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HUMIRA - HUMIRA - CT 2893 - English version

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Introduction 40 mg, solution for injection in pre-filled syringe 2 x 0.8 ml pre-filled glass syringes with two alcohol wipes Posted on Jan 18 2006 Active substance (DCI) adalimumab ATC Code L04AA17 Laboratory / Manufacturer ABBOTT 40 mg, solution for injection in pre-filled syringe 2 x 0.8 ml pre-filled glass syringes with two alcohol wipes Posted on Jan 18 2006
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  The legally binding text is the original French version  TRANSPARENCY COMMITTEE
Opinion  18 October 2006   HUMIRA 40 mg, solution for injection in pre-filled syringe 2 x 0.8 ml pre-filled glass syringes with two alcohol wipes CIP Code: 362 230-5  Applicant: ABBOTT  adalimumab   List I  Initial 6-month hospital prescription restricted to internal medicine and rheumatology specialists.  Date of Marketing Authorisation: 08 September 2003  Date of latest revision of Marketing Authorisation: 01 June 2006 (ankylosing spondylitis indication extension)   Exception drug status      Reason for request: Inclusion on the list of medicines reimbursed by French National Health Insurance and approved for use by hospitals in the extension of indication         
Health Technology Assessment Division
 
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1.1.
1.2.
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CHARACTERISTICS OF THE MEDICINAL PRODUCT
Active substance adalimumab  
Background Adalimumab is a human monoclonal antibody specific to TNF-α (tumour necrosis factor-alpha). 
1.3. Indications  Rheumatoid arthritis  Humira in combination with methotrexate, is indicated for:  The treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate. The treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.  Humira can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.  Humira has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.  Psoriatic arthritis  Humira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate.   New indication evaluated: Ankylosing spondylitis Humira is indicated for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.  
1.4. Dosage  Humira treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. Patients treated with Humira should be given the special alert card.  After proper training in injection technique, patients may self-inject with Humira if their physician determines that it is appropriate and with medical follow-up as necessary.
 
 
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Adults
Rheumatoid arthritis  The recommended dose of Humira for adult patients with rheumatoid arthritis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection. Methotrexate should be continued during treatment with Humira.  In monotherapy, some patients who experience a decrease in their response to Humira may benefit from an increase in dose intensity to 40 mg adalimumab every week.
Psoriatic arthritis and ankylosing spondylitis
The recommended dose of Humira for patients with psoriatic arthritis and ankylosing spondylitis is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection.  For all of the above indications, available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
Elderly patients
No dose adjustment is required.
Children and adolescents
Humira has not been studied in this patient population. Therefore, use of Humira cannot be recommended in patients under 18 years of age until further data become available.
Impaired renal and/or hepatic function
Humira has not been studied in these patient populations. No dose recommendation can be made .  
2.1.  
 
2.2.
 
2 SIMILAR MEDICINAL PRODUCTS
ATC Classification (2005)
L L04 L04A L04AA L04AA17
: Antineoplastic and immunomodulating agents : Immunosuppressive agents : Immunosuppressive agents : Selective immunosuppressive agents : Adalimumab
Medicines in the same therapeutic category Comparator medicines ENBREL 25 mg and 50 mg (etanercept) REMICADE (infliximab)  
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2.3.
 
3.1.
Medicines with a similar therapeutic aim NSAIDs are a fast-acting treatment for ankylosing spondylitis. They may be combined with a slow-acting treatment, such as methotrexate*or sulfasalazine*.
3 ANALYSIS OF AVAILABLE DATA
Efficacy and safety The manufacturer has supplied the results of two phase-III studies (M03-606 and
ATLAS – M03-607) for the ankylosing spondylitis indication extension.  Study M03-606 (unpublished) Comparative, placebo-controlled, randomised, double-blind study assessing the efficacy and safety of HUMIRA 40 mg in the treatment of active ankylosing spondylitis in 82 patients responding inadequately to NSAIDs.  This study included two phases: 1. A 24-week blind phase. 2. An 80-week open-label phase during which the patients were given 40 mg of adalimumab every 2 weeks.  At the request of the US health authorities (FDA), for ethical reasons (biotherapies for this indication were already on the market), patients not meeting the ASAS 20 criteria1 at weeks 12, 16 or 20 (n=59, 72%) were treated open-label with 40 mg adalimumab every 2 weeks and were considered non-responders in the statistical analysis of the double-blind stage.  Inclusion criteria  Over 18 years of age  BASDAI2 4  pain VAS score Spinal40 mm  Morning stiffness1 hour  Primary endpoints - ASAS 20 at week 12 - Change in mSASSS3week 104 compared with initial score (under evaluation).at                                             * These products do not have a marketing authorisation for this indication.  1 ASAS: Assessment in Ankylosing Spondylitis. This is a composite criterion with 4 parts: - according to BASFI  Mobility(Bath Ankylosing Spondylitis Functional Index), which evaluates disability in daily life. It consists of 10 questions on the patient’s degree of functional mobility assessed by the patient him/herself on a visual analogue scale (VAS) - pain VAS score Patient’s -of inflammation, taken as the average of the last 2 BASDAI (Bath Ankylosing Degree Spondylitis Disease Activity Index) VAS scores; the index assesses the intensity and duration of morning stiffness - global VAS score Patient’s ASAS 20: a patient is considered a responder if there is at least 20% improvement in the scores for at least 3 of the 4 ASAS criteria and no worsening in the fourth. 2 BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), a composite index assessing disease activity based on the patient’s response to 6 questions on fatigue, spinal and peripheral joint pain, areas of localised tenderness, and morning stiffness (duration and degree). Each VAS response may range from 0 (none) to 100 mm (very severe). The total score is the average for the 6 questions. It may range between 0 and 100 mm or between 0 and 10 mm. 
 
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 Secondary endpoints % 20 at week 24 ASAS %70 at weeks 12 and 24 ASAS 50 and %20 components at weeks 12 and 24  ASAS % at weeks 12 and 24 BASDAI  CRP at weeks 12 and 24 % % FACIT F -% BASMI % ASQoL % SF-36 physical component % markers of cartilage destruction: MMP-3, CTX-II and NTX Biological % Structural progression by MRI (results not available). Results (ITT)  Initial patient characteristics:   Placebo HUMIRA (n=44) (n=38) Age (years) 40.0 ± 10.87 41.9 ± 11.14 Disease duration 12.14 ± 8.65 14.52 ± 9.02 (years) BASDAI score 6.46 ± 1.64 6.15 ± 1.72 (mean ± s.d.) BASFI score 55.6 ± 21.8 53.3 ± 20.40 (mean ± s.d.) CRP (mg/dL) 2.29 ± 2.64 1.77 ± 1.68 (mean ± s.d.) Spinal pain (mm) 71.7 ± 14.8 67.2 ± 16.7 (mean ± s.d.) Patient’s global score 67.8 ± 19.1 66.1 ± 18.9 (mean ± s.d.)  
 Concomitant treatments  Sulfasalazine n (%)
Placebo (n =44) HUMIRA (n = 38)
5 (11.4) 3 (7.9)
MTX n (%)
4 (9.1) 4 (10.5)
Steroids n (%)
7 (15.9) 37 (84.1)
ASAS 20 response at weeks 12 and 24 Placebo  (n=44)
ASAS 20 at week 12
12 (27.3 %)
NSAIDs n (%)
40 (90.9) 34 (89.5)
HUMIRA (n=38)
18 (47.4%)
ASAS 20 at week 24 7 (15.9%) 13 (34.2 %)  At weeks 12 and 24, no statistically significant difference was found between the two treatments in the level of ASAS 20 response.  However, a statistically significant difference in favour of HUMIRA was found for the set of secondary endpoints.                                                                                                                                         3Modified Stoke Ankylosing Spondylitis Spine Score. This score uses radiographs.
 
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Study M03-607 (ATLAS)4  Comparative, placebo-controlled, randomised, double-blind study assessing the efficacy and safety of HUMIRA 40 mg in the treatment of active ankylosing spondylitis in 315 patients responding inadequately to NSAIDs.   This study comprised two stages: 1. A 24-week blind stage 2. An 80-week open-label stage during which the patients were given 40 mg of adalimumab every 2 weeks.  At the request of the US health authorities (FDA), for ethical reasons (biotherapies for this indication were already on the market), patients not meeting the ASAS 20 criteria at weeks 12, 16 or 20 (n=155, 49.2%) were treated open-label with 40 mg adalimumab every 2 weeks and were considered non-responders in the statistical analysis of the double-blind stage.
Inclusion criteria  Over 18 years of age  Ankylosing spondylitis according to the modified New York criteria  disease: meeting at least two of the following three conditions: Active % BASDAI40   % pain VAS score Spinal40 mm % stiffness Morning1 hour  Failure of at least one NSAID  Patients with total spinal ankylosis were included but did not exceed 10% of the total.
Primary endpoints - ASAS 20 at week 12 - Change in mSASSS5week 104 compared with initial score (under evaluation).at
Secondary endpoints - 20 at week 24 ASAS -70 at weeks 12 and 24 ASAS 50 and -20 components at weeks 12 and 24 ASAS  ASAS 40 at weeks 12 and 24 --ASAS 5/6  - Partial remission -BASDAI at weeks 12 and 24   - (evaluation of disability) BASFI - MASES - BASMI - ASQoL - SF-36  Results (ITT)  Patient characteristics:
 
Placebo HUMIRA (n=107) (n=208) Age (years) 43.4 ± 11.32 41.7 ± 11.69                                             4 D. van der Heijde et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis. Arthritis Rheum 2006; 54 (7): 2136-2146. 5modified Stoke Ankylosing Spondylitis Spine Score. This score uses radiographs.
 
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3.2.
 
Disease duration (years) BASDAI score (mean ± s.d.) BASFI score (mean ± s.d.) CRP (mg/dL) (mean ± s.d.) HLA-B27 positive n (%) Spinal pain (mm) (mean ± s.d.) Patient’s global score (mean ± s.d.)   Concomitant treatments:  Primary Treatment Placebo 22 (20.6%) (n=107) HUMIRA 40 (19.2%) (n = 208)
Leflunomide
1 (0.9%)
0
10.01 ± 8.34
6.34 ± 1.67
56.38 ± 22
2.16 ± 2.84
85 (79.4)
67.24 ± 21.48 64.52 ± 20.38
MTX
8 (7.5)
20 (9.6)
ASAS 20 response at weeks 12 and 24: Placebo  (n=107)
 ASAS 20 at week 12
22 (20.6%)
Sulfasalazine
15 (14)
26 (12.5)
11.28 ± 10
6.25 ± 1.71
52.40 ± 22.12
1.76 ± 2.20
163 (78.4)
64.36 ± 20;86
62.88 ± 21.54
Oral corticoids 6 (5.6)
25 (12)
HUMIRA (n=208)
121 (58.2 %)
NSAIDs
84 (78.5)
106 (79.8)
ASAS 20 at week 24 20 (18.7%) 105 (50.5 %)  At weeks 12 and 24, a statistically significant difference was found in the level of ASAS 20 response in favour of HUMIRA over the placebo, p<0.001.  A statistically significant difference in favour of HUMIRA was also observed for the set of secondary endpoints.  N.B.:  No data are available on the progression of structural lesions with HUMIRA; the results of the mSASSS scores at week 104 are currently being assessed.
Adverse effects In both clinical studies, adverse reactions were more numerous with HUMIRA (75%) than with the placebo (59.8%). The most frequent adverse effects were infections (rhinopharyngitis and upper respiratory infections), but no case of tuberculosis or other opportunist infections, drug-induced lupus, demyelinating disease or heart failure was reported. One case of Hodgkin’s lymphoma was observed with HUMIRA during the open-label stage of study M03-606.  Overall, these relatively short-term studies (24 weeks) provided no new information on the safety of HUMIRA. No adverse reaction not previously mentioned in the SPC was reported in the clinical studies.
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3.3.
 
4.1.
 
Conclusion In a study involving 315 patients with active ankylosing spondylitis, HUMIRA outperformed a placebo on the primary endpoint of ASAS 20 at week 12 and on all the secondary endpoints. The absolute benefit of HUMIRA over the placebo in terms of ASAS 20 responders at week 12 was 37.6%.  In a study on a smaller population of 82 patients, no statistically significant difference in ASAS 20 responders was found between HUMIRA and the placebo.  The Transparency Committee regrets that no direct comparison has been made with the other TNF antagonists (etanercept and infliximab) that have been shown to be effective in ankylosing spondylitis.  
4 TRANSPARENCY COMMITTEE CONCLUSIONS
Actual benefit Ankylosing spondylitis is a chronic disease that may be serious and incapacitating. It most often progresses through inflammatory episodes, the main risks of progression being vertebral ankylosis, hip involvement and extra-skeletal (particularly cardiac) involvement.  Like all other TNF antagonists used in this indication, HUMIRA is a symptomatic treatment.  Public health benefit As a chronic, serious and incapacitating disease, ankylosing spondylitis represents a moderate public health burden, for the patient sub-population covered by the indication.  Improving AS treatment is one of the public health targets included within the GTNDO6tives.  objec  On the basis of current data, Humira is not expected to have any additional impact on patient morbidity and quality of life compared with other TNF antagonists. In view of a concomitant development, however, HUMIRA shares the low impact on morbidity and quality of life expected from the other TNF antagonists.  Consequently, in the current state of knowledge and in view of the other treatments available, HUMIRA has the same expected public health benefit as the other TNF antagonists for this indication. This benefit is low.  The ATLAS study results suggest that the efficacy/adverse reactions balance for HUMIRA in ankylosing spondylitis is high.  
                                            6National Technical Group for Defining Public Health Objectives, under the Directorate-  GTNDO: General for Health (Groupe Technique National de Définition des Objectifs – DGS), 2003.
 
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4.2.
4.3.
4.4.
HUMIRA has a significant role to play in the treatment of ankylosing spondylitis in patients not responding or intolerant to conventional treatments.  The actual benefit of this medicinal product is substantial.
Improvement in actual benefit The Transparency Committee considers that HUMIRA provides the same improvement in actual benefit (IAB II) as the other TNF antagonists (etanercept and infliximab) in the treatment of severe, active ankylosing spondylitis in adults responding inadequately to conventional treatment.
Therapeutic use The aim of treating ankylosing spondylitis with medication is to reduce spinal pain and stiffness and thus to preserve or improve functional capabilities and quality of life. The strategy consists essentially of the primary use of NSAIDs as symptomatic treatment during disease episodes. If one NSAID has no or insufficient effect when used at the maximum tolerated dose, a different NSAID may be tried.  Adjuvant treatments such as analgesics may be combined with NSAIDs during episodes.  In ankylosing spondylitis, disease-modifying drugs (e.g. sulfasalazine and methotrexate) only appear to be effective in forms where peripheral joints are affected. Their efficacy in purely spinal forms has not been demonstrated.  TNF antagonists, including HUMIRA, may be used after NSAIDs have had no or insufficient effect, are not tolerated or are contraindicated, eventually combined with disease-modifying drugs.  
Target population International data give the prevalence of ankylosing spondylitis as being in the range 0.1% to 1.1%. According to the epidemiological survey conducted by the French Rheumatology Association (2001)7, however, the prevalence of ankylosing spondylitis in France in the population aged 18 years and over is 0.14% at most, or approximately 65 000 patients.  Specialist opinion is that approximately 15% of patients respond inadequately to conventional treatments and could benefit from HUMIRA treatment.  On this basis, the maximum target population for HUMIRA in ankylosing spondylitis may be roughly 10 000 patients.  
4.5. Transparency Committee recommendations
The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Health Insurance and on the list of medicines approved for use by hospitals and various public services in the new indication and at the posology in the marketing authorisation. 
                                            7 A. Saraux et al. Prevalence of spondylarthropathies in 2001. Ann Rheum Dis 2005; 64: 1431-1435.  
 
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 4.5.1  4.5.2  4.5.3
 
Packaging: Appropriate for the prescription conditions
Reimbursement rate: 65%
Except
ion drug status
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