INTRINSA - INTRINSA - CT 6937 - English version

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Introduction INTRINSA 300 micrograms/24 h, transdermal patch B/8 (CIP: 376 704-4) Posted on Dec 16 2009 Active substance (DCI) testosterone Gynécologie - Endocrinologie - Nouveau médicament Avis défavorable au remboursement en raison d’un intérêt clinique insuffisant dans le traitement de la baisse du désir sexuel après ménopause chirurgicale INTRINSA est indiqué, en association à une estrogénothérapie, dans le traitement de la baisse du désir sexuel chez des femmes qui ont subi une ovariectomie bilatérale et une hystérectomie.La quantité d’effet observée est minime et l’on s’interroge sur sa pertinence clinique. L’incidence des événements indésirables androgéniques est élevée. La tolérance à plus long terme de ce médicament n’est pas connue. Son rapport efficacité/effets indésirables est faible et sa place dans la stratégie thérapeutique n’est pas établie.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous ATC Code G03BA03 Laboratory / Manufacturer PROCTER & GAMBLE PHARMACEUTICALS FRANCE INTRINSA 300 micrograms/24 h, transdermal patch B/8 (CIP: 376 704-4) Posted on Dec 16 2009

Informations

• Publié par: haute-autorite-sante-maladies-endocriniennes-et-metaboliques
• Publié le: 16 décembre 2009
• Nombre de lectures: 12
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

Extrait

 

    The legally binding text is the original French version       TRANSPARENCY COMMITTEE   OPINION   16 December 2009       INTRINSA 300 micrograms/24 h, transdermal patch B/8 (CIP: 376 704-4)     Applicant: PROCTER & GAMBLE PHARMACEUTICALS FRANCE   Testosterone   List I   ATC code (2009): G03BA03  

  Date of Marketing Authorisation: 28 July 2006 (centralised procedure, reporting Member State: Sweden).  Last amended: 16 September 2008.   Reason for request: Inclusion on the list of medicines reimbursed by National Insurance and approved for hospital use.                                             Medical, Economic and Public Health Assessment Division 1  

 

1. CHARACTERISTICS OF THE MEDICINAL PRODUCT

1.1. Active ingredient Testosterone 

1.2. Background First androgenic hormone replacement treatment for women with hypoactive sexual desire disorder following surgical removal of both ovaries and uterus (surgically-induced menopause). 

1.3. Indication “INTRINSA is indicated for the treatment of hypoactive sexual desire disorder in women who have been bilaterally oophrectomised and hysterectomised (surgically-induced menopause) and are receiving concomitant oestrogen therapy.”

1.4. Dosage “The recommended daily dose of testosterone is 300 micrograms. This is achieved by applying the patch twice weekly on a continuous basis. The patch should be replaced with a fresh patch every 3 to 4 days. A particular application site should be rotated with an interval of at least 7 days between applications. Only one patch is to be worn at a time.   The adhesive side of the patch should be applied to a clean, dry area of skin on the lower abdomen below the waist. Patches should not be applied to the breasts or other body regions. A skin site with minimal wrinkling which is not covered by tight clothing is recommended. The site should not be oily, damaged, or irritated. To prevent interference with the adhesive properties of INTRINSA, no creams, lotions or powder should be applied to the skin where the patch is to be applied.   The patch should be applied immediately after opening the sachet and removing both parts of the protective release liner. The patch should be pressed firmly in place for about 10 seconds, making sure there is good contact with the skin, especially around the edges. If an area of the patch lifts, pressure should be applied to that area. If the patch detaches prematurely, it may be reapplied. If the same patch cannot be reapplied, a new patch should be applied to another location. In either case, the original treatment regimen should be maintained. The patch is designed to remain in place during a shower, bath, swimming or exercising.    Concomitant oestrogen treatment   The appropriate use and restrictions associated with oestrogen therapy should be considered before INTRINSA therapy is initiated and during routine re-evaluation of treatment. Continued use of INTRINSA is only recommended while concomitant use of oestrogen is considered appropriate (i.e. the lowest effective dose for the shortest possible duration).   Patients treated with conjugated equine oestrogen (CEO) are not recommended to use INTRINSA, as efficacy has not been demonstrated (see sections 4.4 and 5.1).

 

 

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Duration of treatment   INTRINSA treatment response should be evaluated within 3-6 months of initiation, to determine if continued therapy is appropriate. Patients who do not experience a meaningful benefit should be reevaluated and discontinuation of therapy be considered.   As the efficacy and safety of INTRINSA have not been evaluated in studies of longer duration than 1 year, it is recommended that an appraisal of the treatment is undertaken every 6 months.   Children and adolescents:   There is no indication for use of INTRINSA in children and adolescents.”

2. COMPARABLE MEDICINAL PRODUCTS

2.1. ATC Classification (2009) G : Genito-urinary G03 : Sex hormone G03B : Androgens G03BA : 3-oxoandroste G03BA03 : Testosterone  

2.2.

system and sex hormones s and modulators of the genital system n derivatives

Medicines in the same therapeutic category

2.2.1. Medicines that are strictly comparable There is no medicine that is strictly comparable. 2.2.2. Medicines that are not strictly comparable There is no medicine that is not strictly comparable.

2.3. Medicines with the same therapeutic aim There is no medicine with the same therapeutic aim.  

 

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3. ANALYSIS OF AVAILABLE DATA

  The company has submitted two phase III studies: INTIMATE SM-1 1 and INTIMATE SM-2 2 . These studies were performed using the same protocol.

3.1. Efficacy

3.1.1.Method    Objective:   The main objective of these studies was to evaluate the efficacy of the testosterone patch providing 300 µg/24 h by comparison with a placebo patch in surgically menopausal women with hypoactive sexual desire disorder and personal distress and receiving oestrogen hormone replacement therapy.   Study design:   Each study comprised a randomised, double-blind, parallel group, placebo-controlled period, followed by an open period during which all patients received the active treatment. Inclusion criteria: o surgical menopause (bilateral oophrectomy) with hysterectomy o hypoactive sexual desire o oestrogen therapy for more than 3 months stable o in a stable relationship o  patientsable to express their concerns about their sexuality   Exclusion criteria: o breast cancer, uterine-cervical cancer o a physical disorder other than a drop in the testosterone level or a psychological disorder capable of inducing a drop in sexual desire o of medicines or food supplements likely to influence sexual function. use   Treatment:   During the double blind period, for 24 weeks, patients received a patch providing 300 µg testosterone/24h or a placebo patch.   Patients applied the patch to the lower abdomen twice a week, following the recommendations of the SPC. Compliance was verified during the studies.   During the open period, all patients received the active treatment for 28 weeks.   Oestrogen replacement therapy (oral or transdermal) was to remain stable for the duration of the study.  

                                             1 et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with J  Simon hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005 ; 90: 5226-33. 2 Buster JE et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomised trial. Obstet Gynecol 2005 ; 105: 944-52.   4  

Endpoints:    The primary efficacy endpoint was the increase in the frequency, over 4 weeks, of any satisfying sexual activity between the start of the study and the end of the double-blind period (weeks 21-24). This criterion was measured using the Sexual Activity Log © (SAL) 3 .   The main secondary endpoints were changes, by comparison with the start of the study, in:   o the results for the parts of the PFSF questionnaire concerning sexual desire 4    o the results of the PDS questionnaire 5      Statistical method:   The number of subjects needed was estimated to be 250 patients per group, as follows: two- tailed analysisα = 0.05, power = 90%, mean inter-group difference of 0.34 for satisfying sexual activity per week. Analysis was on an intention-to-treat basis using the using the last observation carried forward. The statistical tests used were the analysis of covariance (ANCOVA) and the Wilcoxon test.   3.1.2.Results  Populations and main baseline characteristics (cfTable 1)   Table 1   INTIMATE studies SM-1 SM-2 Placebo INTRINSA Placebo INTRINSA n = 279 n = 283 n = 266 n = 267 Mean age (± SD) 48.9 (± 7.36) 49.2 (± 7.72) 49.5 (± 7.55) 48.3 (± 7.45) Oestrogen therapy on inclusion: Oral, n (%) 208 (75) 209 (74) 217 (82) 212 (80) Transdermal route, n (%) 71 (25) 74 (26) 49 (18) 54 (20) Time  sinc ( e ±   o S o D p )  hrectomy  8.2 (6.65) 8.7 (7.01) 9.1 (7.21) 8.9 (7.35)   

                                             3  Sexual Activity Log (SAL): diary of the frequency of sexual activities, orgasms and satisfying sexual activities 4 during thep erivuo s 7adsy itnoeF fo eliforP    ncFul uaex Slema ©  quest(P ychometric  FSF): ps ionnaire completed retrospectively every 30 days which can be used to measure the drop in sexual desire with psychological suffering. The questionnaire has 37 headings classified in seven groups: desire, excitation, pleasure, orgasm, concerns about one’s sexuality, 5  Sssleca  dnveness a receptiesuxla © (P ):DS g l a p m m i od   e . t e ea s id    c f  y l r e ectively retrosp 0adsy ,e evyr3 inadhen vesee th hcihw fo sg  Personal Distre can be used to measure the suffering associated with a drop in libido. 5  

Primary efficacy endpoint: A significant difference between INTRINSA and placebo was shown in the increase in frequency over 4 weeks of any satisfying sexual activity between the start and the end of the double-blind period (week 24) in the 2 studies (cfTables 2 and 3).   Table 2: Study SM-1 – Primary efficacy endpoint      INTRINSA n = 276Placebo n = 273 Mean score at baseline (± SD) 2.94 (± 0.19) 2.82 (± 0.15)  Mean score at the end of the study (± SD) 3.92 (± 0 .27) 4.92 (± 0.30)  Mean intra-group difference (± SD) 0.98 (± 0.19) 2.10 (± 0.25) Mean difference between groups (95% CI) 1.11 (0.50; 1.73)* Difference between the means of least squares (95% CI) 1.15 (0.54; 1.77) †   * p = 0.0011 Wilcoxon test; †: p = 0.0003 ANCOVA increase in frequency adjusted for treatment, age, route of oestrogen administration, grouping of centres and baseline rate of sexual activity; SD: standard deviation from the mean     Table 3: Study SM-2 – Primary efficacy endpoint     Placebo n = 255 INTRINSA n = 258 Mean score at baseline (± SD) 3.19 (± 0.24) 3.04 (± 0.23)  Mean score at the end of the study ‡  3.92 4.60  Mean intra-group difference 0.73 (± 0.25) 1.56 (± 0.29) Mean difference between groups (95% CI) 0.83 (0.07, 1.58) * Difference between the means of least squares (95% CI) 0.65 (- 0.08, 1.39) †   ‡: Standard deviation not specified; * p = 0.001 Wilcoxon test; †: p = 0.0816 ANCOVA adjusted for age, route of  oestrogen administration, centres and the baseline rate of sexual activity – normal distribution of values not observed; SD: standard deviation from the mean. These two studies showed a significant difference between INTRINSA and placebo in the frequency of any satisfying sexual activity.   Secondary endpoints:   Study SM-1   A statistically significant difference in favour of INTRINSA compared to placebo was shown for the change in scores under treatment concerning the part of the PFSF questionnaire on sexual desire and the PDS questionnaire (cf Table 4). Table 4: Study SM-1- Secondary endpoints   Placebo INTRINSA PFSS Mean intra-group difference (± SD)*  6.9 n 0     = (   ± 2  1 6 . 9 1   4) n = 269  :  11.85 (± 1.12)  PFSS: Difference between the means of least squares

  (95% CI)  4.95 (2.13; 7.78) † n = 2 n = 268 PDS: Mean intra-group difference (± SD)*  -16.31 (±  6 1 6 .   66) -23.55 (± 1.63)  PDS: Difference between the means of least squares -7.25 (-11.37; -3.12) †   (95% CI) * adjusted for age, route of oestrogen administration, centres and the baseline rate of sexual activity; † p = 0.0006 ANCOVA adjusted for age, route of oestrogen administration, centres and the baseline rate of sexual activity;

 

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Study SM-2   A statistically significant difference in favour of INTRINSA compared to placebo was shown for the change in scores under treatment concerning the part of the PFSF questionnaire on sexual desire and the PDS questionnaire (cfTable 5).  Table 5: Study SM-2 – Secondary endpoints   Placebo INTRINSA

PFSS: Mean intra-group difference (± SD)* PFSS: Difference between the means of least squares (95% CI) PDS: Mean intra-group difference (± SD)*

n = 257 n = 252 6.21 (± 1.24) 11.38 (± 1.23)  5.17 (2.22; 8.12) †   n = 258 n = 254 -18.27 (± 1.92) -24.34 (± 1.91) ( P 9 D 5 S % :     C D I if ) f   erence between the means of least squares  -6.08 (-10.63; -1.52) ‡   * adjusted for age, route of oestrogen administration, centres and the baseline rate of sexual activity; † p = 0.0006 ANCOVA adjusted for age, route of oestrogen administration, centres and the baseline rate of sexual activity; ‡: p = 0.0091 ANCOVA adjusted for age, route of oestrogen administration, centres and the baseline rate of sexual activity     3.2. Tolerance   3.2.1.Clinical studies   Double-blind period   The global rate of adverse events, serious adverse events and dropouts linked to an adverse event were similar in the INTRINSA and placebo groups in studies SM1 and SM2. (cf Table 6).   Table 6: Rate of adverse events during the double-blind period   SM-1 SM-2

INTIMATE studies  Placebo INTRINSA Placebo INTRINSA n = 279 n = 283 n = 266 n = 266 Glob nt a s l  * i   ncidence of adverse  79.6% 77.7% 74.1% 74.4%  eve Serious adverse events* 2.5% 2.5% 2.3% 1.9% Dropouts linked to an adverse nt 6.8% 8.5% 8.3% 8.3% eve * % of patients who had at least 1 adverse event     Two serious adverse events were considered as being possibly linked to treatment in the INTRINSA group: a transient ischaemic attack and a combination of tachycardia, sweating, diarrhoea and nausea.   In a group analysis of the studies SM1, SM2 and two phase II studies each including a placebo group and a group treated with INTRINSA for 24 weeks 6 , the rate of adverse effects (possibly or probably related) was higher in the group treated with INTRINSA than in the placebo group (26.8% vs. 23.4%); this difference was due mainly to a higher rate of androgenic adverse events in the INTRINSA group 6 .  

                                             6 INTRINSA EPAR http://www.emea.europa.eu/humandocs/PDFs/EPAR/intrinsa/063406en6.pdf  

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  Cutaneous reactions -   The most frequent adverse events were cutaneous reactions at the site of administration (cf Table 7).   Table 7: Cutaneous reactions at the site of administration during the double-blind period   SM-1 SM-2 INTIMATE studies  Placebo INTRINSA Placebo INTRINSA n = 279 n = 283 n = 266 n = 266 Cutaneous reactions at the site of 39.1% 31.1% 28.9% 29.7% administration* Severity of the cutaneous reactions †       Mild 80.5% 77.9% 77.4% 74.7% Moderate 18.7% 18.9% 20.2% 21.8% Severe 0.8% 3.2%% 2.4% 3.4% Dropouts linked to a cutaneous reaction* 4.7% 3.2% 3.0% 2.6% * % of patients who had at least 1 adverse event; †: % of cutaneous reactions   - Androgenic adverse events:   These were more common in the placebo group of study SM1 and in the INTRINSA group of study SM2.   The rate of dropouts due to these adverse events was higher under INTRINSA in the 2 studies (cfTable 8). One dropout was due to clitoromegaly. This effect was regressive and considered to be moderate by the investigator. Another dropout was due to voice deepening. This effect was regressive and considered to be severe by the investigator. Table 8: Androgenic adverse events during the double-blind period   SM-1 SM-2 INTIMATE studies  Placebo INTRINSA Placebo INTRINSA

n = 279 n = 283 n = 266 n = 266 Androgenic adverse event of any kind* 15.8% 12.7% 11.3% 19.5% Acne* 6.1% 6.0% 4.1% 7.5% Alopecia* 3.2% 3.2% 2.6% 5.3% Hirsutism* 6.5% 5.7% 5.3% 9.0% Voice deepening* 2.9% 2.5% 1.5% 3.0% Severity of the adverse events: Mild 96.2% 98.0% 97.5% 91.5% Moderate 3.8% 2.0% 2.5% 7.0% Severe 0% 0% 0% 1.4% Drop erse  0 event o   uts linked to an androgenic adv .4% 1.1% 0.8% 2.3%  * % of patients who had at least 1 adverse event   The rate of androgenic adverse events (acne, alopecia, hirsutism and voice deepening) was higher under INTRINSA (17.7%) than in women who received placebo (14.4%) in the pooled analysis of studies SM1 and SM2 and two phase II studies 6 .

 

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  Open follow-up period in studies SM1 and SM2   During the open follow-up period of studies SM1 and SM2, the rates of adverse events and serious adverse events were similar in the group of patients who had previously been treated with INTRINSA and in the group of patients who had previously received placebo (cf Table 9). The causal link with treatment was considered to be questionable for all serious adverse events. The rate of dropouts due to adverse events was higher in patients previously treated with INTRINSA.   Table 9: Rate of adverse events during the open period   SM-1 SM-2 INTIMATE studies  Placebo→ INTRINSA→ Placebo→ INTRINSA→  INTRINSA INTRINSA INTRINSA INTRINSA n = 229 n = 220 n = 189 n = 199 Global  * incidence of adverse  61.6% 65.0% 49.7% 50.3%  events Serious adverse events* 1.3% 2.7% 2.1% 0.5% Drop t outs linked to an adverse  4.8% 6.4% 7.4% 10.6%  even * % of patients who had at least 1 adverse event   The rate of androgenic adverse events and their severity were similar in patients who previously received placebo and in those previously treated with INTRINSA; however, more patients previously treated with INTRINSA (2.4%) dropped out of the study on account of hirsutism than patients who received placebo (1%) 6 .   3.2.2.Pharmacovigilance data   The SPC was updated in April 2008: “Hirsutism was also very commonly reported. Most reports concerned the chin and upper lip, were mild (> 90%) and less than 1% of all patients withdrew from the studies due to hirsutism. Hirsutism was reversible in the majority of patients.”   The analysis of PSURs since INTRINSA went on the market is consistent with the adverse effects observed in clinical studies.   3.2.3.European risk management plan (RMP)   This plan entails performing safety of use studies and a risk minimisation plan. A survey and 3 observational cohort studies are intended to monitor androgenic effects, unexpected effects and off-label prescriptions.   A European observational cohort study (the EMPOWER study) is intended to collect information about events of particular interest: breast cancer, gynaecological cancers, cardiovascular safety, clitoromegaly and voice deepening.   3.2.4.National prescription monitoring   In addition to the RMP, the French Healthcare Product Safety Agency (AFSSAPS) set up an intensified pharmacovigilance tracking plan with national monitoring.

 

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3.3. Conclusion   Two randomised double-blind studies versus placebo (SM-1 and SM-2) performed in women with surgically induced menopause who were receiving concomittent oestrogen therapyt showed a significant difference in favour of INTRINSA for the increased frequency at 4 weeks of any satisfying sexual activity (SM-I: 1.15 [0.54; 1.77]; SM-2: 0.83 [0.07, 1.58]). The size of the effect is minimal and the clinical relevance is questionable.   The main adverse events observed during treatment for 28 to 52 weeks were reactions at the site of administration and adverse androgenic effects (acne, alopecia, hirsutism and voice deepening).    The pooled analysis of double-blind studies 6  that the rate of androgenic adverse showed events (acne, alopecia, hirsutism and voice deepening) was higher under INTRINSA than under placebo.   During the open phase of studies SM-1 et SM-2, the rates of dropouts due to adverse events and in particular to androgenic adverse events were higher in patients treated with INTRINSA for 52 weeks (under INTRINSA during the double-blind period) than in the patients treated for 28 weeks (under placebo during the double-blind period).   The longer-term safety of INTRINSA is not known, specifically as regards oncology, cardiovascular system, metabolism and androgenic adverse effects. INTRINSA is subject to a European risk management plan and of national prescription monitoring.  

 

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4.

TRANSPARENCY COMMITTEE CONCLUSIONS

  4.1. Actual benefit   Hypoactive sexual desire can lead to impaired quality of life.   This medicine falls into symptomatic treatment category.   Studies which tested the efficacy of INTRINSA showed a size of effect significantly different to that of placebo. However, this size of effect was minimal and of dubious clinical relevance. During treatment for 24 to 52 weeks, there was found to be an increase in the global incidence of androgenic adverse events which in some cases may prove not to be very reversible when treatment is stopped (expert’s opinion). In addition, the longer-term safety of INTRINSA is not known, specifically as regards oncology, cardiovascular system, metabolism and androgenic adverse effects. INTRINSA is subject to a European risk management plan and of national prescription monitoring.   The efficacy/adverse effects ratio for INTRINSA is low (due in particular to the long-term use).   There is no alternative medicinal product.   Public health benefit As regards public health and since hypoactive sexual desire (HSD) is not a serious condition, the burden represented by reduced sexual desire in women with surgically induced menopause is small.   This disorder does not constitute a public health need.   The associated individual personal distress experienced by these patients is however likely to affect their quality of life which is already impaired by the disorder on account of which the hysterectomy and oophrectomy and the surgical procedure itself were performed.   However, the data available do not allow an assessment to be made of the expected impact of INTRINSA in terms of improved quality of life and long-term safety.   Consequently, it is not expected any public health benefit from the medicine INTRINSA.   A review of efficacy studies with various testosterone medicines in menopausal women with HSD which was published in 2005 concluded that treatment with testosterone could be given after other causes (physical and psychological) had been eliminated, even though there was not shown to be any connection between the level of endogenous androgen and sexual function in menopausal women.   A recommendation published in 2006 on androgenic treatments in women advised against diagnosing an androgen deficit in women because of the absence of a clearly defined clinical syndrome and of any data regarding the total testosterone level or free testosterone level that could be used to define such a deficit. Although short-term studies have shown the efficacy of testosterone in selected populations such as women with surgically induced menopause, its general use is not advisable because the indications are not adequately defined and there are no long-term safety data (> 1 year). The safety data required concerned the long-term effect on the endometrium and the breast, cardiovascular safety and androgenic adverse effects.

 

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