Botulinum toxin type A for the prevention of headaches in adults with chronic migraine

Management of migraines  Offer topiramate 1 or propranolol for the prophylactic treatment of migraine according to the person's preference, comorbidities and risk of adverse events. Advise women and girls of childbearing potential that topiramate is associated with a risk of fetal malformations and can impair the effectiveness of hormonal contraceptives. Ensure they are offered suitable contraception.  If both topiramate 1 and propranolol are unsuitable or ineffective, consider a course of up to 10 sessions of acupuncture over 5–8 weeks or gabapentin 2 (up to 1200 mg per day) according to the person's preference, comorbidities and risk of adverse events.

Management of migraines  Review the need for continuing migraine prophylaxis 6 months after the start of prophylactic treatment.  Advise people with migraine that riboflavin (400 mg 4 once a day) may be effective in reducing migraine frequency and intensity for some people.  For people who are already having treatment with another form of prophylaxis such as amitriptyline 3, and whose migraine is well controlled, continue the current treatment as required.

Who is eligible to receive botulinum toxin type A?  Botulinum toxin type A is indicated if a patient suffers chronic migraine (that is, headaches on at least 15 days each month, with migraine on at least 8 of these days) and:  you have already tried at least three different drug treatments to prevent your chronic migraine headaches, but these have not worked and  Medication overuse headache has been rulled out

Headache and any of the following features, and consider the need for further investigations and/or referral[6]: worsening headache with fever  Sudden-onset headache reaching maximum intensity within 5 minutes  New-onset neurological deficit  New-onset cognitive dysfunction  Change in personality  Impaired level of consciousness  Recent (typically within the past 3 months) head trauma  Headache triggered by cough, valsalva (trying to breathe out with nose and mouth blocked) or sneeze

  Symptoms suggestive of giant cell arteritisgiant cell arteritis  Symptoms and signs of acute narrow-angle glaucomaacute narrow-angle glaucoma  A substantial change in the characteristics of their headache.  Headache triggered by exercise  Orthostatic headache (headache that changes with posture) Headache and any of the following features, and consider the need for further investigations and/or referral[6]: worsening headache with fever

Botulinum toxin type A treatment should be stopped if:  The number of days you have a chronic migraine headache each month hasn’t reduced by at least 30% after two courses of botulinum toxin type A treatment or  your chronic migraine changes to episodic migraine (that is, you have fewer than 15 days with headaches each month) for 3 months in a row.

Dosing  The recommended reconstituted dose is 155–195 units, administered intramuscularly as 0.1 ml (5 units) injections to between 31 and 39 sites around the head and back of the neck. The recommended re-treatment schedule is every 12 weeks

Adverse reactions  Headache, migraine, facial paresis, eyelid ptosis, pruritus, rash, neck pain, myalgia, musculoskeletal pain, musculoskeletal stiffness, muscle spasms, muscle tightness, muscular weakness, and injection site pain.  Although the clinical trial evidence demonstrated statistically significant benefits of botulinum toxin type A treatment compared with placebo for a number of outcomes, the absolute numerical differences were small to modest. Further, there was a large placebo effect seen in the clinical trials.

 The reduction in frequency of headache days (the primary endpoint) was statistically significant in both trials. In PREEMPT 1, there was a reduction of 7.8 headache days from 20.0 (per 28 days) at baseline for patients treated with botulinum toxin type A, compared with a reduction of 6.4 headache days from 19.8 at baseline for those in the placebo arm (p=0.006). In PREEMPT 2, there was a reduction of 9.0 headache days from a baseline of 19.9 in the botulinum toxin type A arm, compared with a reduction of 6.7 headache days from a baseline of 19.7 days for those in the placebo arm (p<0.001). Adverse reactions

Mean change from baseline in number of headache days for study 1

 The clinical fundamentals of BOTOX ® (onabotulinumtoxinA) treatment for Chronic Migraine patients  First and only therapy approved for prophylaxis of headaches in adults with Chronic Migraine (≥ 15 headache days per month with headache lasting 4 hours or more)  Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in 7 placebo- controlled studies

 Dosing recommended once every 12 weeks 1  8 to 9 fewer headache days per month (vs 6 to 7 days with placebo) 1  4% discontinuation rate due to adverse events for BOTOX ® vs 1% for placebo (see Adverse Reactions below) 1  Approved dose is 155 Units administered at 31 injection sites divided across 7 specific head/neck muscle areas 1

Mean change from baseline in number of headache days for study 2

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 2 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.

 4% discontinuation rate due to adverse events for BOTOX ® vs 1% for placebo  8 to 9 fewer headache days per month (vs 6 to 7 days with placebo) 1

Total dose155 Units divided in 31 sites Following is recommended dosing by muscle 1 :  Order of Injection Muscle Recommended Dose,  Number of Sites a Corrugator b 10 Units divided in 2 sites Procerus5 Units in 1 site Frontalis b 20 Units divided in 4 sites Temporalis b 40 Units divided in 8 sites Occipitalis b 30 Units divided in 6 sites Cervical paraspinal muscle group b 20 Units divided in 4 sites Trapezius b 30 Units divided in 6 sites

 Patients on BOTOX ® (onabotulinumtoxinA) had 8 to 9 fewer headache days per month compared with baseline (vs 6 to 7 days with placebo) at 24 weeks

A.Corrugator: 5 Unit each side B.Procerus: 5 unit 1 Side C.Frontalis: 10 Unit each side

D. Temporalis: 20 Unit each side

E. Occipitalis: 15 Unit each site

F.Cervical Paraspinal: 10 Unit each side G.Trapezius: 15 Unit each side

 The clinical fundamentals of BOTOX ® (onabotulinumtoxinA) treatment for Chronic Migraine patients  First and only therapy approved for prophylaxis of headaches in adults with Chronic Migraine (≥ 15 headache days per month with headache lasting 4 hours or more)  Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in 7 placebo- controlled studies

 Dosing recommended once every 12 weeks 1  8 to 9 fewer headache days per month (vs 6 to 7 days with placebo) 1  4% discontinuation rate due to adverse events for BOTOX ® vs 1% for placebo (see Adverse Reactions below) 1  Approved dose is 155 Units administered at 31 injection sites divided across 7 specific head/neck muscle areas 1

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