Clostridium botulinum type A toxin haemagglutinin complex, lyophilised powder for I.M. injection, 300 units and 500 units, Dysport® - July 2011
Page last updated: 28 October 2011
Public Summary Document
Product: Clostridium botulinum type A toxin
haemagglutinin complex, lyophilised powder for I.M. injection, 300
units and 500 units, Dysport®
Sponsor: Ipsen Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought:
1) To extend the current Section 100 (Botulinum Toxin Program)
listing for the 500 units formulation to include treatment of
blepharospasm and hemifacial spasm in adults;
2) Section 100 (Botulinum Toxin Program) listing for a new, lower
strength formulation (300 units) for the same PBS-listed
indications as the 500 unit formulation.
2. Background
Clostridium botulinum type A toxin-haemagglutinin complex had not
previously been considered by the PBAC for treatment of
blepharospasm and hemifacial spasm.
Botulinum toxin type A (Botox®) has been listed in
the Section 100 – Botulinum toxin program for the treatment
of blepharospasm associated with dystonia, including benign
blepharospasm and VIIth nerve disorders (hemifacial spasm) in
patients 12 years and older since 1 October 1994.
3. Registration Status
Clostridium botulinum type A toxin – haemagglutinin complex
is TGA registered for the following indications: treatment of
spasticity of the upper limb in adults following a stroke;
spasmodic torticollis in adults; dynamic equinus foot deformity due
to spasticity in ambulant paediatric cerebral palsy patients, two
years of age or older; blepharospasm in adults; hemifacial spasm in
adults; and moderate to severe glabellar lines in adults.
4. Listing Requested and PBAC’s View
Section 100 – Botulinum Toxin Program
Note
Arrangements to prescribe this item should be made by medical
practitioners with Medicare Australia, contact telephone number
1800 700 720.
Criteria for availability
Treatment of blepharospasm and hemifacial spasm in adults;
Treatment of dynamic equinus foot deformity due to spasticity in an
ambulant paediatric cerebral palsy patient aged from 2 to 17 years
inclusive;
Continuing PBS-subsidised treatment of dynamic equinus foot
deformity due to spasticity in an ambulant cerebral palsy patient
18 years of age or older who was commenced on PBS-subsidised
treatment with clostridium botulinum type A toxin-haemagglutinin
complex as a paediatric patient;
Treatment of spasmodic torticollis, either as monotherapy or as
adjunctive therapy to current standard care.
Criteria for availability
Treatment of moderate to severe spasticity [defined as MAS greater
than or equal to 3 using modified Ashworth scale] of the upper limb
in adults following a stroke, as second line therapy when standard
management has failed (e.g. physiotherapy and/or oral spasticity
agents) or as an adjunct to physical therapy.
Maximum number of treatment to be authorised is 4 (total Botox and
Dysport) per upper limb per lifetime. Treatment should not be
initiated until 3 months post-stroke in patients who do not have
established severe contracture. Treatment should be discontinued if
the patient does not respond (decrease of MAS greater than 1 in at
least one joint) after two treatments.
The date of the stroke must be provided.
Contraindications to treatment include established severe
contracture and known sensitivity to botulinum toxin.
Note
The units used to express the potency of botulinum toxin
preparations currently available for PBS subsidy are not
equivalent.
The PBAC agreed that the prescribing of Dysport for blepharospasm
and hemifacial spasm should be restricted to medical practitioners
who hold ophthalmology, neurology, plastic surgery or otolaryngeal
head and neck surgery specialist qualifications, consistent with
Botox, under the Arrangements – Botulinum Toxin
Program.
5. Clinical Place for the Proposed Therapy
Idiopathic blepharospasm is a focal dystonia involving the
orbicularis oculi muscle of both eyes and is characterised by
repeated, forceful and involuntary closure of the eyelids. It
progresses to cause severe visual disability in the majority of
cases and disfiguring periocular spasms that often extend into the
jaw or neck.
Hemifacial spasm consists of intermittent synchronous contraction
of the ipsilateral muscles innervated by the seventh (facial)
cranial nerve. Typically the spasms begin in the orbicularis oculi
muscles and spread to the brow, mid and lower face, and neck over
several years. Hemifacial spasm is intractable and can cause
considerable social embarrassment.
The submission proposed that Dysport would be an alternative
treatment choice to Botox for blepharospasm and hemifacial
spasm.
6. Comparator
The submission nominated botulinum toxin type A (Botox) as the
comparator. This was considered appropriate by the
PBAC.
7. Clinical Trials
The submission presented two direct randomised trials comparing
Dysport with Botox in patients with blepharospasm or hemifacial
spasm. The primary outcome in both trials was the duration of
relief from symptoms.
The submission also presented two placebo controlled trials of
Dysport or Botox in patients with blepharospasm or hemifacial
spasm. The placebo controlled trials did not measure the same
outcomes and therefore the submission did not perform an indirect
comparison.
Details of the published trials presented in the submission are in
the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Direct randomised trials | ||
| Nussgens et al. (1997) | Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm. | Graefe's Archive for Clinical and Experimental Ophthalmology 235(4): 197-199 |
| Sampaio et al. (1997) | DYSBOT: A single-blind, randomised parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A - Dysport and Botox - Assuming a ratio of 4:1. | Movement Disorders 12(6): 1013-1018 |
| Supplementary randomised trials (placebo controlled trials) | ||
| Truong et al. (2008) | Dysport Benign Essential Blepharospasm Study Group. Efficacy and safety of purified botulinum toxin type A (Dysport) for the treatment of benign essential blepharospasm: A randomised, placebo-controlled, phase II trial. | Parkinsonism and Related Disorders 14 (5): 407-414 |
| Girlanda et al. (1996) | Botulinum toxin for cranial / cervical dystonia: A double-blind placebo-controlled study. | Mov Disord Jan 11(1): 27-31 |
The PBAC noted that both direct randomised trials used a fixed dose
ratio of 4:1 (Dysport : Botox).
8. Results of Trials
The table below presents the primary outcome results from the direct randomised trials.
|
Trial |
Duration of response |
Patients needing repeat injections during trial |
||||
|
Population analysed |
Dysport |
Botox |
Difference |
Dysport |
Botox |
|
| Nussgens 1997 | ITT |
8.03 (4.6) |
7.98 (3.8) |
p=0.42 |
NA | |
| Sampaio 1997 | ITT b^ |
12.8 (5.6) |
13.1 (11.8) |
-0.3 |
11/48 (22.9%)a |
5/43 |
| ITT* |
12.8 (5.6) |
10.9 (5.9) |
1.85 |
|||
| OT c |
13.3 (5.6) |
11.2 (5.8) |
NR |
|||
SEM = standard error of the mean; ITT = intention to treat; OT= on treatment; NA =
not applicable; NR = not reported; w = weeks
a p = 0.26.
b n = 48 for Dysport, n = 43 for Botox
c On treatment excluded patients who required adjustment for injection technique by
having either additional or fewer muscles injected compared with the standard pre-specified
injection plan (n = 36 for Dysport, n = 35 for Botox)
^ analysis including outlier from Botox arm
* analysis excluding outlier from Botox arm
The PBAC considered that the results of the direct randomised trials indicated that
Dysport is no worse than the comparator Botox for the primary efficacy outcome of
duration of response, at a fixed dose relativity of 4:1. Nussgens et al. (1997) showed
no difference in duration of response (8.03 weeks versus 7.98 weeks [p=0.42]). In
Sampaio et al. (1997), analyses of the difference in the duration of response, both
including and excluding an outlier in the Botox arm had confidence intervals that
reach slightly outside the stated clinically important difference of 3.8 weeks, favouring
Botox when the Botox outlier is included (-0.3 [95% CI: -4.08, 3.48]) and favouring
Dysport when the Botox outlier is excluded (1.85 [95% CI: -1.53, 5.23]).
Adverse events (AEs) such as ptosis, diplopia, tearing and blurred vision are common
and dose dependent, but generally of mild or moderate severity and resolve after a
short duration. There were significantly fewer AEs associated with Botox compared
to Dysport in Nussgens et al. (1997) (p<0.05). No deaths were reported in the randomised
trials. Three patients reported serious AEs (pneumonia and/or congestive heart failure),
but none were considered by the investigator to be related to the study medication.
Based on the fixed dose ratio of 4:1 in the direct randomised trials, Dysport is associated
with more AEs than Botox.
9. Clinical Claim
The submission claimed that Dysport is non-inferior to Botox in terms of efficacy
with a similar safety profile. The submission made this conclusion at a dose ratio
of 3:1 (Dysport : Botox). The PBAC noted that no evidence derived from direct randomised
trials using a dose ratio of 3:1 was presented in the submission to support this claim.
For PBAC’s view, see Recommendations and Reasons.
10. Economic Analysis
A cost-minimisation analysis was presented by the submission using a dose ratio of
3:1. Sensitivity analyses were also presented in the submission using dose ratios
of 2:1 to 4:1.
The PBAC noted that the clinical evidence derived from direct randomised trials presented
in the submission used a dose relativity of 4:1. The PBAC recalled its previous recommendations
for dose relativities for Dysport and Botox in spasmodic torticollis, dynamic equinus
foot deformity and moderate to severe spasticity of the upper limb in adults following
a stroke were all made based on clinical trial data and recommended that the dose
relativity in the blepharospasm and hemifacial spasm indication should be 4:1, consistent
with the data presented and with the approach used in previous recommendations.
11. Estimated PBS Usage and Financial Implications
The likely number of patients treated was estimated in the submission to be less than
10,000 in Year 5 using a market share approach.
Financial savings to the PBS of less than $10 million in year 5 of listing were estimated
in the submission, based on Dysport replacing Botox at a dose ratio of 3:1.
These estimates were uncertain and would have been affected by the dose ratio realised
in practice. At a dose ratio of 4:1, Dysport would cost the PBS less than $10 million
in year 5. There may also be some additional MBS costs for AEs associated with Dysport.
The financial implications were to be further verified by the Department.
12. Recommendation and Reasons
The PBAC recommended extending the Section 100 – Botulinum Toxin Program listing of
the 500 unit vial of clostridium botulinum type A toxin-haemagglutinin complex, lyophilised
powder for I.M. injection (Dysport®) to include treatment of blepharospasm or hemifacial spasm in adults on a cost-minimisation
basis with botulinum toxin type A (Botox®) with 4 Ipsen units of Dysport being equivalent to 1 unit of Botox.
The PBAC recommended listing of a new vial size (300 units) of clostridium botulinum
type A toxin-haemagglutinin complex, lyophilised powder for I.M. injection (Dysport®) on the PBS under the Section 100 Botulinum Toxin Program for the same indications
for which the 500 unit vial is listed.
The PBAC also recommended listing of the 300 unit vial for the treatment of blepharospasm
or hemifacial spasm in adults on a cost-minimisation basis with botulinum toxin type
A (Botox®) with 4 Ipsen units of Dysport being equivalent to 1 unit of Botox.
The PBAC agreed that the prescribing of Dysport for blepharospasm and hemifacial spasm
should be restricted to medical practitioners who hold ophthalmology, neurology, plastic
surgery or otolaryngeal head and neck surgery specialist qualifications, consistent
with Botox, under the Arrangements – Botulinum Toxin Program.
The PBAC considered that the results of the direct randomised trials indicated that
Dysport was no worse than the comparator Botox for the primary efficacy outcome of
duration of response, at a dose relativity of 4:1. Nussgens et al. (1997) showed no
difference in duration of response (8.03 weeks versus 7.98 weeks [p=0.42]). In Sampaio
et al. (1997), analyses of the difference in the duration of response, both including
and excluding an outlier in the Botox arm had confidence intervals that reach slightly
outside the stated clinically important difference of 3.8 weeks, favouring Botox when
the Botox outlier is included (-0.3 [95% CI: -4.08, 3.48]) and favouring Dysport when
the Botox outlier is excluded (1.85 [95% CI: -1.53, 5.23]).
The PBAC noted that the submission requested listing on a cost-minimisation basis
with Botox using a dose relativity of 3:1 (Dysport : Botox), while the clinical evidence
presented in the submission used a dose relativity of 4:1. No evidence from direct
randomised trials was presented in the submission to support the claim of non-inferiority
of Dysport to Botox using a dose ratio of 3:1. The PBAC recalled its previous recommendations
for dose relativities for Dysport and Botox in spasmodic torticollis, dynamic equinus
foot deformity and moderate to severe spasticity of the upper limb in adults following
a stroke were all made based on clinical trial data and that the dose relativity in
the blepharospasm and hemifacial spasm indication should be 4:1, consistent with the
data presented and with the approach used in previous recommendations.
The PBAC recommended that clostridium botulinum is not suitable for inclusion in the
PBS medicines for prescribing by nurse practitioners.
Recommendation:
CLOSTRIDIUM BOTULINUM type A toxin-haemagglutinin complex, lyophilised powder for
I.M. injection, 500 units per vial
Restriction:
Section 100 – Botulinum Toxin Program
Treatment of blepharospasm or hemifacial spasm in adults;
Pack size 1
CLOSTRIDIUM BOTULINUM type A toxin-haemagglutinin complex, lyophilised powder for
I.M. injection, 300 units per vial
Restriction:
Section 100 – Botulinum Toxin Program
Note
Arrangements to prescribe this item should be made by medical practitioners with Medicare
Australia, contact telephone number 1800 700 720.
Criteria for availability Treatment of blepharospasm or hemifacial spasm in an adult;
Treatment of dynamic equinus foot deformity due to spasticity in an ambulant paediatric
cerebral palsy patient aged from 2 to 17 years inclusive;
Continuing PBS-subsidised treatment of dynamic equinus foot deformity due to spasticity
in an ambulant cerebral palsy patient 18 years of age or older who was commenced on
PBS-subsidised treatment with clostridium botulinum type A toxin-haemagglutinin complex
as a paediatric patient;
Treatment of spasmodic torticollis, either as monotherapy or as adjunctive therapy
to current standard care.
Criteria for availability
Treatment of moderate to severe spasticity [defined as MAS greater than or equal to
3 using modified Ashworth scale] of the upper limb in adults following a stroke, as
second line therapy when standard management has failed (e.g. physiotherapy and/or
oral spasticity agents) or as an adjunct to physical therapy.
Maximum number of treatment to be authorised is 4 (total Botox and Dysport) per upper
limb per lifetime. Treatment should not be initiated until 3 months post-stroke in
patients who do not have established severe contracture. Treatment should be discontinued
if the patient does not respond (decrease of MAS greater than 1 in at least one joint)
after two treatments.
The date of the stroke must be provided.
Contraindications to treatment include established severe contracture and known sensitivity
to botulinum toxin.
Note
The units used to express the potency of botulinum toxin preparations currently available
for PBS subsidy are not equivalent.
Pack size: 1
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor has no comments.
