MEZAVANT - MEZAVANT - CT 8220 - English version

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Introduction MEZAVANT LP 1200 mg, prolonged-release gastro-resistant tablets B/60 (CIP code: 378 689-2) Posted on Jun 04 2012 Active substance (DCI) mesalazine Gastro-entérologie - Nouveau médicament Pas d’avantage clinique démontré par rapport aux autres traitements des poussées de rectocolite hémorragique et de maintien de la rémission MEZAVANT LP est indiqué en traitement d’induction et pour le maintien de la rémission clinique et endoscopique de patients atteints de poussées de rectocolite hémorragique (RCH) légères à modérées.Aucune conséquence clinique de sa présentation à libération prolongée n’a été démontrée.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous ATC Code A07EC02 Laboratory / Manufacturer SHIRE FRANCE SA MEZAVANT LP 1200 mg, prolonged-release gastro-resistant tablets B/60 (CIP code: 378 689-2) Posted on Jun 04 2012

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• Publié par: haute-autorite-sante-maladies-appareil-digestif
• Publié le: 20 octobre 2010
• Nombre de lectures: 65
• Licence : En savoir +
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• Langue: English

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  The legally binding text is the original French version

TRANSPARENCY COMMITTEE   OPINION     20 October 2010     MEZAVANT LP 1200 mg, prolonged-release gastro-resistant tablets B/60 (CIP code: 378 689-2)     Applicant : SHIRE FRANCE SA   mesalazine ATC code: A07EC02   List II     Date of marketing Authorisation: 26 March 2007     Reason for request: Inclusion on the list of medicines refundable by National Health Insurance and approved for hospital use.                                               Medical, Economic and Public Health Assessment Division

1

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1.1. Active ingredient Mesalazine    1.2. nd uorgkcaB MEZAVANT is a prolonged-release gastro-resistant form of mesalazine. It comprises a multi- matrix release system (MMX formulation).     1.3. Indication “For the induction of clinical and endoscopic remission in patients with episodes of mild to moderate, active ulcerative colitis. For maintenance of remission.”     1.4. Dosage “Mezavant LP is intended for once daily, oral administration. The tablets must not be crushed or chewed and should be taken with food.     Adults, including the elderly (>65 years): For induction of remission: 2.4 to 4.8 g (two to four tablets) should be taken once daily. The highest dose of 4.8 g/d is recommended for patients not responding to lower doses of mesalazine. When using the highest dose (4.8 g/d), the effect of the treatment should be evaluated at 8 weeks.     For maintenance of remission: 2.4 g (two tablets) should be taken once daily.   Children and adolescents : Mezavant LP is not recommended for use in children below the age of 18 years due to a lack of data on tolerance and efficacy.   Specific studies have not been performed to investigate Mezavant LP in patients with hepatic or renal impairment” (see sections 4.3 and 4.4 of ht e SPC).”

2 SIMILAR MEDICINAL PRODUCTS

  2.1. ATC Classification   A : Alimentary tract and metabolism   A07 : Antidiarrhoeal, intestinal anti-inflammatory / antiseptic agents   A07E : Intestinal anti-inflammatory agents   A07EC : Aminosalicylic acid and similar agents   A07EC02 : Mesalazine     2.2. Medicines in the same therapeutic category These are medicines in the class of aminosalicylic acids (5-ASA) and similar agents administered orally:   - Mesalazine: FIVASA 400 and 800 mg, and ROWASA 250 and 500 mg gastro- resistant tablets and PENTASA 500 mg tablets and 1 or 2 g granules in sachets, - Olsalazine: DIPENTUM 250 mg and 500 mg gelatine-coated capsules, - Sulfasalazine: SALAZOPYRINE 500 mg gastro-resistant tablets.   For local administration: - Mesalazine: FIVASA and ROWASA suppositories, PENTASA rectal suspension, - Sodium p-aminosalicylate: QUADRASA powder for rectal solution.  

2.3. Medicines with a similar therapeutic aim Slow-acting anti-inflammatories, oral or local glucocorticoids, immunosuppressants and/or immunomodulators (ciclosporin, azathioprine, 6-mercaptopurine, infliximab).      

3 ANALYSIS OF AVAILABLE DATA   3.1. Efficacy The efficacy and tolerance of MEZAVANT have been assessed in five clinical studies. Three studies have assessed the efficacy of MEZAVANT in induction treatment: - studies SPD476-301 1  SPD476-302, which compared MEZAVANT 4.8g/d and and   MEZAVANT 2.4 g/d with placebo in terms of clinical and endoscopic remission in patients with ulcerative colitis (UC) who were monitored for 8 weeks - study SPD476-201 2 which compared the efficacy of MEZAVANT with that of a colonic lavage of mesalazine (4 g) in terms of clinical remission in patients with UC who were monitored for 4 to 8 weeks.   Two studies have assessed the efficacy of MEZAVANT in maintenance treatment:   - the open-label study SPD476-303 assessed MEZAVANT in maintaining remission (maintenance treatment) in patients who had taken part in the aforementioned studies 301 and 302. The patients were monitored for 12 months. - study SPD476-306 3  compared MEZAVANT with mesalazine 2.4 g/d gastro- which resistant tablets in maintaining remission in patients with UC. The patients were monitored for 12 months.     3.1.1. Induction treatment   Studies SPD476 301 and SPD476 302   Method: randomised, double-blind studies comparing MEZAVANT LP 2.4 g/d and 4.8 g/d to placebo, conducted on 262 (study 301) and 341 (study 302) patients with ulcerative colitis who were monitored for 8 weeks. Study 302 also had a group taking mesalazine 0.8 g 3 times a day (ASACOL*) in the form of gastro-resistant (GR) tablets.   * ASACOL is a proprietary medicinal product available only in the USA. It is a GR oral form of mesalazine whose distribution in the intestine depends on pH levels. The closest proprietary medicinal products in France are ROWASA and FIVASA.     Inclusion criteria: patients aged over 18, suffering from slight to moderate ulcerative colitis for less than 6 weeks, with a modified UC-DAI score 4 of 4 to 10, an endoscopic score of≥1 and a PGA (physician’s global assessment) score of≤ Histological confirmation of the 2. diagnosis was required.

                                             1  et al. « Effect of once or twice daily MMX  Lichensteinmesalazine for the induction of remission of mild to moderately active 2 .2 -5015;9:0270 al.a etnter Praled laro wen A“ or femstsyy eriv H pea dngo ytaloroenGastlogyteroC ”sitil lacinilerlcucoe ivat 05 . 20  5-ASA: preliminary clinical findings for MMX” Inflamm Bowel Dis May;11(5):421-7. 3  et al. Clinical trial : ulcerative colitis maintenance treatment with 5-ASA : a 1-year, randomized multicentre study Prantera comparin MMX Mesalazine with ASACOL – Aliment Pharmacol Ther 30, 908-918. 4 Sutherland LRet al roctitis”. moiditis, and acid enema in the treatment of distal ulcerative colitis, roctosi“5- Aminosalic lic .  Gastroenterology 1987; 92: 1894-8. (cf. description in the appendix)  

  Treatments: Study 301: - MEZAVANT 1.2 g twice a day (2.4 g / d), n=88, - MEZAVANT 4.8 g/d, n=89, - Placebo, n = 85, Study 302:  MEZAVANT 2.4 g/d, n=84, - - MEZAVANT 4.8 g/d, n=85, - Placebo, n = 86 - Mesalazine GR 0.8 g/ three times a day (ASACOL 2.4 g/d), n=86.   Primary efficacy endpoint: percenta e of atients in com lete clinical and endosco ic remission after 8 weeks of treatment. Com lete remission was defined b a com osite score: modified clinical UC-DAI score≤ stool and with a sub-score of 0 for rectal bleedin 1, fre uenc , and a reduction in endosco score of at least 1 com ared to inclusion.   The rimar efficac endpoint was analysed by comparing the efficacy of the two doses of MEZAVANT to placebo.   Secondary endpoints, in particular: comparison of the percentages of patients in complete (clinical and endosco ic remission observed in each rou treated after 8 weeks of treatment. A comparison with mesalazine GR 2.4 g/d (ASACOL, active comparator) was conducted only in study 302.     RESULTS: primary efficacy endpoint, ITT analysis (see table 1)   Table 1: number and percentage of patients in complete remission after 8 weeks of treatment.  MEZAVANT 1.2g, MEZAVANT 4.8 g,   Placebo   twice a day (2.4 g/d)   once a day   Study 301     - number of patients 30 26 11 - percentage remission 34.1% 29.2% 12.9 % - OR [95% CI] 3.48 [1.44. 8.41] 2.78 [1.27. 6.06]  0.009 - p vs. placebo   0.001     AZEM. 4NTVAEMAVAZ2 d  T y N,   g e 4   . a   8 g,   Placebo   once a day   onc a Study 30     2 - number of patients 34 35 19 - percentage remission 40.5% 41.2% 22.1% - OR [95% CI] 2.40 [1.23. 4.69] 2.47 [1.15. 5.30] - p vs. placebo   0.01 0.007 After 8 weeks of treatment, significantly higher percentages of patients were observed to be in complete (clinical and endoscopic) remission with MEZAVANT 2.4 g/d and MEZAVANT 4.8 g/d compared to placebo: - study 301: 34.1% in the group taking MEZAVANT 1.2 g/d twice a day versus 12.9% in the placebo group, OR 3.48 [1.44, 8.41], p=0.001 and 29.2%, OR 2.78 [1.27, 6.06], p=0.009 in the MEZAVANT 4.8 g/d group, - study 302: 40.5% in the group taking MEZAVANT 2.4 g/d versus 22.1% in the placebo group, OR 2.40 [1.23, 4.69], p=0.01 and 41.2%, OR 2.47 [1.15, 5.30], p=0.007 in the MEZAVANT 4.8 g/d group,   Secondary endpoint:   No significant difference between the MEZAVANT 2.4 g/d and 4.8 g/d was observed in terms of complete remission after 8 weeks of treatment:   - study 301: OR 1.25 [0.66; 2.36], NS, - study 302: OR 0.97 [0.53; 1.79], NS,    

In addition, no significant difference between the groups was observed in study 302:   - MEZAVANT 2.4 g/d and mesalazine GR 2.4 g/d (ASACOL): OR 1.41 [0.75; 2.64], S,   N - MEZAVANT 4.8 g/d and mesalazine GR 2.4 g/d (ASACOL): OR 1.45 [0.78; 2.71],   NS.       Study SPD476 201 1   Method: randomised, double-blind study comparing MEZAVANT LP 1.2 g/three times a day versus mesalazine rectal suspension 4 g/day (ASACOL) conducted on 78 patients with distal ulcerative colitis (UC) who were monitored for 8 weeks.     Inclusion criteria: patients aged 18 to 65 with UC extending over more than 15 cm but not passing beyond the left colonic angle and a clinical activity index (CAI 5 )≥6.   Treatments: - MEZAVANT 1.2 g/ 3 times/day, n=40, - Mesalazine rectal suspension 4 g/d (ASACOL), n=38 .   Primary efficac end oint: ercenta e of atients in com lete remission after 8 weeks of treatment. Complete remission was defined as a CAI score of≤4.     RESULTS: primary efficacy endpoint, ITT analysis (see table 2)   Table 2: number and percentage of patients in complete remission after 8 weeks of treatment    MEZAVANT   Mesalazine   1.2 g / 3 times/dayrectal suspension     95% CI N=40   4 g/d (ASACOL)  of the difference   N=38   - number of tients 24 19 pa   - percentage remission [95% CI] 60% [44.8; 75.2] 50% [34.1; 65.9]  [-12 to +32]  NS     After 8 weeks of treatment, no significant difference in terms of remission was observed between the MEZAVANT 1.2 g/ 3 times/day group and the mesalazine rectal suspension 4 g/d (ASACOL) group: 95% CI of the difference [-12; 32], NS.     3.1.2. Maintenance treatment   Open-label follow-up study: study SPD476 303 This study was conducted on 459 patients who had taken part in studies 301 and 302, distributed as follows: - patients in remission after 8 weeks of treatment in these studies, - patients not in remission who started an acute treatment phase (MEZAVANT 2.5 g/d or 4.8 g/d) lasting 2 months and who achieved remission at the end of this treatment phase. The primary aim of this study was to assess tolerance; maintenance of (clinical and endoscopic) remission was assessed as a secondary endpoint. After 12 months, 451 patients were examined and the proportion of patients in complete (clinical and endoscopic) remission was found to be 68.5% (159/232 patients) in the MEZAVANT 2.4 g twice a day group versus 64.4% (141/219 patients) in the MEZAVANT 2.4 g once a day group, NS.    

                                             5 See description in the appendix  

Study SPD476 306 Method: randomised, double-blind study comparing MEZAVANT LP 2.4 g/d with ASACOL (mesalazine 2.4 g/d gastro-resistant (GR) tablets), conducted on 323 patients with distal UC who were monitored for 12 months.     Inclusion criteria: patients aged 18 to 75 with distal UC (extending over more than 15 cm but not passing beyond the left colonic angle) in remission for at least one month, a UC-DAI score of≤1 and who had been observed to relapse during the previous year.   Treatments: - MEZAVANT 2.4 g/d, n=156, - Mesalazine GR 2.4 g/d (ASACOL), GR tablets, n=167.   Primar efficacy end oint: success rate, defined as maintenance of clinical remission UC- DAI score ≤ , 1 or failure rate, defined as clinical relapse or withdrawal from the trial for another reason during the 12 months of treatment.   RESULTS: primary efficacy endpoint, ITT analysis (see table 3)   Table 3: number and percentage of patients in complete remission after 12 months of treatment   MEZAVANT Mesalazine GR Difference vs. OR p   2.4g/d 2.4g/d mesalazine GR [95% CI]  ASACOL ASACOL    N=167   [95% CI] N=156     Percentage remission 68% (n=106)   65.9% (n=110)   2.1% 1.10 NS   (n)   [-8.2 ; 12.4]   [0.69 ; 1.75]     After 12 months of treatment, no significant difference in terms of remission was observed between the MEZAVANT 2.4 g/d group and the mesalazine GR 2.4 g/d (ASACOL) group: difference 2.1% 95% CI [-8.2; 12.4], NS.     3.2. Adverse effects Most of the adverse events observed with MEZAVANT in these studies were transient, and slight to moderate in intensity. The SPC for MEZAVANT states that 14% of patients treated with the product experienced adverse events.   The events most frequently observed (>1%) were headache, flatulence and nausea.     3.3. luncCo onsi The efficacy and tolerance of MEZAVANT were assessed in five randomised studies carried out on patients suffering from haemorrhagic rectocolitis or distal ulcerative colitis of slight to moderate intensity; 3 double-blind studies investigating its use as induction treatment (studies SPD476-301, 302 and 201) and two on its use as maintenance treatment (studies SPD476-303 (open-label) and 306 (double-blind)).   Induction treatment:   After 8 weeks of treatment of patients with UC (studies 301 and 302 , the ercenta e of patients in complete clinical and endoscopic remission (modified UC-DAI score≤ 1) was significantly higher among patients taking MEZAVANT than among those taking placebo: - study 301: MEZAVANT 1.2 g / twice a day (34.1%) versus placebo (12.9%) OR 3.48 [1.44, 8.41], p=0.001 and MEZAVANT 4.8 g/d (29.2%), OR 2.78 [1.27, 6.06], p=0.009,

- study 302: MEZAVANT 2.4 g/d (40.5%) versus placebo (22.1%) OR 2.40 [1.23, 4.69], p=0.01 and MEZAVANT 4.8 g/d (41.2%), OR 2.47 [1.15, 5.30], p=0.007.   There was no significant difference between the MEZAVANT 2.4 g/d and 4.8 g/d groups in terms of the percentage of patients in complete remission: - study 301: OR 1.25 [0.66; 2.36], NS, - study 302: OR 0.97 [0.53; 1.79], NS. There was no significant difference between the groups in respect of the percentage of patients in complete remission:  - MEZAVANT 2.4 g/d and mesalazine 2.4 g/d gastro-resistant tablets (ASACOL): OR 1.41 [0.75; 2.64], NS,   - MEZAVANT 4.8 g/d and mesalazine 2.4 g/d gastro-resistant tablets (ASACOL): OR 1.45 [0.78; 2.71], NS.     After 8 weeks of treatment (study 201) of 78 patients with distal ulcerative colitis, there was no significant difference in the percentage of patients in complete remission (CAI≤ 4) between the MEZAVANT 1.2 g/ three times a day group (60%) and the mesalazine rectal suspension (ASACOL) 4 g/d group (50%): 95% CI of the difference [-12; 32], NS.   Maintenance treatment:   There was no significant difference in terms of the percentage of patients in complete clinical and endoscopic remission (UC-DAI score≤ 1) between MEZAVANT 2.4 g twice a day (68.5%) and MEZAVANT 2.4 g once a day (64.4%) in 451 patients with UC who were monitored on an open-label basis for 12 months (study 303).   There was no significant difference in respect of the percentage of patients in complete clinical remission (UC-DAI score≤1) after 12 months of treatment between the MEZAVANT 2.4 g/d group (68%)   and the mesalazine GR (2.4 g/d) tablets group (65.9%) in 323 patients with distal UC who took part in a randomised double-blind follow-up study for 12 months (study 306).   These studies did not find that the specific galenic form of MEZAVANT (multi-matrix system which helps extend the release of effective levels of mesalazine throughout the inflamed parts of the colon over an extended period of 6 to 24 hours after administration) had any clinical consequences. This administration form allows patients to be treated with a single daily dose for both induction and maintenance treatment.     The adverse events most frequently observed in patients taking MEZAVANT were headache, flatulence and nausea.   No study versus the other active comparators available on the market is currently available.

  4 TRANSPARENCY COMMITTEE CONCLUSIONS   4.1. Actual benefit   Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) which is manifested by severe, chronic, bloody diarrhoea and progresses episodically. It causes a marked deterioration in quality of life and exposes patients to serious complications, such as acute colitis, dysplasia and bowel cancer.   This proprietary product is part of treatment addressing the symptoms.   The efficacy of mesalazine in this indication has been established.   The efficacy/adverse effects ratio of MEZAVANT in the induction and maintenance treatment of UC s high.   i   There are numerous treatment alternatives.   Public health benefit:   The public health burden represented by ulcerative colitis is moderate.   The improved management of ulcerative colitis is a public health need that falls within the scope of identified priorities (GTNDO*, Public Health Act of 2004**, National Rare Diseases Plan). The available clinical data does not provide any information on the effect of MEZAVANT on morbidity and on requirement for surgery. The potential impact of the ease of use of the proprietary medicinal product MEZAVANT on quality of life and treatment compliance has not been demonstrated.   It does not therefore seem that the medicinal product MEZAVANT will be able to make an additional contribution to meeting the public health need identified. Consequently, it is not expected that MEZAVANT will benefit public health in this indication.   GTNDO: Groupe Technique National de Définition des Objectifs [National Technical Objective * Definition Group] (DGS) 2003 ** Public Health Act 2004 –no. 2004-806 dated 9 August 2004 [rapport_DREES_indicateurs - July 2005]    The actual benefit of this medicinal product is substantial.   4.2. Improvement in actual benefit (IAB)   MEZAVANT LP does not provide any improvement in actual benefit (IAB V) compared to the other mesalazine-based proprietary medicinal products that are available on the market for the induction and maintenance treatment of patients suffering from slight to moderate attacks of ulcerative colitis.   4.3  use Therapeutic 6 Ulcerative colitis is an inflammatory bowel disease (IBD).   Symptomatic treatment makes use of aminosalicylates, corticosteroids, immunosuppressants and/or immunomodulators. The substance and mode of administration are selected according to the severity and location of the intestinal inflammation and the adverse effects of the medicinal products. The aminosalicylates are represented by 5-ASA, mesalazine, olsalazine and sulfasalazine. Despite their pharmacological differences, no difference in efficacy between the various proprietary medicinal products available has been shown. However, there are differences in terms of tolerance and toxicity, with mesalazine being the best-tolerated product.                                                  6   “Evolutive ulcerative colitis”, Long-term Conditions Guide, HAS, May 2008.  

Induction of remission: Initial treatment of slight to moderate rectitis is based on rectal 5-ASA (mesalazine) at a dose of 1 g/day. If the symptoms are disabling or a complete result is not achieved after 4 to 6 weeks, oral 5-ASA (mesalazine) is added at the doses specified in the marketing authorisation. In the event of failure after at least 8 weeks of treatment, oral corticosteroid treatment (40 mg/d of prednisolone followed by gradually reducing doses for 8 to 12 weeks) can be considered, while continuing the patient on rectal 5-ASA (mesalazine).     The initial treatment of slight to moderate left-sided colitis is based on an initial combination of 5-ASA (mesalazine) administered by lavage and oral 5-ASA (mesalazine). In the event of failure after 8 weeks of treatment, oral corticosteroid treatment (40 mg/d of prednisolone or 1 mg/kg/d in forms with a general impact) is advised.     The initial treatment of extensive colitis is based on oral 5-ASA (mesalazine), associated with oral corticosteroid treatment in the case of moderate activity. In the event of failure, an immunosuppressant and/or immunomodulator (azathioprine 2.5mg/kg/d and/or infliximab 5 mg/kg in W0, W2 and W6, thereafter every 8 weeks) can be considered. A total colectomy must be discussed in the event of failure.     Maintenance of remission: The principle is to continue with the treatment that is effective, except for corticosteroid treatment which must not be continued for a prolonged period.   Patients suffering from rectitis should resume rectal 5-ASA (mesalazine) as soon as the symptoms recur. Patients with left-sided colitis or extensive colitis should continue on oral 5-ASA (mesalazine) if the condition is mild and was initially controlled by this treatment.   Patients who are corticodependent must be offered ongoing treatment with an immunosuppressant (azathioprine) and/or immunomodulator (infliximab).     Role of MEZAVANT: Like the other mesalazine-based proprietary medicinal products on the market, MEZAVANT can be used to induce and maintain UC remission.   4.4 Target population The target population for MEZAVANT LP is made up of patients suffering from slight to moderate ulcerative colitis. It can be estimated on the basis of the following factors:     - In 2008, data from the general health insurance scheme indicated that there were 105,494 patients being treated under ALD 24, ”Evoltuive ulcerative colitis and Crohn’s  disease” 7 . Since the general health insurance scheme accounts for close to 80% of individuals covered by National Health Insurance, the number of persons treated under ALD 24 is estimated at about 132,000. - On the basis of incidence data it can be estimated that ulcerative colitis accounts for around 40% of these conditions 8 , equivalent to almost 53,000 individuals.   Data from the EPIMAD register 8 puts the estimated incidence of ulcerative colitis at 3.5 (95% CI [3.2-3.8]) in 100,000 individuals, which means that between 2,000 and 2,500 people are newly diagnosed with the condition each year in France 9 . The target population for MEZAVANT could therefore increase by 2,000 to 2,500 patients a year.                                                7   French national health insurance (CNAMTS). http://www.ameli.fr/l-assurance-maladie/statistiques-et- publications/donnees-statistiques/affection-de-longue-duree-ald/prevalence/frequence-des-ald-au-31- 12-2008.php 8  F, Gower-Rousseau C, Yzet T et al. Opposite evolution in incidence of Crohn’s disease and ulcerative Molinie colitis in Northern France (1988-1999). Gut 2004;53:843-8.   9   Based on the total French population as of 1 January 2010, estimated at 64,667,374 (Source: http://www.insee.fr)

    4.5 Transparency Committee recommendations The transparency Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use and various public services, based on the indication and dosage specified in the Marketing Authorisation.   Packaging: Appropriate for the prescription conditions   Reimbursement rate: 65%

                                                                                                                                          

Appendix   UC-DAI score   The efficacy of MEZAVANT ® in studies SPD476-301 and SPD476-302 was assessed  LP using the modified UC-DAI (Ulcerative Colitis Disease Activity Index) score.   UC-DAI score (Sutherland LR et al. “.L. 5-aminosalicylic Acid Enemas in treatment of distal ulcerative colitis, proctosigmoiditis and Proctitis”. Gastroentérology 1987, 92: 1894-8.)  

  The UC-DAI score used in studies SPD476-301 and SPD476-302 was amended from the original score in the light of comments by the FDA (see table extracted from amendment 1 to study SPD476-302): the term “friability” was removed from grade 1 of the endoscopic sub- score (“Mucosal appearance”) and placed in grade 2of the same sub-score.     This modification is explained in the publication by Lichtenstein GR et al. “Effect of once- or twice-daily MMX Mesalazine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis” - Clinical Gastroenterology and Hepatology 2007;5;95-102