AND BOTOX by mikeholy


									 Industry Science
For personal use only. Not to be reproduced without permission of the publisher (

 RETROSPECTIVE EVALUATION OF THE                                                            DOSES OF DYSPORT®
 AND BOTOX® IN THE MANAGEMENT                                                               OF DYSTONIA
                                                                                      Sponsored by an educational grant from Allergan

 A retrospective case note review to assess relative dose requirements and costs of two botulinum
 toxin type A products in the management of dystonias at Sheffield Teaching Hospitals NHS Trust.
 Study objective: To evaluate doses of BOTOX and Dysport used in clinical practice to treat dystonia.
 Background: There are two preparations of Botulinum toxin type A - BOTOX and Dysport. They are not interchangeable and
 there is no conversion factor. In 2002, Sheffield Teaching Hospitals changed contracts from Dysport to BOTOX.
 Methods: Case notes of patients treated with both toxins for at least one year who had documented response to both were
 reviewed. Injections given in the one year period before the switch and between one and two years after the switch were included
 in the analysis. The mean dose of each toxin and the ratio was calculated, together with associated costs.
 Results: Of the 100 patient notes reviewed, 42 fit the criteria of which 36 were treated for spasmodic torticollis. The mean doses
 of BOTOX and Dysport were 89 (range 53 to 120) and 397 (range 200 to 500) units respectively for this indication. The mean
 ratio (Dysport : BOTOX) was found to be 4.48:1 (95% confidence interval 4.22:1 to 4.73:1; range 2.60:1 to 6.25:1). The mean
 costs per administration were found to be £115 (€170) and £122 (€180) based on units used and £140 (€207) and £153 (€226)
 based on whole vials for BOTOX and Dysport respectively. Similar ratios were found in dosages administered for other types
 of dystonia giving an overall mean dose ratio of 4.56:1 (Dysport : BOTOX). Conclusions: The observed dose ratio of 4.56:1 is
 consistent with the results of previous studies. BOTOX is associated with lower costs than Dysport.

 Introduction                                   for BOTOX®, for example, states that,           amount of toxin delivered to the injec-
 There are two widely available commer-         “Doses recommended for BOTOX® are               tion site compared with Dysport® [5].
 cial preparations of botulinum toxin type      not interchangeable with other prepara-         Finally, differences in LD50 assay condi-
 A-haemagglutinin complex (BoNT-A):             tions of botulinum toxin” [1]. Similarly,       tions yield different estimates of poten-
 BOTOX® (Allergan Inc., Irvine, CA,             the product licence for Dysport® states         cy, with each formulation uniquely
 USA) and Dysport® (Ipsen Ltd, Slough,          that, “The units of Dysport® are specific       affected by changes in assay conditions,
 Berkshire, UK). Both are intramuscular         to the preparation and are not inter-           including inter-laboratory variation [6].
 injections. When deciding which product        changeable with other preparations of
 to use, clinicians and decision makers         botulinum toxin” [2].                           In clinical practice, intramuscular injec-
 need to be satisfied that they are getting                                                     tion of BoNT-A causes a temporary
 the best value for their money, taking         The dose recommendations in the SPCs            relaxation of targeted muscles, normally
 into account effectiveness, safety and         for both products do not allow easy com-        lasting for around 12 weeks. Conse-
 tolerability. Comparing the two products,      parison. Furthermore, higher doses than         quently, BoNT-A is used to treat a
 however, is not straightforward because        those stated in the SPCs are commonly           variety of dystonic conditions where
 they are of unequal potency; that is, one      used in clinical practice.                      prolonged muscle relaxation may pro-
 unit of BOTOX® is not equivalent to one                                                        vide clinical benefit to the patient.
 unit of Dysport®, even though both             The non-equivalence of BOTOX and                Evidence from systematic reviews
 products are standardised in murine            Dysport has been attributed to differences      demonstrate the efficacy and safety of
 intraperitoneal LD50 (median lethal            in their production, formulation, and           BoNT-A in focal dystonias, the most
 dose) units. Indeed, the clinical literature   potency assessment. The two products are        common of which are spasmodic torti-
 shows that one unit of BOTOX is                isolated from different strains of              collis (ST) [7] and blepharospasm (BP)
 required to achieve a comparable efficacy      Clostridium botulinum and are purified          [8]. There have been six controlled trials
 outcome to three to five units of Dysport      using different processes [3]. BOTOX® is        published which compare the two
 and this has led regulatory agencies           stabilised by vacuum drying [4], Dysport®       products in a clinical setting [9-14]. Five
 worldwide to conclude that commercial          by lyophilisation [2]. Additionally, there is   of these concluded that the products
 BoNT-A formulations are unique and             a greater amount of human serum albumin         were comparable in terms of efficacy
 not interchangeable. The product licence       in BOTOX“, which may increase the               and one concluded that Dysport® was

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superior, though was associated with            Methods                                                                           • Treatment with Dysport for at least one
significantly more adverse events than          A retrospective case note review was                                                year before the switch
BOTOX [13]. It should be noted, how-            undertaken. Approval for the study was                                            • Treatment with BOTOX® for at least
ever, that all these trials used fixed dose     sought from the Local Research Ethics                                               one year post switch
ratios. This limits their relevance to clin-    Committee. The committee advised that                                             • Documented response to both brands
ical practice where dose titration against      ‘opt-in’ patient consent was required                                               of toxin
clinical response is the norm. They are         before researchers could access case
therefore of limited value in informing         notes. Patients who may have received                                             The principle adopted was that any
decision making on financial grounds.           both products were identified using the                                           doses of Dysport® included in the analy-
                                                hospital Patient Administration System.                                           sis needed to have been administered
Observational studies have compared             These patients were sent a patient infor-                                         more than one year after the first dose of
doses of the two products, in a normal          mation leaflet and consent form. The case                                         Dysport® and less than one year before
practice setting, in patients who were          notes of those patients who provided con-                                         the first dose of BOTOX®. Similarly, any
switched from one product to another.           sent were reviewed by a research pharma-                                          doses of BOTOX® included needed to
The largest study, The REAL DOSE                cist (DJ). The main source of data was                                            have been given more than one year after
Study [15], a retrospective review of the       from the botulinum toxin treatment                                                the first. This is summarised in Figure 1.
case notes of 119 patients, was conduct-        record, a dedicated proforma which is                                             This meant that, with a usual dose inter-
ed at six sites in five European countries.     used for documentation of BoNT-A dose,                                            val of two to four months, between one
Patients with ST throughout the paper or        site of injection and response to last injec-                                     and six administrations could have typi-
BP were recruited if they had been              tion and any adverse effects experienced.                                         cally been included for a given patient in
switched from BOTOX to Dysport® or              Correspondence to the patient’s general                                           each phase.
vice versa and had received each treat-         practitioner, summarising the clinic visit,
ment for a minimum of one year. Ratios          was also examined if further clarification                                        Patients were deemed to have responded
of mean dose (units of Dysport® : units         was required.                                                                     to treatment if the documented response
of BOTOX®) ranged from 2:1 to 11:1,                                                                                               was mainly ‘fair’, ‘fairly good’, ‘good’
with an overall mean dose ratio of              Patients with a confirmed diagnosis of,                                           or ‘very good.’ In practice, patients were
4.48:1. The study also assessed the inci-       ST, hemifacial spasm (HS), BP, or other                                           discontinued or changed to other treat-
dence of adverse effects; these were doc-       focal dystonic conditions were included in                                        ments (for example botulinum toxin
umented for 11% of Dysport injections           the review. Essentially the study was a ret-                                      type B) if response was consistently
and 4.25% of BOTOX® injections.                 rospective single arm crossover design                                            poor. In the Dysport® phase, patients
These findings reinforced the recom-            with patients acting as their own control.                                        who were changed to Botulinum toxin
mendations that the two products are not        In order to ensure that only stable, respon-                                      type B were excluded. Similarly, in the
interchangeable and provide some indi-          sive patients were included, the following                                        BOTOX® phase, patients who were
cation of the relative cost-effectiveness       inclusion criteria were adopted:                                                  changed back to Dysport® at any time
of each product to treat a patient population
                                                 Figure 1: Flow chart showing interventions received by patients and
                                                           corresponding data collection
In 2002, Sheffield Teaching Hospitals
changed purchase contracts from Dysport®
to BOTOX®. A cohort of 135 patients who               At least 1 year                   Up to 1st year                          1st year             Up to 2 years
                                                      post initiation                   pre-switch                            post-switch             post-switch
attended the movement disorder clinic
have received both products. The aim of                              Treatment with Dysport                                   BOTOX dose             Treatment
this study was to establish the dose ratio in                                                                                   titration           with BOTOX
this population by means of retrospective
                                                                                           Clinic visits                        Clinic visits        Clinic visits
case note review. Other outcomes of inter-
est in this study were the incidence of
adverse events and the comparative costs
of the two products. Based on UK list                                                        Mean                                                     Mean
                                                                                             dose                          Dose changes               dose
prices of £128.93 (€189.20) for a 100 unit
vial of BOTOX® and £164.74 (€241.50)
for a 500 unit vial of Dysport® [16] the
switch would be cost neutral to the pre-
scribing budget if the mean dose ratio
                                                                                                                        Dose ratio
across a patient population were 3.9:1.

                • Volume 13 • 2007/3                EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP)          85
Industry Science

during the two year period following the      Table 1: Patient characteristics
switch were also excluded.

Patients were excluded if they were
under 18 years of age, pregnant or had
received surgical intervention during
the study period. Treatment with other
muscle relaxants was not an exclusion
criterion unless it was judged to have
had a differential influence on the dosing
requirements of the two products.

The following data were collected:
• Demographics – age, gender
• Diagnosis / indication for botulinum       Results                                       157 Dysport® administrations and 143
  toxin                                      Consent forms were sent to 135 patients.      BOTOX® administrations were included
• Date of first dose of Dysport®             Of these 106 replied, with 100 patients       in the study. However, this represents a
• Date, dose, response and side effects      providing consent to access their case        heterogeneous group of patients; as the
  for each eligible dose of Dysport® or      notes. Of the 100 patient notes reviewed,     majority of patients were being treated
  BOTOX® administered                        42 patients fit the criteria. Figure 1 pro-   for ST, the results for these patients are
                                             vides a summary of patients recruited         considered in greater detail.
The following parameters were calculated     and reasons for exclusion. The main
for each patient:                            reason for exclusion (26 patients) was        Table 2 summarises the findings for the
• Mean dose of Dysport®                      because Dysport® treatment had been           36 patients with ST. The mean doses of
• Mean dose of BOTOX®                        received for less than one year. Fifteen      BOTOX® and Dysport® were 89 (range
• Ratio of mean doses                        patients had been changed back to             53 to 120) and 397 (range 200 to 500)
                                             Dysport® and eight patients had received      units respectively. The mean ratio for
The mean dose ratio for the cohort of        botulinum toxin type B (BTX-B) as an          this indication (Dysport® : BOTOX®)
patient was calculated with 95% confi-       alternative to Dysport®. Characteristics      was found to be 4.48:1 (95% confidence
dence intervals.                             of the 42 patients included in the            interval 4.22:1 to 4.73:1; range 2.60:1 to
                                             study are summarised in Table 1. In total,    6.25:1). The distribution of mean ratios
Two cost values were calculated for each
administration. Firstly, a cost based on      Table 2: Dose and cost data - spasmodic torticollis
the exact number of units used and sec-
ondly a cost based on the number of
vials required to provide the dose. The
former is the cost associated with the
most efficient practice possible, where
no botulinum toxin is wasted and vial
sharing occurs. However, this practice is
outside of the licensed use (the
Summary of Product Characteristics for
each product states that vials are for
single use) and so the cost of whole vials
(associated with the practice of discard-
ing any excess toxin remaining in a vial
after administration to a patient) was
also calculated. BNF prices (list price
excluding VAT) were used for the cost
analyses [15]. As patients were consid-
ered to be equally responsive to both
treatments, a cost minimisation analysis
was possible.

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Figure 2: Summary of patient recruitment and exclusion                                                                        All patients were initially switched at a
                                                                                                                              ratio of 5:1. However, a significant
                                                                                                                              number of patients required dose
                                                                                                                              changes. Most who were changed
                                                                                                                              following the switch had doses
                                                                                                                              increased, though five patients had doses
                                                                                                                              decreased. The range of ratios observed
                                                                                                                              was narrower than that reported in The
                                                                                                                              REAL DOSE study [15]. This may be
                                                                                                                              because of a more conservative approach
                                                                                                                              to dose titration in this study. Our
                                                                                                                              methodology assumed that if reasonable
                                                                                                                              responses had been documented for
                                                                                                                              both products, then the effect could be
                                                                                                                              considered equivalent. However, the
                                                                                                                              sensitivity and reliability of this infor-
                                                                                                                              mal approach could be questioned.
                                                                                                                              Ideally, a standard and reliable method
                                                                                                                              of assessing response to treatment in a
                                                                                                                              number of domains (for example range
                                                                                                                              of movement, cosmesis, pain, functioning)
                                                                                                                              should be developed to allow a more
                                                                                                                              reliable assessment of patient response.

                                                                                                                              Some patients (15) did not respond to
                                                                                                                              BOTOX® as well as Dysport® and so
across this patient cohort is summarised     ical practice. In this respect, it is the                                        were changed to the original product.
in Figure 2. The mean costs per admin-       largest single site study of its type.                                           This is expected as most drug switches
istration were found to be £115 (€170)       Moreover, it provides a reflection of real                                       will generate a ‘rebound’ of at least 10%.
for BOTOX ® and £122 (€180) for              life clinical practice and so overcomes                                          Patients undergoing the switch were
Dysport® based on units used. The            some of the disadvantages of fixed dose                                          clearly informed of the product change.
mean costs per administration were           ratio clinical trials. Furthermore, the                                          This may have had an influence.
found to be £140 (€207) for BOTOX®           same specialist nurse administered the                                           However, this rebound, together with the
and £153 (€226) for Dysport® based on        vast majority of doses and made most of                                          wide range of observed ratios supports
whole vials required. Similar ratios         the dose titration decisions. This sug-                                          the advice that the two products are not
were found for other types of dystonia       gests that there was a high degree of                                            interchangeable and also challenges
giving an overall mean dose ratio of         consistency in practice throughout the                                           the readiness to label similar products
4.56:1 (Dysport® : BOTOX®).                  study period.                                                                    as ‘biosimilars’. This study was not
                                                                                                                              designed to assess the relative response
Adverse effects were documented for          The dose ratio in the study cohort was                                           rates of each product and so it is not
five doses of Dysport® and three doses       found to range from 2.6:1 to 6.25:1                                              appropriate to draw any conclusions.
of BOTOX® , a rate of 3.2% (95% CI =         which reinforces the position that the                                           Furthermore, patients had received
0.44 to 5.93%) and 2.1% (95% CI = 0.76       two toxins are not clinically inter-                                             Dysport® for a mean period of six years
to 3.43%) of administrations, respective-    changeable. The mean dose ratio was                                              prior to the switch, whereas all patients
ly.                                          found to be 4.56:1 (95% confidence                                               were naive to BOTOX.
                                             interval 4.28:1 to 4.84:1). This is consis-
Discussion                                   tent with the REAL DOSE study which                                              In terms of cost per dose, further evi-
This study consisted of a retrospective      observed a mean ratio of 4.44:1 for                                              dence is provided that BOTOX® is less
review of the case notes of patients who     patients switched from Dysport® to                                               expensive, both when calculated on a
had been switched from Dysport® to           BOTOX®. These observed mean ratios                                               cost per unit basis or cost per whole vial
BOTOX® and provides further evidence         can provide useful insight into the rela-                                        basis. The study did not evaluate the
for the relative dosing requirements (and    tive cost-effectiveness of the two prod-                                         comparative duration of clinical effect
the observed levels of variation) in clin-   ucts.                                                                            nor the impact on frequency of clinic

               • Volume 13 • 2007/3             EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP)       87
Industry Science                                                                                                                                           Sponsored Section

                                                                                                                                    affecting potency. Toxicon. 1996 Sep;34(9):
   Figure 3: Distribution of dose ratios - spasmodic torticollis
                     16                                                                                                         7. Costa J, Espírito-Santo C, Borges A, Ferreira
                                                                                                                                    JJ, Coelho M, Moore P, Sampaio C. Botulinum
                     14                                                                                                             toxin type B for cervical dystonia. The
                                                                                                                                    Cochrane Database of Systematic Reviews.
                     12                                                                                                             2004, Issue 4.
                                                                                                                                8. Costa J, Espírito-Santo C, Borges A, Ferreira
 Number of patient

                     10                                                                                                             JJ, Coelho M, Moore P, Sampaio C. Botulinum
                                                                                                                                    toxin type A therapy for blepharospasm. The
                      8                                                                                                             Cochrane Database of Systematic Reviews.
                                                                                                                                    2004, Issue 2.
                      6                                                                                                         9. Nußgens and Roggenkämper. Comparison of
                                                                                                                                    two botulinum-toxin preparations in the treat-
                                                                                                                                    ment of essential blepharospasm. Graefes
                                                                                                                                    Arch Clin Exp Ophthalmol. 1997 Apr;235(4):
                                                                                                                                10. Sampaio C, Ferreira JJ, Simoes F, Rosas MJ,
                          2 to < 3 : 1       3 to < 4 : 1             4 to < 5 : 1           5 to < 6 : 1   6 to < 7 : 1
                                                                                                                                    Magalhaes M, Correia AP, Bastos-Lima A,
                                                            Ratio (units Dysport to BOTOX)                                          Martins R, Castro-Caldas A. DYSBOT: a
                                                                                                                                    single-blind, randomized parallel study to
                                                                                                                                    determine whether any differences can be
visits. Further work is required, prefer-                                  Authors                                                  detected in the efficacy and tolerability of two
ably prospective in nature, to establish                                   Duncan Jenkins, PhD                                      formulations of botulinum toxin type A--
any difference in real clinical practice.                                  MORPh Consultancy Ltd, Worcester, UK                     Dysport and Botox--assuming a ratio of 4:1.
                                                                                                                                    Mov Disord. 1997;12:1013-8.
                                                                           Ben Dorward, BPharm
                                                                                                                                11. Odergren T, Hjaltason H, Kaakkola S, Solders
Conclusions                                                                Pharmacy Department                                      G, Hanko J, Fehling C, Marttila RJ, Lundh H,
• The observed ratios of Dysport® to                                       Sheffield Teaching Hospitals NHS                         Gedin S, Westergren I, Richardson A, Dott C,
  BOTOX® ranged from 2.6:1 to 6.5:1,                                       Foundation Trust, Sheffield, UK                          Cohen H. A double blind, randomised, parallel
  with a mean of 4.56:1. This is similar                                   Richard Grünewald, DPhil                                 group study to investigate the dose equivalence
  to that reported in previous observa-                                    Department of Neurology                                  of Dysport and Botox in the treatment of cervi-
  tional studies. The wide range of ratios                                 Sheffield Teaching Hospitals NHS                         cal dystonia. J Neurol Neurosurg Psychiatry.
  observed supports the position that the                                  Foundation Trust, Sheffield, UK                          1998;64:6-12.
                                                                                                                                12. Annese V, Bassotti G, Coccia G, D'onofrio V,
  products are not interchangeable in
                                                                                                                                    Gatto G, Repici A, Andriulli A. Comparison of
  clinical practice.                                                       Contact for correspondence                               two different formulations of botulinum toxin
• Differences in response and the range                                    Duncan Jenkins, PhD                                      A for the treatment of oesophageal achalasia.
  of observed ratios provide further evi-                                  MORPh Consultancy Ltd                                    The Gismad Achalasia Study Group. Aliment
  dence that the two products are not                                      The Church House, Burleigh Road                          Pharmacol Ther. 1999;13:1347-50.
  interchangeable in clinical practice.                                    Dines Green, Worcester WR2 5QT, UK                   13. Ranoux D, Gury C, Fondarai J, Mas JL, Zuber
• The cost per dose of BOTOX® was                                          Tel: +44 1905 424666                                     M. Respective potencies of Botox and
  found to be less expensive than that of                                                    Dysport: a double blind, randomised, crossover
  Dysport®, with a mean saving of                                                                                                   study in cervical dystonia. J Neurol Neurosurg
                                                                                                                                    Psychiatry. 2002;72:459-62.
  between £12.55 (€18.42) and £20.05                                       References
                                                                                                                                14. Simonetta Moreau M, Cauhepe C, Magues JP,
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This research was supported by an unre-                                       RD. Measurement of botulinum toxin activity:      15. A. Marchetti, R. Magar, L. Findley, et al.
stricted educational grant from Allergan                                      evaluation of the lethality assay. Toxicol Appl       Retrospective Evaluation of the Dose of
Inc.                                                                          Pharmacol. 1994;128:69-77.                            Dysport® and BOTOX® in the Management of
                                                                           4. Anon. BOTOX Prescribing Information.                  Cervical Dystonia and Blepharospasm: The
Kirsty Askwith for valuable admin sup-
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88                                       • Volume 13 • 2007/3                                                                                              

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