BOTOX Powder for solution for injection Ref.[6581] Active ingredients: Botulinum toxin type A

ATC class: M03AX01 and D11AX

The active constituent in BOTOX is a protein complex derived from Clostridium botulinum. The protein consists of type A neurotoxin and several other proteins. Under physiological conditions it is presumed that the complex dissociates and releases the pure neurotoxin.

Clostridium botulinum toxin type A neurotoxin complex blocks peripheral acetyl choline release at presynaptic cholinergic nerve terminals.

Intramuscular injection of the neurotoxin complex blocks cholinergic transport at the neuromuscular junction by preventing the release of acetylcholine. The nerve endings of the neuromuscular junction no longer respond to nerve impulses and secretion of the chemotransmitter is prevented (chemical denervation). Re-establishment of impulse transmission is by newly formed nerve endings and motor end plates. Clinical evidence suggests that BOTOX reduces pain and neurogenic inflammation and elevates cutaneous heat pain thresholds in a capsaicin induced trigeminal sensitization model. Recovery after intramuscular injection takes place normally within 12 weeks of injection as nerve terminals sprout and reconnect with the endplates.

After intradermal injection, where the target is the eccrine sweat glands, the effect lasted for about 4-7 months in patients treated with 50 Units per axilla.

There is limited clinical trial experience of the use of BOTOX in primary axillary hyperhidrosis in adolescents between the ages of 12 and 18. A single, year long, uncontrolled, repeat dose, safety study was conducted in US paediatric patients 12 to 17 years of age (N=144) with severe primary hyperhidrosis of the axillae. Participants were primarily female (86.1%) and Caucasian (82.6%). Participants were treated with a dose of 50 Units per axilla for a total dose of 100 Units per patient per treatment. However, no dose finding studies have been conducted in adolescents so no recommendation on posology can be made. Efficacy and safety of BOTOX in this group have not been established.

BOTOX blocks the release of neurotransmitters associated with the genesis of pain. The presumed mechanism for headache prophylaxis is by blocking peripheral signals to the central nervous system, which inhibits central sensitisation, as suggested by pre-clinical and clinical pharmacodynamic studies.

Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release. In addition BOTOX inhibits afferent neurotransmitters and sensory pathways.

Clinical efficacy and safety

NEUROLOGIC DISORDERS

Focal spasticity of the upper limb in paediatric patients

The efficacy and safety of BOTOX for the treatment of upper limb spasticity in paediatric patients of ages 2 years and older was evaluated in a randomised, multi-centre, double-blind, placebo-controlled study. The study included 234 paediatric patients (77 BOTOX 6 Units/kg, 78 BOTOX 3 Units/kg and 79 placebo) with upper limb spasticity because of cerebral palsy (87%) or stroke (13%) and baseline MAS elbow or wrist score of at least 2. A total dose of 3 Units/kg (maximum 100 Units) or 6 Units/kg (maximum 200 Units) or placebo was injected intramuscularly and divided between the elbow or wrist and finger muscles. All patients received standardised occupational therapy. The use of electromyographic guidance, nerve stimulation, or ultrasound techniques was required to assist in proper muscle localisation for injections. The primary endpoint was the average of the change from baseline in MAS score of the principal muscle group (elbow or wrist) at weeks 4 and 6 and the key secondary endpoint was the average of the Clinical Global Impression of Overall Change by Physician (CGI) at weeks 4 and 6. The Goal Attainment Scale (GAS) by Physician for active and passive goals was evaluated as a secondary endpoint at weeks 8 and 12. Pain was assessed using the Faces Pain Scale (FPS) in a subset of patients. Patients were followed for 12 weeks.

Eligible patients could enter an open-label extension study, in which they received up to five treatments at doses up to 10 Units/kg (maximum 340 Units), when also treating the lower limb in combination with the upper limb.

Statistically significant improvements compared to placebo were demonstrated in patients treated with BOTOX 3 and 6 Units/kg for the primary endpoint and at all timepoints through week 12. The improvement in MAS score was similar across both BOTOX treatment groups. However, at no point was the difference from placebo ≥1 point on the MAS. See table below. Responder analysis treatment effect ranged from approximately 10-20%.

Primary and Secondary Efficacy Endpoints Results:

^* Statistically significantly different from placebo (p<0.05)
^a The MAS is a 6-point scale (0 [no increase in muscle tone], 1, 1+, 2, 3, and 4 [limb rigid in flexion or extension]) which measures the force required to move an extremity around a joint, with a reduction in score representing improvement in spasticity.
^b 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).
^c The GAS is a 6-point scale (-3[worse than start], -2 [equal to start], -1 [less than expected], 0 [expected goal], +1 [somewhat more than expected], +2 [much more than expected]).
^d Pain was assessed in participants who were 4 years of age and older and had a pain score >0 at baseline using Faces Pain Scale (FPS: 0 =no pain to 10 = very much pain).

Focal spasticity of the lower limb in paediatric patients

The efficacy and safety of BOTOX for the treatment of lower limb spasticity in paediatric patients of ages 2 years and above was evaluated in a randomised, multi-centre, double-blind, placebo-controlled study. The study included 384 paediatric patients (128 BOTOX 8 Units/kg, 126 BOTOX 4 Units/kg and 128 placebo) with lower limb spasticity because of cerebral palsy and ankle score of at least 2. A total dose of 4 Units/kg (maximum 150 Units) or 8 Units/kg (maximum 300 Units) or placebo was injected intramuscularly and divided between the gastrocnemius, soleus and tibialis posterior. All patients received standardised physical therapy. The use of electromyographic guidance, nerve stimulation, or ultrasound techniques was required to assist in proper muscle localisation for injections. The primary endpoint was the average of the change from baseline in MAS ankle score at weeks 4 and 6, and the key secondary endpoint was the average of the CGI at weeks 4 and 6. The GAS by Physician for active and passive functional goals was a secondary endpoint at weeks 8 and 12. Gait was assessed using the Edinburgh Visual Gait (EVG) at weeks 8 and 12 in a subset of patients. Patients were followed for 12 weeks.

Eligible patients could enter an open-label extension study, in which they received up to five treatments at doses up to 10 Units/kg (maximum 340 Units), if treating more than one limb.

Statistically significant improvements compared to placebo were demonstrated in patients treated with BOTOX 4 and 8 Units/kg for the primary endpoint and at most timepoints through Week 12. The improvement in MAS score was similar across both BOTOX treatment groups. However, at no point was the difference from placebo ≥1 point on the MAS. See table below. Responder analysis treatment effect was less than 15% at all time points.

Primary and Secondary Efficacy Endpoints Results:

^* Statistically significantly different from placebo (p<0.05)
^a The MAS is a 6-point scale (0 [no increase in muscle tone], 1, 1+, 2, 3, and 4 [limb rigid in flexion or extension]) which measures the force required to move an extremity around a joint, with a reduction in score representing improvement in spasticity.
^b 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).
^c The GAS is a 6-point scale (-3[worse than start], -2 [equal to start], -1 [less than expected], 0 [expected goal], +1 [somewhat more than expected], +2 [much more than expected]).

In paediatric lower limb spasticity patients with analysed specimens from one phase 3 study and the open-label extension study, neutralising 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.

Focal upper limb spasticity associated with stroke in adult patients

In controlled and open, non-controlled studies, doses between 200 and 240 Units in wrist and flexor muscles were divided among the selected muscles at a given treatment session. In controlled studies, improvement in muscle tone occurred within two weeks with the peak effect generally seen within four to six weeks. In an open, non-controlled continuation study, most patients were re-injected after an interval of 12 to 16 weeks, when the effect on muscle tone had diminished. These patients received up to four injections with a maximal cumulative dose of 960 Units over 54 weeks.

Focal lower limb spasticity associated with stroke in adult patients

The efficacy and safety of BOTOX was evaluated in a randomised, multicentre, double-blind, placebo-controlled study which included 468 post-stroke patients (233 BOTOX and 235 placebo) with ankle spasticity (Modified Ashworth Scale [MAS] ankle score of at least 3) who were at least 3 months post-stroke. BOTOX 300 to 400 Units or placebo were injected intramuscularly into the study mandatory muscles gastrocnemius, soleus, and tibialis posterior and optional muscles including flexor hallucis longus, flexor digitorum longus, flexor digitorum brevis, extensor hallucis, and rectus femoris.

The primary endpoint was the average change from baseline of weeks 4 and 6 MAS ankle score and a key secondary endpoint was the average CGI (Physician Global Assessment of Response) at weeks 4 and 6. Statistically and clinically significant differences were demonstrated between BOTOX and placebo for these measures as shown in the table below.

For the primary endpoint of average MAS ankle score at weeks 4 and 6, no improvement from baseline was observed for patients aged 65 and older in the BOTOX group compared to placebo

^* Significantly different from placebo (p<0.05)

Another double-blind, placebo-controlled, randomised, multicentre, phase 3 clinical study was conducted in adult post-stroke patients (average 6.5 years) with lower limb spasticity affecting the ankle. A total of 120 patients were randomised to receive either BOTOX (n=58; total dose of 300 Units) or placebo (n=62).

Significant improvement compared to placebo was observed in the primary endpoint for the overall change from baseline up to week 12 in the MAS ankle score, which was calculated using the area under the curve (AUC) approach. Significant improvements compared to placebo were also observed for the mean change from baseline in MAS ankle score at individual post-treatment visits at weeks 4, 6 and 8. The proportion of responders (patients with at least a 1-grade improvement) was also significantly higher (67%-68%) than in placebo-treated patients (31%-36%) at these visits.

BOTOX treatment was also associated with significant improvement in the investigator’s clinical global impression (CGI) of functional disability compared to placebo although the difference was not significant for the patient’s CGI.

Cervical dystonia

In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of reconstituted BOTOX ranged from 140 to 280 Units. In more recent studies, doses ranged from 95 to 360 Units (with an approximate mean of 240 Units). Clinical improvement generally occurs within the first two weeks after injection. The maximum clinical benefit generally occurs by six weeks post-injection. The duration of beneficial effect reported in clinical studies showed substantial variation (from 2 to 33 weeks) with a typical duration of approximately 12 weeks.

Chronic migraine

Chronic migraine patients without any concurrent headache prophylaxis who, during a 28-day baseline, had at least 4 episodes and ≥ 15 headache days (with at least 4 hours of continuous headache) with at least 50% being migraine/probable migraine, were studied in two Phase 3 clinical trials. Patients were allowed to use acute headache treatments and 66% overused acute treatments during the baseline period.

During the double-blind phase of the trials, the main results achieved after two BOTOX treatments administered at a 12-week interval are shown in the table below.

^* Headache Impact Test

The treatment effect appeared smaller in the subgroup of male patients (n=188) than in the whole study population.

BLADDER DISORDERS

Overactive bladder

Two double-blind, placebo-controlled, randomised, 24-week phase 3 clinical studies were conducted in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. A total of 1105 patients (mean age of 60 years), whose symptoms had not been adequately managed with at least one anticholinergic therapy (inadequate response or intolerable side effects), were randomised to receive either 100 Units of BOTOX (n=557), or placebo (n=548), after having discontinued anticholinergics for more than one week.

Primary and Secondary Endpoints at Baseline and Change from Baseline in Pooled Pivotal Studies:

^† Least Squares (LS) mean changes are presented
^a Co-primary endpoints
^b Secondary endpoints
^c Pre-defined minimally important change from baseline was +10 points for I-QOL and -5 points for KHQ

The median duration of response following BOTOX treatment, based on patient request for re-treatment, was 166 days (~24 weeks). The median duration of response, based on patient request for re-treatment, in patients who continued into the open label extension study and received treatments with only BOTOX 100 Units (N=438), was 212 days (~30 weeks).

A total of 839 patients were evaluated in a long-term open-label extension study. For all efficacy endpoints, patients experienced consistent response with re-treatments. The mean reductions from baseline in daily frequency of urinary incontinence were -3.07 (n=341), -3.49 (n=292), and -3.49 (n=204) episodes at week 12 after the first, second, and third BOTOX 100 Unit treatments, respectively. The corresponding proportions of patients with a positive treatment response on the Treatment Benefit Scale were 63.6% (n=346), 76.9% (n=295), and 77.3% (n=207), respectively.

In the pivotal studies, none of the 615 patients with analysed serum specimens developed neutralising antibodies after 1–3 treatments. In patients with analysed specimens from the pivotal phase 3 and the open-label extension studies, neutralising 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. One of these three patients continued to experience clinical benefit. Compared to the overall BOTOX treated population, patients who developed neutralising antibodies generally had shorter duration of response and consequently received treatments more frequently (see section 4.4).

Adult urinary incontinence due to neurogenic detrusor overactivity

Pivotal Phase 3 Clinical Trials:

Two double-blind, placebo-controlled, randomised phase 3 clinical studies were conducted in a total of 691 patients with spinal cord injury or multiple sclerosis, who were not adequately managed with at least one anticholinergic agent and were either spontaneously voiding or using catheterisation. These patients were randomised to receive either 200 Units of BOTOX (n=227), 300 Units of BOTOX (n=223), or placebo (n=241).

Primary and Secondary Endpoints at Baseline and Change from Baseline in Pooled Pivotal Studies:

^† LS mean changes are presented
^a Primary endpoint
^b Secondary endpoints
^c I-QOL total score scale ranges from 0 (maximum problem) to 100 (no problem at all).
^d In the pivotal studies, the pre-specified minimally important difference (MID) for I-QOL total score was 8 points based on MID estimates of 4-11 points reported in neurogenic detrusor overactivity patients.

The median duration of response, based on time to qualification for re-treatment (time to <50% reduction in incontinence episodes), was 42 weeks in the 200 Unit dose group. The median interval between the first and second administrations was 42 weeks in patients with spinal cord injury and 45 weeks in patients with multiple sclerosis. The median duration of response, based on time to qualification for re-treatment (at least 1 urinary incontinence episode in a 3 day diary), in patients who continued into the open label extension study and received treatments with only BOTOX 200 Units (N=174), was 264 days (~38 weeks).

For all efficacy endpoints in the pivotal phase 3 studies, patients experienced consistent response with re-treatment (n=116).

None of the 475 patients with analysed serum specimens developed neutralising antibodies after 1-2 treatments. In patients with analysed specimens in the drug development program (including the open-label extension study), neutralising 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. Four of these eight patients continued to experience clinical benefit. Compared to the overall BOTOX treated population, patients who developed neutralising antibodies generally had shorter duration of response and consequently received treatments more frequently (see section 4.4).

In the multiple sclerosis (MS) patients enrolled in the pivotal studies, the MS exacerbation annualised rate (i.e. number of MS exacerbation events per patient year) was 0.23 in the 200 Unit dose group and 0.20 in the placebo group. With repeated BOTOX treatments, including data from a long term study, the MS exacerbation annualised rate was 0.19 during each of the first two BOTOX treatment cycles.

Post-approval Study:

A placebo controlled, double-blind post-approval study was conducted in multiple sclerosis (MS) patients with urinary incontinence due to neurogenic detrusor overactivity who were not adequately managed with at least one anticholinergic agent and not catheterising at baseline. These patients were randomised 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, including the percentage of dry patients. Significant improvements in urodynamic parameters, and Incontinence Quality of Life questionnaire (I-QOL), including avoidance limiting behaviour, psychosocial impact and social embarrassment were also observed.

Results from the post-approval study are presented below:

Primary and Secondary Endpoints at Baseline and Change from Baseline in Post-Approval Study of BOTOX 100 Units in MS patients not catheterising at baseline:

^* Percentage of dry patients (without incontinence) throughout week 6 was 53.0% (100 Unit BOTOX group) and 10.3% (placebo)
^a Primary endpoint
^b Secondary endpoints
^c I-QOL total score scale ranges from 0 (maximum problem) to 100 (no problem at all).
^d The pre-specified minimally important difference (MID) for I-QOL total score was 11 points based on MID estimates of 4-11 points reported in neurogenic detrusor overactivity patients.

The median duration of response in this study, based on patient request for re-treatment, was 362 days (~52 weeks) for BOTOX 100 Unit dose group compared to 88 days (~13 weeks) with placebo.

Paediatric neurogenic detrusor overactivity

One double-blind, parallel-group, randomised, multicentre clinical study (191622-120) was 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 catheterisation. 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. The median age was 11 years and 42.5% were female. These patients were randomised to 50 Units, 100 Units or 200 Units, not to exceed 6 Units/kg bodyweight. Patients receiving less than the randomised dose due to this maximum were assigned to the nearest dose group for analysis: N= 38, 45 and 30 for BOTOX 50 Units, BOTOX 100 Units, and BOTOX 200 Units, respectively. Prior to treatment administration, patients received anaesthesia based on age and local site practice. One hundred and nine patients (97.3%) received general anaesthesia or conscious sedation and 3 patients (2.7%) received local anaesthesia.

The study results demonstrated within group improvements in the primary efficacy variable of change from baseline in daytime urinary incontinence episodes (normalised 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, defined as the highest value in the Pdet channel during the storage phase [i.e., 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.

Summary of results in the paediatric study:

CI = Confidence Interval
^* Least Squares (LS) mean change and 95% CI are based on 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 request for re-treatment was 214 (31 weeks), 169 (24 weeks), and 207 days (30 weeks) for BOTOX 50 Units, BOTOX 100 Units, and BOTOX 200 Units, respectively.

Out of 99 paediatric patients who had a negative baseline result for antibodies and had at least one evaluable post-baseline value, none developed neutralising antibodies after receiving up to 4 treatments of 50 to 200 Units of BOTOX.

SKIN AND SKIN APPENDAGE DISORDERS

Glabellar lines

537 patients with moderate to severe glabellar lines between the eyebrows seen at maximum frown have been included in clinical studies.

BOTOX injections significantly reduced the severity of glabellar lines seen at maximum frown for up to 4 months, as measured by the investigator assessment of glabellar line severity at maximum frown and by subject’s global assessment of change in appearance of his/her glabellar lines seen at maximum frown. Improvement generally occurred within one week of treatment. None of the clinical endpoints included an objective evaluation of the psychological impact. Thirty days after injection, 80% (325/405) of BOTOX-treated patients were considered by investigators as treatment responders (none or mild severity at maximum frown), compared to 3% (4/132) of placebo-treated patients. At this same timepoint, 89% (362/405) of BOTOX-treated patients felt they had a moderate or better improvement, compared to 7% (9/132) of placebo-treated patients.

BOTOX injections also significantly reduced the severity of glabellar lines at rest. Of the 537 patients enrolled, 39% (210/537) had moderate to severe glabellar lines at rest (15% had no lines at rest). Of these, 74% (119/161) of BOTOX-treated patients were considered treatment responders (none or mild severity) thirty days after injection, compared with 20% (10/49) of placebo-treated patients.

There is limited phase 3 clinical data with BOTOX in patients older than 65 years. Only 6.0% (32/537) of subjects were >65 years old and efficacy results obtained were lower in this population.

Crow’s feet lines

1362 patients with moderate to severe crow’s feet lines seen at maximum smile, either alone (n=445, Study 191622-098) or also with moderate to severe glabellar lines seen at maximum frown (n=917, Study 191622-099), were enrolled.

BOTOX injections significantly reduced the severity of crow’s feet lines seen at maximum smile compared to placebo at all timepoints (p <0.001) for up to 5 months (median 4 months). Improvement assessed by the investigator occurred within one week of treatment. This was measured by the proportion of patients achieving a crow’s feet lines severity rating of none or mild at maximum smile in both pivotal studies; until day 150 (end of study) in Study 191622-098 and day 120 (end of first treatment cycle) in Study 191622-099. For both investigator and subject assessments, the proportion of subjects achieving none or mild crow’s feet lines severity seen at maximum smile was greater in patients with moderate crow’s feet lines seen at maximum smile at baseline, compared to patients with severe crow’s feet lines seen at maximum smile at baseline. Table 1 summarises results at day 30, the timepoint of the primary efficacy endpoint.

In Study 191622-104 (extension to Study 191622-099), 101 patients previously randomised to placebo were enrolled to receive their first treatment at the 44 Units dose. Patients treated with BOTOX had a statistically significant benefit in the primary efficacy endpoint compared to placebo at day 30 following their first active treatment. The response rate was similar to the 44 Units group at day 30 following first treatment in Study 191622-099. A total of 123 patients received 4 cycles of 44 Units BOTOX for combined crow’s feet and glabellar lines treatment.

Day 30. Investigator and Patient Assessment of Crow’s Feet Lines Seen at Maximum Smile – Responder Rates (% of Patients Achieving Crow’s Feet Lines Severity Rating of None or Mild):

* p<0.001 (BOTOX vs placebo)

Improvements from baseline in subject-assessment of the appearance of crow’s feet lines seen at maximum smile were seen for BOTOX (24 Units and 44 Units) compared to placebo, at day 30 and at all timepoints following each treatment cycle in both pivotal studies (p<0.001).

Treatment with BOTOX 24 Units also significantly reduced the severity of crow’s feet lines at rest. Of the 528 patients treated, 63% (330/528) had moderate to severe crow’s feet lines at rest at baseline. Of these, 58% (192/330) of BOTOX-treated patients were considered treatment responders (none or mild severity) thirty days after injection, compared with 11% (39/352) of placebo-treated patients.

Improvements in subject’s self-assessment of age and attractiveness were also seen for BOTOX (24 Units and 44 Units) compared to placebo using the Facial Line Outcomes (FLO-11) questionnaire, at the primary timepoint of day 30 (p<0.001) and at all subsequent timepoints in both pivotal studies.

In the pivotal studies, 3.9% (53/1362) of patients were older than 65 years of age. Patients in this age group had a treatment response as assessed by the investigator, of 36% (at day 30) for BOTOX (24 Units and 44 Units).When analysed by age groups of ≤50 years and >50 years, both populations demonstrated statistically significant improvements compared to placebo. Treatment response for BOTOX 24 Units, as assessed by the investigator, was lower in the group of subjects >50 years of age than those ≤50 years of age (42.0% and 71.2%, respectively).

Overall BOTOX treatment response for crow’s feet lines seen at maximum smile is lower (60%) than that observed with treatment for glabellar lines seen at maximum frown (80%).

916 patients (517 patients at 24 Units and 399 patients at 44 Units) treated with BOTOX had specimens analysed for antibody formation. No patients developed the presence of neutralising antibodies.

Forehead Lines

Forehead lines were treated in conjunction with glabellar lines to minimise the potential of brow ptosis. 822 patients with moderate to severe forehead lines and glabellar lines seen at maximum contraction, either alone (N=254, Study 191622-142) or also with moderate to severe crow’s feet lines seen at maximum smile (N=568, Study 191622-143), were enrolled and included for analyses of all primary and secondary efficacy endpoints.

For both investigator and patient assessments, the proportion of patients achieving none or mild forehead lines seen at maximum eyebrow elevation following BOTOX injections was greater than patients treated with placebo at day 30. This primary endpoint along with additional endpoints are provided in the table below.

Day 30 (primary timepoint). Investigator and Patient Assessment of Forehead Lines and Upper Facial Lines at Maximum Contraction and Rest:

^a Proportion of patients achieving none or mild FHL severity at maximum eyebrow elevation
^b Proportion of patients with at least a 1-grade improvement from baseline of FHL severity at rest
^c Proportion of responders defined as the same patient achieving none or mild in forehead lines, glabellar lines, and crow’s feet lines for each facial region at maximum contraction

BOTOX injections significantly reduced the severity of forehead lines seen at maximum eyebrow elevation compared to placebo for up to 6 months (p<0.05): This was measured by the proportion of patients achieving a forehead lines severity rating of none or mild in both pivotal studies; until day 150 in Study 191622-142 (21.6% with BOTOX treatment compared to 0% with placebo) and day 180 in Study 191622-143 (6.8% with BOTOX treatment compared to 0% with placebo).

When all 3 areas were treated simultaneously in Study 191622-143 (BOTOX 64 U group), BOTOX injections significantly reduced the severity of glabellar lines for up to 6 months (5.5% with BOTOX treatment compared to 0% with placebo), lateral canthal lines for up to 6 months (3.4% with BOTOX treatment compared to 0% with placebo) and forehead lines for up to 6 months (9.4% with BOTOX treatment compared to 0% with placebo).

A total of 116 and 150 patients received 3 cycles over 1 year of BOTOX 40 Units and 64, respectively. The response rate for forehead lines improvement was similar across all treatment cycles.

Using the Facial Lines Satisfaction Questionnaire (FLSQ), 78.1% of patients in Study 191622-142 and 62.7% in Study 191622-143 reported improvements in appearance-related and emotional impacts (as defined by items pertaining to feeling older, negative self-esteem, looking tired, feeling unhappy, looking angry) with BOTOX 40 Units treatment compared to patients treated with placebo 19.0% in Study 191622-142 and 18.9% in Study 191622-143 at day 30 (p<0.0001 in both studies).

On the same questionnaire, 90.2% of patients in Study 191622-142 and 79.2% (40 Units), or 86.4% (64 Units) in Study 191622-143 reported they were “very satisfied”/“mostly satisfied” with BOTOX 40 Units or 64 Units compared to patients treated with placebo (1.7%, 3.6% in Study 191622-142 and Study 191622-143, respectively), at the primary timepoint of day 60 using the FLSQ (p<0.0001 in both studies).

The pivotal studies, 3.7% of patients were older than 65 years of age. Responder rates in this BOTOX-treated subgroup were similar to those in the overall population, but statistical significance was not reached due to the small number of patients.