustment of dose. The mean BOTOX dose administered to patients in this study was 236 Units (25th to 75th percentile range of 198 Units to 300 Units). The BOTOX dose was divided among the affected muscles [see Clinical Studies (14.7)]. Dosing in initial and sequential treatment sessions should be tailored to the individual patient based on the patient’s head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history. The initial dose for a patient without prior use of BOTOX should be at a lower dose, with subsequent dosing adjusted based on individual response. Limiting the total dose injected into the sternocleidomastoid muscle to 100 Units or less may decrease the occurrence of dysphagia [see Warnings and Precautions (5.1, 5.5, 5.6)]. The recommended dilution is 200 Units/2 mL, 200 Units/4 mL, 100 Units/1 mL, or 100 Units/2 mL with preservative-free 0.9% Sodium Chloride Injection, USP, depending on volume and number of injection sites desired to achieve treatment objectives (see Table 1). In general, no more than 50 Units per site should be administered using a sterile needle (e.g., 25-30 gauge) of an appropriate length. Localization of the involved muscles with electromyographic guidance may be useful. Clinical improvement generally begins within the first two weeks after injection with maximum clinical benefit at approximately six weeks post-injection. In the double-blind, placebo-controlled study most subjects were observed to have returned to pre-treatment status by 3 months post-treatment. Primary Axillary Hyperhidrosis The recommended dose is 50 Units per axilla. The hyperhidrotic area to be injected should be defined using standard staining techniques, e.g., Minor’s Iodine-Starch Test. The recommended dilution is 100 Units/4 mL with preservative-free 0.9% Sodium Chloride Injection, USP (see Table 1). Using a sterile 30 gauge needle, 50 Units of BOTOX (2 mL) is injected intradermally in 0.1 to 0.2 mL aliquots to each axilla evenly distributed in multiple sites (10-15) approximately 1-2 cm apart. Repeat injections for hyperhidrosis should be administered when the clinical effect of a previous injection diminishes. Instructions for the Minor’s Iodine-Starch Test Procedure: Patients should shave underarms and abstain from use of over-the-counter deodorants or antiperspirants for 24 hours prior to the test. Patient should be resting comfortably without exercise or hot drinks for approximately 30 minutes prior to the test. Dry the underarm area and then immediately paint it with iodine solution. Allow the area to dry, then lightly sprinkle the area with starch powder. Gently blow off any excess starch powder. The hyperhidrotic area will develop a deep blue-black color over approximately 10 minutes. Each injection site has a ring of effect of up to approximately 2 cm in diameter. To minimize the area of no effect, the injection sites should be evenly spaced as shown in Figure 6. Figure 6: Injection Pattern for Primary Axillary Hyperhidrosis Each dose is injected to a depth of approximately 2 mm and at a 45° angle to the skin surface, with the bevel side up to minimize leakage and to ensure the injections remain intradermal. If injection sites are marked in ink, do not inject BOTOX directly through the ink mark to avoid a permanent tattoo effect. Blepharospasm For blepharospasm, reconstituted BOTOX is injected using a sterile, 27-30 gauge needle without electromyographic guidance. The initial recommended dose is 1.25 Units-2.5 Units (0.05 mL to 0.1 mL volume at each site) injected into the medial and lateral pre- tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid. Avoiding injection near the levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia. Ecchymosis occurs easily in the soft eyelid tissues. This can be prevented by applying pressure at the injection site immediately after the injection. The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5 Units it is 100 Units/4 mL (see Table 1). In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient, usually defined as an effect that does not last longer than two months. However, there appears to be little benefit obtainable from injecting more than 5 Units per site. Some tolerance may be found when BOTOX is used in treating blepharospasm if treatments are given any more frequently than every three months, and is rare to have the effect be permanent. The cumulative dose of BOTOX treatment for blepharospasm in a 30-day period should not exceed 200 Units. Strabismus BOTOX is intended for injection into extraocular muscles utilizing the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle. Injection without surgical exposure or electromyographic guidance should not be attempted. Physicians should be familiar with electromyographic technique. To prepare the eye for BOTOX injection, it is recommended that several drops of a local anesthetic and an ocular decongestant be given several minutes prior to injection. The volume of BOTOX injected for treatment of strabismus should be between 0.05-0.15 mL per muscle. The initial listed doses of the reconstituted BOTOX [see Dosage and Administration (2.2)] typically create paralysis of the injected muscles beginning one to two days after injection and increasing in intensity during the first week. The paralysis lasts for 2-6 weeks and gradually resolves over a similar time period. Overcorrections lasting over six months have been rare. About one half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose, or because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilize the alignment. Initial Doses in Units Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.  For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1.25 Units-2.5 Units in any one muscle.  For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2.5 Units-5 Units in any one muscle.  For persistent VI nerve palsy of one month or longer duration: 1.25 Units-2.5 Units in the medial rectus muscle. Subsequent Doses for Residual or Recurrent Strabismus  It is recommended that patients be re-examined 7-14 days after each injection to assess the effect of that dose.  Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.  Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to two-fold compared to the previously administered dose.  Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.  The maximum recommended dose as a single injection for any one muscle is 25 Units. The recommended dilution to achieve 1.25 Units is 100 Units/8 mL; for 2.5 Units it is 100 Units/4 mL (see Table 1). DOSAGE FORMS AND STRENGTHS For Injection: sterile 100 Units or 200 Units vacuum-dried powder in single-dose vials for reconstitution only with sterile, preservative-free 0.9% Sodium Chloride Injection, USP prior to injection. CONTRAINDICATIONS BOTOX is contraindicated:  In patients who are hypersensitive to any botulinum toxin product or to any of the components in the formulation [see Warnings and Precautions (5.4)].  In the presence of infection at the proposed injection site(s).  For intradetrusor injection in patients with a urinary tract infection; or in patients with urinary retention or post-void residual (PVR) urine volume >200 mL who are not routinely performing clean intermittent self-catheterization (CIC) [see Warnings and Precautions (5.12, 5.13)]. WARNINGS AND PRECAUTIONS Spread of Toxin Effect Postmarketing safety data from BOTOX and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, and particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia and spasticity. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders occur. No definitive serious adverse event reports of distant spread of toxin effect associated with BOTOX for blepharospasm at the recommended dose (30 Units and below), severe primary axillary hyperhidrosis at the recommended dose (100 Units), strabismus, or for chronic migraine at the labeled doses have been reported. Lack of Interchangeability between Botulinum Toxin Products The potency Units of BOTOX are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method [see Description (11)]. Serious Adverse Reactions with Unapproved Use Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant spread of toxin, but may have resulted from the administration of BOTOX to the site of injection and/or adjacent structures. In several of the cases, patients had pre-existing dysphagia or other significant disabilities. There is insufficient information to identify factors associated with an increased risk for adverse reactions associated with the unapproved uses of BOTOX. The safety and effectiveness of BOTOX for unapproved uses have not been established. Hypersensitivity Reactions Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs, further injection of BOTOX should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined. Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given botulinum toxin. Patients with known or unrecognized neuromuscular disorders or neuromuscular junction disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from therapeutic doses of BOTOX [see Warnings and Precautions (5.1, 5.6)]. Dysphagia and Breathing Difficulties Treatment with BOTOX and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre- existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing [see Warnings and Precautions (5.1)]. Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several months, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised. Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been postmarketing reports of serious breathing difficulties, including respiratory failure. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscle for the treatment of cervical dystonia have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia. Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [see Warnings and Precautions (5.1)]. Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity Associated with a Neurologic Condition Patients with compromised respiratory status treated with BOTOX for spasticity should be monitored closely. In a double-blind, placebo-controlled, parallel group study in adult patients treated for upper limb spasticity with stable reduced pulmonary function (defined as FEV1 40-80% of predicted value and FEV1/FVC ≤ 0.75), the event rate in change of Forced Vital Capacity (FVC) ≥15% or ≥20% was generally greater in patients treated with BOTOX than in patients treated with placebo (see Table 8). Table 8: Event Rate Per Patient Treatment Cycle Among Adult Upper Limb Spasticity Patients with Reduced Lung Function Who Experienced at Least a 15% or 20% Decrease in FVC From Baseline at Week 1, 6, 12 Post- injection with Up to Two Treatment Cycles with BOTOX or Placebo BOTOX 360 Units BOTOX 240 Units Placebo >15% >20% Week1 Week6 Week 12 In adult spasticity patients with reduced lung function, upper respiratory tract infections were also reported more frequently as adverse reactions in patients treated with BOTOX than in patients treated with placebo [see Warnings and Precautions (5.10)]. In a double-blind, placebo-controlled, parallel group study in adult patients with detrusor overactivity associated with a neurologic condition and restrictive lung disease of neuromuscular etiology [defined as FVC 50-80% of predicted value in patients with spinal cord injury between C5 and C8, or MS] the event rate in change of Forced Vital Capacity ≥15% or ≥20% was generally greater in patients treated with BOTOX than in patients treated with placebo (see Table 9). Table 9: Week 2 Week 6 Week 12 Number and Percent of Patients Experiencing at Least a 15% or 20% Decrease in FVC From Baseline at Week 2, 6, 12 Post-Injection with BOTOX or Placebo BOTOX 200 Units Placebo Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm Reduced blinking from BOTOX injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus During the administration of BOTOX for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred. It is recommended that appropriate instruments to decompress the orbit be accessible. Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity Bronchitis was reported more frequently as an adverse reaction in adult patients treated for upper limb spasticity with BOTOX (3% at 251 Units-360 Units total dose), compared to placebo (1%). In adult patients with reduced lung function treated for upper limb spasticity, upper respiratory tract infections were also reported more frequently as adverse reactions in patients treated with BOTOX (11% at 360 Units total dose; 8% at 240 Units total dose) compared to placebo (6%). In adult patients treated for lower limb spasticity, upper respiratory tract infections were reported more frequently as an adverse reaction in patients treated with BOTOX (2% at 300 Units to 400 Units total dose) compared to placebo (1%). In pediatric patients treated for upper limb spasticity, upper respiratory tract infections were reported more frequently as an adverse reaction in patients treated with BOTOX (17% at 6 Units/kg and 10% at 3 Units/kg) compared to placebo (9%). In pediatric patients treated for lower limb spasticity, upper respiratory tract infection was not reported with an incidence greater than placebo. Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity Associated with a Neurologic Condition 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 adult patients treated with BOTOX 200 Units compared with placebo (1.5% versus 0.4%, respectively). Urinary Tract Infections in Patients with Overactive Bladder BOTOX increases the incidence of urinary tract infection [see Adverse Reactions (6.1)]. Clinical trials for overactive bladder excluded patients with more than 2 UTIs in the past 6 months and those taking antibiotics chronically due to recurrent UTIs. Use of BOTOX for the treatment of overactive bladder in such patients and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is likely to outweigh the potential risk. Urinary Retention in Adults Treated for Bladder Dysfunction Due to the risk of urinary retention, treat only patients who are willing and able to initiate catheterization post-treatment, if required, for urinary retention. In patients who are not catheterizing, post-void residual (PVR) urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks, particularly in patients with multiple sclerosis or diabetes mellitus. Depending on patient symptoms, institute catheterization if PVR urine volume exceeds 200 mL and continue until PVR falls below 200 mL. Instruct patients to contact their physician if they experience difficulty in voiding as catheterization may be required. The incidence and duration of urinary retention is described below for adult patients with overactive bladder and detrusor overactivity associated with a neurologic condition who received BOTOX or placebo injections. Overactive Bladder In double-blind, placebo-controlled trials in patients with OAB, the proportion of subjects who initiated clean intermittent catheterization (CIC) for urinary retention following treatment with BOTOX or placebo is shown in Table 10. The duration of post- injection catheterization for those who developed urinary retention is also shown. Table 10: Proportion of Patients Catheterizing for Urinary Retention and Duration of Catheterization Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials in OAB Timepoint BOTOX 100 Units (N=552) Placebo (N=542) 0.4% (n=2) 11 3, 18 Proportion of Patients Catheterizing for Urinary Retention At any time during complete treatment cycle 6.5% (n=36) Duration of Catheterization for Urinary Retention (Days) Median 63 Min, Max 1, 214 Patients with diabetes mellitus treated with BOTOX were more likely to develop urinary retention than those without diabetes, as shown in Table 11. Table 11: Proportion of Patients Experiencing Urinary Retention Following an Injection in Double-Blind, Placebo- Controlled Clinical Trials in OAB According to History of Diabetes Mellitus Patients with Diabetes BOTOX 100 Units Placebo (N=81) (N=69) Urinary retention 12.3% (n=10) 0 Patients without Diabetes BOTOX 100 Units (N=526) 6.3% (n=33) Placebo (N=516) 0.6% (n=3) Adult Detrusor Overactivity associated with a Neurologic Condition In two double-blind, placebo-controlled trials in adult patients with detrusor overactivity associated with a neurologic condition (NDO-1 and NDO-2), the proportion of subjects who were not using clean intermittent catheterization (CIC) prior to injection and who subsequently required catheterization for urinary retention following treatment with BOTOX 200 Units or placebo is shown in Table 12. The duration of post-injection catheterization for those who developed urinary retention is also shown. Table 12: Proportion of Adult Patients Not Using CIC at Baseline and then Catheterizing for Urinary Retention and Duration of Catheterization Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials Timepoint BOTOX 200 Units (N=108) Placebo (N=104) 6.7% (n=7) 358 2, 379 Proportion of Patients Catheterizing for Urinary Retention At any time during complete treatment cycle 30.6% (n=33) Duration of Catheterization for Urinary Retention (Days) Median 289 Min, Max 1, 530 Among adult patients not using CIC at baseline, those with Multiple Sclerosis (MS) were more likely to require CIC post-injection than those with Spinal Cord Injury (SCI) (see Table 13). Table 13: Proportion of Adult Patients by Etiology (MS and SCI) Not Using CIC at Baseline and then Catheterizing for Urinary Retention Following an Injection in Double-Blind, Placebo-Controlled Clinical Trials Timepoint At any time during complete treatment cycle MS BOTOX 200 Units (N=86) 31% (n=27) Placebo (N=88) 5% (n=4) SCI BOTOX 200 Units (N=22) 27% (n=6) Placebo (N=16) 19% (n=3) A placebo-controlled, double-blind post-approval 52 week study with BOTOX 100 Units (Study NDO-3) was conducted in non- catheterizing adult MS patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition. Catheterization for urinary retention was initiated in 15.2% (10/66) of patients following treatment with BOTOX 100 Units versus 2.6% (2/78) on placebo at any time during the complete treatment cycle. The median duration of post-injection catheterization for those who developed urinary retention was 64 days for BOTOX 100 Units and 2 days for placebo. Human Albumin and Transmission of Viral Diseases This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would also be considered extremely remote. No cases of transmission of viral diseases, CJD or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products. ADVERSE REACTIONS The following adverse reactions to BOTOX (onabotulinumtoxinA) for injection are discussed in greater detail in other sections of the labeling:  Spread of Toxin Effects [see Warnings and Precautions (5.1)]  Serious Adverse Reactions with Unapproved Use [see Warnings and Precautions (5.3)]  Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.4)]  Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders [see Warnings and Precautions (5.5)]  Dysphagia and Breathing Difficulties [see Warnings and Precautions (5.6)]  Pulmonary Effects of BOTOX in Patients with Compromised Respiratory Status Treated for Spasticity or for Detrusor Overactivity Associated with a Neurologic Condition [see Warnings and Precautions (5.7)]  Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm [see Warnings and Precautions (5.8)]  Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus [see Warnings and Precautions (5.9)]  Bronchitis and Upper Respiratory Tract Infections in Patients Treated for Spasticity [see Warnings and Precautions (5.10)]  Autonomic Dysreflexia in Patients Treated for Detrusor Overactivity Associated with a Neurologic Condition [see Warnings and Precautions (5.11)]  Urinary Tract Infections in Patients with Overactive Bladder [see Warnings and Precautions (5.12)]  Urinary Retention in Patients Treated for Bladder Dysfunction [see Warnings and Precautions (5.13)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. BOTOX and BOTOX Cosmetic contain the same active ingredient in the same formulation, but with different labeled Indications and Usage. Therefore, adverse reactions observed with the use of BOTOX Cosmetic also have the potential to be observed with the use of BOTOX. In general, adverse reactions occur within the first week following injection of BOTOX and, while generally transient, may have a duration of several months or longer. Localized pain, infection, inflammation, tenderness, swelling, erythema, and/or bleeding/bruising may be associated with the injection. Symptoms associated with flu-like symptoms (e.g., nausea, fever, myalgia) have been reported after treatment. Needle-related pain and/or anxiety may result in vasovagal responses (including syncope, hypotension), which may require appropriate medical therapy. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of nearby muscles may also occur due to spread of toxin [see Warnings and Precautions (5.1)]. Overactive Bladder Table 14 presents the most frequently reported adverse reactions in double-blind, placebo-controlled clinical trials for overactive bladder occurring within 12 weeks of the first BOTOX treatment. Table 14: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Often than in Placebo-Treated Patients Within the First 12 Weeks after Intradetrusor Injection, in Double-Blind, Placebo-Controlled Clinical Trials in Patients with OAB BOTOX 100 Units Placebo Adverse Reactions (N=552) (N=542) %% Urinary tract infection Dysuria Urinary retention Bacteriuria Residual urine volume* 18 9 6 4 3 6 7 0 2 0 *Elevated PVR not requiring catheterization. Catheterization was required for PVR >350 mL regardless of symptoms, and for PVR >200 mL to <350 mL with symptoms (e.g., voiding difficulty). A higher incidence of urinary tract infection was observed in patients with diabetes mellitus treated with BOTOX 100 Units and placebo than in patients without diabetes, as shown in Table 15. Table 15: Proportion of Patients Experiencing Urinary Tract Infection Following an Injection in Double-Blind, Placebo- Controlled Clinical Trials in OAB According to History of Diabetes Mellitus Patients with Diabetes Patients without Diabetes Urinary tract infection 31 12 26 10 (UTI) The incidence of UTI increased in patients who experienced a maximum post-void residual (PVR) urine volume >200 mL following BOTOX injection compared to those with a maximum PVR <200 mL following BOTOX injection, 44% versus 23%, respectively. No change was observed in the overall safety profile with repeat dosing during an open-label, uncontrolled extension trial. Adult Detrusor Overactivity associated with a Neurologic Condition Table 16 presents the most frequently reported adverse reactions in the double-blind, placebo-controlled studies within 12 weeks of injection for patients with detrusor overactivity associated with a neurologic condition treated with BOTOX 200 Units. Table 16: Adverse Reactions Reported by >2% of BOTOX-Treated Patients and More Frequent than in Placebo-Treated Patients Within the First 12 Weeks after Intradetrusor Injection in Double-Blind, Placebo-Controlled Clinical Trials BOTOX 100 Units (N=81) % Placebo (N=69) % BOTOX 100 Units (N=526) % Placebo (N=516) % Adverse Reactions Urinary tract infection Urinary retention Hematuria BOTOX 200 Units Placebo (N=262) (N=272) %% 24 17 17 3 4 3 The following adverse reactions with BOTOX 200 Units were reported at any time following initial injection and prior to re-injection or study exit (median duration of exposure was 44 weeks): urinary tract infections (49%), urinary retention (17%), constipation (4%), muscular weakness (4%), dysuria (4%), fall (3%), gait disturbance (3%), and muscle spasm (2%). In the Multiple Sclerosis (MS) patients enrolled in the double-blind, placebo-controlled trials, the MS exacerbation annualized rate (i.e., number of MS exacerbation events per patient-year) was 0.23 for BOTOX and 0.20 for placebo. No change was observed in the overall safety profile with repeat dosing. Table 17 presents the most frequently reported adverse reactions in a placebo-controlled, double-blind post-approval 52 week study with BOTOX 100 Units (Study NDO-3) conducted in MS patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition. These patients were not adequately managed with at least one anticholinergic agent and not catheterized at baseline. The table below presents the most frequently reported adverse reactions within 12 weeks of injection. Table 17: Adverse Reactions Reported in a Post Approval Study (NDO-3) by >2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients Within the First 12 Weeks after Intradetrusor Injection BOTOX 100 Units Placebo Adverse Reactions (N=66) (N=78) %% * Elevated PVR not requiring catheterization. Catheterization was required for PVR >350 mL regardless of symptoms, and for PVR >200 mL to <350 mL with symptoms (e.g., voiding difficulty). The following adverse events with BOTOX 100 Units were reported at any time following initial injection and prior to re-injection or study exit (median duration of exposure was 51 weeks): urinary tract infections (39%), bacteriuria (18%), urinary retention (17%), Urinary tract infection Bacteriuria Urinary retention Dysuria Residual urine volume* 26 9 15 5 17 6 5 1 1 1 residual urine volume* (17%), dysuria (9%), and hematuria (5%). No difference in the MS exacerbation annualized rate (i.e., number of MS exacerbating events per patient-year) was observed (BOTOX =0, placebo =0.07). Pediatric Detrusor Overactivity associated with a Neurologic Condition Table 18 presents the most frequently reported adverse reactions in Study 191622-120, a double-blind, parallel-group study conducted in pediatric patients with detrusor overactivity associated with a neurologic condition. These patients were not adequately managed with at least one anticholinergic agent and were using clean intermittent catheterization at baseline [see Clinical Studies (14.3)]. The table below presents the most frequently reported adverse reactions during the 12 weeks following intradetrusor administration of BOTOX 200 Units. Table 18: Adverse Reactions Reported by ≥ 3% of BOTOX Treated Pediatric Patients within the First 12 Weeks after Intradetrusor Injection, Study 191622-120 Adverse Reactions Urinary tract infection Bacteriuria Leukocyturia Hematuria BOTOX 200 Unit (N=30) 2 (7%) 6 (20%) 2 (7%) 1 (3%) No change was observed in the overall safety profile with repeat dosing. The most common adverse reactions in patients who received BOTOX 6 U/kg and less than a total dose of 200 U in Study 191622-120 were urinary tract infection (UTI), bacteriuria and hematuria. Chronic Migraine In double-blind, placebo-controlled chronic migraine efficacy trials (Study 1 and Study 2), the discontinuation rate was 12% in the BOTOX treated group and 10% in the placebo-treated group. Discontinuations due to an adverse event were 4% in the BOTOX group and 1% in the placebo group. The most frequent adverse events leading to discontinuation in the BOTOX group were neck pain, headache, worsening migraine, muscular weakness and eyelid ptosis. The most frequently reported adverse reactions following injection of BOTOX for chronic migraine appear in Table 19. Table 19: Adverse Reactions Reported by >2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Two Chronic Migraine Double-Blind, Placebo-Controlled Clinical Trials Adverse Reactions BOTOX 155 Units-195 Units (N=687) % Placebo (N=692) % Nervous system disorders Headache Migraine Facial paresis 5 4 2 3 3 0 Eye disorders Eyelid ptosis Infections and Infestations Bronchitis General disorders and administration site conditions Injection site pain Vascular Disorders Hypertension 4 <1 3 2 3 2 2 1 Musculoskeletal and connective tissue disorders Neck pain Musculoskeletal stiffness Muscular weakness Myalgia Musculoskeletal pain Muscle spasms 9 4 4 3 3 2 3 1 <1 1 1 1 Other adverse reactions that occurred more frequently in the BOTOX group compared to the placebo group at a frequency less than 1% and potentially BOTOX related include: vertigo, dry eye, eyelid edema, dysphagia, eye infection, and jaw pain. Severe worsening of migraine requiring hospitalization occurred in approximately 1% of BOTOX treated patients in Study 1 and Study 2, usually within the first week after treatment, compared to 0.3% of placebo-treated patients. Adult Upper Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX for adult upper limb spasticity appear in Table 20. Table 20: Adverse Reactions Reported by ≥2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Adult Upper Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trials Gastrointestinal disorder Nausea 3221 Adverse Reactions BOTOX 251 Units - 360 Units (N=115) % BOTOX 150 Units - 250 Units (N=188) % BOTOX <150 Units (N=54) % Placebo (N=182) % General disorders and administration site conditions Fatigue Infections and infestations Bronchitis Musculoskeletal and connective tissue disorders Pain in extremity Muscular weakness 32 20 32 01 65 94 04 21 Twenty-two adult patients, enrolled in double-blind placebo controlled studies, received 400 Units or higher of BOTOX for treatment of upper limb spasticity. In addition, 44 adults received 400 Units of BOTOX or higher for four consecutive treatments over approximately one year for treatment of upper limb spasticity. The type and frequency of adverse reactions observed in patients treated with 400 Units of BOTOX were similar to those reported in patients treated for upper limb spasticity with 360 Units of BOTOX. Adult Lower Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX for adult lower limb spasticity appear in Table 21. Two hundred thirty-one patients enrolled in a double-blind placebo controlled study (Study 7) received 300 Units to 400 Units of BOTOX, and were compared with 233 patients who received placebo. Patients were followed for an average of 91 days after injection. Table 21: Adverse Reactions Reported by >2% of BOTOX Treated Patients and More Frequent than in Placebo-Treated Patients in Adult Lower Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 7) Adverse Reactions Infections and infestations Upper respiratory tract infection General disorders and administration site conditions Injection site pain Pediatric Upper Limb Spasticity BOTOX Placebo (N=231) (N=233) %% 2 1 2 1 Musculoskeletal and connective tissue disorders Arthralgia Back pain Myalgia 3 3 2 1 2 1 The most frequently reported adverse reactions following injection of BOTOX in pediatric patients 2 to 17 years of age with upper limb spasticity appear in Table 22. In a double-blind, placebo-controlled trial (Study 1), 78 patients were treated with 3 Units/kg of BOTOX, and 77 patients received 6 Units/kg to a maximum dose of 200 Units of BOTOX, and were compared to 79 patients who received placebo [see Clinical Studies (14.5)]. Patients were followed for an average of 91 days after injection. Table 22: Adverse Reactions Reported by >2% of BOTOX 6 Units/kg Treated Patients and More Frequent than in Placebo-Treated Patients in Pediatric Upper Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 1) Adverse Reactions BOTOX 6 Units/kg (N=77) % BOTOX 3 Units/kg (N=78) % Placebo (N=79) % Infections and infestations Upper respiratory tract infection* General disorders and administration site conditions Injection site pain Gastrointestinal disorders Nausea Constipation Respiratory, thoracic and mediastinal disorders Rhinorrhea Nasal congestion Nervous system disorders Seizure** *Includes upper respiratory tract infection and viral upper respiratory tract infection **Includes seizure and partial seizure Pediatric Lower Limb Spasticity The most frequently reported adverse reactions following injection of BOTOX in pediatric patients 2 limb spasticity appear in Table 23. In a double-blind, placebo-controlled trial (Study 2), 126 patients were treated with 4 Units/kg of BOTOX, and 128 patients received 8 Units/kg to a maximum dose of 300 Units of BOTOX, and were compared to 128 patients who received placebo [see Clinical Studies (14.6)]. Patients were followed for an average of 89 days after injection. to 17 years of age with lower Table 23: Adverse Reactions Reported by >2% of BOTOX 8 Units/kg Treated Patients and More Frequent than in Placebo-Treated Patients in Pediatric Lower Limb Spasticity Double-Blind, Placebo-Controlled Clinical Trial (Study 2) Adverse Reactions BOTOX 8 Units/kg (N=128) % BOTOX 4 Units/kg (N=126) % Placebo (N=128) % General disorders and administration site conditions Injection site erythema Injection site pain Respiratory, thoracic and mediastinal disorders Oropharyngeal pain Injury, poisoning and procedural complications Ligament sprain Skin abrasion Metabolism and nutrition disorders Decreased appetite Cervical Dystonia In cervical dystonia patients evaluated for safety in double-blind and open-label frequently reported adverse reactions were dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%). Other events reported in 2-10% of patients in any one study in decreasing order of incidence include: increased cough, flu syndrome, back pain, rhinitis, dizziness, hypertonia, soreness at injection site, asthenia, oral dryness, speech disorder, fever, nausea, and drowsiness. Stiffness, numbness, diplopia, ptosis, and dyspnea have been reported. Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of BOTOX resulting from the spread of the toxin outside the injected muscles [see Warnings and Precautions (5.1, 5.6)]. The most common severe adverse reaction associated with the use of BOTOX injection in patients with cervical dystonia is dysphagia with about 20% of these cases also reporting dyspnea [see Warnings and Precautions (5.1, 5.6)]. Most dysphagia is reported as mild or moderate in severity. However, it may be associated with more severe signs and symptoms [see Warnings and Precautions (5.6)]. Additionally, reports in the literature include a case of a female patient who developed brachial plexopathy two days after injection of 120 Units of BOTOX for the treatment of cervical dystonia, and reports of dysphonia in patients who have been treated for cervical dystonia. Primary Axillary Hyperhidrosis The most frequently reported adverse reactions (3-10% of adult patients) following injection of BOTOX in double-blind studies included injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety. The data reflect 346 patients exposed to BOTOX 50 Units and 110 patients exposed to BOTOX 75 Units in each axilla. Blepharospasm In a study of blepharospasm patients who received an average dose per eye of 33 Units (injected at 3 to 5 sites) of the currently manufactured BOTOX, the most frequently reported adverse reactions were ptosis (21%), superficial punctate keratitis (6%), and eye dryness (6%). Other events reported in prior clinical studies in decreasing order of incidence include: irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia, entropion, diffuse skin rash, and local swelling of the eyelid skin lasting for several days following eyelid injection. In two cases of VII nerve disorder, reduced blinking from BOTOX injection of the orbicularis muscle led to serious corneal exposure, persistent epithelial defect, corneal ulceration and a case of corneal perforation. Focal facial paralysis, syncope, and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm. studies following injection of BOTOX, the most Strabismus Extraocular muscles adjacent to the injection site can be affected, causing vertical deviation, especially with higher doses of BOTOX. The incidence rates of these adverse effects in 2058 adults who received a total of 3650 injections for horizontal strabismus was 17%. The incidence of ptosis has been reported to be dependent on the location of the injected muscles, 1% after inferior rectus injections, 16% after horizontal rectus injections and 38% after superior rectus injections. In a series of 5587 injections, retrobulbar hemorrhage occurred in 0.3% of cases. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to onabotulinumtoxinA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In a long term, open-label study evaluating 326 cervical dystonia patients treated for an average of 9 treatment sessions with the current formulation of BOTOX, 4 (1.2%) patients had positive antibody tests. All 4 of these patients responded to BOTOX therapy at the time of the positive antibody test. However, 3 of these patients developed clinical resistance after subsequent treatment, while the fourth patient continued to respond to BOTOX therapy for the remainder of the study. One patient among the 445 hyperhidrosis patients (0.2%), two patients among the 380 adult upper limb spasticity patients (0.5%), and no patients among 406 migraine patients with analyzed specimens developed the presence of neutralizing antibodies. In one Phase 3 study and the open-label extension study in patients with pediatric lower limb spasticity, neutralizing antibodies developed in 2 of 264 patients (0.8%) treated with BOTOX for up to 5 treatment cycles. Both patients continued to experience clinical benefit following subsequent BOTOX treatments. In overactive bladder patients with analyzed specimens from the two phase 3 studies and the open-label extension study, neutralizing antibodies developed in 0 of 954 patients (0.0%) while receiving BOTOX 100 Unit doses and 3 of 260 patients (1.2%) after subsequently receiving at least one 150 Unit dose. Response to subsequent BOTOX treatment was not different following seroconversion in these three patients. In detrusor overactivity associated with neurologic condition patients with analyzable specimens in the adult drug development program (including the open-label extension study), neutralizing antibodies developed in 3 of 300 patients (1.0%) after receiving only BOTOX 200 Unit doses and 5 of 258 patients (1.9%) after receiving at least one 300 Unit dose. Following development of neutralizing antibodies in these 8 patients, 4 continued to experience clinical benefit, 2 did not experience clinical benefit, and the effect on the response to BOTOX in the remaining 2 patients is not known. In 99 pediatric patients who had a negative baseline result for binding antibodies or neutralizing antibodies and had at least one evaluable post-baseline value from one randomized double-blind study and one double-blind extension study, no patients developed neutralizing antibodies after receiving 50 Units to 200 Units of BOTOX. The data reflect the patients whose test results were considered positive for neutralizing activity to BOTOX in a mouse protection assay or negative based on a screening ELISA assay or mouse protection assay. Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin. The critical factors for neutralizing antibody formation have not been well characterized. The results from some studies suggest that BOTOX injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections. Postmarketing Experience The following adverse reactions have been identified during post-approval use of BOTOX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include: abdominal pain; alopecia, including madarosis; anorexia; brachial plexopathy; denervation/muscle atrophy; diarrhea; dry eye; eyelid edema (following periocular injection); hyperhidrosis; hypoacusis; hypoaesthesia; localized muscle twitching; malaise; paresthesia; peripheral neuropathy; radiculopathy; erythema multiforme, dermatitis psoriasiform, and psoriasiform eruption; strabismus; tinnitus; and visual disturbances. There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin [see Warnings and Precautions (5.4, 5.6)]. There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been established. New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events. The exact relationship of these events to the botulinum toxin injection has not been established. DRUG INTERACTIONS Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission Co-administration of BOTOX and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated. Anticholinergic Drugs Use of anticholinergic drugs after administration of BOTOX may potentiate systemic anticholinergic effects. Other Botulinum Neurotoxin Products The effect of administering different botulinum neurotoxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Muscle Relaxants Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of BOTOX. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no studies or adequate data from postmarketing surveillance on the developmental risk associated with use of BOTOX in pregnant women. In animal studies, administration of BOTOX during pregnancy resulted in adverse effects on fetal growth (decreased fetal weight and skeletal ossification) at clinically relevant doses, which were associated with maternal toxicity [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Data Animal Data When BOTOX (4, 8, or 16 Units/kg) was administered intramuscularly to pregnant mice or rats two times during the period of organogenesis (on gestation days 5 and 13), reductions in fetal body weight and decreased fetal skeletal ossification were observed at the two highest doses. The no-effect dose for developmental toxicity in these studies (4 Units/kg) is approximately equal to the human dose of 400 Units, on a body weight basis (Units/kg). When BOTOX was administered intramuscularly to pregnant rats (0.125, 0.25, 0.5, 1, 4, or 8 Units/kg) or rabbits (0.063, 0.125, 0.25, or 0.5 Units/kg) daily during the period of organogenesis (total of 12 doses in rats, 13 doses in rabbits), reduced fetal body weights and decreased fetal skeletal ossification were observed at the two highest doses in rats and at the highest dose in rabbits. These doses were also associated with significant maternal toxicity, including abortions, early deliveries, and maternal death. The developmental no- effect doses in these studies of 1 Unit/kg in rats and 0.25 Units/kg in rabbits are less than the human dose of 400 Units, based on Units/kg. When pregnant rats received single intramuscular injections (1, 4, or 16 Units/kg) at three different periods of development (prior to implantation, implantation, or organogenesis), no adverse effects on fetal development were observed. The developmental no-effect level for a single maternal dose in rats (16 Units/kg) is approximately 2 times the human dose of 400 Units, based on Units/kg. Lactation Risk Summary There are no data on the presence of BOTOX in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BOTOX and any potential adverse effects on the breastfed infant from BOTOX or from the underlying maternal conditions. Pediatric Use Overactive Bladder Safety and effectiveness in patients below the age of 18 years have not been established. Detrusor Overactivity associated with a Neurologic Condition The safety and effectiveness of BOTOX for detrusor overactivity associated with a neurologic condition have been established in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication. Use of BOTOX in this patient population is based on the results of a randomized, double-blind, parallel group trial in 113 pediatric patients 5 to 17 years of age (inclusive) with detrusor overactivity associated with a neurologic condition (Study 191622-120) and a long-term, multicenter, double-blind, long-term extension trial (Study 191622-121) [see Clinical Studies (14.3)]. The most common adverse reactions in this population were urinary tract infection, bacteriuria, hematuria, and leukocyturia [see Adverse Reactions (6.1)]. The safety and effectiveness of BOTOX have not been established in patients with NDO younger than 5 years of age. Prophylaxis of Headaches in Chronic Migraine Safety and effectiveness in patients below the age of 18 years have not been established. In a 12-week, multicenter, double-blind, placebo-controlled clinical trial, 123 adolescent patients (ages 12 to below 18 years) with chronic migraine were randomized to receive BOTOX 74 Units, BOTOX 155 Units, or placebo, for one injection cycle. This trial did not establish the efficacy of BOTOX, compared with placebo, for the prophylaxis of headaches in adolescents with chronic migraine. Spasticity Safety and effectiveness have been established in pediatric patients 2 to 17 years of age [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Studies (14.6)]. The safety and effectiveness of BOTOX have been established by evidence from adequate and well-controlled studies of BOTOX in patients 2 to 17 years of age with upper and lower limb spasticity. Safety and effectiveness in pediatric patients below the age of 2 years have not been established [see Boxed Warning and Warnings and Precautions (5.1)]. Juvenile Animal Data In a study in which juvenile rats received intramuscular injection of BOTOX (0, 8, 16, or 24 Units/kg) every other week from postnatal day 21 for 12 weeks, changes in bone size/geometry associated with decreased bone density and bone mass were observed at all doses, in association with limb disuse, decreased muscle contraction, and decreased body weight gain. Impairment of fertility and male reproductive organ histopathology (degeneration of seminiferous tubules of the testis) were observed at the mid and high doses. Bone and male reproductive organ effects showed evidence of reversibility after dosing cessation. The no-effect dose for adverse developmental effects in juvenile animals (8 Units/kg) is similar to the human dose (400 Units) on a body weight (kg) basis. Axillary Hyperhidrosis Safety and effectiveness in patients below the age of 18 years have not been established. Cervical Dystonia Safety and effectiveness in pediatric patients below the age of 16 years have not been established. Blepharospasm and Strabismus Safety and effectiveness in pediatric patients below the age of 12 years have not been established. Geriatric Use Of the 2145 adult patients in placebo-controlled clinical studies of BOTOX for the treatment of spasticity, 33.5% were 65 or older, and 7.7% were 75 years of age or older. No overall differences in safety were observed between elderly patients and adult patients younger than 65 years of age. In clinical studies of BOTOX across other indications, no overall differences in safety were observed between elderly patients and younger adult patients, with the exception of Overactive Bladder (see below). Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. Overactive Bladder Of 1242 overactive bladder patients in placebo-controlled clinical studies of BOTOX, 41.4% were 65 years of age or older, and 14.7% were 75 years of age or older. Adverse reactions of UTI and urinary retention were more common in patients 65 years of age or older in both placebo and BOTOX groups compared to younger patients (see Table 24). Otherwise, there were no overall differences in the safety profile following BOTOX treatment between patients aged 65 years and older compared to adult patients younger than 65 years of age in these studies. Table 24: Incidence of Urinary Tract Infection and Urinary Retention according to Age Group during First Placebo- Controlled Treatment, Placebo-Controlled Clinical Trials in Patients with OAB <65 Years 65 to 74 Years 30 13 8 0 ≥75 Years 38 19 9 1 Adverse Reactions BOTOX 100 Units (N=344) % Placebo (N=348) % BOTOX 100 Units (N=169) % Placebo (N=151) % BOTOX 100 Units (N=94) % Placebo (N=86) % Urinary tract infection 21 Urinary retention 6 7 0.6 Observed effectiveness was comparable between these age groups in placebo-controlled clinical studies. OVERDOSAGE Excessive doses of BOTOX (onabotulinumtoxinA) for injection may be expected to produce neuromuscular weakness with a variety of symptoms. Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection or oral ingestion occur or overdose be suspected, the person should be medically supervised for several weeks for signs and symptoms of systemic muscular weakness which could be local, or distant from the site of injection [see Boxed Warning and Warnings and Precautions (5.1, 5.6)]. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization. If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care. In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 1-770-488-7100. More information can be obtained at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm. DESCRIPTION OnabotulinumtoxinA is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A, and intended for intramuscular, intradetrusor and intradermal use. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying. The primary release procedure for BOTOX uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to Allergan’s products BOTOX and BOTOX Cosmetic. One Unit of BOTOX corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice. Due to specific details of this assay such as the vehicle, dilution scheme, and laboratory protocols, Units of biological activity of BOTOX cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. The specific activity of BOTOX is approximately 20 Units/nanogram of neurotoxin protein complex. Each vial of BOTOX (onabotulinumtoxinA) for injection contains either 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride; or 200 Units of Clostridium botulinum type A neurotoxin complex, 1 mg of Albumin Human, and 1.8 mg of sodium chloride in a sterile, vacuum-dried form without a preservative. CLINICAL PHARMACOLOGY Mechanism of Action BOTOX blocks neuromuscular transmission by binding to acceptor sites on motor or autonomic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX. When injected intradermally, BOTOX produces temporary chemical denervation of the sweat gland resulting in local reduction in sweating. Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release. Pharmacokinetics Using currently available analytical technology, it is not possible to detect BOTOX in the peripheral blood following intramuscular injection at the recommended doses. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long term studies in animals have not been performed to evaluate the carcinogenic potential of BOTOX. Mutagenesis BOTOX was negative in a battery of in vitro (microbial reverse mutation assay, mammalian cell mutation assay, and chromosomal aberration assay) and in vivo (micronucleus assay) genetic toxicology assays. Impairment of Fertility In fertility studies of BOTOX (4, 8, or 16 Units/kg) in which either male or female rats were injected intramuscularly prior to mating and on the day of mating (3 doses, 2 weeks apart for males: 2 doses, 2 weeks apart for females) to untreated animals, reduced fertility was observed in males at the intermediate and high doses and in females at the high dose. The no-effect doses for reproductive toxicity (4 Units/kg in males, 8 Units/kg in females) are approximately equal to the human dose of 400 Units, on a body weight basis (Units/kg). Animal Toxicology and/or Pharmacology In a study to evaluate inadvertent peribladder administration, bladder stones were observed in 1 of 4 male monkeys that were injected with a total of 6.8 Units/kg divided into the prostatic urethra and proximal rectum (single administration). No bladder stones were observed in male or female monkeys following injection of up to 36 Units/kg (~12X the highest human bladder dose) directly to the bladder as either single or 4 repeat dose injections or in female rats for single injections up to 100 Units/kg (~33X the highest human bladder dose [200 Units], based on Units/kg). CLINICAL STUDIES Overactive Bladder (OAB) Two double-blind, placebo-controlled, randomized, multi-center, 24-week clinical studies were conducted in patients with OAB with symptoms of urge urinary incontinence, urgency, and frequency (Studies OAB-1 and OAB-2). Patients needed to have at least 3 urinary urgency incontinence episodes and at least 24 micturitions in 3 days to enter the studies. A total of 1105 patients, whose symptoms had not been adequately managed with anticholinergic therapy (inadequate response or intolerable side effects), were randomized to receive either 100 Units of BOTOX (n=557), or placebo (n=548). Patients received 20 injections of study drug (5 Units of BOTOX or placebo) spaced approximately 1 cm apart into the detrusor muscle. In both studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in daily frequency of urinary incontinence episodes were observed for BOTOX 100 Units at the primary time point of week 12. Significant improvements compared to placebo were also observed for the secondary efficacy variables of daily frequency of micturition episodes and volume voided per micturition. These primary and secondary variables are shown in Table 25 and Table 26, and Figure 7 and Figure 8. Table 25: Baseline and Change from Baseline in Urinary Incontinence Episode Frequency, Micturition Episode Frequency and Volume Voided Per Micturition, Study OAB-1 Daily Frequency of Urinary Incontinence Episodesa Mean Baseline Mean Change* at Week 2 Mean Change* at Week 6 Mean Change* at Week 12** Daily Frequency of Micturition Episodesb Mean Baseline Mean Change† at Week 12** Volume Voided per Micturitionb (mL) Mean Baseline Mean Change† at Week 12** BOTOX 100 Units Placebo Treatment (N=278) (N=272) Difference 5.5 5.1 -2.6 -1.0 -1.6 -2.8 -1.0 -1.8 -2.5 -0.9 -1.6 (-2.1, -1.2) 12.0 11.2 -1.9 -0.9 -1.0 (-1.5, -0.6) 156 161 38 8 30 (17, 43) p-value <0.001 <0.001 <0.001 * Least squares (LS) mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and treatment group and investigator as factors. Last observation carried forward (LOCF) values were used to analyze the primary efficacy variable. † LS mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and stratification factor, treatment group and investigator as factors. ** Primary timepoint a Primary variable b Secondary variable Table 26: Baseline and Change from Baseline in Urinary Incontinence Episode Frequency, Micturition Episode Frequency and Volume Voided Per Micturition, Study OAB-2 Daily Frequency of Urinary Incontinence Episodesa Mean Baseline Mean Change* at Week 2 Mean Change* at Week 6 Mean Change* at Week 12** Daily Frequency of Micturition Episodesb Mean Baseline Mean Change† at Week 12** Volume Voided per Micturitionb (mL) Mean Baseline Mean Change† at Week 12** BOTOX 100 Units Placebo Treatment (N=275) (N=269) Difference 5.5 5.7 -2.7 -1.1 -1.6 -3.1 -1.3 -1.8 -3.0 -1.1 -1.9 (-2.5, -1.4) 12.0 11.8 -2.3 -0.6 -1.7 (-2.2, -1.3) 144 153 40 10 31 (20, 41) p-value <0.001 <0.001 <0.001 * LS mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and treatment group and investigator as factors. LOCF values were used to analyze the primary efficacy variable. † LS mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and stratification factor, treatment group and investigator as factors. ** Primary timepoint a Primary variable b Secondary variable Figure 7: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes Following Intradetrusor Injection in Study OAB-1 Figure 8: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes Following Intradetrusor Injection in Study OAB-2 The median duration of response in Study OAB-1 and OAB-2, based on patient qualification for re-treatment, was 19-24 weeks for the BOTOX 100 Unit dose group compared to 13 weeks for placebo. To qualify for re-treatment, at least 12 weeks must have passed since the prior treatment, post-void residual urine volume must have been less than 200 mL and patients must have reported at least 2 urinary incontinence episodes over 3 days. Adult Detrusor Overactivity Associated with a Neurologic Condition Two double-blind, placebo-controlled, randomized, multi-center clinical studies were conducted in patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition who were either spontaneously voiding or using catheterization (Studies NDO-1 and NDO-2). A total of 691 spinal cord injury (T1 or below) or multiple sclerosis patients, who had an inadequate response to or were intolerant of at least one anticholinergic medication, were enrolled. These patients were randomized to receive either 200 Units of BOTOX (n=227), 300 Units of BOTOX (n=223), or placebo (n=241). In both studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in weekly frequency of incontinence episodes were observed for BOTOX (200 Units) at the primary efficacy time point at week 6. Increases in maximum cystometric capacity and reductions in maximum detrusor pressure during the first involuntary detrusor contraction were also observed. These primary and secondary endpoints are shown in Table 27 and Table 28, and Figure 9 and Figure 10. No additional benefit of BOTOX 300 Units over 200 Units was demonstrated. Table 27: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH2O) Study NDO-1 BOTOX Placebo Treatment p-value* 200 Units Difference* Weekly Frequency of Urinary Incontinence Episodesa N Mean Baseline Mean Change* at Week 2 Mean Change* at Week 6** Mean Change* at Week 12 134 32.3 -15.3 -19.9 -19.8 146 28.3 -10.0 -10.6 -8.8 -5.3 -9.2 (-13.1, -5.3) -11.0 ─ p<0.001 ─ Maximum Cystometric Capacityb (mL) N Mean Baseline Mean Change* at Week 6** 123 253.8 135.9 129 259.1 12.1 123.9 (89.1, 158.7) p<0.001 Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O) N Mean Baseline Mean Change* at Week 6** 41 63.1 -28.1 103 57.4 -3.7 -24.4 ─ * LS mean change, treatment difference and p-value are based on an analysis using an ANCOVA model with baseline weekly endpoint as covariate and treatment group, etiology at study entry (spinal cord injury or multiple sclerosis), concurrent anticholinergic therapy at screening, and investigator as factors. LOCF values were used to analyze the primary efficacy variable. ** Primary timepoint a Primary endpoint b Secondary endpoint Table 28: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH2O) in Study NDO-2 BOTOX Placebo Treatment p-value* 200 Units Difference* Weekly Frequency of Urinary Incontinence Episodesa N Mean Baseline Mean Change* at Week 2 Mean Change* at Week 6** Mean Change* at Week 12 91 32.7 -18.0 -19.6 -19.6 91 36.8 -7.9 -10.8 -10.7 -10.1 -8.8 (-14.5, -3.0) -8.9 ─ p=0.003 ─ Maximum Cystometric Capacityb (mL) N Mean Baseline Mean Change* at Week 6** 88 239.6 150.8 85 253.8 2.8 148.0 (101.8, 194.2) p<0.001 Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O) N Mean Baseline Mean Change* at Week 6** 29 65.6 -28.7 68 43.7 2.1 -30.7 ─ * LS mean change, treatment difference and p-value are based on an analysis using an ANCOVA model with baseline weekly endpoint as covariate and treatment group, etiology at study entry (spinal cord injury or multiple sclerosis), concurrent anticholinergic therapy at screening, and investigator as factors. LOCF values were used to analyze the primary efficacy variable. ** Primary timepoint a Primary endpoint b Secondary endpoint Figure 9: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-1 Figure 10: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-2 The median duration of response in study NDO-1 and NDO-2, based on patient qualification for re-treatment was 295-337 days (42-48 weeks) for the 200 Units dose group compared to 96-127 days (13-18 weeks) for placebo. Re-treatment was based on loss of effect on incontinence episode frequency (50% of effect in Study NDO-1; 70% of effect in Study NDO-2). A placebo-controlled, double-blind randomized post-approval 52 week study (Study NDO-3) was conducted in MS patients with urinary incontinence due to neurogenic detrusor overactivity who were not adequately managed with at least one anticholinergic agent and not catheterizing at baseline. These patients were randomized to receive either 100 Units of BOTOX (n=66) or placebo (n=78). Significant improvements compared to placebo in the primary efficacy variable of change from baseline in daily frequency of incontinence episodes were observed for BOTOX (100 Units) at the primary efficacy time point at week 6. Increases in maximum cystometric capacity and reductions in maximum detrusor pressure during the first involuntary detrusor contraction were also observed. These primary and secondary endpoints are shown in Table 29. Table 29: Baseline and Change from Baseline in Daily Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH2O) in Study NDO-3 BOTOX Placebo Treatment p-value* 100 Units Difference* Daily Frequency of Urinary Incontinence Episodesa N Mean Baseline Mean Change* at Week 2 Mean Change* at Week 6** Mean Change* at Week 12 66 4.2 -2.9 -3.4 -2.7 78 4.3 -1.2 -1.1 -1.0 -1.7 -2.3 (-3.0, -1.7) -1.8 ─ p<0.001 ─ Maximum Cystometric Capacityb (mL) N Mean Baseline Mean Change* at Week 6** 62 248.9 134.4 72 245.5 3.5 130.9 (94.8, 167.0) p<0.001 Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O) N Mean Baseline Mean Change* at Week 6** 25 42.4 -19.2 51 39.0 2.7 -21.9 (-37.5, -6.3) * LS mean change, treatment difference and p-value are based on an analysis using an ANCOVA model with baseline daily endpoint as covariate and treatment group and propensity score stratification as factors. LOCF values were used to analyze the primary efficacy variable. ** Primary timepoint a Primary endpoint b Secondary endpoint The median duration of response in study NDO-3, based on patient qualification for re-treatment was 362 days (52 weeks) for the BOTOX 100 Units dose group compared to 88 days (13 weeks) for placebo. To qualify for re-treatment, at least 12 weeks must have passed since the prior treatment, post-void residual urine volume must have been less than 200 mL and patients must have reported at least 2 urinary incontinence episodes over 3 days with no more than 1 incontinence-free day. Pediatric Detrusor Overactivity Associated with a Neurologic Condition Study 191622-120 (NCT01852045) was a multicenter, randomized, double-blind, parallel-group clinical study conducted in patients 5 to 17 years of age with urinary incontinence due to detrusor overactivity associated with a neurologic condition and using clean intermittent catheterization. A total of 113 patients (including 99 with spinal dysraphism such as spina bifida, 13 with spinal cord injury and 1 with transverse myelitis) who had an inadequate response to or were intolerant of at least one anticholinergic medication were enrolled. The median age was 11 years (range: 5 to 17 years), 49% were female; 75% were White, 10% were Black. These patients were randomized to 50 Units, 100 Units or 200 Units, not to exceed 6 Units/kg body weight. Patients receiving less than the randomized dose due to the 6 Units/kg maximum, were assigned to the nearest dose group for analysis. The sample size for BOTOX 50 Units, 100 Units, and 200 Units were 38, 45 and 30, respectively. Prior to treatment administration, patients received anesthesia based on age and local site practice. One hundred and nine patients (97.3%) received general anesthesia or conscious sedation and 3 patients (2.7%) received local anesthesia. The study results demonstrated within group improvements in the primary efficacy variable of change from baseline in daytime urinary incontinence episodes (normalized to 12 hours) at the primary efficacy time point (Week 6) for all 3 BOTOX treatment groups. Additional benefits were seen with BOTOX 200 Units for measures related to reducing maximum bladder pressure when compared to 50 Units. The decrease in maximum detrusor pressure (MDP) during the storage phase (MDP defined as the highest value in the Pdet channel during the storage phase [e.g., the greater of the following: the maximum Pdet during the highest amplitude IDC, the maximum Pdet during a terminal detrusor contraction, the Pdet at the end of filling, or the highest Pdet at any other time during the storage phase]) for BOTOX 200 Units at Week 6 was greater than the decrease observed for 50 Units. Within group improvements for the primary and secondary endpoints for the 200 Units dose group are shown in Table 30. The efficacy of BOTOX 6 U/kg for pediatric patients with NDO weighing less than 34 kg was comparable to that of BOTOX 200 U. Table 30: Baseline and Change from Baseline in Daily Daytime Frequency of Urinary Incontinence Episodes, Urine Volume at First Morning Catheterization, Maximum Detrusor Pressure during the Storage Phase (cmH2O), and Maximum Cystometric Capacity (mL) in Study191622-120 Daily average frequency of daytime urinary incontinence episodesa Mean Baseline Mean Change* at Week 2 (95% CI) Mean Change* at Week 6** (95% CI) Mean Change* at Week 12 (95% CI) Urine Volume at First Morning Catheterization (mL)b Mean Baseline Mean Change* at Week 2 (95% CI) Mean Change* at Week 6** (95% CI) Mean Change* at Week 12 (95% CI) Maximum Detrusor Pressure (PdetMax) During the Storage Phase (cm H2O)b Mean Baseline Mean Change* at Week 6** (95% CI) Maximum Cystometric Capacity (mL) (MCC)b Mean Baseline Mean Change* at Week 6** (95% CI) CI = Confidence Interval BOTOX 200 U N=30 3.7 -1.1 (-1.7, -0.6) -1.3 (-1.8, -0.9) -0.9 (-1.5, -0.4) 187.7 63.2 (27.9, 98.6) 87.5 (52.1, 122.8) 45.2 (10.0, 80.5) 56.7 -27.3 (-36.4, -18.2) 202.3 63.6 (29.0, 98.1) * LSmean change and 95% CI are based on an ANCOVA model with baseline value as covariate and treatment group, age (< 12 years or >= 12 years), baseline daytime urinary incontinence episodes (<= 6 or > 6) and anticholinergic therapy (yes/no) at baseline as factors. ** Primary timepoint a Primary endpoint b Secondary endpoint The median duration of response in this study, based on patient qualification for re-treatment was 207 days (30 weeks) for BOTOX 200 Units dose group. To qualify for re-treatment, patients must have reported at least 2 urinary incontinence episodes over 2 days and at least 12 weeks have passed from the prior bladder injection. Chronic Migraine BOTOX was evaluated in two randomized, multi-center, 24-week, 2 injection cycle, placebo-controlled double-blind studies. Study 1 and Study 2 included chronic migraine adults who were not using any concurrent headache prophylaxis, and during a 28-day baseline period had >15 headache days lasting 4 hours or more, with >50% being migraine/probable migraine. In both studies, patients were randomized to receive placebo or 155 Units to 195 Units BOTOX injections every 12 weeks for the 2-cycle, double-blind phase. Patients were allowed to use acute headache treatments during the study. BOTOX treatment demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for key efficacy variables (see Table 31). Table 31: Week 24 Key Efficacy Variables for Study 1 and Study 2 Study 1 Study 2 Efficacy per 28 days Change from baseline in frequency of headache days Change from baseline in total cumulative hours of headache on headache days * Significantly different from placebo (p<0.05) BOTOX Placebo (N=341) (N=338) -7.8* -6.4 -107* -70 BOTOX (N=347) Placebo (N=358) -9.2* -6.9 -134* -95 Patients treated with BOTOX had a significantly greater mean decrease from baseline in the frequency of headache days at most timepoints from Week 4 to Week 24 in Study 1 (Figure 11), and all timepoints from Week 4 to Week 24 in Study 2 (Figure 12), compared to placebo-treated patients. Figure 11: Mean Change from Baseline in Number of Headache Days for Study 1 Figure 12: Mean Change from Baseline in Number of Headache Days for Study 2 Adult Spasticity Adult Upper Limb Spasticity The efficacy of BOTOX for the treatment of adult upper limb spasticity was evaluated in several randomized, multi-center, double- blind, placebo-controlled studies (Studies 1 through 6). Study 1 included 126 adult patients (64 BOTOX and 62 placebo) with upper limb spasticity (Ashworth score of at least 3 for wrist flexor tone and at least 2 for finger flexor tone) who were at least 6 months post-stroke. BOTOX (a total dose of 200 Units to 240 Units) and placebo were injected intramuscularly (IM) into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and if necessary into the adductor pollicis and flexor pollicis longus (see Table 32). Use of an EMG/nerve stimulator was recommended to assist in proper muscle localization for injection. Patients were followed for 12 weeks. Table 32: BOTOX Dose and Injection Sites in Study 1 Muscles Injected Wrist Volume BOTOX (mL) (Units) Number of Injection Sites Flexor Carpi Radialis 1 Flexor Carpi Ulnaris 1 Finger Flexor Digitorum Profundus 1 Flexor Digitorum Sublimis 1 Thumb Adductor Pollicisa 0.4 Flexor Pollicis Longusa 0.4 a Injected only if spasticity is present in this muscle 50 1 50 1 50 1 50 1 20 1 20 1 The primary efficacy variable was wrist flexors muscle tone at week 6, as measured by the Ashworth score. The Ashworth Scale is a 5-point scale with grades of 0 [no increase in muscle tone] to 4 [limb rigid in flexion or extension]. It is a clinical measure of the force required to move an extremity around a joint, with a reduction in score clinically representing a reduction in the force needed to move a joint (i.e., improvement in spasticity). Key secondary endpoints included Physician Global Assessment, finger flexors muscle tone, and thumb flexors tone at Week 6. The Physician Global Assessment evaluated the response to treatment in terms of how the patient was doing in his/her life using a scale from -4 = very marked worsening to +4 = very marked improvement. Study 1 results on the primary endpoint and the key secondary endpoints are shown in Table 33. Table 33: Primary and Key Secondary Endpoints by Muscle Group at Week 6 in Study 1 BOTOX (N=64) Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale†a -2.0* Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††b -1.0* Median Change from Baseline in Thumb Flexor Muscle Tone on the Ashworth Scale††c -1.0 Median Physician Global Assessment of Response to Treatment†† 2.0* Placebo (N=62) 0.0 0.0 -1.0 0.0 † Primary endpoint at Week 6 †† Secondary endpoints at Week 6 * Significantly different from placebo (p<0.05) a BOTOX injected into both the flexor carpi radialis and ulnaris muscles b BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles c BOTOX injected into the adductor pollicis and flexor pollicis longus muscles Study 2 compared 3 doses of BOTOX with placebo and included 91 adult patients [BOTOX 360 Units (N=21), BOTOX 180 Units (N=23), BOTOX 90 Units (N=21), and placebo (N=26)] with upper limb spasticity (expanded Ashworth score of at least 2 for elbow flexor tone and at least 3 for wrist flexor tone) who were at least 6 weeks post-stroke. BOTOX and placebo were injected with EMG guidance into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and biceps brachii (see Table 34). Table 34: BOTOX Dose and Injection Sites in Study 2 and Study 3 Total Dose Muscles Injected Wrist Flexor Carpi Ulnaris Flexor Carpi Radialis Finger Flexor Digitorum Profundus Flexor Digitorum Sublimis Elbow Biceps Brachii BOTOX low dose BOTOX mid dose BOTOX high dose Volume (mL) Injection Sites (n) (90 Units) 10 Units 15 Units 7.5 Units 7.5 Units 50 Units (180 Units) 20 Units 30 Units 15 Units 15 Units 100 Units (360 Units) 40 Units 60 Units 30 Units 30 Units 200 Units per site 0.4 1 0.6 1 0.3 1 0.3 1 0.5 4 The primary efficacy variable in Study 2 was the wrist flexor tone at Week 6 as measured by the expanded Ashworth Scale. The expanded Ashworth Scale uses the same scoring system as the Ashworth Scale, but allows for half-point increments. Key secondary endpoints in Study 2 included Physician Global Assessment, finger flexors muscle tone, and elbow flexors muscle tone at Week 6. Study 2 results on the primary endpoint and the key secondary endpoints at Week 6 are shown in Table 35. Table 35: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at Week 6 in Study 2 BOTOX low dose (90 Units) (N=21) -1.5* -0.5 -0.5 1.0* BOTOX mid dose (180 Units) (N=23) -1.0* -0.5 -1.0* 1.0* BOTOX high dose (360 Units) (N=21) Placebo (N=26) Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale†b Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††c Median Change from Baseline in Elbow Flexor Muscle Tone on the Ashworth Scale††d Median Physician Global Assessment of Response to Treatment † Primary endpoint at Week 6 -1.5* -1.0 -1.0 -0.5 -0.5a -0.5 1.0* 0.0 †† Secondary endpoints at Week 6 * Significantly different from placebo (p<0.05) a p=0.053 b Total dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles c Total dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles d Dose of BOTOX injected into biceps brachii muscle Study 3 compared 3 doses of BOTOX with placebo and enrolled 88 adult patients [BOTOX 360 Units (N=23), BOTOX 180 Units (N=23), BOTOX 90 Units (N=23), and placebo (N=19)] with upper limb spasticity (expanded Ashworth score of at least 2 for elbow flexor tone and at least 3 for wrist flexor tone and/or finger flexor tone) who were at least 6 weeks post-stroke. BOTOX and placebo were injected with EMG guidance into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and biceps brachii (see Table 34). The primary efficacy variable in Study 3 was wrist and elbow flexor tone as measured by the expanded Ashworth score. A key secondary endpoint was assessment of finger flexors muscle tone. Study 3 results on the primary endpoint at Week 4 are shown in Table 36. Table 36: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at Week 4 in Study 3 BOTOX low dose (90 Units) (N=23) -1.0 -1.0 -0.5 BOTOX mid dose (180 Units) (N=21) -1.0 -1.0 -0.5 BOTOX high dose (360 Units) (N=22) Placebo (N=19) Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale†b Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††c Median Change from Baseline in Elbow Flexor Muscle Tone on the Ashworth Scale†d -1.5* -0.5 -1.0* -0.5 -1.0* -0.5 † Primary endpoint at Week 4 †† Secondary endpoints at Week 4 * Significantly different from placebo (p<0.05) b Total dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles c Total dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles d Dose of BOTOX injected into biceps brachii muscle Study 4 (NCT01153815) included 170 adult patients (87 BOTOX and 83 placebo) with upper limb spasticity who were at least 6 months post-stroke. In Study 4, patients received 20 Units of BOTOX into the adductor pollicis and flexor pollicis longus (total BOTOX dose = 40 Units in thumb muscles) or placebo (see Table 37). Study 5 (NCT00460564) included 109 patients with upper limb spasticity who were at least 6 months post-stroke. In Study 5, adult patients received 15 Units (low dose) or 20 Units (high dose) of BOTOX into the adductor pollicis and flexor pollicis longus under EMG guidance (total BOTOX low dose = 30 Units, total BOTOX high dose = 40 Units), or placebo (see Table 37). The duration of follow-up in Study 4 and Study 5 was 12 weeks. Table 37: BOTOX Dose and Injection Sites in Studies 4 and 5 Study 4 Study 5 Number of Injection Sites for Studies 4 and 5 1 1 Muscles Injected Thumb Adductor Pollicis Flexor Pollicis Longus BOTOX Volume (Units) (mL) BOTOX low dose (Units) BOTOX high dose (Units) Volume low dose (mL) Volume high dose (mL) 20 0.4 20 0.4 15 20 0.3 0.4 15 20 0.3 0.4 The results of Study 4 for the change from Baseline to Week 6 in thumb flexor tone measured by modified Ashworth Scale (MAS) and overall treatment response by Physician Global Assessment at week 6 are presented in Table 38. The MAS uses a similar scoring system as the Ashworth Scale. Table 38: Efficacy Endpoints for Thumb Flexors at Week 6 in Study 4 BOTOX (N=66) Median Change from Baseline in Thumb Flexor Muscle Tone on the modified Ashworth Scale††a -1.0* Median Physician Global Assessment of Response to Treatment†† 2.0* Placebo (N=57) 0.0 0.0 †† Secondary endpoints at Week 6 * Significantly different from placebo (p<0.001) a BOTOX injected into the adductor pollicis and flexor pollicis longus muscles In Study 5, the results of the change from Baseline to Week 6 in thumb flexor tone measured by modified Ashworth Scale and Clinical Global Impression (CGI) of functional assessment scale assessed by the physician using an 11-point Numeric Rating Scale [-5 worst possible function to +5 best possible function] are presented in Table 39. Table 39: Efficacy Endpoints for Thumb Flexors at Week 6 in Study 5 BOTOX low dose (30 Units) (N=14) Placebo low dose (N=9) BOTOX high dose (40 Units) (N=43) Placebo high dose (N=23) Median Change from Baseline in Thumb Flexor Muscle Tone on the modified Ashworth Scale†††a Median Change from Baseline in Clinical Global Impression Score by Physician †† -1.0 -1.0 1.0 0.0 -0.5* 0.0 2.0* 0.0 †† Secondary endpoint at Week 6 ††† Other endpoint at Week 6 * Significantly different from placebo (p<0.010) a BOTOX injected into the adductor pollicis and flexor pollicis longus muscles Study 6 (NCT03261167) enrolled 124 post-stroke adult patients with upper limb spasticity. In Study 6, 61 patients received 160 Units BOTOX divided among 3 elbow flexors (biceps brachii, brachioradialis, and brachialis) and 63 patients received placebo (see Table 40). EMG, nerve stimulation, or ultrasound techniques were recommended to assist in proper muscle localization for injections. The duration of follow-up was 12 weeks. Table 40: BOTOX Dose and Injection Sites in Study 6 BOTOX 160 U (Units) Volume (mL) Number of Injection Sites Muscles Injected Elbow Biceps Brachii Brachioradialis Brachialis The change from baseline in elbow flexor tone measured by modified Ashworth Scale at Week 6 is presented in Table 41. Table 41: Primary Efficacy Endpoint Results for Elbow Flexors at Week 6 in Study 6 70 1.4 2 45 0.9 1 45 0.9 1 Mean Change from Baseline in Elbow Flexor Muscle Tone on the modified Ashworth Scale at Week 6 *nominal p value <0.05 Adult Lower Limb Spasticity BOTOX 160 U (N=61) -1.09* Placebo (N=63) -0.71 The efficacy and safety of BOTOX for the treatment of adult lower limb spasticity was evaluated in Study 7, a randomized, multi- center, double-blind, placebo-controlled study. Study 7 included 468 post-stroke adult patients (233 BOTOX and 235 placebo) with ankle spasticity (modified Ashworth Scale ankle score of at least 3) who were at least 3 months post-stroke. A total dose of 300 Units of BOTOX or placebo were injected intramuscularly and divided between the gastrocnemius, soleus, and tibialis posterior, with optional injection into the flexor hallucis longus, flexor digitorum longus, flexor digitorum brevis, extensor hallucis, and rectus femoris (see Table 42) with up to an additional 100 Units (400 Units total dose). The use of electromyographic guidance or nerve stimulation was required to assist in proper muscle localization for injections. Patients were followed for 12 weeks. Table 42: BOTOX Dose and Injection Sites in Study 7 Muscles Injected Mandatory Ankle Muscles Gastrocnemius (medial head) Gastrocnemius (lateral head) Soleus Tibialis Posterior Optional Muscles Flexor Hallucis Longus Flexor Digitorum Longus Flexor Digitorum Brevis Extensor Hallucis Rectus Femoris BOTOX Number of (Units) Injection Sites 75 3 75 3 75 3 75 3 50 2 50 2 25 1 25 1 100 4 The co-primary endpoints were the average of the change from baseline in modified Ashworth Scale (MAS) ankle score at Week 4 and Week 6, and the average of the Physician Global Assessment of Response (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of how the patient was doing in his/her life using a 9-point scale from -4=very marked worsening to +4=very marked improvement. Statistically significant between-group differences for BOTOX over placebo were demonstrated for the co-primary efficacy measures of MAS and CGI (see Table 43). Table 43: Co-Primary Efficacy Endpoints Results in Study 7 (Intent-To-Treat Population) Mean Change from Baseline in Ankle Plantar Flexors on the modified Ashworth Scale Week 4 and 6 Average Mean Clinical Global Impression Score by Investigator Week 4 and 6 Average * Significantly different from placebo (p<0.05) BOTOX Placebo 300 to 400 Units (N=233) (N=235) -0.8* -0.6 0.9* 0.7 Compared to placebo, significant improvements in MAS change from baseline for ankle plantar flexors (see Figure 13) and CGI (see Figure 14) were observed at Week 2, Week 4, and Week 6 for patients treated with BOTOX. Figure 13: Modified Ashworth Scale Ankle Score for Study 7 – Mean Change from Baseline by Visit Figure 14: Clinical Global Impression by Physician for Study 7 – Mean Scores by Visit Pediatric Spasticity Pediatric Upper Limb Spasticity The efficacy and safety of BOTOX for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age was evaluated in Study 1 (NCT01603602), a randomized, multi-center, double-blind, placebo-controlled study. Study 1 included 234 pediatric patients (78 BOTOX 3 Units/kg, 77 BOTOX 6 Units/kg, and 79 placebo) with upper limb spasticity (modified Ashworth Scale elbow or wrist score of at least 2) because of cerebral palsy or stroke. A total dose of 3 Units/kg BOTOX (maximum 100 Units), 6 Units/kg BOTOX (maximum 200 Units), or placebo was injected intramuscularly and divided between the elbow or wrist and finger muscles (see Table 44). Electromyographic guidance, nerve stimulation, or ultrasound techniques were used to assist in muscle localization for injections. Patients were followed for 12 weeks after injection. Table 44: BOTOX Dose and Injection Sites in Study 1 BOTOX 3 Units/kg* BOTOX 6 Units/kg** (maximum Units per muscle) Number of Injection Sites Muscles Injected Elbow Flexor Muscles Biceps Brachialis Brachioradialis Wrist and Finger Muscles Flexor carpi radialis Flexor carpi ulnaris Flexor digitorum profundus Flexor digitorum sublimis (maximum Units per muscle) 1.5 Units/kg (50 Units) 1 Unit/kg (30 Units) 0.5 Units/kg (20 Units) 1 Unit/kg (25 Units) 1 Unit/kg (25 Units) 0.5 Units/kg (25 Units) 0.5 Units/kg (25 Units) 3 Units/kg (100 Units) 4 2 Units/kg (60 Units) 2 1 Unit/kg (40 Units) 2 2 Units/kg (50 Units) 2 2 Units/kg (50 Units) 2 1 Unit/kg (50 Units) 2 1 Unit/kg (50 Units) 2 * Did not exceed a total dose of 100 Units ** Did not exceed a total dose of 200 Units The co-primary endpoints were the average of the change from baseline in modified Ashworth Scale (MAS) principal muscle group score (elbow or wrist) at Week 4 and Week 6, and the average of the Clinical Global Impression of Overall Change by Physician (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of how the patient was doing in his/her life using a 9-point scale (-4=very marked worsening to +4=very marked improvement). Compared to placebo, significant improvements in MAS change from baseline were observed at all timepoints for BOTOX-treated patients (see Table 45, Figure 15 and Figure 16). Although CGI scores numerically favored BOTOX over placebo, the difference was not statistically significant. Table 45: Co-Primary Efficacy Endpoints Results in Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To-Treat Population) Mean Change from Baseline in Principal Muscle Group (Elbow or Wrist) on the modified Ashworth Scale Week 4 and 6 Average Mean Clinical Global Impression Score BOTOX 3 Units/kg (N=78) -1.92* BOTOX 6 Units/kg (N=77) -1.87* Placebo (N=79) -1.21 Week 4 and 6 Average Figure 15: Modified Ashworth Scale Score for Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To-Treat Population) – Mean Change from Baseline by Visit Figure 16: Clinical Global Impression of Overall Change for Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To- Treat Population) – Mean Scores by Visit 1.87 *Nominal p value <0.05 Pediatric Lower Limb Spasticity 1.88 1.66 The efficacy and safety of BOTOX for the treatment of lower limb spasticity in pediatric patients 2 to 17 years of age was evaluated in Study 2 (NCT01603628), a randomized, multi-center, double-blind, placebo-controlled study. Study 2 included 381 pediatric patients (125 BOTOX 4 Units/kg, 127 BOTOX 8 Units/kg, and 129 placebo) with lower limb spasticity (modified Ashworth Scale ankle score of at least 2) because of cerebral palsy. A total dose of 4 Units/kg BOTOX (maximum 150 Units), 8 Units/kg BOTOX (maximum 300 Units), or placebo was injected intramuscularly and divided between the gastrocnemius, soleus, and tibialis posterior (see Table 46). Electromyographic guidance, nerve stimulation, or ultrasound techniques were used to assist in muscle localization for injections. Patients were followed for 12 weeks after injection. Table 46: BOTOX Dose and Injection Sites in Study 2 BOTOX 4 Units/kg* BOTOX 8 Units/kg** (maximum Units per muscle) Number of Injection Sites Muscles Injected Mandatory Ankle Muscles Gastrocnemius medial head Gastrocnemius lateral head Soleus Tibialis Posterior (maximum Units per muscle) 1 Unit/kg (37.5 Units) 1 Unit/kg (37.5 Units) 1 Unit/kg (37.5 Units) 1 Unit/kg (37.5 Units) 2 Units/kg (75 Units) 2 2 Units/kg (75 Units) 2 2 Units/kg (75 Units) 2 Units/kg (75 Units) 2 2 * did not exceed a total dose of 150 Units ** did not exceed a total dose of 300 Units The co-primary endpoints were the average of the change from baseline in modified Ashworth Scale (MAS) ankle score at Week 4 and Week 6, and the average of the Clinical Global Impression of Overall Change by Physician (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of how the patient was doing in his/her life using a 9-point scale (-4=very marked worsening to +4=very marked improvement). Statistically significant differences between BOTOX and placebo were demonstrated for the MAS and CGI for the 8 Units/kg dose only (see Table 47). Table 47: Co-Primary Efficacy Endpoints Results in Study 2 (Pediatric Lower Limb Spasticity, Modified Intent-To-Treat Population) Mean Change from Baseline in Plantar Flexors on the modified Ashworth Scale Week 4 and 6 Average Mean Clinical Global Impression Score Week 4 and 6 Average * Significantly different from placebo (p<0.05) ** Nominal p value <0.05 BOTOX 4 Units/kg (N = 125) -1.01** 1.49 BOTOX 8 Units/kg (N=127) -1.06* 1.65* Placebo (N=129) -0.80 1.36 Compared to placebo, improvements in mean change from baseline for the MAS, and mean CGI score for lower limb spasticity were observed at timepoints up to Week 12 for BOTOX-treated patients (see Figure 17 and Figure 18). Figure 17: Modified Ashworth Scale Ankle Score for Study 2 (Pediatric Lower Limb Spasticity, Modified Intent-To-Treat Population) – Mean Change from Baseline by Visit Figure 18: Clinical Global Impression of Overall Change for Study 2 (Pediatric Lower Limb Spasticity, Modified Intent- To-Treat Population) – Mean Scores by Visit Cervical Dystonia A randomized, multi-center, double-blind, placebo-controlled study of the treatment of cervical dystonia was conducted. This study enrolled adult patients with cervical dystonia and a history of having received BOTOX in an open label manner with perceived good response and tolerable side effects. Patients were excluded if they had previously received surgical or other denervation treatment for their symptoms or had a known history of neuromuscular disorder. Subjects participated in an open label enrichment period where they received their previously employed dose of BOTOX. Only patients who were again perceived as showing a response were advanced to the randomized evaluation period. The muscles in which the blinded study agent injections were to be administered were determined on an individual patient basis. There were 214 subjects evaluated for the open label period, of which 170 progressed into the randomized, blinded treatment period (88 in the BOTOX group, 82 in the placebo group). Patient evaluations continued for at least 10 weeks post-injection. The primary outcome for the study was a dual endpoint, requiring evidence of both a change in the Cervical Dystonia Severity Scale (CDSS) and an increase in the percentage of patients showing any improvement on the Physician Global Assessment Scale at 6 weeks after the injection session. The CDSS quantifies the severity of abnormal head positioning and was newly devised for this study. CDSS allots 1 point for each 5 degrees (or part thereof) of head deviation in each of the three planes of head movement (range of scores up to theoretical maximum of 54). The Physician Global Assessment Scale is a 9 category scale scoring the physician’s evaluation of the patients’ status compared to baseline, ranging from –4 to +4 (very marked worsening to complete improvement), with 0 indicating no change from baseline and +1 slight improvement. Pain is also an important symptom of cervical dystonia and was evaluated by separate assessments of pain frequency and severity on scales of 0 (no pain) to 4 (constant in frequency or extremely severe in intensity). Study results on the primary endpoints and the pain-related secondary endpoints are shown in Table 48. Table 48: Efficacy Outcomes of the Phase 3 Cervical Dystonia Study (Group Means) Baseline CDSS Change in CDSS at Week 6 % Patients with Any Improvement on Physician Global Assessment Pain Intensity Baseline Change in Pain Intensity at Week 6 Pain Frequency Baseline Change in Pain Frequency at Week 6 Placebo BOTOX (N=82) (N=88) 9.3 9.2 -0.3 -1.3 31% 51% 1.8 1.8 -0.1 -0.4 1.9 1.8 -0.0 -0.3 95% CI on Difference (-2.3, 0.3)[a,b] (5%, 34%)[a] (-0.7, -0.2)[c] (-0.5, -0.0)[c] [a] Confidence intervals are constructed from the analysis of covariance table with treatment and investigational site as main effects, and baseline CDSS as a covariate. [b] These values represent the prospectively planned method for missing data imputation and statistical test. Sensitivity analyses indicated that the 95% confidence interval excluded the value of no difference between groups and the p-value was less than 0.05. These analyses included several alternative missing data imputation methods and non-parametric statistical tests. [c] Confidence intervals are based on the t-distribution. Exploratory analyses of this study suggested that the majority of patients who had shown a beneficial response by week 6 had returned to their baseline status by 3 months after treatment. Exploratory analyses of subsets by patient sex and age suggest that both sexes receive benefit, although female patients may receive somewhat greater amounts than male patients. There is a consistent treatment- associated effect between subsets greater than and less than age 65. There were too few non-Caucasian patients enrolled to draw any conclusions regarding relative efficacy in racial subsets. In this study the median total BOTOX dose in patients randomized to receive BOTOX (N=88) was 236 Units, with 25th to 75th percentile ranges of 198 Units to 300 Units. Of these 88 patients, most received injections to 3 or 4 muscles; 38 received injections to 3 muscles, 28 to 4 muscles, 5 to 5 muscles, and 5 to 2 muscles. The dose was divided amongst the affected muscles in quantities shown in Table 49. The total dose and muscles selected were tailored to meet individual patient needs. Table 49: Number of Patients Treated per Muscle and Fraction of Total Dose Injected into Involved Muscles Muscle Number of Patients Treated in this Muscle (N=88) Mean % Dose per Muscle Mid-Range of % Dose per Muscle* 83 38 77 25 52 20 49 29 16 21 15 15 25-50 17-31 16-25 18-33 13-25 6-21 17-41 Splenius capitis/cervicis Sternocleidomastoid Levator scapulae Trapezius Semispinalis Scalene Longissimus There were several randomized studies conducted prior to the double-blind, placebo-controlled study, which were supportive but not adequately designed to assess or quantitatively estimate the efficacy of BOTOX. Primary Axillary Hyperhidrosis The efficacy and safety of BOTOX for the treatment of primary axillary hyperhidrosis were evaluated in two randomized, multi- center, double-blind, placebo-controlled studies. Study 1 included adult patients with persistent primary axillary hyperhidrosis who 8 29 * The mid-range of dose is calculated as the 25th to 75th percentiles. scored 3 or 4 on a Hyperhidrosis Disease Severity Scale (HDSS) and who produced at least 50 mg of sweat in each axilla at rest over 5 minutes. HDSS is a 4-point scale with 1 = “underarm sweating is never noticeable and never interferes with my daily activities”; to 4 = “underarm sweating is intolerable and always interferes with my daily activities”. A total of 322 patients were randomized in a 1:1:1 ratio to treatment in both axillae with either 50 Units of BOTOX, 75 Units of BOTOX, or placebo. Patients were evaluated at 4-week intervals. Patients who responded to the first injection were re-injected when they reported a re-increase in HDSS score to 3 or 4 and produced at least 50 mg sweat in each axilla by gravimetric measurement, but no sooner than 8 weeks after the initial injection. Study responders were defined as patients who showed at least a 2-grade improvement from baseline value on the HDSS 4 weeks after both of the first two treatment sessions or had a sustained response after their first treatment session and did not receive re-treatment during the study. Spontaneous resting axillary sweat production was assessed by weighing a filter paper held in the axilla over a period of 5 minutes (gravimetric measurement). Sweat production responders were those patients who demonstrated a reduction in axillary sweating from baseline of at least 50% at week 4. In the three study groups the percentage of patients with baseline HDSS score of 3 ranged from 50% to 54% and from 46% to 50% for a score of 4. The median amount of sweat production (averaged for each axilla) was 102 mg, 123 mg, and 114 mg for the placebo, 50 Units and 75 Units groups respectively. The percentage of responders based on at least a 2-grade decrease from baseline in HDSS or based on a >50% decrease from baseline in axillary sweat production was greater in both BOTOX groups than in the placebo group (p<0.001), but was not significantly different between the two BOTOX doses (see Table 50). Duration of response was calculated as the number of days between injection and the date of the first visit at which patients returned to 3 or 4 on the HDSS scale. The median duration of response following the first treatment in BOTOX treated patients with either dose was 201 days. Among those who received a second BOTOX injection, the median duration of response was similar to that observed after the first treatment. In study 2, 320 adults with bilateral axillary primary hyperhidrosis were randomized to receive either 50 Units of BOTOX (n=242) or placebo (n=78). Treatment responders were defined as subjects showing at least a 50% reduction from baseline in axillary sweating measured by gravimetric measurement at 4 weeks. At week 4 post-injection, the percentages of responders were 91% (219/242) in the BOTOX group and 36% (28/78) in the placebo group, p<0.001. The difference in percentage of responders between BOTOX and placebo was 55% (95% CI=43.3, 65.9). Table 50: Study 1 - Study Outcomes Treatment Response HDSS Score change >2 (n)a >50% decrease in axillary sweat production % (n) BOTOX 50 Units (N=104) 55% (57) 81% (84) BOTOX 75 Units (N=110) 49% (54) 86% (94) Placebo (N=108) 6% (6) 41% (44) BOTOX 50-placebo (95% CI) 49.3% (38.8, 59.7) 40% (28.1, 52.0) BOTOX 75-placebo (95% CI) 43% (33.2, 53.8) 45% (33.3, 56.1) a Patients who showed at least a 2-grade improvement from baseline value on the HDSS 4 weeks after both of the first two treatment sessions or had a sustained response after their first treatment session and did not receive re-treatment during the study. Blepharospasm Botulinum toxin has been investigated for use in patients with blepharospasm in several studies. In an open label, historically controlled study, 27 patients with essential blepharospasm were injected with 2 Units of BOTOX at each of six sites on each side. Twenty-five of the 27 patients treated with botulinum toxin reported improvement within 48 hours. One patient was controlled with a higher dosage at 13 weeks post initial injection and one patient reported mild improvement but remained functionally impaired. In another study, 12 patients with blepharospasm were evaluated in a double-blind, placebo-controlled study. Patients receiving botulinum toxin (n=8) improved compared with the placebo group (n=4). The effects of the treatment lasted a mean of 12 weeks. One thousand six hundred eighty-four patients with blepharospasm who were evaluated in an open label trial showed clinical improvement as evaluated by measured eyelid force and clinically observed intensity of lid spasm, lasting an average of 12 weeks prior to the need for re-treatment. Strabismus Six hundred seventy-seven patients with strabismus treated with one or more injections of BOTOX were evaluated in an open label trial. Fifty-five percent of these patients improved to an alignment of 10 prism diopters or less when evaluated six months or more following injection. HOW SUPPLIED/STORAGE AND HANDLING How Supplied BOTOX (onabotulinumtoxinA) for injection is a sterile, vacuum-dried powder supplied in a single-dose vial in the following sizes: 100 Units NDC 0023-1145-01 200 Units NDC 0023-3921-02 The top and bottom flaps of the BOTOX cartons have a tamper-evident seal that contains a translucent silver Allergan logo and the BOTOX vial labels have a holographic film that contains the name “Allergan” within rainbow colored horizontal lines (rotate the vial back and forth between your fingers under a desk lamp or fluorescent light source to see the hologram). (Note: the holographic film on the label is absent in the date/lot area.) Each BOTOX vial label and carton also contains the U.S. License number: 1145 [see Dosage and Administration (2.1)]. Do not use the product and contact Allergan for additional information at 1-800-890-4345 from 7:00 AM to 3:00 PM Pacific Time if the labeling is not described as above. Storage and Handling Unopened vials of BOTOX should be stored in a refrigerator between 2° to 8°C (36o to 46oF) for up to 36 months. Do not use after the expiration date on the vial. Reconstituted BOTOX may be stored in a refrigerator (2° to 8°C) for up to 24 hours until time of use [see Dosage and Administration (2.2)]. PATIENT COUNSELING INFORMATION Advise the patient or caretaker to read the FDA-approved patient labeling (Medication Guide). Swallowing, Speaking or Breathing Difficulties, or Other Unusual Symptoms Advise patients or their caretaker(s) to inform their doctor or pharmacist if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing), or if any existing symptom worsens [see Boxed Warning and Warnings and Precautions (5.1, 5.6)]. Ability to Operate Machinery or Vehicles Advise patients or their caretaker(s) that if loss of strength, muscle weakness, blurred vision, dizziness, or drooping eyelids occur, they should avoid driving a car or engaging in other potentially hazardous activities. Voiding Symptoms after Bladder Injections After bladder injections for urinary incontinence, advise patients to contact their physician if they experience difficulties in voiding or burning sensation upon voiding. Manufactured by: Allergan Pharmaceuticals Ireland a subsidiary of: Allergan, Inc. U.S. License Number 1145 Distributed by: Allergan USA, Inc. Madison, NJ 07940 © 2021 Allergan. All rights reserved. All trademarks are the property of their respective owners. Patented. See: www.allergan.com/patents v8.0USPI1145 MEDICATION GUIDE BOTOX® BOTOX® Cosmetic (Boe-tox) (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor, or intradermal use What is the most important information I should know about BOTOX and BOTOX Cosmetic? BOTOX and BOTOX Cosmetic may cause serious side effects that can be life threatening, including:  Problems breathing or swallowing  Spread of toxin effects These problems can happen hours, days, to weeks after an injection of BOTOX or BOTOX Cosmetic. Call your doctor or get medical help right away if you have any of these problems after treatment with BOTOX or BOTOX Cosmetic:  Problems swallowing, speaking, or breathing. These problems can happen hours, days, to weeks after an injection of BOTOX or BOTOX Cosmetic usually because the muscles that you use to breathe and swallow can become weak after the injection. Death can happen as a complication if you have severe problems with swallowing or breathing after treatment with BOTOX or BOTOX Cosmetic. o People with certain breathing problems may need to use muscles in their neck to help them breathe. These people may be at greater risk for serious breathing problems with BOTOX or BOTOX Cosmetic. o Swallowing problems may last for several months. People who cannot swallow well may need a feeding tube to receive food and water. If swallowing problems are severe, food or liquids may go into your lungs. People who already have swallowing or breathing problems before receiving BOTOX or BOTOX Cosmetic have the highest risk of getting these problems.  Spread of toxin effects. In some cases, the effect of botulinum toxin may affect areas of the body away from the injection site and cause symptoms of a serious condition called botulism. The symptoms of botulism include: o loss of strength and muscle weakness all over the body o double vision, blurred vision and drooping eyelids o hoarseness or change or loss of voice (dysphonia) o trouble saying words clearly (dysarthria) o loss of bladder control o trouble breathing o trouble swallowing These symptoms can happen hours, days, to weeks after you receive an injection of BOTOX or BOTOX Cosmetic. These problems could make it unsafe for you to drive a car or do other dangerous activities. See "What should I avoid while receiving BOTOX or BOTOX Cosmetic?" 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, or when BOTOX Cosmetic has been used at the recommended dose to treat frown lines, crow’s feet lines, and/or forehead lines. What are BOTOX and BOTOX Cosmetic? 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 when another type of medicine (anticholinergic) does not work well enough or cannot be taken.  to treat leakage of urine (incontinence) in adults with overactive bladder due to neurologic disease when another type of medicine (anticholinergic) does not work well enough or cannot be taken.  to treat overactive bladder due to a neurologic disease in children 5 years of age and older when another type of medicine (anticholinergic) does not work well enough or cannot be taken.  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.  to treat increased muscle stiffness in people 2 years of age and older with spasticity.  to treat the abnormal head position and neck pain that happens with cervical dystonia (CD) in adults.  to treat certain types of eye muscle problems (strabismus) or abnormal spasm of the eyelids (blepharospasm) in people 12 years of age 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. BOTOX Cosmetic is a prescription medicine for adults that is injected into muscles and used for a short period of time (temporary) to improve the look of:  moderate to severe frown lines between the eyebrows (glabellar lines)  moderate to severe crow’s feet lines  moderate to severe forehead lines You may receive treatment for frown lines, crow’s feet lines, and forehead lines at the same time. It is not known whether BOTOX is safe and effective in people younger than: 18 years of age for treatment of urinary incontinence 18 years of age for treatment of chronic migraine 16 years of age for treatment of cervical dystonia       BOTOX Cosmetic is not recommended for use in children younger than 18 years of age. 18 years of age for treatment of hyperhidrosis 12 years of age for treatment of strabismus or blepharospasm 2 years of age for treatment of spasticity It is not known whether BOTOX and BOTOX Cosmetic are safe and effective to prevent headaches in people with migraine who have 14 or fewer headache days each month (episodic migraine). It is not known whether BOTOX and BOTOX Cosmetic are safe and effective for severe sweating anywhere other than your armpits. It is not known if BOTOX Cosmetic is safe and effective for use more than 1 time every 3 months. Who should not receive BOTOX or BOTOX Cosmetic? Do not receive BOTOX or BOTOX Cosmetic if you:  are allergic to any of the ingredients in BOTOX or BOTOX Cosmetic. See the end of this Medication Guide for a complete list of ingredients in BOTOX and BOTOX Cosmetic.  had an allergic reaction to any other botulinum toxin product such as Myobloc®, Dysport®, or Xeomin®.  have a skin infection at the planned injection site.  are being treated for urinary incontinence and have a urinary tract infection (UTI).  are being treated for urinary incontinence and find that you cannot empty your bladder on your own (only applies to people who are not routinely catheterizing). What should I tell my doctor before receiving BOTOX or BOTOX Cosmetic? Tell your doctor about all your medical conditions, including if you:  have a disease that affects your muscles and nerves (such as amyotrophic lateral sclerosis [ALS or Lou Gehrig's disease], myasthenia gravis or Lambert-Eaton syndrome). See "What is the most important information I should know about BOTOX and BOTOX Cosmetic?"  have allergies to any botulinum toxin product.  had any side effect from any botulinum toxin product in the past.  have or have had a breathing problem, such as asthma or emphysema.  have or have had swallowing problems.  have or have had bleeding problems.  have plans to have surgery.  had surgery on your face.  have weakness of your forehead muscles, such as trouble raising your eyebrows.  have drooping eyelids.  have any other change in the way your face normally looks.  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 or BOTOX Cosmetic can harm your unborn baby.  are breastfeeding or plan to breastfeed. It is not known if BOTOX or BOTOX Cosmetic 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 or BOTOX Cosmetic 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 or BOTOX Cosmetic in the past. Especially tell your doctor if you:  have received any other botulinum toxin product in the last four months.  have received injections of botulinum toxin, such as Myobloc® (rimabotulinumtoxinB), Dysport® (abobotulinumtoxinA), or Xeomin® (incobotulinumtoxinA) in the past. Be sure your doctor knows 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 anti-platelets (aspirin-like products) or anti-coagulants (blood thinners). Ask your doctor if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine. How will I receive BOTOX or BOTOX Cosmetic?  BOTOX or BOTOX Cosmetic is an injection that your doctor will give you.  BOTOX is injected into your affected muscles, skin, or bladder.  BOTOX Cosmetic is injected into your affected muscles.  Your doctor may change your dose of BOTOX or BOTOX Cosmetic, until you and your doctor find the best dose for you.  Your doctor will tell you how often you will receive your dose of BOTOX or BOTOX Cosmetic injections. What should I avoid while receiving BOTOX or BOTOX Cosmetic? BOTOX and BOTOX Cosmetic may cause loss of strength or general muscle weakness, vision problems, or dizziness within hours to weeks of taking BOTOX or BOTOX Cosmetic. If this happens, do not drive a car, operate machinery, or do other dangerous activities. See "What is the most important information I should know about BOTOX and BOTOX Cosmetic?" What are the possible side effects of BOTOX and BOTOX Cosmetic? BOTOX and BOTOX Cosmetic can cause serious side effects. See "What is the most important information I should know about BOTOX and BOTOX Cosmetic?" Other side effects of BOTOX and BOTOX Cosmetic 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, and dry eyes.  drooping eyebrows.  urinary tract infection in both children and adults being treated for urinary incontinence.  painful urination in adults being treated for urinary incontinence.  bacteria in the urine of children being treated for urinary incontinence.  inability to empty your bladder on your own and are being treated for urinary incontinence. If you have difficulty fully emptying your bladder after getting 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.  allergic reactions. Symptoms of an allergic reaction to BOTOX or BOTOX Cosmetic may include: itching, rash, red itchy welts, wheezing, asthma symptoms, or dizziness or feeling faint. Tell your doctor or get medical help right away if you are wheezing or have asthma symptoms, or if you become dizzy or faint.  upper respiratory tract infection. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of BOTOX and BOTOX Cosmetic. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088. General information about the safe and effective use of BOTOX and BOTOX Cosmetic: Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about BOTOX and BOTOX Cosmetic. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about BOTOX and BOTOX Cosmetic that is written for health professionals. What are the ingredients in BOTOX and BOTOX Cosmetic? Active ingredient: onabotulinumtoxinA Inactive ingredients: human albumin and sodium chloride Manufactured by: Allergan Pharmaceuticals Ireland a subsidiary of: Allergan, Inc. U.S. License Number 1145 Distributed by: Allergan USA, Inc. Madison, NJ 07940 2021 Allergan. All rights reserved. All trademarks are the property of their respective owners. Patented. See: www.allergan.com/patents v5.0MG1145 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 2/2021

If you’ve had Botox®, or are considering having the treatment, you’ll want to know how to care for yourself afterwards. You’ll receive full Botox® aftercare instructions after having treatment with Health & Aesthetics, but the expert advice below will give you a good idea of what to expect. Potential side effects after having Botox® What to do and what to avoid after having Botox® What happens when Botox® wears off Further frequently asked questions on Botox aftercare Potential side effects after having Botox® What are some of the possible side effects? Although they are very rare, there are some adverse effects associated with having Botox. After treatment you’ll receive full aftercare instructions, including a list of potential side effects. They include: excessive bruising, swelling or redness at injection site infection nausea, headache or flu-like symptoms occasional numbness drooping eyebrow or upper eyelid red and swollen eyelids muscle weakness1 allergic reactions rash and itchiness facial swelling If you experience any of the above after having Botox®, speak to your practitioner immediately. How will I know if I’ve had an allergic reaction to Botox®? An allergic reaction to Botox® is very rare. However, if you experience any of the following symptoms, this could be an indication of an allergic reaction and you should seek medical help immediately: Itching and swelling of the face A rash Dizziness Having trouble breathing If it’s the injection sites are red and tender this might be a sign that the area has become infected. But don’t worry—this is extremely unlikely to happen if your Botox® was administered by a reputable clinic with qualified staff. What are the side effects of Botox® for migraines? They are the same as having Botox® for cosmetic reasons. Some patients may also experience neck pain, although—as with other side effects—this is very rare. You can find out more about Botox® treatment for migraines and headaches here. What are the side effects of underarm Botox® injections for excessive sweating? They are very similar to those that come with having Botox® as a facial treatment. You can find out more in the risks and side effects section of our page How Botox Stops Excessive Sweating & How It Can Help You. Will I experience bruising after Botox®? Bruising is one of the most common side effects of having Botox® treatment. It sometimes happens where the needles are inserted into the skin. However, unless it’s excessive, it’s nothing to worry about and is a natural part of the healing process. How long does Botox® bruising last? This varies from person to person, but if you do experience bruising after Botox®, you can expect it to last for around a week. My forehead is swollen after having Botox®—is this normal? Yes, some swelling is normal after having Botox® treatment. Ways you can reduce swelling include: applying a cold compress to the area (though make sure you don’t rub the area or hold the compress in place for too long) applying arnica cream to the area (some people have found that arnica works at making swelling go down) avoiding lying down for four hours after treatment If you’re worried that the swelling is excessive, speak to your Botox® clinic. I have tightness in my forehead after Botox®—is this normal? Yes, you may experience tightness on your forehead around four or five days after having treatment. It can last for five or six days. What can I do to reduce swelling, bruising and bleeding after having Botox®? There are certain medications, supplements and vitamins you should stop taking before having Botox® treatment, as they can cause any swelling and bruising to worsen. These include: ibuprofen or aspirin—stop at least one week before having treatment blood thinning medication St John’s wort gingko biloba vitamin E If a doctor has prescribed you any of these medicines, you must check with them first that it’s safe to stop. When you come to Dr. Vigo for your consultation, we will take a full medical history from you, including any current medications and supplements you’re taking. Can Botox® cause dizziness? Yes, dizziness can be a side effect of Botox®, although it is very rare. If you experience dizziness after having Botox® injections, speak to your practitioner immediately. Could Botox® cause hair loss? No, there is no scientific evidence that Botox® causes hair loss. Does Botox® make you tired? No, there is no scientific evidence that Botox® causes tiredness. Why do I have droopy eyelids after Botox®? If the Botox® has been injected too low in the forehead, it can cause the muscle to overly relax and ‘push down’ on your upper eyelids. However, this effect isn’t permanent and will wear off in three to four months. Choosing a qualified and experienced practitioner will help avoid having negative results such as droopy eyelids. I’ve had Botox® without realising I was pregnant. What should I do? It’s not advisable to have Botox® injections when pregnant because there have been no large-scale, long-term studies to assess the effect Botox® has on a developing baby. However, as the amount of Botox® administered is small and won’t easily move to other areas of the body once injected, the risk of it harming your baby is extremely small. Can you reverse Botox®? No, it isn’t possible to reverse the effects of Botox®. So, if you’re unhappy with the results, you’ll need to wait around 10–12 weeks for the effects to wear off. Choosing a highly experienced and qualified Botox® practitioner will ensure you’re happy with your results. However, if you’re not satisfied for any reason, speak to your practitioner, as they may be able to do some corrective work. What to do and what to avoid before and after having Botox® To ensure you get the best possible results from your Botox®, there are a few do’s and don’ts you should follow after having the treatment. Pain management after Botox® Should I apply ice after having Botox®? Dr. Vigo recommends not applying any pressure to the area as this can move the Botox, this includes pressing ice onto the area. Instead we suggest you take arnica tablets to help reduce the risk of bruising and also to help any bruising to settle What painkillers can I take before or after having Botox®? You can take paracetamol before and after the procedure but avoid anti-inflammatory medications such as Can I take ibuprofen before having Botox®? You should avoid taking ibuprofen before having Botox® as the medicine is an anticoagulant. This means it can prevent blood from clotting properly, which can increase the risk of bruising. You should also avoid taking ibuprofen for at least four days before having Botox® treatment. Botox aftercare and sleeping Can I sleep on my side after having Botox®? Yes, provided you wait at least four hours before lying down. Botox® takes a few hours to settle into place, so lying down straightaway could cause it to migrate to other muscles in your face and increase the risk of complications. Should I sleep in a certain position? You can sleep in any position after having Botox®, but you should avoid lying down for at least four hours following the treatment. How long after having Botox® can I lie down? We recommend not lying down for at least four hours after having Botox®. Not only will it help prevent any excessive swelling but it will stop the Botox® migrating to other parts of the face and causing muscle weakness in those areas, a rare but possible side effect of having the treatment. Exposure to heat after Botox® Should I avoid heat after Botox®? Yes, as heat can increase the chance of you suffering bruising where you were at the injection site. You should avoid hot showers, baths and hot tubs for 24 hours after having Botox®. Can I go on a sunbed after having Botox®? After having Botox®, you should wait at least four hours before you use a sunbed. This is because lying down for extended periods immediately after the procedure could cause the Botox® to move to other muscles in the face, away from the muscles that were injected. Although exposure to UV light won’t affect the results of your Botox® treatment, it’s the number one cause of wrinkles. So, if you want your skin to look younger for as long as possible, avoid using sunbeds and use a strong sunscreen if you’re out in the sun. How soon can I go out in the sun after having Botox®? You can go out in the sun immediately after having Botox®. Sun exposure can cause wrinkles though, so be sure to wear a strong sunscreen. Exercise and movement after Botox® How soon can I exercise after Botox®? It’s best to avoid strenuous aerobic exercise for 24 hours after having Botox®. Strenuous exercise can result in bruising and, in rarer cases, cause the Botox® to move to other areas of your face and temporarily paralyse the muscles there. For the same reason, you should avoid doing yoga for 24 hours—the inverted positions can cause Botox® move to other muscles in the face. What happens if I bend over after having Botox®? It’s possible that the Botox® may shift from where it was injected to other areas of your face. However, the risk is very small, so unless you’re bending forward repeatedly or for substantial periods of time (for example, if performing yoga moves) straight after having Botox®, you should be fine. Should I do facial exercises after having Botox®? Certain studies have shown that doing facial exercises after having Botox can speed up the effects of having the treatment2. Drinking, driving and flying after having Botox® How soon after having Botox® can I consume alcohol? It’s best to avoid drinking alcohol for a day or two before and after the procedure. As alcohol increases fluid retention and thins the blood, it can worsen the mild bruising that often occurs where the needles are injected. Drinking alcohol is highly unlikely to have any long-term detrimental effects on the results of your treatment. Can I drink coffee before Botox® treatment? Yes, the caffeine in coffee shouldn’t cause any problems with your Botox® treatment. How soon after having Botox® can I fly? We advise our patients to avoid flying for 24–48 hours after treatment. There are concerns that the changes in air pressure in an aeroplane cabin can affect the results of Botox® by moving the substance to other muscles in the face. Make-up, face washing and facial treatments after having Botox® How soon after having Botox® can I wash my face? You can gently wash your face straight after having Botox®. However, for seven days after the procedure you should avoid facials, massages and other treatments that put direct pressure on the face. Can I touch my face after having Botox®? Yes, you can continue your regular skin care routine, including touching your face to cleanse and moisturise it. However, it’s best to wait at least six hours—ideally 24 hours—before massaging or rubbing the skin. How soon can I have a facial or a microdermabrasion after having Botox®? It’s best to wait at least seven days before having facials or a microdermabrasion. You should also avoid chemical peels, laser treatment and sunbeds for at least seven days. I rubbed my face after having Botox®. Will this affect the results? No, it should have no effect, especially if it happened several hours after having the procedure. However, rubbing your face immediately after having Botox® isn’t recommended, in case it causes the Botox® to move away from the injected part of your face and into other areas. Can I get my eyebrows waxed after Botox®? Yes, as long as you wait two weeks first. Having Botox® can influence the shape of your eyebrows, so allow two weeks for the treated part of your face to fully heal and show the full results. Waiting two weeks before having waxing, or any form of hair removal treatment is recommended. Can I wear make-up after having Botox? We recommend not applying make-up for at least four hours after having treatment. After this time you can return to your usual make-up and skincare routine. What happens when Botox® wears off What happens when the results of Botox® wear off? After around three to four months, you’ll start to notice the areas you had treated with Botox® gradually returning to how they looked before having treatment. How long will the results of Botox® last? Most people’s results last for 10–12 weeks. Can you feel Botox® wearing off? You shouldn’t be able to feel Botox® wearing off but you’ll gradually notice its effects subsiding and wrinkles starting to reappear. When Botox® wears off, are wrinkles worse? No. If you feel your wrinkles look more pronounced after Botox® treatment has worn off, it will most likely be because you’ve become used to your face looking smoother. How long does it take for Botox to work? You should start to see the effects of Botox® around two to three days3 after having the treatment. You’ll gradually notice the effects become more pronounced until the full results appear after about 14 days. What should I do after having Botox® in my forehead? You’ll be able to resume most of your regular activities straightaway. The only things you’ll be told to avoid immediately after treatment are: drinking alcohol having a hot shower or bath rubbing your face lying down or leaning forward for extended periods You’ll be advised to avoid these activities for up to 24 hours after treatment. To help work the Botox® into your facial muscles, you can exercise those areas of your face (for example, by raising your eyebrows or pursing your lips). Can I do anything after having Botox® to ensure the treatment works as well as possible? Yes. Four hours after the treatment, you can begin to exercise the treated muscles by making facial expressions such as frowning, squinting or raising your eyebrows. This will help to work the Botox® into your facial muscles.

How does Botox treatment work? Botulinum Toxin (Botox ®) when injected into a muscle temporarily relaxes the muscle by blocking nerve impulses. As the nerve impulses are blocked the muscle is temporarily unable to contract so that dynamic wrinkles are not formed. This gives the overlying facial skin a softer, smoother and more youthful appearance. Botox FAQsBotox is very well tolerated and usually problem-free. Side effects are minimal.uthful appearance. Is Botox treatment safe Botulinum Toxin as a muscle relaxant has an excellent safety record and a long record of use in medicine. It has been used successfully in adults and children in variety medical conditions over the last 20 years. It has been used cosmetically to treat facial wrinkles for about 15 years and has become one of the most popular and frequently used cosmetic treatments. Who can have Botox? Botox Treatment can be used for treating wrinkles in men and women, however men often need slightly higher doses than women. It should not be used in People with infection at the proposed injection site. People who have previously had an allergic reaction to Botulinum toxin type A injections. People with muscle problems or chronic diseases affecting the muscles, such as Myasthenia Gravis, Eaton Lambert syndrome. Children under the age of 18 years. Women who are pregnant or breast feeding. It should be used cautiously in (please let the doctor know if the following applies to you) People at risk of bleeding as there is an increased risk of bruising post procedure. These include people who have blood clotting disorders such as Haemophilia, those who are taking treatments with anticoagulant medicines such as Warfarin, Heparin, Aspirin and Anti-Inflammatory medicines. Certain herbal remedies such as Gingiko Bilboa, St John’s Wort and Vitamin E People with excessive weakness or wasting in the muscle to be injected, such as those patients with history of Strokes or Bell’s Palsy People with Chronic Breathing difficulties Does the injection hurt Botox injections are relatively painless as the injections are performed using a very fine needle. Patients therefore and do not require any anaesthesia. The full treatment takes about 15-20 minutes to perform and you are able to drive and go to work the same day. How Long Do The Effects Last? It can take about 2-14 days to see the full effects after the initial treatment. The cosmetic effects can last up to six months but typically range from three to four months. Eventually most people require re treatment as the wrinkles reappear. However in some treated areas (such as frown wrinkles), the wrinkles may return less severe after repeated treatments as the unconscious muscle contraction habit is broken. We offer all our patients a free two week follow up appointment to assess the effect of treatment and administer any top up treatments if necessary. Are there any side effects? Most people find that the injections cause only mild local pain and tenderness. Immediately after the injection there may be mild swelling at the injection site which usually subsides within 48 hours. Slight bruising is also possible. Side effects of these treatments are extremely rare. Occasionally, the treatment may relax nearby muscle groups causing temporary drooping of the eyebrow or eyelids. This may last for a few weeks but will resolve with time. As with any medicine an allergic reaction may occur, this is however quite rare. Conversely there may be some unintended benefits in some people such as easing of tension type headaches as the muscles in the forehead relax. Botox has been used for over 20 years and does not appear to cause any negative long-term effects. Once administered, Botox typically leaves the body within 3-4 days, although, as with any medical procedure, it is important to seek advice from a qualified professional beforehand. How Often can I have treatments? When the effect of the Botox injection wears off the wrinkles will always return to their pre-treatment state. Treatments can be repeated at a minimum of three monthly intervals, but the effects may last longer for some individuals, especially if they have had previous treatments to the same area. Will I still have expression in my face? Botox treatments are designed to smooth dynamic wrinkles in the forehead and around eyes, they do not affect your facial expression. The final result can be tailored to each patient and can be discussed at the initial free consultation. What After Care Advice Should I Follow? Try to contract the treated muscle areas for up to four hours after treatment, by frowning and lifting eyebrows to allow the toxin to reach all of the treated muscle. Avoid rubbing or touching the injected areas and avoid having facials and massage for 48 hours this is to ensure that the treatment remains at the site of injection. Avoid vigorous exercise and alcohol-based products on the area treated for 48 hours. If bruising develops the you can apply Arnica cream Paracetamol can be taken for mild pain post procedure

BOTOX® Cosmetic is a technique-sensitive treatment. You can trust BOTOX® Cosmetic to deliver subtle results when you are treated by someone who is licensed, trained, and a medical expert in facial anatomy. So you’ll look like yourself - only with less noticeable lines. No one should be able to tell you’ve had anything done. WHAT IS BOTOX® COSMETIC? BOTOX® Cosmetic is the #1 selling treatment of its kind*: It’s the first and only treatment FDA-approved to temporarily make moderate to severe frown lines, crow’s feet, and forehead lines look better in adults Treatment requires minimal downtime. You can return to your daily routine immediately after you leave your specialist’s office You may begin to notice results within 24 to 48 hours for moderate to severe frown lines. Full results in 30 days It delivers predictable, subtle results, so you look like you, only with less noticeable facial lines Join the millions of men and women who make BOTOX® Cosmetic part of what they do to care for their appearance. Ask for the first and only BOTOX® Cosmetic by name. See Why BOTOX Cosmetic Is Different *Data collected through 2020. HOW MUCH RESEARCH HAS GONE INTO BOTOX® COSMETIC? When you choose BOTOX® Cosmetic, you can trust in its established track record. Backed by over 16 years of published studies, BOTOX® Cosmetic is the most widely researched and studied treatment of its kind, approved for use in 95 countries. The safety and efficacy of BOTOX® Cosmetic have been described in more than 528 peer-reviewed articles in scientific and medical journals. Learn The Story of BOTOX Cosmetic HOW DOES BOTOX® COSMETIC WORK? BOTOX® Cosmetic targets one of the underlying causes of frown lines, crow’s feet and forehead lines — the repeated muscle contractions from frowning, squinting, smiling and raising the eyebrows over the years. Your specialist will inject these muscles with BOTOX® Cosmetic to temporarily reduce muscle activity. You will begin to notice a visible smoothing of the frown lines between your brows, your crow’s feet lines and your forehead lines. Learn How BOTOX Cosmetic Works IS THERE A SUBSTITUTE FOR BOTOX® COSMETIC? BOTOX® Cosmetic is a biologic product that cannot be interchanged – or substituted – for another product. In fact, the FDA has stated BOTOX® Cosmetic is “non-interchangeable,” which means that its safety and effectiveness cannot be claimed by any other product. The potency – or strength – of BOTOX® Cosmetic is measured in scientifically defined units that cannot be compared to any other product, due to our unique manufacturing process. There are no substitutes for our product. People who are prescribed a biologic product have a right to know exactly what they are receiving. Be sure to ask which product you are being prescribed and why. WILL MY FACE LOOK OVERDONE OR UNNATURAL? BOTOX® Cosmetic is a technique-sensitive treatment. You can trust BOTOX® Cosmetic to deliver subtle results when you are treated by someone who is licensed, trained, and a medical expert in facial anatomy. So you’ll look like yourself—only with less noticeable lines. No one should be able to tell you’ve had anything done. Compare the before and after pictures of real patients in our gallery, and see the difference for yourself. See Real Results HOW CAN I SAVE ON BOTOX® COSMETIC? Be wary of discount products or “cheap” BOTOX® Cosmetic – if it sounds too good to be true, it probably is. Your cost of BOTOX® Cosmetic not only includes the price of the product, but more importantly, the skill and expertise of the specialist or healthcare professional who is administering your treatment. The best way to save money on your treatments is to enroll in AllēSM, the aesthetics loyalty program by the makers of BOTOX® Cosmetic. With AllēSM, you can earn points and rewards for savings on future treatments. It’s easy and free to join! Use your existing Brilliant Distinctions® information or create a new account to unlock all that AllēSM has to offer. Join AllēSM IS BOTOX® COSMETIC ONLY FOR WOMEN? Not at all! Many men make BOTOX® Cosmetic part of what they do to care for their appearance. The number of men choosing treatments like BOTOX® Cosmetic has risen fast – in the past three years alone, men have received over one million botulinum toxin treatments. When surveyed, the majority of men say they want to look good and they’re bothered by the changes they see in the mirror. 80% would choose to treat their crow’s feet first, while 74% would prioritize their forehead lines, and 60% would most like to treat their frown lines.† †Results from a survey of men to determine most likely treatment areas and top areas of concern for injectable-naive, aesthetically-oriented men aged 30 to 65 years (N=600). Proportion of respondents selecting that area as highest priority to treat using the Maximum Difference (MaxDiff) scaling system. DO I NEED TO BE OVER 40 TO START USING BOTOX® COSMETIC? It’s not your age that determines when BOTOX® Cosmetic is right for you, it’s the severity of your lines. In fact, 64% of plastic surgeons report seeing a rise in cosmetic surgery or injectable treatments for patients in their early 30’s. The truth is, everyone’s lines form differently. The timing can be influenced by a combination of factors, from cellular changes that may occur over time, to reduction of collagen, to genetic factors, or damage caused by free radicals from the sun and the environment. Whenever your lines start to bother you, go speak with your doctor. They can help you determine if treatment is right for you. Find a Specialist HOW MUCH TIME DOES BOTOX® COSMETIC TREATMENT TAKE? WILL IT HURT? Your specialist will discuss your treatment goals and perform a facial analysis to determine the appropriate treatment areas for you. If the HCP deems you to be an appropriate candidate, the injection may take place on that same day. Some patients report that being injected with BOTOX® Cosmetic feels like a pinch. Your specialist may use ice to numb the treatment area. Or, if you are concerned about discomfort, your specialist may apply a topical numbing cream before administering your treatment. Treatment requires minimal downtime. So you can return to your daily routine immediately after you leave your specialist’s office. WILL I SEE RESULTS QUICKLY? HOW LONG DOES BOTOX® COSMETIC LAST? You may begin to notice results within 24 to 48 hours, with full results in 30 days, with results lasting up to four months for moderate to severe frown lines. Remember that results vary from patient to patient though, so your physician will plan your next appointment based on your results and aesthetic goals. Start talking about your goals with a specialist today and find out what you could expect. Find a Specialist HOW LONG IS THE RECOVERY TIME AFTER TREATMENT? Treatment requires minimal downtime. So you can return to your daily routine immediately after you leave your specialist’s office. Learn How BOTOX Cosmetic Works HOW MANY INJECTIONS WILL I RECEIVE? Treatment with BOTOX® Cosmetic is customized to your goals and needs. When you meet with your specialist, he or she will determine the appropriate treatment for any areas you wish to address, including moderate to severe frown lines, crow’s feet and forehead lines. Remember, only BOTOX® Cosmetic is approved to treat all three of these areas. For the crow’s feet area, your specialist will inject 3 areas of the muscle that frames the side of the eye. This will be repeated on the muscle that frames the other eye. For the frown lines area, your specialist will administer 5 injections into the muscles between your brows and in your forehead. For the forehead lines area, your specialist will administer 5 injections into a muscle in your forehead. Learn How BOTOX Cosmetic Works WHAT WERE COMMON SIDE EFFECTS SEEN IN CLINICAL STUDIES? Three percent of patients experienced eyelid drooping in the frown lines studies, one percent of patients experienced eyelid swelling in the crow’s feet studies, and one percent of patients experienced brow drooping in the forehead lines studies. Other possible side effects include: dry mouth; discomfort or pain at the injection site; tiredness; headache; neck pain; eye problems: double vision, blurred vision, decreased eyesight and dry eyes; and allergic reactions. These are not all of the possible serious side effects of BOTOX® Cosmetic. Please see the Important Safety Information including Boxed Warning and Medication Guide and talk to your specialist. IS THERE A “GENERIC” BOTOX® COSMETIC? There is no such thing as a “generic” form of BOTOX® Cosmetic. Be wary of discount products or “cheap” BOTOX® Cosmetic. Medical formulations, potency, and approved doses vary among products, so no one product can take the place of another. FDA labeling states that BOTOX® Cosmetic is not interchangeable with any other product. If it doesn’t say BOTOX® Cosmetic on the vial, then it isn’t BOTOX® Cosmetic. BOTOX® Cosmetic has a one-of-a-kind formulation. And BOTOX® Cosmetic is the most widely researched and studied treatment of its kind. Backed by more than 16 years of published studies, the safety and efficacy of BOTOX® Cosmetic have been described in 528 peer-reviewed articles in scientific and medical journals. Finally, Allergan, the maker of BOTOX® Cosmetic, owns the entire manufacturing and packaging process, which helps ensure the reliability and safety of each vial. For proven results, ask for BOTOX® Cosmetic.

The main benefit of Botox is its ability to smooth lines and wrinkles, giving a smoother appearance to the skin. However, Botox is also used medically for issues including migraines, TMJ, cervical dystonia and hyperhidrosis (excessive sweating). Q. How does Botox work? A. Botox is just one of many brands of botulinum toxin - an injectable substance that is used as an anti-wrinkle treatment. It’s injected into the target area to reduce movement in the muscle, which leads to smoother skin with reduced lines and wrinkles. Other brands of botulinum toxin include Vistabel, Dysport, Azzalure, Xeomin and Bocouture. Muscles contract when they get a message from a nerve ‘telling them’ to contract. Botulinum toxin prevents this message from passing from the nerve to the muscle, so the muscle becomes temporarily paralysed. This reduced the movement, folding and scrunching of the skin above the muscle, so the lines are softened. In time, the toxin is broken down and movement returns. Q. What are the main Botox benefits? A. The main benefit of Botox is its ability to smooth lines and wrinkles, giving a smoother appearance to the skin. However, Botox is also used medically for issues including migraines, TMJ, cervical dystonia and hyperhidrosis (excessive sweating). Q. What are the main Botox areas? A. Anti-wrinkle injections are used on dynamic lines, so you can have Botox for forehead lines, Botox for frown lines (AKA 11s), and Botox for crow’s feet, lipstick lines and bunny lines. It’s effective at significantly reducing lines and wrinkles in these areas. For static lines and wrinkles, dermal fillers are used instead. But it’s not only used for cosmetic reasons. It’s used in tonnes of medical instances too! There’s Botox for migraine, underarm Botox (i.e. Botox for sweating), masseter Botox and loads more. Q. What are the main Botox side effects? A. Anti-wrinkle injections such as Botox are FDA-approved, meaning lots of research has been conducted on them to ensure they are safe for use. However, after anti-wrinkle treatment, it’s common to experience redness, pinprick marks and sometimes bruising, but these should subside relatively quickly. If you notice prolonged bruising, irritation or infection around the area, drooping or difficulty swallowing, call your practitioner right away so they can provide you with the advice and Botox aftercare you need. Be sure to avoid exercise, alcohol, aspirin and ibuprofen for the next 24 hours, and don’t rub the treated area as it can lead to the toxin moving. Find out more about the dos and don’ts before and after Botox here. Q. How long is a Botox appointment? A. Botox injections are relatively quick and straightforward, and take around just 15 minutes. However, prior to your treatment, you should expect an in-depth and thorough medical consultation with your practitioner. So allow for around an hour for a wrinkle relaxing appointment. Q. How long does Botox take to work? A. How long it takes for the effects of Botox to start varies from person to person, but it generally takes around 3 to 14 days before it kicks in. When this happens, you’ll start to see minimised lines and wrinkles. Q. Is there any Botox downtime? A. There’s no downtime with Botox, which means you can get on with your day as normal. However, because you might experience some redness or pin prick marks afterwards, you might not want to do it right before a big event. Q. Does Botox hurt? A. The needles used for Botox are extremely small, so shouldn’t be uncomfortable. Of course, everyone’s pain threshold is different, so if you have a particularly low pain tolerance, it may be worth taking paracetamol around an hour before your appointment. You should avoid ibuprofen and other blood thinning medication, though, as this can lead to increased bruising. Occasionally, numbing cream may be used in cases where pain threshold levels are particularly low. Q. Who can perform Botox injections? A. Anti-wrinkle injections such as Botox are prescription only medicine and should only be performed by medically qualified practitioners, as they require expert skill and experience. You should also have a face-to-face consultation with the prescriber prior to your treatment. When conducted by an expert, Botox injections are safe and effective, but in the wrong hands, could be very dangerous. Q. What’s the difference between Botox and fillers? A. Botox and dermal fillers can both be used to rejuvenate the skin, but, in fact, they work in different ways. Botox is a prescription only medicine, which relaxes the muscles, reducing movement which minimises dynamic lines, such as forehead lines and 11s. Dermal fillers, on the other hand, are also injectable treatments, but they work by plumping up lines to smooth them out. Fillers are also used for enhancing features such as the nose, jawline and lips. Q. Will I be able to move my face after Botox? A. One of the biggest concerns people have with Botox is that they think it will give them a ‘frozen’ look or ‘Botox face’, removing their ability to make facial expressions as usual. This comes down to how much is used. If a practitioner uses too much, this can happen. However, when it’s performed by an experienced, medically qualified practitioner, the treatment should look natural, still allowing you to express your emotions. Q. How long does Botox last? A. The effects of Botox vary from person to person as people metabolise it at different rates. However, on average, the anti-wrinkle injection lasts between 3 and 6 months, after which you’ll start to see lines and wrinkles return. Q. When should I start getting Botox? A. People often start getting Botox from their 30s+, when dynamic fine lines and wrinkles are more visible. This prevents the skin from folding and creasing, giving a younger look. Some people get Botox from their mid-20s as a preventative measure - minimising lines before they have a chance to form. But it’s always best to speak to a medically qualified practitioner, have a thorough consultation, to see what treatment they recommend for you. Q. Can I have Botox if I’m pregnant? A. Botox is not suitable for women who are pregnant, breastfeeding or trying to get pregnant. This is due to the fact that there is not enough known about the impact of the toxin on babies and their health. No ethical medical practitioner will conduct anti-wrinkle treatments on a pregnant or breastfeeding woman. Q. Do I need to let my practitioner know about any illnesses before a Botox appointment? A. You will be asked to complete a detailed health questionnaire before your Botox appointment to assess whether the treatment is right for you. There may be other treatment options available to you. You should let your practitioner know if you have a muscular disease such as Bell’s Palsy or any nervous system or blood disorders. You should also tell them about any medications you are taking as these may interfere with the effectiveness of the Botox, and vice versa. This is particularly important if you are taking medications that affect blood clotting. You should also tell them about any psychological concerns you have.

Botox is not designed to remove facial expressions,. It’s designed to soften lines of excessive facial expression from squinting, frowning, and smiling. It does paralyze your muscles, but it will not affect the nerves that cause sensation, or make you feel numb. When it is used correctly, it can lift the brow to give an appealing and sincere look. But if too much is injected in the danger zone — the horizontal lines in the forehead — you can look Spocked, as in Spock from Star Trek. That’s why it’s important to be treated by an experienced doctor who can judge the size of your muscles and how much Botox you will need. Botulinum toxin injection for treatment of facial wrinkles is the most frequently performed cosmetic procedure in the United States, and it is one of the most common entry procedures for clinicians seeking to incorporate aesthetic treat- ments into their practice. Treatment of frown lines and crow’s feet, which are the cosmetic indications approved by the U.S. Food and Drug Administration, and horizontal forehead lines, offers predictable results, has few adverse effects, and is associated with high patient satisfaction. Wrinkles are formed by dermal atrophy and repetitive contraction of underlying facial musculature. Botulinum toxin is a potent neurotoxin that inhibits release of acetylcholine at the neuromuscular junction. Injection of small quantities of botulinum toxin into specific overactive muscles causes local- ized muscle relaxation that smooths the overlying skin and reduces wrinkles. Botulinum toxin effects take about two weeks to fully develop and last three to four months. Dynamic wrinkles, seen during muscle contraction, yield more dramatic results than static wrinkles, which are visible at rest. Botulinum toxin injection is contraindicated in per- sons with keloidal scarring, neuromuscular disorders (e.g., myasthenia gravis), allergies to constituents of botulinum toxin products, and body dysmorphic disorder. Minor bruising can occur with botulinum toxin injection. Temporary blepharoptosis and eyebrow ptosis are rare complications that are technique-dependent; incidence declines as injector skill improves. CME This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions on page 145. Author disclosure: No rel- evant financial affiliations. See related editorial on page 136. Patient information: A handout on this topic, written by the author of this article, is available at http://www.aafp.org/ afp/2014/0801/168-s1. html. Botulinum toxin injection for treat- temporary chemical denervation. At the cel- ment of facial wrinkles is the most frequently performed cosmetic 1 procedure in the United States, and it is one of the most common entry pro- cedures for clinicians seeking to incorporate aesthetic treatments into their practice.2 Botulinum toxin injection, particularly in the upper one-third of the face, offers pre- dictable results,3 has few adverse effects,4 and is associated with high patient satisfaction.5 This article reviews relevant facial anatomy, patient selection, complications, and injec- tion technique for cosmetic botulinum toxin treatment with a focus on frown lines. It is, however, not intended as a replacement for a formal instructional course. Mechanism of Action Wrinkles are formed by dermal atrophy and repetitive contraction of underlying facial musculature. Injection of small quantities of botulinum toxin into specific overactive muscles causes localized muscle relaxation that smooths the overlying skin and reduces wrinkles.6 Botulinum toxin is a potent neurotoxin protein derived from the Clostridium botu- linum bacterium. It exerts its effect at the neuromuscular junction by inhibiting the release of acetylcholine, which causes lular level, botulinum toxin functions by cleaving a docking protein (synaptosomal- associated protein of 25 kDA [SNAP-25]) on the internal surface of neuronal membranes, thereby inhibiting vesicle fusion and release of acetylcholine.7 Botulinum toxin effects in the targeted muscles diminish over time as SNAP-25 regenerates, and neuromuscu- lar signaling and muscle contractility are restored. Indications Botulinum toxin has been used for more than 20 years to treat a variety of conditions including blepharospasm, strabismus, cervi- cal dystonia, migraines, hyperhidrosis, and muscle spasticity. Botulinum toxin was first approved by the U.S. Food and Drug Admin- istration (FDA) for cosmetic use in 2002 as Botox to treat glabellar complex muscles that form frown lines and in 2013 to treat lateral orbicularis oculi muscles that form crow’s feet8; it is used off-label for all other cos- metic facial indications. It has become the treatment of choice for wrinkles occurring in the upper one-third of the face (i.e., frown lines, horizontal forehead lines, and crow’s feet). It is also used in the lower two-thirds of the face, but this is more technically chal- lenging and is an advanced application.9-14 1D6ow8nloAamdeedrfircoamnthFeaAmmileyricPahnyFsaimcialynPhysician website at www.aafp.worwg/waf.pa.aCfopp.yorrigh/ta©fp2014 American Academy VofoFluamiley 9Ph0y,sNiciuanms.bFeorr3the pAruivgautes,tn1o,n2co0m14- mercial use of one individual user of the website. Botulinum Toxin Injection 1. Frontalis 2. Temporalis 3. Corrugator supercilii 4. Procerus 5. Depressor supercilii 6. Orbicularis oculi 7. Nasalis 8. Levator labii superioris alaeque nasi 9. Levator labii superioris 10. Zygomaticus minor 11. Zygomaticus major 12. Orbicularis oris 13. Modiolus 14. Risorius 15. Platysma 16. Depressor anguli oris 17. Depressor labii inferioris 18. Mentalis 1. Horizontal forehead lines (frontalis) 2. Frown lines (glabellar complex) 3. Crow’s feet (orbicularis oculi) 4. Bunny lines (nasalis) 5. Nasolabial folds (levator labii superioris alaequae nasi) 6. Radial lip lines (orbicularis oris) 7. Marionette lines (depressor anguli oris) 8. Chin line (mentalis) Figure 1. Musculature of the face. Reprinted with permission from Small R, Hoang D. A Practical Guide to Botu- linum Toxin Procedures. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2012. Anatomy The muscles of facial expression are unique in that they have soft tissue attachments to skin through the superfi- cial muscular aponeurotic system, unlike most muscles, which have bony attachments (Figure 115). When facial muscles contract, the overlying skin also moves, form- ing dynamic wrinkles perpendicular to the direction of muscle contraction (Figure 215). Glabellar wrinkles, or frown lines, are vertical lines occurring between the medial aspects of the eyebrows. The muscles contributing to formation of frown lines are Figure 2. Wrinkles of the face (associated muscle). Reprinted with permission from Small R, Hoang D. A Practical Guide to Botu- linum Toxin Procedures. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2012. the glabellar complex depressor muscles, which include the corrugator supercilii, procerus, and depressor super- cilii. Contraction of these muscles pulls the brows medi- ally and inferiorly (Figure 315). Patient Selection Patients with dynamic wrinkles demonstrate the most dramatic improvements from botulinum toxin injec- tion and are ideal candidates for treatment (Figure 415). Patients with static wrinkles that are visible at rest are also candidates (Figure 515), but results are slower and patients may require two or three consecutive Expression lines Muscle Action Frown lines Corr ugator supercilii Eyebrows drawn medially Procerus and depressor supercilii Eyebrow depressors Horizontal forehead lines Fron talis Eyebrow levator Crow’s feet Lateral orbicularis oculi Lateral eyebrow depressor Eyebrow lift Superior lateral orbicularis oculi Superior lateral eyebrow depressor Bunny lines Nasalis Nose drawn up and medially Radial lip lines Orbi cularis oris Lip puckering Marionette lines and downturned smile Depressor anguli oris Corner of mouth depressor Gummy smile and nasolabial fold Levator labii superioris alaeque nasi Central lip levator Chin line and pebbly chin Men talis Chin texture and lower lip levator Key: orange = depressor muscles; purple = levator muscles; gray = sphincteric muscles. Figure 5. (A) Dynamic frown lines with glabellar complex muscle contraction and (B) static lines with glabellar mus- cles at rest. Copyright © Rebecca Small, MD. Reprinted from Small R, Hoang D. A Practical Guide to Botulinum Toxin linum Toxin Procedures. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2012. 170 American Family Physician www.aafp.org/afp Volume 90, Number 3 ◆ August 1, 2014 Figure 3. Functional anatomy of the face. Reprinted with permission from Small R, Hoang D. A Practical Guide to Botu- Procedures. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2012. Botulinum Toxin Injection Table 1. Contraindications to Botulinum Toxin Injection Body dysmorphic disorder Dependency on facial expression for livelihood (e.g., actors, singers) Dermatoses in the treatment area (e.g., psoriasis, eczema) Gross motor weakness in the treatment area (e.g., Bell palsy) Immunocompromised Infection in the treatment area Keloidal scarring Neuromuscular disorder (e.g., amyotrophic lateral sclerosis, myasthenia gravis, Lambert-Eaton syndrome, myopathies) Pregnancy or breastfeeding Sensitivity or allergy to constituents of the botulinum toxin product (e.g., cow’s milk protein allergy with abobotulinumtoxinA [Dysport]) Unrealistic expectations Information from references 14, and 16 through 18. botulinum toxin treatments for significant improve- ments.15 Deep static lines may not fully respond to botulinum toxin injection alone and may require com- bination treatment with dermal fillers or other cosmetic procedures to achieve optimal results. Setting realistic expectations at the time of consultation is important for patient satisfaction and success with botulinum toxin treatments. Contraindications to botulinum toxin injec- tion include keloidal scarring, neuromuscular disorders (e.g., myasthenia gravis), allergy to constituents of botu- linum toxin product, unrealistic expectations, and body dysmorphic disorder (Table 1).14,16-18 Botulinum Toxin Products The C. botulinum bacterium produces eight serotypes of botulinum toxin protein (A, B, Cα, Cβ, D, E, F, and G). Botulinum toxin serotype A is the most potent and is used for cosmetic treatments. Botulinum toxin serotype B is used for medical conditions such as dystonia. There are currently three botu- linum toxin serotype A products approved by the FDA for cosmetic use to treat glabel- lar complex muscles that form frown lines: onabotulinumtoxinA (Botox), abobotu- linumtoxinA (Dysport), and incobotulinum- toxinA (Xeomin), which are summarized in Table 2.19,20 All three serotype A products have a 150 kDa core botulinum toxin protein and differ in whether they have complexing pro- teins surrounding the core neurotoxin. Ona- botulinumtoxinA and abobotulinumtoxinA have hemagglutinin complexing proteins, whereas incobotulinumtoxinA is free from complexing proteins.19,21 Lack of complexing proteins may reduce antigenicity and hence antibody formation against botu- linum toxin, but the clinical significance of complexing proteins has yet to be determined. Botulinum toxin prod- ucts are not interchangeable because they vary in their formulation, dosing, and clinical response. Aesthetic Consultation Facial areas of concern are assessed by the physician and patient simultaneously using a handheld mirror during the consultation. Asymmetries such as uneven eyebrow height and eye aperture are identified. Areas are priori- tized and treatment options discussed, including antici- pated results and possible complications. Botulinum toxin is the only treatment for dynamic wrinkles cur- rently approved by the FDA. Treatment options for static Table 2. Botulinum Toxin Injectable Products Trade name Botox Dysport Xeomin Company Allergan, Inc. Medicis Pharmaceutical Corporation Merz Pharmaceuticals Toxin component OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA Other components Human albumin, sodium chloride Human albumin, bovine protein,† lactose monohydrate Human albumin, sucrose Dose for frown line treatment* 20 to 25 units 50 to 60 units‡ 20 to 25 units§ *—These starting doses are intended as general guidelines and may be adjusted at the time of treatment based on the patient’s anatomy and glabellar complex muscle mass. †—AbobotulinumtoxinA should not be used in patients with cow’s milk protein allergy. ‡—OnabotulinumtoxinA to abobotulinumtoxinA strength of action ratio 1:2.5. §—OnabotulinumtoxinA to incobotulinumtoxinA strength of action ratio 1:1. Information from references 19 and 20. August 1, 2014 ◆ Volume 90, Number 3 www.aafp.org/afp American Family Physician 171 Botulinum Toxin Injection wrinkles include resurfacing procedures (e.g., chemi- cal peels, microdermabrasion, lasers), topical products (e.g., retinoids), and surgical procedures. Photographic documentation is recommended with any aesthetic pro- cedure. Dynamic and static photographs of treatment areas are typically taken before treatment and two weeks after treatment, once clinical effects are evident.22 Procedure Preparation In preparation for botulinum toxin treatment, or any injectable procedure, bruising can be minimized by advising patients to discontinue aspirin and any medica- tion or dietary supplement that has anticoagulant effects two weeks before treatment.17,23 Anesthesia is not typi- cally necessary for botulinum toxin treatments. Botulinum Toxin Injection Botulinum toxin is supplied as a powder and is recon- stituted at the time of treatment into a solution using sterile normal saline. Dilution volumes range from 1 to 4 mL per 100-unit vial. The botulinum toxin dose injected into glabellar complex muscles for the treatment of frown lines is based on the specific botulinum toxin product used and mass of the target muscles. Table 2 lists starting doses used for treatment of frown lines with the three FDA-approved botulinum toxin products.19,20 The targeted glabellar complex muscles can be iden- tified by having the patient actively frown, and injec- tions are placed into the contracted muscles (Figure 6 15). Small volumes of botulinum toxin solution are injected, typically 1 mL or less, using a 30-gauge, 1-inch needle. There are five injection sites, one injection in the pro- cerus muscle and two in each of the corrugator super- cilii muscles.15,20,24 Botulinum toxin is commonly used to treat other lines in the upper one-third of the face, such as horizontal forehead lines with injection in the frontalis muscle, and crow’s feet with injection in the lateral orbicularis oculi muscles.10,11,25 Localized burn- ing or stinging sensation during injection is commonly reported and resolves within a few minutes.15,17 Aftercare Patients are advised to avoid lying supine following treatment for four hours. They are also advised to avoid massaging or applying heat to the treatment area, and to avoid activities that cause flushing (such as exercis- ing heavily, consuming alcohol, and hot tub use) on the day of treatment.15,26 These aftercare practices are used to reduce potential spread of the toxin, however; they are not supported by randomized controlled trials. Results and Follow-Up Partial reduction in function of the targeted glabellar complex muscles is seen by the third day after botuli- num toxin injection, with maximal reduction visible two weeks after injection.27 Figure 7shows reduction of dynamic frown lines one month after treatment of the glabellar complex muscles with 20 units of onabotu- linumtoxinA.15 Return of muscle function is gradual, typically three to four months after treatment. Subse- quent treatment is advised when muscle contraction is visible in the treatment area before facial lines return to their pretreatment appearance.28 After multiple treat- ments, botulinum toxin effects may be prolonged and, for some patients, treatment intervals can be extended beyond three to four months.29 Complications Complications with cosmetic botulinum toxin injec- tions are uncommon and those that occur are usually mild and transient.30 They can be categorized into injec- tion reactions and undesired botulinum toxin effects (Table 3).30-32 INJECTION REACTIONS Botulinum toxin injections are performed using small- gauge needles to minimize discomfort and bruising. 172 American Family Physician www.aafp.org/afp Volume 90, Number 3 ◆ August 1, 2014 Botulinum Toxin Injection A B Figure 7. Dynamic frown lines with glabellar complex muscle contraction (A) before and (B) one month after onabotulinumtoxinA (Botox) treatment. Figure 8. Right-sided blepharoptosis three weeks after botulinum toxin treatment of the glabellar complex for frown lines. Reprinted from Small R, Hoang D. A Practical Guide to Botulinum Toxin Mild erythema, edema, and tenderness at injection sites are expected and resolve within a day. Bruising is com- mon and ranges from pinpoint needle insertion marks to quarter-sized ecchymoses that can take up to two weeks to resolve. Application of ice and pressure to a bruise can minimize enlargement.15 Headaches can occur with facial injections; most are mild and spontaneously resolve a few days after treatment.33 There are reports of idiosyncratic severe headaches lasting two to four weeks.34 Nonsteroidal anti-inflammatory drugs or opi- oids may be used to manage headaches based on severity. Infection is rare, but can occur with any procedure that breaches the skin barrier. Paresthesia or dysesthesia in the treatment area is rare, and may be caused by nerve trauma. Anxiety with injection procedures is common. Vasovagal episodes associated with severe anxiety can occur and it is advisable to have appropriate emergency protocols and medications available in the office when performing injection procedures.35 UNDESIRED EFFECTS Complications related to botulinum toxin effects occur less frequently than injection reactions, and are primar- ily caused by temporary denervation of adjacent muscles outside of the intended treatment area. These compli- cations are technique-dependent; incidence declines as injector skill improves.30,31 Temporary blepharoptosis (upper eyelid droop) is uncommon (1% to 5%) but is distressing for patients.9 It is almost always unilateral, seen as a 2- to 3-mm lowering of the affected eyelid that is most marked at the end of the day with muscle fatigue (Figure 815). Blepharoptosis is caused by deep migration of botulinum toxin through the orbital septum fascia to the levator palpebrae superioris, an upper eyelid levator muscle. Incidence of blepharoptosis is reduced by plac- ing botulinum toxin injections at least 1 cm above the Table 3. Complications with Botulinum Toxin Injection Injection reactions Anxiety or vasovagal episode Ecchymosis Erythema, edema, and tenderness Headache Infection Pain Paresthesia or dysesthesia Undesired botulinum toxin effects Allergic reaction Antibodies against botulinum toxin Blepharoptosis Distant spread from the injection site Eyebrow ptosis Facial asymmetry Medication interactions Undesired eyebrow shape or unsatisfactory result Information from references 30 through 32. Botulinum Toxin Injection supraorbital ridge at the midpupillary line when treating the corrugator muscles.14,17 Blepharoptosis may be treated using oph- thalmic solutions that have alpha-adrenergic effects, such as over-the-counter naphazo- line 0.025%/pheniramine 0.3% or prescrip- tion apraclonidine 0.5% (Iopidine). Both medications cause contraction of Müller muscle, an adrenergic levator muscle of the upper eyelid, resulting in elevation of the upper eyelid. Apraclonidine is reserved for refractory cases and should be used with caution because it can exacerbate or unmask underlying glaucoma.32 Eyebrow ptosis and undesired eyebrow shape are usually related to unintended botulinum toxin effects in the frontalis muscle. Some of these compli- cations can be corrected with botulinum toxin injection in muscles that antagonize the affected muscles; however, complications caused by involvement of adjacent muscles are temporary and will spontane- ously resolve as botulinum toxin effects diminish. Facial asymmetry can result from uneven dosing of botuli- num toxin. Consistent technique and careful attention to injection volumes at the time of treatment can reduce the incidence of asymmetries. Other rare complications associated with botuli- num toxin injections include formation of antibodies (less than 1%), which can render treatments ineffec- tive.36 Medications that inhibit neuromuscular signaling such as aminoglycosides, quinidine, anticholinergics, and muscle relaxants, may potentiate botulinum toxin effects.37 AbobotulinumtoxinA is contraindicated in patients with cow’s milk protein allergy because bovine protein is a constituent.38,39 Although extremely rare, immediate hypersensitivity and allergic reactions may occur, with signs of urticaria, edema, and possibly ana- phylaxis. Using standard emergency protocols and med- ications such as epinephrine and methylprednisolone (Solu-Medrol) is advised when indicated, rather than diphenhydramine (Benadryl) because of its anticho- linergic effects.40 Case reports of adverse effects due to distant spread from the injection site have been reported with large doses of botulinum toxin (e.g., 300 units in the calves), which include generalized muscle weakness, ptosis, dysphagia, dysarthria, urinary incontinence, respiratory difficulties, and death from respiratory com- promise.41 Distant spread has not been reported with cosmetic use of botulinum toxin for frown lines or other facial indications. There are case reports of botulism with injected botulinum toxin; however, these instances involved research-grade botulinum toxin that was not approved or intended for human use.42,43 Financial Considerations and Coding The current procedural terminology (CPT) designation for botulinum toxin injection of the face is chemodenerva- tion of muscles innervated by the facial nerve (CPT code: 64612). Cosmetic botulinum toxin treatments are not coveredbyinsurance.Feesforinjectionsrangefrom$250 to $550 per treatment area and are based on the number of botulinum toxin units used or on the area treated (i.e., frown lines, crow’s feet, or horizontal forehead lines). Data Sources: A PubMed, Cochrane database, POEMs, and Essential Evi- dence search was completed in Clinical Queries using the key terms botuli- num toxin, safety, efficacy, cosmetic, and frown lines. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. AlsosearchedweretheFDAwebsite,aestheticproceduretextbooks,and UpToDate. Search dates: February 2, 2013, and April 24, 2014. The Author REBECCA SMALL, MD, is an associate clinical professor in the Department of Family and Community Medicine at the University of California–San Francisco School of Medicine and the director of medical aesthetic training at Natividad Medical Center in Salinas, Calif. Address correspondence to Rebecca Small, MD, 820 Bay Ave., Ste. 246, Capitola, CA 95010 (e-mail: DrSmall@mbla.me). Reprints are not avail- able from the author. REFERENCES 1. American Society for Aesthetic Plastic Surgery. Cosmetic Surgery National Data Bank statistics 2013. http://www.surgery.org/media/ statistics. Accessed February 26, 2014. 2. Small R. Aesthetic procedures in office practice. Am Fam Physician. 2009;80 (11):1231-1237. SORT: KEY RECOMMENDATIONS FOR PRACTICE Clinical recommendation Evidence rating References Botulinum toxin serotype A is safe and effective for reduction of frown lines. 21 Botulinum toxin serotype A is safe and effective for reduction of crow’s feet. In preparation for botulinum toxin treatment, patients should be advised to discontinue aspirin and any medication or dietary supplements associated with bruising for two weeks before treatment. A 9, 12, 13, 20, A 12, 21, 24, 25 C 17, 23 A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited- quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort. 174 American Family Physician www.aafp.org/afp Volume 90, Number 3 ◆ August 1, 2014 Botulinum Toxin Injection 3. Carruthers JD, Carruthers A. The use of botulinum toxin type A in the upper face. Facial Plast Surg Clin North Am. 2006;14(3):253-260. 4. Cavallini M, Cirillo P, Fundarò SP, et al. Safety of botulinum toxin A in aesthetic treatments: a systematic review of clinical studies. Dermatol Surg. 2014;40(5):525-536. 5. Stotland MA, Kowalski JW, Ray BB. Patient-reported benefit and satis- faction with botulinum toxin type A treatment of moderate to severe glabellar rhytides: results from a prospective open-label study. Plast Reconstr Surg. 2007;120(5):1386-1393, discussion 1394. 6. Dressler D, Benecke R. Pharmacology of therapeutic botulinum toxin preparations. Disabil Rehabil. 2007;29(23):1761-1768. 7. Blasi J, Chapman ER, Link E, et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature. 1993;365(6442):160-163. 8. FDA approves Botox Cosmetic to improve the appearance of crow’s feet lines [news release]. Silver Springs, Md.: U.S. Food and Drug Administration; September 11, 2013. http://www.fda.gov/newsevents/ newsroom/pressannouncements/ucm367662.htm. Accessed April 18, 2014. 9. CarruthersJA,LoweNJ,MenterMA,etal.;BOTOXGlabellarLinesIStudy Group. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treat- ment of glabellar lines. J Am Acad Dermatol. 2002;46(6):840-849. 10. Carruthers A, Carruthers J, Cohen JL. A prospective, double-blind, ran- domized, parallel- group, dose-ranging study of botulinum toxin type a in female subjects with horizontal forehead rhytides. Dermatol Surg. 2003;29(5):461-467. 11. Lowe NJ, Lask GP, Yamauchi PS, Moore D. Bilateral, double-blind, ran- domized comparison of 3 doses of botulinum toxin type A and placebo in patients with crow’s feet. J Am Acad Dermatol. 2002;47(6):834-840. 12. Michaels BM, Csank GA, Ryb GE, Eko FN, Rubin A. Prospective random- ized comparison of onabotulinumtoxinA (Botox) and abobotulinum- toxinA (Dysport) in the treatment of forehead, glabellar, and periorbital wrinkles. Aesthet Surg J. 2012;32(1):96-102. 13. Sattler G, Callander MJ, Grablowitz D, et al. Noninferiority of incobotu- linumtoxinA, free from complexing proteins, compared with another botulinum toxin type A in the treatment of glabellar frown lines. Der- matol Surg. 2010;36(suppl 4):2146-2154. 14. Ascher B, Talarico S, Cassuto D, et al. International consensus recom- mendations on the aesthetic usage of botulinum toxin type A (Spey- wood Unit)–Part I: upper facial wrinkles. J Eur Acad Dermatol Venereol. 2 0 1 0 ; 2 4 ( 11 ) : 1 2 7 8 - 1 2 8 4 . 15. Small R, Hoang D. A Practical Guide to Botulinum Toxin Procedures. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2012. 16. Klein AW. Contraindications and complications with the use of botuli- num toxin. Clin Dermatol. 2004;22(1):66-75. 17. Carruthers J, Fagien S, Matarasso SL; Botox Consensus Group. Consen- sus recommendations on the use of botulinum toxin type a in facial aesthetics. Plast Reconstr Surg. 2004;114(6 suppl):1S-22S. 18. Dysport (abobotulinumtoxin A) injection [prescribing information]. Scottsdale, Ariz.: Medicis Aesthetics, Inc.; 2012 http://pi.medicis.us/ dysport.pdf. Accessed April 18, 2014. 19. Bakshi E, Hartstein ME. Compositional differences among commer- cially available botulinum toxin type A. Curr Opin Ophthalmol. 2011; 22(5):407-412. 20. Dessy LA, Fallico N, Mazzocchi M, Scuderi N. Botulinum toxin for gla- bellar lines: a review of the efficacy and safety of currently available products. Am J Clin Dermatol. 2011;12(6):377-388. 21. Kassir R, Kolluru A, Kassir M. Triple-blind, prospective, internally con- trolled comparative study between abobotulinumtoxinA and onabotu- linumtoxinA for the treatment of facial rhytids. Dermatol Ther (Heidelb). 2013;3 (2):179-189. 22. Small R. Aesthetic Principles and Consultation. In: Usatine R, Pfenninger J, Stuhlberg D, Small R, eds. Dermatologic and Cosmetic Procedures in Office Practice. Philadelphia, Pa.: Elsevier/Saunders; 2012:230-240. 23. Ciocon JO, Ciocon DG, Galindo DJ. Dietary supplements in primary care. Botanicals can affect surgical outcomes and follow-up. Geriatrics. 2004;59(9):20-24. 24. Small R. Botulinum Toxin. In: Usatine R, Pfenninger J, Stuhlberg D, Small R, eds. Dermatologic and Cosmetic Procedures in Office Practice. Phila- delphia, Pa.: Elsevier/Saunders; 2012:248-258. 25. Prager W, Wissmüller E, Kollhorst B, Williams S, Zschocke I. Compar- ison of two botulinum toxin type A preparations for treating crow’s feet: a split-face, double-blind, proof-of-concept study. Dermatol Surg. 2010;36(suppl 4):2155-2160. 26. Edward M, Zimmerman. Botolinum toxin. In: Pfenninger JL, Fowler GC, eds. Pfenninger and Fowler’s Procedures for Primary Care. Philadelphia, Pa.: Elsevier/Saunders; 2012:363-372. 27. Beer KR, Boyd C, Patel RK, Bowen B, James SP, Brin MF. Rapid onset of response and patient-reported outcomes after onabotulinumtoxinA treatment of moderate-to-severe glabellar lines. J Drugs Dermatol. 2011;10(1):39-44. 28. Small R. Botulinum toxin type A for facial rejuvenation. In: Mayeaux E, ed. The Essential Guide to Primary Care Procedures. Philadelphia, Pa.: Lippincott Williams & Wilson; 2009:200-213. 29. Flynn TC. Botulinum toxin: examining duration of effect in facial aes- thetic applications. Am J Clin Dermatol. 2010;11(3):183-199. 30. Cox SE, Adigun CG. Complications of injectable fillers and neurotoxins. Dermatol Ther. 2011;24(6):524-536. 31. Klein AW. Complications, adverse reactions, and insights with the use of botulinum toxin. Dermatol Surg. 2003;29(5):549-556, discussion 556. 32. Wollina U, Konrad H. Managing adverse events associated with botuli- num toxin type A: a focus on cosmetic procedures. Am J Clin Dermatol. 2005;6(3):141-150. 33. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 2004;20(7):981-990. 34. Alam M, Arndt KA, Dover JS. Severe, intractable headache after injec- tion with botulinum a exotoxin: report of 5 cases. J Am Acad Dermatol. 2002;46(1):62-65. 35. Toback SL. Medical emergency preparedness in office practice. Am Fam Physician. 2007;75(11):1679-1684. 36. Naumann M, Carruthers A, Carruthers J, et al. Meta-analysis of neutral- izing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications. Mov Disord. 2010;25(13):2211-2218. 37. Botox cosmetic (onabotulinumtoxinA) for injection, for intramuscular use [prescribing information]. Irvine, Calif.: Allergen, Inc.; 2013. http:// www.allergan.com/assets/pdf/botox_cosmetic_pi.pdf. Accessed Febru- ary 26, 2014. 38. U.S. Food and Drug Administration. Information for healthcare pro- fessionals: onabotulinumtoxinA (marketed as Botox/Botox Cosmetic), abobotulinumtoxinA (marketed as Dysport) and rimabotulinumtoxinB (marketed as Myobloc). http://www.fda.gov/Drugs/DrugSafety/Post marketDrugSafetyInformationforPatientsandProviders/DrugSafetyInfo rmationforHeathcareProfessionals/ucm174949.htm. Accessed Febru- ary 20 2013. 39. U.S. Food and Drug Administration. Medication guide: Dysport (abob- otulinumtoxin A). http://www.fda.gov/downloads/Drugs/DrugSafety/ UCM165110.pdf. Accessed February 26, 2014. 40. Derksen DJ. Anaphylaxis. In: Pfenninger JL, Fowler GC, eds. Pfenninger and Fowler’s Procedures for Primary Care. Philadeplhia, Pa.: Mosby Else- vier; 2011:1507-1509. 41. Nong LB, He WQ, Xu YH, et al. Severe respiratory failure after injection of botulinum toxin: case report and review of the literature [in Chinese]. Zhongus Jie He He Hu Xi Za Zhi. 2008;31(5):369-371. 42. Souayah N, Karim H, Kamin SS, McArdle J, Marcus S. Severe botulism after focal injection of botulinum toxin. Neurology. 2006;67(10):1855-1856. 43. Chertow DS, Tan ET, Maslanka SE, et al. Botulism in 4 adults following cosmetic injections with an unlicensed, highly concentrated botulinum preparation. JAMA. 2006;296(20):2476-2479.

This varies — and it’s mostly up to you! You don’t need it before you have wrinkles to hide, or you can use it preventatively. To be clear, it is much more about anatomy (as a result of genetic and environmental factors) than it is about a stereotypical age at which to begin. Prevention is the new mantra, [but] I have seen women in [their] 40s with few or no wrinkles who require very little [Botox], and women in their 20s who require more. Basically, a patient can have Botox safely whenever they are bothered by their wrinkles or simply want to prevent them from forming in the first place. There is no issue with long term use, either: “I’ve had patients who have used it repeatedly for over 20 years without bad effects,” says Dr. Vigo. BOTOX, 50 Allergan Units, Powder for Solution for Injection BOTOX, 100 Allergan Units, Powder for Solution for Injection BOTOX, 200 Allergan Units, Powder for Solution for Injection Botulinum toxin type A Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or pharmacist or healthcare practitioner. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor or pharmacist or healthcare practitioner. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What BOTOX is and what it is used for 2. What you need to know before you use BOTOX 3. How to use BOTOX 4. Possible side effects 5. How to store BOTOX 6. Contents of the pack and other information 1. What BOTOX is and what it is used for BOTOX is a muscle relaxant used to treat a number of conditions within the body. It contains the active substance Botulinum toxin type A and is injected into either the muscles, the bladder wall or deep into the skin. It works by partially blocking the nerve impulses to any muscles that have been injected and reduces excessive contractions of these muscles. In the case of chronic migraine, it is thought that BOTOX blocks pain signals, which indirectly block the development of a migraine. When injected into the skin, BOTOX works on sweat glands to reduce the amount of sweat produced. When injected into the bladder wall, BOTOX works on the bladder muscle to prevent leakage of urine (urinary incontinence) due to uncontrolled contractions of the bladder muscle. 1 1) BOTOX can be injected directly into the muscles, and can be used to treat the following conditions: • persistent muscle spasms in the ankle and foot in children aged two years or older with cerebral palsy, who can walk. BOTOX is used to support rehabilitation therapy;persistent muscle spasms in the wrist, hand, ankle or foot of adult patients who have suffered a stroke; • persistent muscle spasms in the eyelid and face of adult patients; • persistent muscle spasms in the neck and shoulders of adult patients 2) BOTOX is used to prevent headaches in adult patients with chronic migraine. Chronic migraine is a disease affecting the nervous system. To be diagnosed with chronic migraine, you must have headaches 15 days or more a month. In addition, on 8 or more days a month, your headaches must have at least two of the following characteristics: • affect only one side of the head • cause a pulsating pain • cause moderate to severe pain • are aggravated by routine physical activity and they must cause at least one of the following: • nausea, vomiting, or both • sensitivity to light and sound. BOTOX has been shown to significantly reduce the frequency of days with headache and to improve the quality of life of patients suffering from chronic migraine. After two treatment sessions, approximately 47% of patients had a 50% or greater reduction from baseline in the number of days with headache they experienced. 3) When injected into the bladder wall, BOTOX works on the bladder muscle to reduce leakage of urine (urinary incontinence) and control the following conditions in adults: • overactive bladder with leakage of urine, the sudden urge to empty your bladder and needing to go to the toilet more than usual; • leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis. In patients who have not managed to control overactive bladder with leakage of urine with medicines called anticholinergics, BOTOX has been shown to reduce leakage of urine from an average of about 5 episodes per day down to 2 after 12 weeks. 27% of patients had no leakage of urine at all. In patients with bladder problems associated with spinal cord injury or multiple sclerosis who have not managed to control leakage of urine with medicines called anticholinergics, BOTOX has been shown to reduce leakage of urine, from an average of about 30 episodes per week down to 10 after 6 weeks. 37% of patients had no leakage of urine at all. 2 4) In adults, BOTOX can be injected deep into the skin and can work on sweat glands to reduce excessive sweating of the armpits, which affects the activities of daily living when other local treatments do not help. 5) BOTOX is used for the temporary improvement in the appearance of: • Vertical lines between the eyebrows seen at maximum frown and/or • Fan-shaped lines from the corner of the eyes seen at maximum smile and/or, • Forehead lines seen at maximum raised eyebrows, When the severity of the facial lines has an important psychological impact in adult patients. 2. What you need to know before you use BOTOX Do not use BOTOX • if you are allergic (hypersensitive) to botulinum toxin type A or any of the other ingredients of this medicine (listed in section 6); • if you have an infection at the proposed site of injection; • when you are being treated for leakage of urine and have either a urinary tract infection or a sudden inability to empty your bladder (and are not regularly using a catheter), or if you have bladder stones; • if you are being treated for leakage of urine and are not willing to begin using a catheter if required. Warnings and precautions Talk to your doctor or pharmacist or healthcare practitioner before using BOTOX: • if you have ever had problems with swallowing or food or liquid accidentally going into your lungs, especially if you will be treated for persistent muscle spasms in the neck and shoulders; • if you are over 65 years of age and have other serious illnesses; • if you suffer from any other muscle problems or chronic diseases affecting your muscles (such as myasthenia gravis or Eaton Lambert Syndrome); • suffer from certain diseases affecting your nervous system (such as amyotrophic lateral sclerosis or motor neuropathy); • if you have significant weakness or wasting of the muscles which your doctor or healthcare practitioner plans to inject; • if you have had any surgery that may have in some way changed the muscle to be injected; • if you have had any problems with injections (such as fainting) in the past; • if you have inflammation in the muscles or skin area where your doctor or healthcare practitioner plans to inject; • if you have had problems in the past with previous botulinum toxin injections; • if you suffer from cardiovascular disease (disease of the heart or blood vessels); • if you suffer of have suffered from seizures; • if you have an eye disease called closed-angle glaucoma (high pressure in the eye) or were told you are at risk for developing this type of glaucoma; • if you will have an operation soon; • if you are taking any blood thinning medicine. 3 After you have been given BOTOX You or your caregiver should contact your doctor and seek medical attention immediately if you experience any of the following: • difficulty in breathing, swallowing, or speaking; • hives, swelling including swelling of the face or throat, wheezing, feeling faint and shortness of breath (possible symptoms of severe allergic reaction). If you have been treated for vertical and/or fan-shaped and/or forehead lines, please inform your doctor or healthcare practitioner if you see no significant improvement of your lines one month after your first course of treatment. General precautions As with any injection, it is possible for the procedure to result in infection, pain, swelling, burning and stinging, increased sensitivity, tenderness, redness, and/or bleeding/bruising at the site of injection. Side effects possibly related to the spread of toxin distant from the site of administration have been reported with botulinum toxin (e.g. muscle weakness, difficulty swallowing or unwanted food or liquid in the airways). This is a particular risk for patients with an underlying illness that makes them susceptible to these symptoms. If you are given BOTOX too often or the dose is too high, you may experience muscle weakness and side effects related to the spread of toxin, or your body may start producing some antibodies, which can reduce the effect of BOTOX. To limit this risk, the interval between two treatments must not be less than two or three months depending on the indication. When BOTOX is used in the treatment of a condition that it is not listed in this leaflet, it could result in serious reactions, particularly in patients who already experience difficulty in swallowing or have significant debility. If you have not done much exercise for a long time before receiving BOTOX treatment, then after your injections you should start any activity gradually. It is unlikely that this medicine will improve the range of motion of joints where the surrounding muscle has lost its ability to stretch. When treating adults with post-stroke ankle muscle spasms, BOTOX should only be used if it is expected to result in improvement in function (e.g. walking) or symptoms (e.g. spasms or pain) or to help with patient care. Furthermore, for patients who may be more likely to fall, your doctor or healthcare practitioner will judge if this treatment is suitable. When BOTOX is used in the treatment of persistent muscle spasms in the eyelid, it could make your eyes blink less often, which may harm the surface of your eyes. In order to prevent this, you may need treatment with eye drops, ointments, soft contact 4 lenses or even protective covering which closes the eye. Your doctor or healthcare practitioner will tell you if this is required. BOTOX does not prevent headaches in patients with episodic migraine, which occur less than 15 days a month. When BOTOX is used in the treatment of vertical and/or fan-shaped and/or forehead lines drooping of eyelid may occur after treatment. Other medicines with BOTOX Tell your doctor or pharmacist or healthcare practitioner if: • you are using any antibiotics (used to treat infections), or any medicines that affect the nerves that control muscles (for example anticholinesterase medicines or muscle relaxants). Some of these medicines may increase the effect of BOTOX. • you have recently been injected with a medicine containing a botulinum toxin (the active substance of BOTOX), as this may increase the effect of BOTOX too much. • you are using any anti-platelet (aspirin-like) products and/or anticoagulants (blood thinners). Tell your doctor or pharmacist or healthcare practitioner if you are taking or have recently taken or might take any other medicine. Pregnancy and breast-feeding The use of BOTOX is not recommended during pregnancy and in women of childbearing potential not using contraception. BOTOX is not recommended in breast-feeding women. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist or healthcare practitioner for advice before using this medicine. Driving and using machines BOTOX may cause dizziness, sleepiness, tiredness or problems with your vision. If you experience any of these effects, do not drive or use any machines. If you are not sure, ask your doctor or healthcare practitioner for advice. 5 3. How to use BOTOX BOTOX must only be injected by doctors or healthcare practitioners with specific skills and experience on how to use the medicine. Method and route of administration BOTOX is injected into your muscles (intramuscularly), into the bladder wall via a specific instrument (cystoscope) to inject into the bladder or into the skin (intradermally). It is injected directly into the affected area of your body; your doctor or healthcare practitioner will usually inject BOTOX into several sites within each affected area. General information about dosage • The number of injections per muscle and the dose vary depending on the indications. Therefore, your doctor or healthcare practitioner will decide how much, how often, and in which muscle(s) BOTOX will be given to you. It is recommended that your doctor or healthcare practitioner uses the lowest effective dose; • Dosages for older people are the same as for other adults. The dosage of BOTOX and the duration of its effect will vary depending on the condition for which you are treated. Below are details corresponding to each condition. The safety and effectiveness of BOTOX has been established in children/adolescents over the age of two years for the treatment of persistent muscle spasms in the ankle and foot, associated with cerebral palsy. Limited information is available on the use of BOTOX in the following conditions in children/adolescents over the age of 12 years. No recommendation on dosage can be made for these indications. Persistent muscle spasms in the eyelid 12 years and face Persistent muscle spasms in neck and 12 years shoulder In addition, there is limited experience of using BOTOX in the treatment of vertical and/or fan-shaped and/or forehead lines in patients older than 65 years. Excessive sweating of the armpits 12 years (limited experience in adolescents between 12 and 17 years, speak to your doctor or healthcare practitioner for further information) 6 The total dose for treatment of forehead lines (20 Units) in conjunction with glabellar lines (20 Units) is 40 Units. Dosage The dosage of BOTOX and the duration of its effect will vary depending on the condition for which you are treated. Below are details corresponding to each condition. Indication Maximum dose (Units per affected area) Minimal time between treatments First treatment Following treatments Persistent muscle spasms in the ankle and foot in children who have cerebral palsy Ankle & foot: 4 to 8 Units/kg or 300 Units, whichever is lower When treating the ankle & foot of both legs the maximum dose is not to exceed the lower of 10 Units/kg or 340 Units 12 weeks* Persistent muscle spasms in the wrist and hand of adult patients who have had a stroke The exact dosage and number of injection sites per hand/wrist is tailored to individual needs up to a maximum of 240 Units The exact dosage and number of injection sites is tailored to individual needs up to a maximum of 240 Units 12 weeks Persistent muscle spasms in the ankle and foot of adult patients who have had a stroke Multiple injections in the affected muscles. The total dose is 300 Units to 400 Units divided among up to 6 muscles The total dose is 300 Units to 400 Units divided among up to 6 muscles 12 weeks Persistent muscle spasms of the eyelid and face Persistent muscle spasms of the neck and shoulders Headache in adults who have chronic migraine Up to 25 Units per eye Up to 200 Units 155 to 195 Units Up to 100 Units Up to 300 Units 155 to 195 Units 3 months 10 weeks 12 weeks 7 Overactive bladder with leakage of urine Excessive sweating of the armpits Fan-shaped lines from the corner of the eyes seen at maximum smile Forehead lines seen at maximum raised eyebrows 100 Units 100 Units 50 Units per 50 Units per armpit armpit 3 months 16 weeks 3 months 3 months Leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis in adult patients 200 Units 200 Units 3 months The effects of more than two treatment sessions have not been evaluated. Vertical lines between the eyebrows seen at maximum frown 20 Units** Up to 50 Units 3 months The effects of more than four treatment sessions have not been evaluated. 24 Units** 20 Units*** 24 Units * The doctor or healthcare practitioner may select a dose that would mean the treatment may be up to 6 months apart. ** If you are treated for fan-shaped lines from the corner of the eyes seen at maximum smile at the same time as vertical lines between the eyebrows seen at maximum frown, you will receive a total dose of 44 Units. *** If you are treated for all 3 facial lines at the same time (fan-shaped lines from the corner of the eyes seen at maximum smile, vertical lines between the eyebrows seen at maximum frown, and forehead lines seen at maximum raised eyebrows) you will receive a total dose of 64 Units Information for patients treated for leakage of urine Your doctor or healthcare practitioner will give you antibiotics around the time of the injection to help prevent urinary tract infection. The injection will be administered by a procedure called cystoscopy. An instrument with a light source at the end will be introduced into your bladder through the opening by which you let out the urine (called urethra). This enables the doctor or healthcare practitioner to see the inside of the bladder and place the injections into the bladder wall. Please ask your doctor or healthcare practitioner to explain further details of the procedure to you. If you were not using a catheter (a soft, hollow tube that is inserted into your urethra to help empty urine from the bladder) before treatment with BOTOX, you should be seen by your doctor approximately 2 weeks after the injection. You will be asked to pass urine and will then have the volume of urine left in your bladder measured. If 8 your doctor assesses you have too much urine left in your bladder you will be instructed to use a catheter to empty your bladder. Your doctor will decide if and when you need to return for the same test. For overactive bladder with leakage of urine You may be given a local anaesthetic before the injections (your bladder would be filled with anaesthetic solution for a while and then drained). You may also be given a sedative. You will be observed for at least 30 minutes after the injection before you can leave to see if you can pass urine spontaneously. You must contact your doctor or healthcare practitioner if at any time you are unable to pass urine because it is possible that you may need to start using a catheter. In clinical trials, approximately 6 out of 100 patients not using a catheter before treatment may need to use a catheter after treatment. For leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis You may be given a local or general anaesthetic before the procedure. You will be observed for at least 30 minutes after the injection before you can leave. At the time of the injection, due to the procedure by which the injection is delivered into your bladder, you may experience possible uncontrolled reflex reaction of your body (e.g. profuse sweating, throbbing headache or increase in pulse rate). You must contact your doctor or healthcare practitioner if at any time you are unable to pass urine because it is possible that you may need to start using a catheter. In clinical trials, approximately one fifth of patients reported an inability to completely empty their bladder after BOTOX treatment. At least one third of patients not using a catheter before treatment may need to use a catheter after treatment. Time to Improvement and Duration of Effect For persistent muscle spasms in the ankle and foot in children two years and older, the improvement usually appears within the first 2 weeks after the injection. For persistent muscle spasms in the wrist and hand of adult patients who have had a stroke, you will usually see an improvement within the first 2 weeks after the injection. The maximum effect is usually seen about 4 to 6 weeks after treatment. For persistent muscle spasms in the ankle and foot of adult patients who have had a stroke, when the effect starts to wear off, you can have the treatment again if needed, but not more often than every 12 weeks. For persistent muscle spasms of the eyelid and face, you will usually see an improvement within 3 days after the injection and the maximum effect is usually seen after 1 to 2 weeks. 9 For persistent muscle spasms of the neck and shoulders, you will usually see an improvement within 2 weeks after the injection. The maximum effect is usually seen about 6 weeks after treatment. For leakage of urine due to overactive bladder, you will usually see an improvement within 2 weeks after the injection. Typically patients find the effect lasts approximately 6-7 months after the injection. For leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis, you will usually see an improvement within 2 weeks after the injection. Typically patients find the effect lasts approximately 9-10 months after the injection. For excessive sweating of the armpits, you will usually see an improvement within the first week after injection. On average the effect usually lasts 4-7 months after the first injection. For vertical lines between the eyebrows seen at maximum frown, you will usually see an improvement within 1 week after treatment, the maximum effect being observed 5 to 6 weeks after injection. The treatment effect has been demonstrated for up to 4 months after injection. For fan-shaped lines from the corner of the eyes seen at maximum smile you will usually see an improvement within 1 week after treatment. The treatment effect has been demonstrated for an average of 4 months after injection. For forehead lines seen at maximum eyebrow elevation you will usually see an improvement within 1 week after treatment. The treatment effect has been demonstrated for an average of 4 months after injection. If you have received more BOTOX than you should The signs of too much BOTOX may not appear for several days after the injection. Should you swallow BOTOX or have it accidentally injected, you should see your doctor or healthcare practitioner who might keep you under observation for several weeks. If you have received too much BOTOX, you may have any of the following symptoms and you must contact your doctor or healthcare practitioner immediately. He/she will decide if you have to go to hospital: • muscle weakness which could be local or distant from the site of injection; • difficulty in breathing, swallowing or speaking due to muscle paralysis; • food or liquid accidentally going into your lungs which might cause pneumonia (infection of the lungs) due to muscle paralysis; • drooping of the eyelids, double vision; • generalised weakness. If you have any further questions on the use of this product, ask your doctor or pharmacist or healthcare practitioner. 10 4. Possible side effects If you have any difficulty in breathing, swallowing or speaking after receiving BOTOX, contact your doctor immediately. If you experience hives, swelling including swelling of the face or throat, wheezing, feeling faint and shortness of breath, contact your doctor immediately. Like all medicines, this medicine 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. As expected for any injection procedure, pain/burning/stinging, swelling and/or bruising may be associated with the injection. The side effects are classified into the following categories, depending on how often they occur: Very common Common Uncommon Rare Very rare may affect more than 1 in 10 people may affect up to 1 in 10 people may affect up to 1 in 100 people may affect up to 1 in 1,000 people may affect up to 1 in 10,000 people Below are lists of side effects which vary depending on the part of the body where BOTOX is injected. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist or healthcare practitioner. Injections for children with persistent muscle spasms in the ankle and foot Uncommon • Muscle weakness There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with BOTOX. Injections in the wrist and hand of adult patients who have had a stroke Common • Stretching or tearing of ligaments, shallow wound to the skin, • Problems with walking, pain where the injection was given • Rash Common • Muscle weakness, increased muscle tension • Pain in the hand and fingers • Bruising and bleeding under the skin causing red patches (ecchymosis or purpura) • Bleeding, burning, pain where the injection was given 11 • Fever, flu manifestations Uncommon • Depression, difficulty in sleeping (insomnia) • A fall in blood pressure on standing up which causes dizziness, light headedness or fainting • Feeling of dizziness or “spinning” (vertigo) • Lack of coordination of movements, loss of memory, decreased skin sensation, numbness, headache • General weakness, feeling generally unwell • Feeling sick, numbness around the mouth • Pain, swelling of the extremities such as the hands and feet • Joint pain or inflammation • Inflammation of the skin (dermatitis), rash, itching, increased sensitivity where the injection was given Some of these uncommon side effects may also be related to your disease. Injections in the ankle and foot of adult patients who have had a stroke Injections in the eyelid and face for muscle spasms Very Common • Drooping of the eyelid Common • Rash • Joint pain or inflammation, stiff or sore muscles, muscular weakness • Swelling of the extremities such as the hands and feet • Fall Common • Swelling of the face • Pinpoint damage of the cornea (transparent surface covering the front of the eye), difficulty in completely closing the eye, overflow of tears, dry eyes, eye irritation and sensitivity to light • Bruising under the skin • Irritation Uncommon • Dizziness, weakness of the face muscles, drooping of the muscles on one side of the face • Visual disturbance, blurred vision, double vision, inflammation of the cornea (transparent surface covering the front of the eye), abnormal turning of the eyelids outwards or inwards • Rash • Tiredness Rare • Swelling of the eyelid 12 Very rare • Damage to the cornea (transparent surface covering the front of the eye) including ulcer and perforation Injections in the neck and shoulder Very Common • Difficulty in swallowing • Pain • Muscle weakness Common • Dizziness, sleepiness, headache • Feeling of weakness or generally unwell, flu manifestations • Feeling sick, dry mouth • Muscle cramps, stiff or sore muscles, increased muscle tension • Decreased skin sensation • Swelling and irritation inside the nose (rhinitis), signs of infection of the nose or throat (blocked or runny nose, cough, sore throat) Uncommon • Shortness of breath, changes in voice • Double vision, drooping of the eyelid • Fever Injections in the head and neck to prevent headache in patients who suffer from chronic migraine Common • Increase in headache or migraine • Weakness of the face muscles • Drooping of the eyelid • Rash, itching • Pain where the injection was given • Muscle weakness, neck pain, muscle pain or cramp, muscle stiffness or tightness Uncommon • Difficulty in swallowing • Swollen eyelid • Skin pain • Jaw pain Injections in the bladder wall for overactive bladder with leakage of urine Very common • Urinary tract infection, painful urination after the injection* *This side effect is related to the injection procedure. Injections in the bladder wall of adult patients for leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis Common • Inability to empty the bladder (urinary retention), incomplete emptying of the bladder, frequent daytime urination • Bacteria or white blood cells in the urine 13 Very common • Urinary tract infection (in about half the patients) • Inability to empty the bladder (urinary retention; see section 3) Common • Muscle spasm • Bulge in the bladder wall (bladder diverticulum) The following side effects have only be reported in multiple sclerosis: • Difficulty in sleeping (insomnia) • Tiredness, problems with walking (gait disturbance) • Constipation • Muscle weakness, fall The following side effects are related to the injection procedure: • Blood in the urine after the injection • Uncontrolled reflex reaction of the body (profuse sweating, throbbing headache or increase in pulse rate) around the time of the injection (autonomic dysreflexia; see section 3) Injections in the bladder wall of paediatric patients for leakage of urine due to bladder problems associated with spina bifida, spinal cord injury or transverse myelitis Very Bacteria in the urine Common Common Urinary tract infection, white blood cells in the urine, blood in the urine after the injection Injections for excessive sweating of the armpits Very common • Pain where the injection was given Common • Headache, numbness • Hot flushes • Increased sweating at sites other than the armpit, abnormal skin odour, itching, lump under the skin • Hair loss • Pain in the extremities, such as the hands and fingers • Pain, reaction where the injection was given such as swelling, bleeding, burning or increased sensitivity Uncommon • Muscle weakness, muscle pain, problem with the joints • Feeling weak • Feeling sick 14 Possible Side Effects Injection in the forehead for vertical lines Injections in the fan- shaped lines from the corner of the eyes, when treated with or without vertical lines between the eyebrows seen at frown Injections in the forehead lines and vertical lines between the eyebrows seen at frown when treated with or without the fan-shaped lines from the corner of the eyes • Headache • Drooping of the eyelid • Localised muscle weakness • Face pain • Skin redness • Injection site haematoma* • Injection site bruising* • Skin tightness • Infection • Anxiety • Numbness, dizziness • Eyelid swelling • Feeling sick, dry mouth • Muscle twitching • Fever, flu manifestations, feeling weak • Injection site bleeding* • Injection site pain* Common Common Common Common Common n/a n/a Uncommon Uncommon Uncommon Uncommon n/a Common n/a Common1 n/a n/a n/a n/a n/a n/a Common Common n/a Common n/a Common n/a n/a n/a n/a n/a n/a • Inflammation of the eyelid, eye pain, visual disturbance Uncommon n/a n/a • Swelling (face, around the eyes), skin sensitivity to light, dry skin, itching Uncommon n/a n/a Uncommon Uncommon Uncommon Uncommon n/a n/a Uncommon n/a n/a n/a n/a n/a n/a n/a Uncommon n/a Uncommon Uncommon 15 • • Injection site n/a Uncommon n/a tingling or numbness Drooping eyebrow2 n/a n/a Common n/a – not reported as possible side effect *Some of these side effects may also be related to the injection procedure. 1.The median time to onset of drooping eyelid was 9 days following treatment 2. The median time to onset of drooping eyebrow was 5 days following treatment General information about other side effects The following list describes additional side effects reported for BOTOX, in any disease, since it has been marketed: Affecting the immune system • sudden allergic reactions, which can be serious (swelling of the face or throat, difficulty in breathing, feeling faint) • delayed reaction which may include fever, skin reaction, joint pain (serum sickness) • hives Affecting metabolism • loss of appetite Affecting the nervous system • nerve damage (brachial plexopathy) • slurred speech, speech problems • weakness or drooping of the muscles on one side of the face • decreased skin sensation • muscle weakness • chronic disease affecting the muscles (myasthenia gravis) • difficulty moving the arm and shoulder • numbness, tingling and pain in hands and feet • pain/numbness/or weakness starting from the spine • seizures, fainting Affecting the eyes • increase in eye pressure • drooping eyelid • difficulty in completely closing the eye • strabismus (squint) • blurred vision • visual disturbance • dry eye • swelling of the eyelid Affecting the ears • decreased hearing • noises in the ear 16 • feeling of dizziness or “spinning” (vertigo) Affecting the cardiovascular system • heart problems including heart attack Affecting the respiratory system • aspiration pneumonia (lung inflammation caused by accidentally breathing in food, drink, saliva or vomit) • breathing problems, respiratory depression and/or respiratory failure Affecting the gastrointestinal system • abdominal pain • diarrhoea, constipation • dry mouth • difficulty swallowing • feeling sick, vomiting Affecting the skin • hair loss, loss of eyebrows • drooping eyebrow • different types of red blotchy skin rashes • excessive sweating • itching • rash Affecting muscles • muscles pain, loss of nerve supply to/shrinkage of injected muscle • localised muscle twitching/involuntary muscle contractions Affecting the body • feeling generally unwell • fever Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple Pay Store. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store BOTOX Keep out of the sight and reach of children. Store in a refrigerator (2°C – 8°C), or store in a freezer (-5°C to -20°C). 17 After the solution is made up, immediate use of the solution is recommended; however it can be stored for up to 24 hours in a refrigerator (2°C – 8°C). Your doctor or healthcare practitioner should not use BOTOX after the expiry date which is stated on the label after ‘EXP’. The expiry date refers to the last day of that month. 6. Contents of the pack and other information What BOTOX contains • The active substance is: Botulinum toxin type A from Clostridium botulinum. • The other ingredients are human albumin and sodium chloride. What BOTOX looks like and content of the pack BOTOX is presented as a thin white powder that may be difficult to see on the bottom of a transparent glass vial. Prior to injection, the product must be dissolved in sterile unpreserved normal saline (0.9% sodium chloride for injection). Each vial contains either 50, 100 or 200 Allergan Units of botulinum toxin type A. Each pack contains 1, 2, 3 or 6 vials. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: Allergan Ltd., Marlow International, The Parkway, Marlow, Bucks, SL7 1YL, UK. Manufacturer: Allergan Pharmaceuticals Ireland Castlebar Road Westport County Mayo Ireland This leaflet was last revised in August 2021. Version 18 -------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only: 18 Please refer to the Summary of Product Characteristics for complete prescribing information for BOTOX. For all indications: Side effects related to spread of toxin distant from the site of administration have been reported, sometimes resulting in death, which in some cases was associated with dysphagia, pneumonia and/or significant debility. The symptoms are consistent with the mechanism of action of botulinum toxin and have been reported hours to weeks after injection. The risk of symptoms is probably greatest in patients who have underlying conditions and comorbidities that would predispose them to these symptoms, including children and adults treated for spasticity, and are treated with high doses. Patients treated with therapeutic doses may also experience exaggerated muscle weakness. Pneumothorax associated with injection procedure has been reported following administration of BOTOX near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices or other vulnerable anatomic structures. Serious adverse events including fatal outcomes have been reported in patients who had received off-label injections of BOTOX directly into salivary glands, the oro- lingual-pharyngeal region, oesophagus and stomach. Some patients had pre-existing dysphagia or significant debility. There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin, including following off-label use (e.g. neck area). Extreme caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease. Treatment in patients with poor underlying health status should be administered only if the potential benefit to the individual patient is considered to outweigh the risks. Refer to the Summary of Product Characteristics for complete information for BOTOX. Reconstitution of the medicinal product: It is good practice to perform vial reconstitution and syringe preparation over plastic- lined paper towels to catch any spillage. Reconstitute BOTOX only with sterile unpreserved normal saline (0.9% sodium chloride for injection). Draw up an appropriate amount of diluent (see dilution table or instructions below) into a syringe. Dilution table for BOTOX 50, 100 and 200 Allergan Units vial size for all indications except bladder disorders: Resulting dose (Units per 0.1 ml) 50 unit vial Amount of diluent (sterile unpreserved normal saline (0.9% sodium chloride for 100 unit vial Amount of diluent (sterile unpreserved normal saline (0.9% sodium chloride for 200 unit vial Amount of diluent (sterile unpreserved normal saline (0.9% sodium chloride for 19 20 Units 10 Units 5 Units 4 Units 2.5 Units 1.25 Units injection)) added in a 50 unit vial 0.25 ml 0.5 ml 1 ml 1.25 ml 2 ml 4 ml injection)) added in a 100 unit vial 0.5 ml 1 ml 2 ml 2.5 ml 4 ml 8 ml injection)) added in a 200 unit vial 1 ml 2 ml 4 ml 5 ml 8 ml N/A Since BOTOX is denatured by bubbling or similar vigorous agitation, inject the diluent gently into the vial. Discard the vial if a vacuum does not pull the diluent into the vial. Reconstituted BOTOX is a clear colourless to slightly yellow solution free of particulate matter. The reconstituted solution should be visually inspected for clarity and absence of particles prior to use. When reconstituted in the vial, BOTOX may be stored in a refrigerator (2°C - 8°C) for up to 24 hours prior to use. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C. Dilution instructions for treatment of urinary incontinence due to overactive bladder: It is recommended that a 100 Unit or two 50 Unit vials are used for convenience of reconstitution. Should you need to use a 200 Unit vial, reconstitute a 200 Unit vial of BOTOX with 8 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) and mix gently. Draw 4 ml from the vial into a 10 ml syringe. Complete the reconstitution by adding 6 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) into the 10 ml syringe and mix gently. This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. Or, reconstitute a 100 Unit vial of BOTOX with 10 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) and mix gently. Draw the 10 ml from the vial into a 10 ml syringe. This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. 20 Or reconstitute two 50 Unit vials of BOTOX, each with 5 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) and mix each vial gently. Draw the 5 ml from each vial into a single 10 ml syringe. This will result in a single 10 ml syringe containing a total of 100 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. This product is for single use only and any unused reconstituted product should be disposed of. Dilution instructions for treatment of urinary incontinence due to neurogenic detrusor overactivity: It is recommended that a 200 Unit or two 100 Unit vials are used for convenience of reconstitution Reconstitute a 200 Unit vial of BOTOX with 6 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) and mix gently. Draw 2 ml from the vial into each of three 10 ml syringes. Complete the reconstitution by adding 8 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) into each of the 10 ml syringes, and mix gently. This will result in three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. Or, reconstitute two 100 Unit vials of BOTOX, each with 6 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) and mix the vials gently. Draw 4 ml from each vial into each of two 10 ml syringes. Draw the remaining 2 ml from each vial into a third 10 ml syringe. Complete the reconstitution by adding 6 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) into each of the 10 ml syringes, and mix gently. This will result in three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. Should you need to use 50 Unit vials, reconstitute four 50 Unit vials of BOTOX, each with 3 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) and mix the vials gently. Draw 3 ml from the first vial and 1 ml from the second vial into one 10 ml syringe. Draw 3 ml from the third vial and 1 ml from the fourth vial into a second 10 ml syringe. Draw the remaining 2 ml from the second and fourth vials into a third 10 ml syringe. Complete the reconstitution by adding 6 ml of sterile unpreserved normal saline (0.9% sodium chloride for injection) into each of the three 10 ml syringes, and mix gently. This will result in three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline. This product is for single use only and any unused solution should be discarded. Procedure to follow for safe disposal of vials, syringes and materials used For safe disposal, unused vials should be reconstituted with a small amount of water and then autoclaved. Any used vials, syringes, and spillages etc. should be autoclaved, or the residual BOTOX inactivated using dilute hypochlorite solution (0.5%) for 5 minutes. 21 Identification of the product In order to verify receipt of actual BOTOX product from Allergan, look for a tamper- evident seal that contains a translucent silver Allergan logo on the top and bottom flaps of the BOTOX cartons and a holographic film on the vial label. In order to see this film, examine the vial under a desk lamp or fluorescent light source. Rotating the vial back and forth between your fingers, look for horizontal lines of rainbow colour on the label and confirm that the name “Allergan” appears within the rainbow lines. Do not use the product and contact your local Allergan office for additional information if: • the horizontal lines of rainbow colour or the word “Allergan” are not present on the vial label • the tamper-evident seal is not intact and present on both ends of the carton • the translucent silver Allergan logo on the seal is not clearly visible or has a black circle with a diagonal line through it (i.e., prohibition sign) Additionally, Allergan has created detachable stickers on the BOTOX vial label, which include the lot number and expiry date of the product you have received. These stickers can be peeled off and placed in your patient’s clinical file for traceability purposes. Note that once you remove the sticker off the BOTOX vial label, the word “USED” will show, which is to provide you with further assurance that you are using an authentic BOTOX product manufactured by Allergan.

Neuromodulators are naturally-occurring proteins that temporarily block muscle movement. Neuromodulation is commonly used to treat and enhance peoples’ quality of life, and botulinum toxin neurotransmitters are no different. Botulinum toxin neurotransmitters – commercially known as Botox, Dysport, and/or Xeomin – are used to treat frown lines, crow’s feet, and wrinkles. By injecting just a miniscule amount of these neuromodulators directly into the underlying muscle, it causes it to relax and gradually smooth out the appearance of the overlying skin.

Botox Dubai specifically prevents wrinkles caused by muscle movements and can reverse mild lines, stopping them from developing at all. Wrinkles are developed over time because your skin weakens and has more difficulty bouncing back from your face’s many motions (laughing, raising your eyebrow, etc.). Botox, when used with a topical product that can stimulate collagen, strengthens your skin and relaxes your facial muscles, preventing them from constricting and wrinkling overlying skin together.

The most common areas treated with Botox include: Frown lines Forehead wrinkles Crow’s feet Under-eye lines (muscles around the eye) Migraine treatment protocol Masseter/Temporalis Muscles for Temporal Mandibular Jaw Pain (TMJ) and teeth grinding Underarms for treatment of hyperhidrosis (excess sweating)

We recommend that you avoid all of the following after a Botox treatment: Heat and direct sunlight Washing your face Rubbing your face for at least the first 4 hours after treatment Excessive exercise within the first 24 hours after treatment Blood thinners Lying on your face – we recommend that you don’t take a nap after your treatment

There is no risk of your wrinkles or lines worsening if you decide to only have one course of treatment. They will simply gradually return to how they used to be, and for many people a single course of treatment in a specific area is a good way of experimenting and enjoying the benefits first hand.