SIGNIFOR - SIGNIFOR - CT 12258 - Version anglaise

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Présentation SIGNIFOR (gamme), solution injectable solution injectable, ampoule de 1 ml (B/6) - Code CIP : 2223520 solution injectable, ampoule de 1 ml (B/60) - Code CIP : 2223514 solution injectable, ampoule de 1 ml (B/60) - Code CIP : 2223566 solution injectable, ampoule de 1 ml (B/60) - Code CIP : 2223603 Mis en ligne le 19 mars 2013 Substance active (DCI) pasiréotide Endocrinologie - Nouveau médicament Progrès mineur dans la prise en charge de la maladie de Cushing lorsque la chirurgie n'est pas envisageable ou a été un échec SIGNIFOR a l’AMM dans la maladie de Cushing chez les patients pour lesquels la chirurgie n'est pas envisageable ou a été un échec.En l’absence d’alternative médicamenteuse et devant une efficacité modeste, il représente un progrès thérapeutique mineur chez ces patients.Sa prescription nécessite l’avis d’une équipe pluridisciplinaire experte dans la prise en charge de la maladie de Cushing, incluant notamment un neurochirurgien expérimenté dans le traitement des tumeurs hypophysaires.L’arrêt de SIGNIFOR doit être envisagé après deux mois de traitement en l’absence de réponse biologique ou clinique. Pour en savoir plus, téléchargez la synthèse ou l'avis complet SIGNIFOR. Code ATC H01CB05 Laboratoire / fabricant Laboratoire NOVARTIS PHARMA S.A.S. SIGNIFOR (gamme), solution injectable solution injectable, ampoule de 1 ml (B/6) - Code CIP : 2223520 solution injectable, ampoule de 1 ml (B/60) - Code CIP : 2223514 solution injectable, ampoule de 1 ml (B/60) - Code CIP : 2223566 solution injectable, ampoule de 1 ml (B/60) - Code CIP : 2223603 Mis en ligne le 19 mars 2013

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• Publié par: haute-autorite-sante-maladies-endocriniennes-et-metaboliques
• Publié le: 18 juillet 2012
• Nombre de lectures: 15
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

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The legally binding text is the original French version

  TRANSPARENCY COMMITTEE   OPINION   18 July 2012       SIGNIFOR 0.3 mg, injectable solution B/60 vials of 1 ml (CIP code: 222 351-4)   SIGNIFOR 0.6 mg, injectable solution B/6 vials of 1 ml (CIP code: 222 352-0) B/60 vials of 1 ml (CIP code: 222 356-6)   SIGNIFOR 0.9 mg, injectable solution B/60 vials of 1 ml (CIP code: 222 360-3)     Applicant: NOVARTIS PHARMA SAS   pasireotide  ATC code: H01CB05 (Hypothalamic hormones – Growth hormone antagonist) List I   Prescription restricted to specialists in endocrinology, diabetes and metabolic disorders or internal medicine. Medicine requiring special monitoring during treatment.   Orphan medicine (date of designation): 8 October 2009   Date of Marketing Authorisation (European centralised procedure): 24 April 2012 43 patients have received these proprietary medicinal products for Cushing's Disease between July 2010 and July 2012 in a TUA for named patients granted by ANSM.   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

 

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1.

CHARACTERISTICS OF THE MEDICINAL PRODUCT

    1.1. Active ingredient   Pasireotide    1.2. Indications   “SIGNIFOR is indicated for the treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery has failed.”   1.3. Originality   Pasireotide is a new injectable somatostatin analogue.   1.4. Dosage   “The recommended initial dose of SIGNIFOR is 0.6 mg by subcutaneous injection twice a day.    Two months after the start of SIGNIFOR therapy, patients should be evaluated for clinical benefit. Patients who experience a significant reduction in urinary free cortisol [UFC] levels should continue to receive SIGNIFOR for as long as benefit is derived. A dose increase to 0.9 mg may be considered based on the response to the treatment, as long as the 0.6 mg dose is well tolerated by the patient. Patients who have not responded to SIGNIFOR after two months of treatment should be considered for discontinuation. Management of suspected adverse reactions at any time during the treatment may require temporary dose reduction of SIGNIFOR. Dose reduction by decrements of 0.3 mg twice a day is suggested.   Special populations  Paediatric population The safety and efficacy of SIGNIFOR in children and adolescents aged 0 to 18 years have not been established. No data are available.   Elderly (≥65 years old)   Data on the use of SIGNIFOR in patients older than 65 years are limited, but there is no evidence to suggest that dose adjustment is required in these patients.   Renal impairment No dose adjustment is required in patients with impaired renal function (see section 5.2).   Hepatic impairment   Dose adjustment is not required in patients with mildly impaired hepatic function (Child Pugh A). The recommended initial dose for patients with moderate hepatic impairment (Child Pugh B) is 0.3 mg twice a day (see section 5.2). The maximum recommended dose for these patients is 0.6 mg twice a day. SIGNIFOR should not be used in patients with severe hepatic impairment (Child Pugh C) (see sections 4.3 and 4.4).   Method of administration SIGNIFOR is to be administered subcutaneously by self injection. Patients should receive instructions from the physician or a healthcare professional on how to inject SIGNIFOR subcutaneously.” 

 

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2.

SIMILAR MEDICINAL PRODUCTS

    2.1. ATC classification (2012)   H:    Systemic hormones, excluding sex hormones. H01: Pituitary and hypothalamic hormones and analogues H01C:    Hypothalamic hormones H01CB:   Growth hormone antagonist H01CB05:   asirpde eoti   2.2. Medicines in the same therapeutic category   None.   2.3. Medicines with a similar therapeutic aim   No other medicine has MA for the treatment of Cushing's Disease.   In practice, some medicines are used off label (PNDS 1  expert opinion) in the treatment and of Cushing's Disease, particularly in adult patients in whom surgery is not an option or has failed: · Medicines with adrenal action: o ketoconazole: this medicinal product was designated an orphan medicinal product by the European Commission on 23/04/2012 for “the treatment of Cushing's Syndrome”. In France, NIZORAL 200 mg, tablet remains available as a TUA for named patients for the management of patients suffering from Cushing's syndrome. o METOPIRONE 250 mg, tablets metyrapone: o mitotane: LYSODREN 500 mg, tablets  Pituitary-acting medicines · o cabergoline: DOSTINEX 0.5 mg, tablets and generic · Peripheral action medicines (glucocorticoid receptor antagonist): o mifepristone:   MIFEGYNE 200 mg, tablets

                                             1 HAS. Physician Guide LTD no. 31. Cushing's syndrome. National diagnostic and care protocol. September 2008. 3/15  

3. ANALYSIS OF AVAILABLE DATA

    The efficacy and safety data on pasireotide (SIGNIFOR) for the treatment of Cushing's Disease in adult patients in whom surgery is not an option or has failed are based mostly on the results of the pivot study B2305, the aim of which was to evaluate SIGNIFOR at doses of 600 µg x2/day and 900 µgx2/day.   The results of the open phase II study B2208 (n=39) and its extension phase B2208E1, were also submitted in support of the pivot study.   3.1. Efficacy   3.1.1 Study B2305 2     Primary objective: The primary objective was to evaluate the efficacy of two doses of SIGNIFOR (600 µg x2/d and 900 µg x2/d), independently, as self-administered subcutaneous injections in adult patients suffering from Cushing's Disease in whom surgery was not an option or had failed.   Methodology:   This was a double-blind, randomised, phase III study lasting 12 months. The lack of a comparator group is justified by the lack of medicinal product with MA, or one which has been unanimously validated for use in the treatment of Cushing's Disease. A placebo group was not used because of the severity of the disease and the serious condition of the patients who were included who require therapeutic management.   The inclusion criteria included: - patients aged 18 years or older with: - persistent or recurrent Cushing's Disease (CD) after pituitary surgery or de novo CD in which surgical treatment was not possible (contraindicated, refused by the patient, inaccessible tumour). - ACTH-dependent Cushing's Disease, the diagnosis of which was confirmed by: - mean urinary free cortisol concentration (mUFC) > at least 1.5 times the upper limit of normal, - a morning plasma ACTH result≥normal limits, - a pituitary adenoma identified on MRI (adenoma≥ 1 cm) or by a petrosal sinus gradient > 3 following administration of CRH (corticotropin-releasing hormone) if the adenoma was < 1 cm, or for patients who had had previous surgery with histology confirming that the adenoma was ACTH-dependent. - patients already treated for Cushing's Disease had to follow a treatment-free period before evaluating efficacy at inclusion. -impaired glucose tolerance or diabetes mellitus could be patients with a past history of included although with increased blood glucose monitoring and adjustment of their diabetic treatment if required.   The non-inclusion criteria included: - pituitary radiotherapy in the previous 10 years - treatment with mitotane in the last 6 months - Cushing's syndrome due to ectopic ACTH secretion, hypercortisolism secondary to an adrenal tumour or primary bilateral nodular adrenal hyperplasia, - poorly controlled treated diabetes (HbA1c > 8%) - patients with risk factors fortorsade de pointe.                                                 2 Colao Annamria et al., A 12-Month Phase 3 Study of Pasireotide in Cushing’s Disease,   N Engl J Med 2012; 366:914-924 4/15  

Primary efficacy endpoint: proportion of patients who responded after 6 months of treatment defined as patients whose mean urinary free cortisol (mUFC≤ULN 3 ) had returned to normal with no increase in dose within 6 months. Patients whose dose of SIGNIFOR was increased before 6 months were deemed to be non-responders.     Statistical analysis: The two doses of SIGNIFOR, 600 µg x2/d and 900 µg x2/d, were evaluated independently of each other. There was no statistical comparison between the two treatment groups. Benefit was established in either group if the lower limit of the 95% CI for the fall in mUFC was > 15% for the primary endpoint.   Treatments: Patients were randomised (1:1) to receive one of the following treatments:  pasireotide (SIGNIFOR) subcutaneously 600 µg 2x/d (n=83) - - pasireotide (SIGNIFOR) subcutaneously 900 µg 2x/d (n=82)   Patients whose mUFC was≤2xULN and≤their baseline mUFC after 3 months continued to be given the same dose of SIGNIFOR for 3 months. Patients who did not meet these criteria were unblinded and their dose was to be increased to 300 µg x2/d. Patients who were not eligible for a dose increase were withdrawn from the study and those whose dose was increased were deemed to be non-responders for the analysis of the primary endpoint (regardless of their mUFC at 6 months).   After 6 months initial treatment the study was continued on an open label basis for a period of 6 months, during which the patients continued at the same dose. If the response to treatment was not maintained or if the patient was a non-responder at any time, the dose could be further increased by 300 µg x2/d, not exceeding 1200 µg x2/d.   Doses could be reduced at any time if poorly tolerated.   After 12 months of the study an extension phase (ongoing) was offered to some patients with continuation of their treatment (if the mUFC had returned to normal or in the event of clinical benefit as assessed by the investigator at the end of the initial phase, subject to acceptable tolerance).    The secondary endpoints included: - percentage response rate at 12 months - changes in plasma ACTH and plasma cortisol compared to inclusion - change in signs and symptoms of Cushing's Disease - change in the quality of life score (Health-related quality of life questionnaire, which is 4 specific for Cushing's Disease).   Results:   A total of 162 patients were included 5 and received at least one dose of the treatment. - characteristics at inclusion: Patient Mean patient age was 40.2 years old. The majority were women (77.8%), which is consistent with the epidemiological findings for the disease. A minority of patients was≥ 65 years old (3.1%). 83.3% of patients had persistent or recurrent Cushing's Disease. The other patients had de novo CD (surgery not indicated or refused). Most (79%) had undergone surgery to treat the CD and fewer than 5% had previously had pituitary radiotherapy. The mean time between the diagnosis and first injection of SIGNIFOR was 63.1 months. The proportions of

                                             3 USN: upper limit of normal. The USN was set at 145 nmol/24h. 4 Webb SM, Nadia X, Baronage ME et al. Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire. Euro J Endocrinology 2008 May; 158 (5): 623-30. 5 Eleven patients were randomised in France in nine centres.   5/15  

patients who had been given medical treatment before the study was 43.9% in the 600 µg x2/d group and 52.5% in the 900 µg x2/d group. Initial characteristics were similar in both groups except for the mUFC which was higher in the 600 µg x2/d group compared to the 900 µg x 2/d group (mean value 1155.9 ± 2629.88 nmol/24 hours compared to 781.9 ± 926.4 nmol/24 hours and median value 730 nmol/24 h compared to 487 nmol/24 h).    Treatment drop-outs (cf. table 1) - Approximately one third of the patients (34%) stopped their treatment during the first 6 months. Only 48.1% (78/165) of patients completed the 12 months of the study. The main reason for patient drop-outs was inadequate unsatisfactory therapeutic effect (25.3%). During the first 6 months treatment drop-outs were mostly due to adverse effects.

Table 1:Study B2305 drop-outs (ITT population) Treatment -    Total 900 x2/d x2/d SIGNIFORSIGNIFOR 600 N=82 N=80 (N=162)   Treatment drop-outs, n (%)  before 6 months 28 (34.1) 27 (33.8) 55 (34.0) - - between 6 and 12 months 15 (18.3) 14 (17.5) 29 (17.9) Reason for discontinuation* n (%)     ,       Unsatisfactory therapeutic effect 19 (23.2) 22 (27.5) 41 (25.3)        Adverse event(s)  13 (15.9) 15 (18.8) 28 (17.3)       Subject withdrew consent  13 (15.9) 11 (13.8) 24 (14.8)       Protocol deviation   4 (4.9) (2.5) 0 4   *Patients who completed Month 12 and did not enter extension phase are not counted as discontinuations.       - Results for the primary endpoint (cf. table 2) At 6 months, 14.6% of patients had responded in the 600 µg x2/d group and 26.3% in the 900 µg x2/d group. Only the group which was given 900 µg x2/d met the pre-defined efficacy criteria for the primary endpoint (lower limit of the 95% CI above the 15% cut-off). As the aim of the study was to demonstrate the efficacy of each of the doses separately, no statistical comparison was performed between the two doses of SIGNIFOR tested. It should be noted that the mUFC at inclusion was higher in the 600 µg x2/d group. Table 2:Study B2305 - Results for the primary endpoint (ITT population)   SIGNIFOR 600 µgx2/d 900 µgx2/d SIGNIFOR N=82 N=80

Responder patients, % (n) 14.6(12) 26.3(21) [95% CI]  [7.0, 22.3]  [16.6, 35.9]   Further analyses: Further analyses were carried out in the primary endpoint as stipulated in the protocol. Three sub-groups of patients were defined according to clinical response: - controlled patients (C): mUFC≤ ULN at 6 months, including patients whose dose was increased at 3 months, - partially controlled patients (PC): mUFC > ULN at 6 months, but mUFC had fallen by at least 50% compared to inclusion, even if the dose was increased. - uncontrolled patients (UP): patients who were neither controlled nor partially controlled at 6 months.        

 

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The proportions of patients who were controlled was 15.9% in the 600 µg x2/d group and 28.8% in the 900 µg x2/d group (cf. table 3) at 6 months. The overall proportions of C or PC patients were 34.2% in the group randomised to receive 600 µg x2/d and 41.3% in the other group.     Table 3:by clinical response sub-group at 6 months (ITT)Study B2305 – Distribution of patients   ts IFO N R 6 8 0 2 0 NIFO N R = 9 8 0 0 0 x2/d Subgroup of patien  SIGN =  SIG x2/d n (%) Controlled 13 (15.9) 23 (28.8) Partially controlled 15 (18.3) 10 (12.5) Uncontrolled   47 (59)54 (66)   Few of the patients controlled at 6 months had increased their initial dose at 3 months (1/13 in the 600 µg x2/d group and 2/23 in the 900 µg x2/d group). A total of 11/36 of the controlled patients had reduced their initial dose by 300 µg x2/d in the first 6 treatment months, (6 in the 600 µg x2/d group and 5 in the 900 µg x2/d group).   A rapid fall in mean UFC was seen from the first month and was maintained up to 12 months. Median mUFC had fallen by 47.9% at 6 months compared to inclusion in each dose group. The fall was over 60% in each group (n=74 total) at 12 months.   - Results for secondary endpoints: Proportions of control patients at 12 months (mUFC returned to normal) were 13.4% (11/82) in the 600 µg x2/d group and 25.0% (20/80) in the 900 µg x2/d group. Mean ACTH and plasma cortisol levels fell during the study and remained below their baseline values between 1 month and the end of the study at 12 months (cf. table 4). The clinical indicators of interest for the disease improved similarly in both groups. At six months in particular, systolic and diastolic blood pressure, 6  body mass index (BMI), total cholesterol and depression score fell (cf. table 4). No changes in bone density were found between inclusion and months 6 or 12. There was a minimal change in triglycerides at 6 months.   Table 4:Study B2305 – Results for secondary endpoints at 6 months (ITT population)     SIGNIFOR 600 µgx2/d SIGNIFOR 900 µgx2/d N=82 N=80    dellotronC llA Corontedll All      patients patients  N=13 N=82 N=13 N=82

Change in blood cortisol, nmol/L (n)

Change in plasma ACTH, pmol/L (n)

Change in systolic pressure, mmHg (n)

Change in diastolic pressure, mmHg (n) Change in BMI, kg/m 2 (n)  

Change in total cholesterol, mmol/L (n)

Change in sBDI-II score: depression, (n) (Scale from 0 to 63) 

Change in Ferriman score: hirsutism, (n) (Scale from 0 to 36)

 -

 -

-13.0 (11)

-7.5 (11)

-1.3 (11)

-0.8 (11)

-3.8 (9)

+0.4 (9)  

-70.2 (59)

-2.6 (58) -6.8 (59) -4.2 (59) -1.9 (59)

-0.4 (59)

-4.6 (56)

-0.9 (44)

Change in score in % fat mass, % (n)  (39)-2.3 (7) -0.4 * Patients controlled: patients with mUFC σ ULN even if the dose was increased at 3 months.  

                                             6 Measured when seated at rest.  

- 

 - -13.7 (21) -7.9 (21)   -2.5 (21) -0.5 (20)

-5.4 (20)

-3.1 (19)

-0.8 (11)

-99.6 (57)

-3.0 (56) -11.4 (57) -5.0 (57) -2.1 (57) -0.4 (55)

-5.5 (55)  

-2.4 (47)

-0.95 (32)

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Some clinical symptoms of Cushing's Disease improved. Improvement in facial rubor   at 6 months was seen in 36.7% (18/49) of patients in the 600 µg x2/d group and in 59.6% (28/47) of patients in the 900 µg x2/d group.   Supraclavicular fat pad and dorsal fat pad distribution improved in almost 40% of patients in each group. Impact on quality of life was evaluated by a further questionnaire specific for Cushing's Disease developed for the study. Changes in the quality of life score at 6 months were +31.3% (+6.2 points) in the 600 µg x2/d group (n=56/82) and +73.0% (i.e. +12.9 points) in the 900 µg x2/d group (n=55/80) compared to the baseline score.   These results for the secondary endpoints should be interpreted with caution because of the low numbers considered.   Exploratory sub-group analyses were also performed according to the baseline mUFC. The overall proportions of patients who responded (primary endpoint) at 6 months were 27.2% (25/92) in the patients with an initial mUFC≤(5/61) in the patients with an5xULN and 8.2% initial mUFC > 5xULN. The proportions of responders in the 600 µg x2/d group were 21.1% (8/38) in patients with an initial mUFC≤ 5xULN and 10.3% (4/39) for those whose initial mUFC was > 5xULN. Corresponding proportions in the 900 µgx2/d group were 31.1% (17/54) and 0.5% (1/22). These results suggest that response to treatment is partially linked to the baseline mUFC. 7      A post-hoc analysis was performed in order to identify predictive factors for failure to respond to treatment. Of the whole study (n=162), 91.7% of the patients who were not controlled at both months 1 and 2 (66/72) remained uncontrolled at 6 months and 88.9% (64/72) remained uncontrolled at 12 months. These results suggest that patients who are not controlled during the first 2 months will remain so at 6 and 12 months. The SPC recommends that practitioners should consider stopping the treatment if there is no response to SIGNIFOR after 2 months.   3.1.2 Study B2208 and its extension phase (study B2208E1)    Study B2208 - The primary objective of study B2208 was to evaluate the efficacy and safety of subcutaneous pasireotide at a dose of 600 µg x2/d for 15 days in Cushing's Disease. The patients who were included were adults suffering from de novo, persistent or recurring CD with mUFC > 2xULN. Patients who were candidates for surgery could be included.   The primary efficacy endpoint was return of urinary free cortisol to normal values from an average taken from two collections on D14 and D15. If poorly tolerated, the dose of SIGNIFOR could be reduced by 150 µg x2/d.   A total of 39 patients were recruited, 38 of whom completed the study. Twenty-nine of these were included in the analysis for the primary endpoint. At the end of this short study the mUFC had returned to normal in 5/29 patients (17.2%). The other results of this study suggest a fall in mean ACTH and plasma cortisol concentrations on D15 which was greater in patients whose mUFC had returned to normal.    Study B2208E1 - Patients who obtained benefit during study B2208 (return of mUFC to normal or clinical benefit in the opinion of the investigator) were offered an extension phase. Patients who were included and who had a normal mUFC at the end of the first phase could continue to be given 600 µg x2/d. This dose could be increased to 900 µg x2/d in the other patients or reduced by 150 µg x2/d if poorly tolerated.  

                                             7 At inclusion 47.6% (39/82) patients in the 600 µg x2/d group had a mUFC of > 5xULN compared to 27.5% (22/80) in the 900 µg x2/d group.  

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The primary efficacy endpoint was the percentage of responders defined as the proportion of patients whose mUFC had returned to normal at 6 months. Nineteen of the 38 patients who completed the initial phase were included in this extension phase. Mean exposure time to treatment was 16 months, 7 patients were treated for more than 12 months and 4 for more than 24 months. Efficacy could be assessed in 18 patients. 22% of patients had responded at 6 months (4/18). In the 8 non-responders, mUFC increased in 2 patients and 6 patients stopped the treatment before the 6th month. Response was maintained in 1 patient at 6 months of the 3 responders in the initial study included in the extension phase.   In view of the methodology of these studies (open, small numbers) they contribute little.   3.2. Adverse effects   3.2.1 Data from clinical studies B2305, B2208 and B2208E1   A total of 201 patients received at least one dose of SIGNIFOR in the phase II or III clinical studies in Cushing's Disease: 162 patients in the pivot study B2305 and 39 patients in the phase II study BB2208 and its extension B2208E1. In view of the different methodologies the safety results from these studies are presented separately.     3.2.1.1 Phase III study B2305 Mean length of exposure to SIGNIFOR was 10.77 months. Approximately 66% of patients (110/162) were exposed for at least 6 months and 39% (63/162) for at least 12 months. Treatment drop-outs due to adverse events (AE) involved 17.3% (28/162) of patients: 15.9% (13/82) of patients in the 600 µg x2/d group and 18.8% (15/80) of patients in the 900 µg x2/d group. The most common AEs leading to treatment being stopped were problems with glucose metabolism (hyperglycaemia and diabetes) and liver disorders.   98.1% (159/162) of patients experienced AEs during the study: 80/82 (97.6%) of patients in the 600 µg x2/d group and 79/80 (98.8%) of patients in the 900 µg x2/d group. At least one of the AEs was attributable to SIGNIFOR in the great majority of patients (95.7%). 47.6% (39/82) of patients developed AEs of grade≥in the 600 µg x2/d group and 50.0%3 (40/80) of patients in the 900 µg x2/d group. The most common related to hyperglycaemia.   The most common AE attributed to treatment were gastrointestinal problems, metabolism and nutrition disorders and cholelithiasis . The following occurred at an incidence of > 15%: - diarrhoea (54.9%) - nausea (46.9%) - hyperglycaemia (38.9%)cholelithiasis (29.6%) - pain (20.4%)diabetes mellitus (17.9%) abdominal The incidence of these effects was similar in the two treatment groups.  

 

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Adverse events of particular interest:  Events due to hyperglycaemia The commonest AEs are related to hyperglycaemia. These were reported in 118 patients (72.8%) (cf. table 5). Most of these AEs (70.4%) were deemed to be related to pasireotide. Ten patients stopped treatment because of these AEs (6.2%).   Table 5: population, N=162) (ITT– Incidence of AEs due to hyperglycaemiaStudy B2305  AE AE, grades 3 or 4 AE related to n (%) n (%) treatment n (%) AE relating to hyperglycaemia   118 (72.8) (24.7) 40 (70.4) 114

65 (40.1) 29 (17.9) 18 (11.1) 15 (9.3) 15 (9.3) 9 (5.6) 5 (3.1) 4 (2.5) 1 (0.6)

Hyperglycaemia 21 (12.9) 63 (38.9) Diabetes 12 (7.4) 29 (17.9) Rise in HbA1c 1 (0.6) 17 (10.5) Type 2 diabetes 7 (4.3) 15 (9.3) Hypoglycaemia* 3 (1.9) 6 (3.7) Raised blood glucose  0 9 (5.6) Reduced blood insulin* 0 5 (3.1) Reduced glucose tolerance 0 4 (2.5) Glycosuria 0 0 HbA1c: Glycated haemoglobin *12 of the 15 patients who developed a hypoglycaemic AE and 4 of the 5 patients who developed an AE involving a fall in blood insulin concentrations also developed at least one AE in the hyperglycaemia category.    Grade 3 or 4 events were reported by 24.7% (40/162) of patients. Thirty-eight patients had grade 3 AE, 21 of whom had a past history of diabetes or were pre-diabetic. The 2 patients who developed a grade 4 AE had reduced diabetes tolerance at the start of the study. The most commonly reported laboratory abnormalities were raised blood glucose. HbA1c and fasting blood glucose levels increased from the 1st month of treatment with SIGNIFOR and then stabilised with the introduction of a blood glucose lowering agent. 8 The available data suggest that patients who are diabetic 9 at inclusion (n=42) reported a greater increase in their fasting blood glucose and HbA1c than patients who were not diabetic 10 at inclusion (n=120). A blood glucose lowering agent was started in 45.7% of patients (74/162) during the study. At least one hypoglycaemic medicine was started in 41% (53/129) of patients who were not taking one at inclusion. 64% (21/33) of patients who were already receiving hypoglycaemic treatment at inclusion were given at least one additional blood glucose lowering agent. The overall proportion of patients being treated with insulin increased by factors of 3 to 5 during the study. Less than 5% of patients were being treated with insulin before randomisation. Warnings and guidelines about starting and monitoring treatment are described in the SPC.   Lengthening of the QT and sinus bradycardia Lengthening of the QT interval was seen in 8.0% (13/162) of patients during the study and was deemed to be related to treatment in 3.7% of patients. The QTc increased to over 500 ms in two patients leading to the treatment being stopped in one of these. Bradycardia was reported in 14.2% of patients (23/162). Warnings and guidelines about starting and monitoring treatment are described in the SPC.        

                                             8 The SPC states that fasting blood glucose concentrations and HbA1c generally fell in the 28 days after pasireotide was stopped but remained above baseline values. diabetic treatment at inclusion. 1 9 0 thwin  aitinl iaP  i e a i i t t a H  s l t   n eva  nni shw oah Patient c HbA1≥ ton cer ohw era c A17%< b g inecvi eer ora rhwnd/o7% a  iviea gnd ynebaic tieatrentmatt i cnulisno .  10/15  

Liver safety Liver profile abnormalities were reported in 16% of patients, mostly grade 1 or 2, and usually involving raisedΧGT (10.5% of patients, 17/162) and ALT (10.5% of patients, 17/162). No patients had simultaneous rises in AST and ALT > 3 x ULN and bilirubin≥2 x ULN. The treatment was stopped in 6 patients because of these AEs (mostly a rise inΧGT) The SPC states that SIGNIFOR is contraindicated in severe hepatic impairment (Child Pugh C).   Serious AEs and deaths Serious AEs occurred in 23.2% of patients (19/82) in the 600 µg x2/d group and 26.3% (21/80) in the 900 µg x2/d group. The most common were related to the Cushing's Disease and were reported by 3.7% (6/162) of patients overall, together with hyperglycaemia, diabetes or gallstones. No deaths were attributable to treatment.   3.2.1.2 Phase II study B2208 and its extension phase B2208E1 The average length of exposure was 14.8 days in study B2208. Average length of exposure was 16 months in study B2208E1 and at least 6 months in 63% of patients. The commonest AEs during these studies were gastrointestinal problems (diarrhoea, nausea) and hyperglycaemia. The incidence of "hyperglycaemia" AEs was 35.9% in study B2208, similar to what was seen in the pivot study B2305. No cases of QTcF > 480 ms were reported in these studies. Two cases of gallstones were reported in study B2208E1. Two patients left these studies because of an AE relating to glucose metabolism.   3.2.2 Risk management plan (RMP)   The risk management plan for SIGNIFOR stipulates monitoring for the following risks: - significant identified risks: hypocortisolism, hyperglycaemia, bradycardia, lengthening of the QTc, gallstones, haematological abnormalities, increased liver enzymes, injection site reactions, gastrointestinal problems. - significant risks: significant reduction in GH/IGF-1 hormones, hypothyroidism, potential pancreatitis, coagulation abnormalities, hypotension, hypocalcaemia, gastrointestinal bleeding, therapeutic interactions particularly related to CYP3A4, off-label use in children or in other indications, tumour progression, hypersensitivity reactions.   It also refers to significant missing data: long-term data, use in pregnant and breastfeeding women and in the elderly, in paediatrics and in patients suffering from liver or cardiac problems.   In order to obtain long-term efficacy and safety data on pasireotide in the treatment of Cushing's Disease, the RMP anticipates an observational study which is being set up (planned to start in 2014).   3.2.3 Data from TUA for named patients   Forty-three patients in France received SIGNIFOR for the treatment of Cushing's Disease between 13 July 2010 and July 2012 (end date of the TUA) as a TUA for named patients. A total of six pharmacovigilance cases were reported spontaneously in these TUA. Five serious adverse events were reported in which pasireotide was suspected to be involved: 3 cases of diabetes, one case of hepatosteatosis with gallstones and one case of gallstones.

 

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