- Email: [email protected]
OnabotulinumtoxinA for chronic migraine: PREEMPT trials establish a safe and effective dose and injection paradigm
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Abstracts Toxins 2011 / Toxicon 68 (2013) 60–123
Use of botulinum toxin type A injections to the levator ani and obturator internus muscles in cases of perineal pain associated with pelvic floor muscle overcontraction and myalgia E. Bautrant, J. Eggermont, D. Thiers-Bautrant, A. Touzaa, M. Mollo, L. Raffi, P. Weber Pelvi-Perineal Rehabilitation Department, Private Medical Centre ‘‘L'Avancée”, Aix-en-Provence, France E-mail address: [email protected] (E. Bautrant).
Purpose of study: To report the effect of injection of a botulinum toxin type A (XeominÒ) into pelvic floor muscle on symptoms of patients presenting perineal pain associated with pelvic floor muscle overcontraction and myalgia at clinical examination. Methods used: Fifty women and 23 men were identified with levator ani and/or obturator internus overcontraction and myalgia with trigger points along the muscles at clinical examination. All of them presented symptoms of perineal, vulva, vaginal, anal and/or inguinal pain for women and perineal, anal, testicular and/or inguinal pain for men. Pain was most of the time described as burning sensation or spasm. Dysfunction associated with the pain ranged from dysuria, constipation, dyspareunia to painful ejaculation in men. Criteria of pudendal neuralgia were also examined according to the Aix-en-Provence criteria . Patients were injected with 100 to 400 IU of Xeomin into one or both levator ani and/or obturator internus muscles over a period of nine months in 2010 and asked to come back after 6-8 weeks. Muscle injections were made under electro-myo-stimulation and ultrasound control. Summary of results: Patients were evaluated on their pain level (VAS), muscle relaxation and trigger point. Fiftyseven (92%) patients had an improvement of their muscle overcontraction and myalgia. Forty-six (74%) had their pain improved going from slight improvement to no pain. Eighteen patients had their pain starting after a physical trauma (sport trauma, fall or traumatic delivery), and 88% of them had an improvement after the injection. Six women had clear history of sexual abuse or psychological trauma, 50% improved in association with psychotherapy. Eleven women had associated vulvodynia; 82% improved. Twenty-eight patients had a history of pudendal nerve release for entrapment; 57% improved. Conclusions: Botulinum toxin type A could be very helpful in cases of perineal pain and dysfunction associated with perineal muscle spasm. http://dx.doi.org/10.1016/j.toxicon.2012.07.128
Stability of reconstituted botulinum toxin type Acontaining products H. Bigalke Department of Pharmacology and Toxicology, Medical School of Hannover, Hannover, Germany E-mail address: [email protected].
Purpose of study: Botulinum toxin (BoNT)type A–containing products are available in dried formulations. Before application the products have to be reconstituted with saline. The dried formulations are easier to handle because in general dried formulations show higher stability compared to liquid formulations at various storage conditions. Thus, XeominÒ in dried form is stable at room temperature for four years and shows no decrease in activity in four weeks when stored at 60 C. Moreover, upon reconstitution the physician can choose an individual concentration to match the patients’ needs. The handling of liquid formulations is more comfortable for the physician because the reconstitution is an extra step that bears additional risks, e.g., dilution error, contaminations, that are avoidable with ready-to-use formulations. The BoNT/B product, MyoblocÒ, is only available as a liquid that is stable for two years. For the users of dried formulations the question arose how long a reconstituted BoNT/A might keep its activity when stored in a refrigerator. According to the prescription information, reconstituted BotoxÒ and Xeomin can be used within 24 h and DysportÒ within 8 h. However, data are available for Botox and Dysport that demonstrate stability over a period of two weeks. Methods used: To achieve comparable data for Xeomin, vials were reconstituted in 4 ml saline pro injectione under sterile conditions and were stored at 2-8 C. The activity of BoNT/A was determined with the mouse phrenic hemidiaphragm preparation. In intervals of seven days and four weeks, respectively, the test was repeated using vials of the stored material. Summary of results: During two weeks all three products kept their full activity. Like Myobloc, Xeomin's stability survived more than 12 months. Conclusions: Complexing proteins are not necessary for protection of the neurotoxin. In spite of high stability, long storage periods should be avoided because under practical conditions in medical units a stringent sterile handling is not accomplishable, in contrast to laboratory conditions where the reconstitution can be performed under an aseptic hood, and because if bacterial or fungal contamination did occur, it could harm the patient or destroy the toxin by enzymes released by the organisms. The vials for the test were provided by Merz Pharmaceuticals. http://dx.doi.org/10.1016/j.toxicon.2012.07.129
OnabotulinumtoxinA for chronic migraine: PREEMPT trials establish a safe and effective dose and injection paradigm A.M. Blumenfeld a, S.D. Silberstein b, D.W. Dodick c, S.K. Aurora d, C.C. Turkel e, W.J. Binder f a
The Neurology Center, Encinitas, CA, USA Thomas Jefferson Univ, Philadelphia, PA, USA c Mayo Clinic Arizona, Phoenix, AZ, USA d Swedish Neuroscience Institute, Seattle, WA, USA e Allergan, Irvine, CA, USA f UCLA School of Medicine, Los Angeles, CA, USA E-mail address: [email protected] (C.C. Turkel). b
Abstracts Toxins 2011 / Toxicon 68 (2013) 60–123
Purpose of study: To establish a safe, effective onabotulinumtoxinA (onabotA; BotoxÒ) dose and injection paradigm for patients with chronic migraine (CM; 15 days/month with headache lasting 4 hours). CM is a prevalent, disabling, undertreated disorder. Few preventive treatments have been investigated. Various onabotA dosages and injection paradigms have been evaluated in studies for prevention of headache including migraine, but until recently, none is uniformly safe and effective for treatment of CM. Methods used: In PREEMPT [two phase 3, 24-week, double-blinded (DB), placebo-controlled studies, followed by 32-week open-label (OL) phase], randomized patients received a minimum dose 155 U onabotA or placebo (PBO) administered as 31 fixed-site/fixed-dose injections across 7 specific head/neck muscle areas (corrugator, procerus, frontalis, temporalis, occipitalis, cervical paraspinal, trapezius). Patients with predominant pain location(s) could receive up to 40 U additional onabotA (max. dose 195 U) or PBO injections to one or both sides in up to three muscle groups (occipitalis, temporalis, trapezius). Using a sterile 30gauge, 0.5-inch needle (with Luer Lock), IM injections of 0.1 ml/site (5 U) of onabotA or PBO were administered every 12 wks (DB: 2 cycles), followed by onabotA (OL: 3 cycles). Summary of results: PREEMPT dose (onabotA 155-195 U) and injection paradigm demonstrated significant improvements with onabotA over PBO across multiple headache symptom measures including reduction in headache days: 8.4 onabotA/ 6.6 PBO; p<0.001 (pooled data). OnabotA using this injection paradigm was safe and well-tolerated. No new safety findings emerged through the 56-wk studies. Conclusions: OnabotulinumtoxinA injections using the “modified” follow-the-pain model were safe and effective in the PREEMPT clinical program and provide an evidencebased injection strategy to optimize clinical outcomes for patients with CM.
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Botox treatment cycles and then switched to an equal amount of Xeomin treatment cycles. Methods used: Eleven CD patients who previously underwent stable Botox therapy were switched in an unblinded manner to Xeomin using a comparable dosing conversion ratio. A retrospective chart review from 2008 to present was performed in each of the 11 CD patients to compare the following parameters: onset and duration of effect, dose, time between visits and safety. For each of the patients, the average of each parameter in their Botox treatment cycles was compared with the average of each parameter in their Xeomin treatment cycles. A two-tailed type one student t-test was performed for statistical comparison. Summary of results: In each of the 11 patient charts assessed retrospectively, no significant differences were observed in each of the parameters when comparing treatment cycles of Botox vs. Xeomin. For both toxins the doses ranged from 100-225 U (mean: Botox 151.737.0, Xeomin 152.747.6). The onset of effect for both toxins ranged from 3-14 days (Mean: Botox 6.23.0, Xeomin 6.13.1). The duration of effect ranged from 45-90 days for Botox-treated patients and 52.5-90 days for Xeomintreated patients (mean: Botox 69.915.9, Xeomin 74.115.6). The days between patient visits for Botox treatments ranged from 93.3-250 days and 89-274.5 days for Xeomin (mean: Botox 143.957.6, Xeomin 141.460.1). Safety was comparable between Botox and Xeomin treatment cycles. Conclusions: This chart review of 11 CD patients demonstrates that, although variability exists in each toxin treatment cycle, the overall profiles for Botox and Xeomin treatment cycles are comparable to each other. http://dx.doi.org/10.1016/j.toxicon.2012.07.131
Repeated incobotulinumtoxinA injections with flexible dosing intervals in blepharospasm
These studies were supported by Allergan. http://dx.doi.org/10.1016/j.toxicon.2012.07.130
M. Brodsky a, J. Jankovic b, D. Truong c, V.G.H. Evidente d, S.K. Grafe e, H.H. Fernandez f a
Oregon Health and Science University, Portland, OR, USA Baylor College of Medicine, Houston, TX, USA c Parkinson's and Movement Disorder Institute, Fountain Valley, CA, USA d Mayo Clinic Arizona, Scottsdale, AZ, USA e Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany, USA f Movement Disorders, Center for Neurological Restoration, Cleveland Clinic, Cleveland, OH, USA E-mail address: [email protected] (M. Brodsky). b
Adult cervical dystonia patients first treated with onabotulinumtoxinA exhibit comparable onset and duration of effect, time between visits, dose usage and safety profiles when switched to incobotulinumtoxinA J. Boileau Department of Neurology, Hôpital Maisonneuve-Rosemont, Montreal, Canada E-mail address: [email protected].
Purpose of study: IncobotulinumtoxinA (XeominÒ), introduced in Canada in 2009 for the treatment of cervical dystonia (CD), blepharospasm and spasticity, is a botulinum toxin type A free of complexing proteins otherwise contained in onabotulinumtoxinA (BotoxÒ) and abobotulinumtoxinA (DysportÒ). This study compared the onset and duration of effect, doses, time between visits and safety profiles in 11 adult CD patients first treated with multiple
Purpose of study: IncobotulinumtoxinA (NT 201, XeominÒ) has been found to have a favorable safety and efficacy profile in certain focal dystonias. Here, we explored the treatment of blepharospasm with repeated incobotulinumtoxinA injections using flexible dosing intervals. Methods used: Adult subjects with blepharospasm who completed a placebo-controlled, double-blinded study (20 weeks) of incobotulinumtoxinA could enter an openlabel extension (OLEX) and were treated with incobotulinumtoxinA (50 U/eye) for 69 weeks (5 treatment cycles). Treatment intervals were 6 weeks; the administration of repeat treatment was based on subject and
Abstracts Toxins 2011 / Toxicon 68 (2013) 60–123
Use of botulinum toxin type A injections to the levator ani and obturator internus muscles in cases of perineal pain associated with pelvic floor muscle overcontraction and myalgia E. Bautrant, J. Eggermont, D. Thiers-Bautrant, A. Touzaa, M. Mollo, L. Raffi, P. Weber Pelvi-Perineal Rehabilitation Department, Private Medical Centre ‘‘L'Avancée”, Aix-en-Provence, France E-mail address: [email protected] (E. Bautrant).
Purpose of study: To report the effect of injection of a botulinum toxin type A (XeominÒ) into pelvic floor muscle on symptoms of patients presenting perineal pain associated with pelvic floor muscle overcontraction and myalgia at clinical examination. Methods used: Fifty women and 23 men were identified with levator ani and/or obturator internus overcontraction and myalgia with trigger points along the muscles at clinical examination. All of them presented symptoms of perineal, vulva, vaginal, anal and/or inguinal pain for women and perineal, anal, testicular and/or inguinal pain for men. Pain was most of the time described as burning sensation or spasm. Dysfunction associated with the pain ranged from dysuria, constipation, dyspareunia to painful ejaculation in men. Criteria of pudendal neuralgia were also examined according to the Aix-en-Provence criteria . Patients were injected with 100 to 400 IU of Xeomin into one or both levator ani and/or obturator internus muscles over a period of nine months in 2010 and asked to come back after 6-8 weeks. Muscle injections were made under electro-myo-stimulation and ultrasound control. Summary of results: Patients were evaluated on their pain level (VAS), muscle relaxation and trigger point. Fiftyseven (92%) patients had an improvement of their muscle overcontraction and myalgia. Forty-six (74%) had their pain improved going from slight improvement to no pain. Eighteen patients had their pain starting after a physical trauma (sport trauma, fall or traumatic delivery), and 88% of them had an improvement after the injection. Six women had clear history of sexual abuse or psychological trauma, 50% improved in association with psychotherapy. Eleven women had associated vulvodynia; 82% improved. Twenty-eight patients had a history of pudendal nerve release for entrapment; 57% improved. Conclusions: Botulinum toxin type A could be very helpful in cases of perineal pain and dysfunction associated with perineal muscle spasm. http://dx.doi.org/10.1016/j.toxicon.2012.07.128
Stability of reconstituted botulinum toxin type Acontaining products H. Bigalke Department of Pharmacology and Toxicology, Medical School of Hannover, Hannover, Germany E-mail address: [email protected].
Purpose of study: Botulinum toxin (BoNT)type A–containing products are available in dried formulations. Before application the products have to be reconstituted with saline. The dried formulations are easier to handle because in general dried formulations show higher stability compared to liquid formulations at various storage conditions. Thus, XeominÒ in dried form is stable at room temperature for four years and shows no decrease in activity in four weeks when stored at 60 C. Moreover, upon reconstitution the physician can choose an individual concentration to match the patients’ needs. The handling of liquid formulations is more comfortable for the physician because the reconstitution is an extra step that bears additional risks, e.g., dilution error, contaminations, that are avoidable with ready-to-use formulations. The BoNT/B product, MyoblocÒ, is only available as a liquid that is stable for two years. For the users of dried formulations the question arose how long a reconstituted BoNT/A might keep its activity when stored in a refrigerator. According to the prescription information, reconstituted BotoxÒ and Xeomin can be used within 24 h and DysportÒ within 8 h. However, data are available for Botox and Dysport that demonstrate stability over a period of two weeks. Methods used: To achieve comparable data for Xeomin, vials were reconstituted in 4 ml saline pro injectione under sterile conditions and were stored at 2-8 C. The activity of BoNT/A was determined with the mouse phrenic hemidiaphragm preparation. In intervals of seven days and four weeks, respectively, the test was repeated using vials of the stored material. Summary of results: During two weeks all three products kept their full activity. Like Myobloc, Xeomin's stability survived more than 12 months. Conclusions: Complexing proteins are not necessary for protection of the neurotoxin. In spite of high stability, long storage periods should be avoided because under practical conditions in medical units a stringent sterile handling is not accomplishable, in contrast to laboratory conditions where the reconstitution can be performed under an aseptic hood, and because if bacterial or fungal contamination did occur, it could harm the patient or destroy the toxin by enzymes released by the organisms. The vials for the test were provided by Merz Pharmaceuticals. http://dx.doi.org/10.1016/j.toxicon.2012.07.129
OnabotulinumtoxinA for chronic migraine: PREEMPT trials establish a safe and effective dose and injection paradigm A.M. Blumenfeld a, S.D. Silberstein b, D.W. Dodick c, S.K. Aurora d, C.C. Turkel e, W.J. Binder f a
The Neurology Center, Encinitas, CA, USA Thomas Jefferson Univ, Philadelphia, PA, USA c Mayo Clinic Arizona, Phoenix, AZ, USA d Swedish Neuroscience Institute, Seattle, WA, USA e Allergan, Irvine, CA, USA f UCLA School of Medicine, Los Angeles, CA, USA E-mail address: [email protected] (C.C. Turkel). b
Abstracts Toxins 2011 / Toxicon 68 (2013) 60–123
Purpose of study: To establish a safe, effective onabotulinumtoxinA (onabotA; BotoxÒ) dose and injection paradigm for patients with chronic migraine (CM; 15 days/month with headache lasting 4 hours). CM is a prevalent, disabling, undertreated disorder. Few preventive treatments have been investigated. Various onabotA dosages and injection paradigms have been evaluated in studies for prevention of headache including migraine, but until recently, none is uniformly safe and effective for treatment of CM. Methods used: In PREEMPT [two phase 3, 24-week, double-blinded (DB), placebo-controlled studies, followed by 32-week open-label (OL) phase], randomized patients received a minimum dose 155 U onabotA or placebo (PBO) administered as 31 fixed-site/fixed-dose injections across 7 specific head/neck muscle areas (corrugator, procerus, frontalis, temporalis, occipitalis, cervical paraspinal, trapezius). Patients with predominant pain location(s) could receive up to 40 U additional onabotA (max. dose 195 U) or PBO injections to one or both sides in up to three muscle groups (occipitalis, temporalis, trapezius). Using a sterile 30gauge, 0.5-inch needle (with Luer Lock), IM injections of 0.1 ml/site (5 U) of onabotA or PBO were administered every 12 wks (DB: 2 cycles), followed by onabotA (OL: 3 cycles). Summary of results: PREEMPT dose (onabotA 155-195 U) and injection paradigm demonstrated significant improvements with onabotA over PBO across multiple headache symptom measures including reduction in headache days: 8.4 onabotA/ 6.6 PBO; p<0.001 (pooled data). OnabotA using this injection paradigm was safe and well-tolerated. No new safety findings emerged through the 56-wk studies. Conclusions: OnabotulinumtoxinA injections using the “modified” follow-the-pain model were safe and effective in the PREEMPT clinical program and provide an evidencebased injection strategy to optimize clinical outcomes for patients with CM.
107
Botox treatment cycles and then switched to an equal amount of Xeomin treatment cycles. Methods used: Eleven CD patients who previously underwent stable Botox therapy were switched in an unblinded manner to Xeomin using a comparable dosing conversion ratio. A retrospective chart review from 2008 to present was performed in each of the 11 CD patients to compare the following parameters: onset and duration of effect, dose, time between visits and safety. For each of the patients, the average of each parameter in their Botox treatment cycles was compared with the average of each parameter in their Xeomin treatment cycles. A two-tailed type one student t-test was performed for statistical comparison. Summary of results: In each of the 11 patient charts assessed retrospectively, no significant differences were observed in each of the parameters when comparing treatment cycles of Botox vs. Xeomin. For both toxins the doses ranged from 100-225 U (mean: Botox 151.737.0, Xeomin 152.747.6). The onset of effect for both toxins ranged from 3-14 days (Mean: Botox 6.23.0, Xeomin 6.13.1). The duration of effect ranged from 45-90 days for Botox-treated patients and 52.5-90 days for Xeomintreated patients (mean: Botox 69.915.9, Xeomin 74.115.6). The days between patient visits for Botox treatments ranged from 93.3-250 days and 89-274.5 days for Xeomin (mean: Botox 143.957.6, Xeomin 141.460.1). Safety was comparable between Botox and Xeomin treatment cycles. Conclusions: This chart review of 11 CD patients demonstrates that, although variability exists in each toxin treatment cycle, the overall profiles for Botox and Xeomin treatment cycles are comparable to each other. http://dx.doi.org/10.1016/j.toxicon.2012.07.131
Repeated incobotulinumtoxinA injections with flexible dosing intervals in blepharospasm
These studies were supported by Allergan. http://dx.doi.org/10.1016/j.toxicon.2012.07.130
M. Brodsky a, J. Jankovic b, D. Truong c, V.G.H. Evidente d, S.K. Grafe e, H.H. Fernandez f a
Oregon Health and Science University, Portland, OR, USA Baylor College of Medicine, Houston, TX, USA c Parkinson's and Movement Disorder Institute, Fountain Valley, CA, USA d Mayo Clinic Arizona, Scottsdale, AZ, USA e Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany, USA f Movement Disorders, Center for Neurological Restoration, Cleveland Clinic, Cleveland, OH, USA E-mail address: [email protected] (M. Brodsky). b
Adult cervical dystonia patients first treated with onabotulinumtoxinA exhibit comparable onset and duration of effect, time between visits, dose usage and safety profiles when switched to incobotulinumtoxinA J. Boileau Department of Neurology, Hôpital Maisonneuve-Rosemont, Montreal, Canada E-mail address: [email protected].
Purpose of study: IncobotulinumtoxinA (XeominÒ), introduced in Canada in 2009 for the treatment of cervical dystonia (CD), blepharospasm and spasticity, is a botulinum toxin type A free of complexing proteins otherwise contained in onabotulinumtoxinA (BotoxÒ) and abobotulinumtoxinA (DysportÒ). This study compared the onset and duration of effect, doses, time between visits and safety profiles in 11 adult CD patients first treated with multiple
Purpose of study: IncobotulinumtoxinA (NT 201, XeominÒ) has been found to have a favorable safety and efficacy profile in certain focal dystonias. Here, we explored the treatment of blepharospasm with repeated incobotulinumtoxinA injections using flexible dosing intervals. Methods used: Adult subjects with blepharospasm who completed a placebo-controlled, double-blinded study (20 weeks) of incobotulinumtoxinA could enter an openlabel extension (OLEX) and were treated with incobotulinumtoxinA (50 U/eye) for 69 weeks (5 treatment cycles). Treatment intervals were 6 weeks; the administration of repeat treatment was based on subject and