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VYNDAQEL - VYNDAQEL - CT 11936 - English version

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Introduction VYNDAQEL 20 mg, soft capsules B/2x15 capsules in blister (PVC/alu) (CIP code: 218 245-9) Posted on Apr 11 2012 Active substance (DCI) tafamidis (as meglumine) Maladies rares - Nouveau médicament Progrès thérapeutique mineur dans la prise en charge d'une polyneuropathie symptomatique liée à une amylose à transthyrétine et compte tenu de l’absence d’alternative médicamenteuse VYNDAQEL a l’AMM dans le traitement de l’amylose à transthyrétine (TTR) chez les patients adultes ayant une polyneuropathie symptomatique de stade 1, pour retarder le déficit neurologique périphérique.L’efficacité du tafamidis pour ralentir l’évolution du déficit neurologique périphérique n’est documentée qu’à un stade précoce de la maladie et en cas de mutation V30M de la TTR. Son intérêt dans la prise en charge est modeste et reste à confirmer. Aucun effet sur les complications cardiaques n’a été établi.Le recul d’utilisation est limité pour évaluer le profil de tolérance à plus long terme, notamment le risque d’infection et d’atteinte hépatique.Pour en savoir plus télécharger la synthèse ou l'avis complet VYNDAQEL. ATC Code N07XX08 Laboratory / Manufacturer PFIZER FRANCE VYNDAQEL 20 mg, soft capsules B/2x15 capsules in blister (PVC/alu) (CIP code: 218 245-9) Posted on Apr 11 2012
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  The legally binding text is the original French version  TRANSPARENCY TTEEMOIMC  OPINION
 11 April 2012    VYNDAQEL 20 mg, soft capsules B/2x15 capsules in blister (PVC/alu) (CIP code: 218 245-9)   Applicant: PFIZER FRANCE  Tafamidis (as meglumine) ATC code: N07XX08  List I – Medicine for hospital prescription only – Prescription restricted to neurology specialists.   Date of European Marketing Authorisation: 16 November 2011 (Centralised registration procedure, CHMP opinion of 21 July 2011)  Orphan medicinal product (28 August 2006)  Conditions for granting the Marketing Authorisation: The Marketing Authorisation states that VYNDAQEL was granted authorisation under “exceptional circumstances”. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information that may become available every year and this SmPC will be updated as necessary.  In France, tafamidis has been available under the system of TUAs for named patients since December 2009. A Cohort TUA was granted by AFSSAPS on 1 August 2011 “in the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to slow the progression of the neurologic impairment”.   Reason for request: Inclusion on the list of medicines refundable by National Health Insurance and approved for use by hospitals.     Medical, Economic and Public Health Assessment Division    1/19
1.
CHARACTERISTICS OF THE MEDICINAL PRODUCT
  1.1. Active ingredient  Tafamidis (as meglumine)   1.2. Background  
Tafamidis (VYNDAQEL) is the first medicinal product indicated in the treatment of transthyretin amyloidosis1(TTR) or transthyretin familial amyloid polyneuropathy (TTR-FAP). Its action relies on dissociation of the transthyretin tetramer to monomers, thus preventing the formation of amyloid deposits.   1.3. Indication  
“VYNDAQEL is indicated for the treatment of transthyretin amyloidosis (TTR) in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment.”   1.4. Dosage  
“Treatment should be initiated by and remain under the supervision of a physician knowledgeable in the management of patients with transthyretin amyloid polyneuropathy. The recommended dosage is 20 mg administered orally once daily. VYNDAQEL should be added to the standard of care for the treatment of the transthyretin familial amyloid polyneuropathy (TTR-FAP) patient. Physicians should monitor patients and continue to assess the need for other therapies, including the need for liver transplantation. As there are no data available regarding the use of VYNDAQEL post-liver transplantation, VYNDAQEL should be discontinued in patients who undergo liver transplantation.  Special populations/situations: Paediatric population There is no relevant use of tafamidis in the paediatric population. The EMA has waived the obligation to submit the results of studies in all the paediatric population sub-classes affected by hereditary familial amyloid polyneuropathy.  Elderly Data in elderly patients are very limited. No dosage adjustment is necessary for elderly patients (65 years).  Renal or hepatic impairment No dosage adjustment is required for patients with renal or mild to moderate hepatic impairment. Use of tafamidis has not been studied in patients with severe hepatic impairment. Caution in these patients is therefore recommended.
                                            1retinol (vitamin A). It is synthesised inTransthyretin is a protein that provides for the transportation of plasma thyroxin (T4) and the liver, choroid plexus and also the retina and pituitary gland. It is made up of four identical monomers (peptides of 127 amino acids). It exists in the body mainly as a tetramer.  2/19
Pregnancy There are no data on the use of VYNDAQEL in pregnant women. Studies in animals have shown reproductive toxicity. VYNDAQEL is not recommended during pregnancy and in women of childbearing potential not using contraception.  Breastfeeding Available pharmacodynamic and toxicological data show that tafamidis is excreted in milk. A risk to newborns/infants cannot be excluded. VYNDAQEL should not be used during breastfeeding.  Method of administration: The capsule should be swallowed whole, not crushed or cut, and taken with or without food. If vomiting occurs shortly after dosing, and the VYNDAQEL capsule is identified, then an additional dose of VYNDAQEL should be administered if possible. If no capsule is identified, then no additional dose is necessary, with resumption of VYNDAQEL dosing the next day as usual.”    
2.
SIMILAR MEDICINAL PRODUCTS
  2.1. ATC Classification (2012)  N Nervous system N07 Other nervous system drugs N07X Other nervous system drugs N07XX Other nervous system drugs N07XX08 Tafamidis  
 2.2. Medicines in the same therapeutic category  None.   2.3. Medicines with a similar therapeutic aim  None.     
 
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3.
ANALYSIS OF AVAILABLE DATA
  The assessment of tafamidis (VYNDAQEL) in the treatment of transthyretin amyloidosis in adults is based on the results of a phase II/III (Fx-0052 study) comparison study pivotal versus placebo and its open-label non-comparison extension phase (study Fx-006). Most of the included patients had stage 1 symptomatic polyneuropathy (98% of the patients) with the V30M mutation.3 A second, non-comparative, phase II, pharmacodynamic study evaluated the effect of tafamidis on transthyretin stabilisation in patients with a different genetic defect (study Fx1A-201). In view of the objective of this study, only the tolerance data are given. It is important to note that carrying out sufficiently powerful clinical studies in these patients is complicated by the very low prevalence of the disease and its heterogeneous nature, coupled with the lack of any standardised clinical criteria or validated specific neurological scores with which to evaluate the course of the disease.  
 3.1. Efficacy data  Fx-005 pivotal study The primary objectives of this study were to evaluate the effect of tafamidis (VYNDAQEL) on the progression of the disease after 18 months of treatment in TTR familial amyloid polyneuropathy patients with the V30M mutation. The secondary endpoints were the study of the effect of tafamidis on the stabilisation (pharmacodynamics) of transthyretin and its pharmacokinetics.  Study design: Randomised, double-blind, comparative superiority study in 2 parallel groups: tafamidis and placebo (1:1 randomisation).  Inclusion criteria: Patients aged at least 18 years with a diagnosis of amyloidosis documented by a biopsy, a documented V30M transthyretin mutation and peripheral or autonomic neuropathy with a Karnofsky performance index4,5of at least 50.
 Among the non-inclusion criteria: - Be taking a nonsteroidal anti-inflammatory (NSAID) more than 3 or 4 times a month. Only NSAIDS without any TTR tetramer stabilisation activity were permitted during the study. - Liver transplantation among the antecedents. - Heart failure of NYHA (New York Heart Association) Class3. - Severe renal impairment (with a creatinine clearance < 30 ml/min). - Active liver disease (ALT and/or AST higher than twice the upper normal limit). - Other aetiologies capable of explaining a sensorimotor neuropathy (vitamin B12 deficiency, diabetes, HIV treated with antiretrovirals, dysthyroidism, alcohol dependency, chronic inflammatory disease). - Lack of measurable sensory perception of vibration in both feet based on “quantitative” sensory testing for pain (QST).                                             2Study not published at the time of the opinion. 3 The V30M mutation is the most commonly observed. V30M amyloid neuropathy differs from non-V30M neuropathy in its clinical presentation and in its response to treatment. 4Karnofsky D. The clinical evaluation of chemotherapeutic agents in cancer. Columbia University Press, New-York 1949 :191-205. 5Karnofsky index measures a person’s capacity to perform everyday activities. It also allows patients’ progress to be  The assessed following a therapeutic trial. Maximum value 100%: no anomalies found.  4/19
Treatments studied: Tafamidis 20 mg/day in a single daily dose or a placebo with a proposed treatment duration of 18 months.  Primary efficacy endpoints:  - Responder rate as defined by an increase in the Neuropathy Impairment Score in the Lower Limbs (NIS-LL) of at least 2 points between inclusion and 18 months. And, - Change in the quality of life between inclusion and 18 months as measured by the Norfolk Quality of Life Questionnaire – Diabetic Neuropathy (QOL-DN).  Among the secondary endpoints: - Treatment response as measured by the NIS-LL score at 6 and 12 months. - Variation in the NIS-LL score and its sub-scales between inclusion and months 6, 12 and 18. - Variation in the quality of life according to the total Norfolk score between inclusion and months 6 and 12. The changes in the electrophysiological function of the large and small nerve fibres6 and in nutritional status7between the start and end of the study were also evaluated.  Method and strategy for the analysis of results: A statistically significant difference for the two primary efficacy endpoints was required to demonstrate the superiority of tafamidis compared with placebo. To establish the superiority of tafamidis with respect to placebo, the calculation of the number of subjects needed is based on the following elements:  Inter-group comparison of NIS-LL scores: on the basis of a 20% expected response rate -under placebo and 50% under tafamidis, a bilateral riskα0,05 and a power of 90%,  = 58 patients/arm should be included. - Comparison between the two groups as regards quality of life according to the Norfolk Test: the inclusion of 58 patients per arm would allow a power of 90% to be reached in order to detect an actual difference of 0.6 SD8between the two arms with a bilateral risk α= 0.05. The lost-to-follow-up rate having been estimated at between 5 and 10%, the sample size necessary for this study was 61 to 64 patients/arm.  Three analysis populations were established: - Modified Intention to Treat population (“mITT”): randomised patients who have been treated with at least one dose of the study treatment (VYNDAQEL or placebo) and who have undergone at least one post-inclusion assessment of the NIS-LL and QOL-DN scores, or who have discontinued the study due to a liver transplant or death. - “Efficacy evaluable” population: patients who have had their NIS-LL and QOL-DN scores evaluated at 18 months and who have received at least 80% of the planned doses of the study treatment and who have not committed any major protocol violation that could have an impact on the efficacy assessment. - Tolerance population: randomised patients who have been treated with at least one dose of the study treatment (VYNDAQEL or placebo).  
                                            6function of the large nerve fibres (nerve conduction, vibration threshold and variation in the heart rate during deepThe breathing) and the small nerve fibres (temperature and pain and variation in the heart rate during deep breathing) were evaluated by composite scores. 7is calculated by multiplying the BMI byNutritional status was evaluated with the aid of an adjusted Body Mass Index (BMI). It the serum albumin concentration (in g/l) to correct a possible oedema. 8SD: standard deviation estimated by ANCOVA. ANCOVA is a statistical technique that combines analysis of variance ANOVA (compares the means of more than two groups) and analyses regression (compares the means of more than two groups taking covariables into account).  5/19
The results were analysed in the modified intention-to-treat population (mITT) by the LOCF method9For the analysis of the responder(in order to impute the missing data at 18 months). level based on the NIS-LL score, patients who discontinued the treatment due to liver transplantation or death were regarded as “non-responders”. Additional (pre-specified) analyses of the primary efficacy endpoints were performed, including not regarding liver transplantation as a treatment failure. Indeed, by eliminating the main source of production of amyloidogenic protein, liver transplantation helps slow the systemic – including neurological, cardiac and renal – progression of the disease. A sensitivity analysis of the NIS-LL score was performed to estimate the progression of patients if they had not undergone transplantation.  Results This study took place between 16 January 2007 and 26 May 2009 in Europe (Germany, Spain, France, United Kingdom, Sweden and Portugal), in South America (Argentina, Brazil) and in the United States. A total of 128 patients were randomised: 65 in the tafamidis group and 63 in the placebo group.  Table 1: Distribution of patient numbers according to the analysis populations   tafamidis placebo Tolerance population: 65 (100) 63 (100) mITT population 64 (98.5) 61 (96.8) “Efficacy evaluable” population 45 (69.2) 42 (66.7)  The difference between the “efficacy evaluable” andmITT populations can be explained essentially by the departure from the study of patients who had had a liver transplant (see Appendix 1: Flow diagram of the patients in Study Fx-005).  Population characteristics The demographic characteristics (median and mean values) of the patients in the tafamidis and placebo groups were similar. As regards the characteristics of the disease on inclusion: - The mean duration of the symptoms was 28 months in the VYNDAQEL group and 21 months in the placebo group. - The median of the NIS-LL scores was 4 in the tafamidis group and 6 in the placebo group. - The median of quality of life scores was 19 in the tafamidis group and 22 in the placebo group.
                                            9 an LOCF analysis (Last Observation Carried Forward), the last observation of each participant is regarded as the result, In even if the time point of this observation does not coincide with the time point scheduled for the measurement.  6/19
Table 2: Patient characteristics on inclusion in Study Fx-005 (mean values)  tafamidis placebo      n = 61n = 64 Age (years)    
Mean (SD) Interval Age group, n(%) 65 years > 65 years Sex, n(%) Women BMI modified at the eligibility phase Mean (SD) Interval NIS-LL score on inclusion (0 to 88) Mean (SD)
39.8 (12.7) 25; 74   59 (92.2) 5 (7.8)   32 (50)   1004.6 (165.2) 655.1; 1510.4   8.4 (11.4) 0; 54
38.4 (12.9) 22; 71   58 (95.1) 3 (4.9)   35 (57.4)   1011.5 (212.9) 533.3; 1581.5   
p
  
0.339
  
0.510
  0.410   
0.739
  
11.04;  (5173 .5) 0089 . Interval QOL-DN score on inclusion (-2 to 138)      IMnteearnv a(lS D) 27-.13;  (12140. 2) 30.08;  (12067. 7) 0.401 Symptom duration (months)      Mean (SD) 47.0 (48.4) 34.7 (323. 9) 0.319 Interval 3; 268 2; 13  The majority of the patients (97.6%) had disorders of the nervous system with antecedents of neuropathy, both peripheral and autonomic (73.4% in the tafamidis group vs. 82% in the placebo group. Around 20% of the patients only had peripheral neuropathy and a minority (3.1% in the tafamidis group and none in the placebo group), and there was only one case of autonomic neuropathy. Among other complaints, 70.4% had gastrointestinal disorders, 34.4% musculoskeletal and systemic disorders; 33.6% had kidney and urinary tract problems, 28.8% metabolism and nutrition disorders. The medical antecedents of the study patients were similar between the treatment groups and are what patients with TTR-FAP generally have.  Primary efficacy endpoints:  NIS-LL score: In the mITT population, the level of patients “responding to treatment” at 18 months showed no difference between the two groups: 45% in the tafamidis group versus 29.5% in the placebo group, p = 0.0682. In the “efficacy evaluable" population, it was higher in the tafamidis group (60%) than in the placebo group (38.1%), p = 0.041.  Secondary analyses (mITT population): Study patients were eligible to receive a liver transplant as soon as possible. Liver transplantation was therefore not a rescue treatment in the event of failure: to consider it a treatment failure is a “conservative” statistical approach. A sensitivity analysis estimated the progression of patients if they had not undergone transplantation: according to this analysis, these patients appeared to have a higher treatment response rate at 18 months (54.7%) than those in the placebo group (36.1%), p = 0.0367.    
 
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Quality of life measured by the Norfolk test (QOL-DN score) In the mITT population, the quality of life measured by the variation in the QOL-DN score at 18 months did not differ between the two groups (2.0 in the tafamidis group versus 7.2 in the placebo group). In the “efficacy evaluable" population, the quality of life showed less deterioration in the tafamidis group (0.1) than in the placebo group (8.9), p = 0.045.  Table 3: Results for the two primary efficacy endpoints (Responders to the NIS-LL score and modification of the TQOL score), according to the Vyndaqel SmPC  Vyndaqel versus Placebo: NIS-LL and TQOL at Month 18 (Study Fx-005) Pla da e   l qcebo Vyn Pre-specified ITT Analysis n = 61 n = 64  NIS-LL Responders (% Patients) 29.5% 45.3%  Difference (Vyndaqel minus 15.8% Placebo) 95% CI of Difference (p-value) -0.9%, 32.5% (0.068) TQOL Change from Baseline LS Mean 7.2 (2.36) 2.0 (2.31) (SE) Difference in LS Means (SE) -5.2 (3.31) 95% CI of Difference (p-value) -11.8, 1.3 (0.116) Pre-specified Efficacy Evaluable Analysis n = 42 n = 45 NIS-LL Responders (% Patients) 38.1% 60.0% Difference (Vyndaqel minus 21.9% Placebo 95% CI of Difference p-value 1.4%, 42.4% (0.041) TQOL Change from Baseline LS 8.9 (3.08) 0.1 (2.98) Mean (SE) Difference in LS -8.8 (4.32) Means (SE) 95% CI of Difference -17.4, -0.2 (0.045) In the pre-specified ITT NIS-LL Responder analysis, patients who discontinued prior to the 18-month time point due to liver transplantation were categorised as non-responders. The pre-specified Efficacy Evaluable analysis used observed data for those patients who completed the 18 month treatment per protocol.   Secondary endpoints:  The pharmacodynamic results (electrophysiological in nature) are not reported in this opinion. The results for the principal secondary endpoints are presented in Table 4.  Table 4. Results for the principal secondary endpoints  mITT population  Tafamidis Placebo n 64 n = 61 = Percentage of responders measured by the M6: 60.9% M6: 54.1% NIS-LL scores at different times M12: 57.4% M12: 32.8% M18: 45.3% M18: 29.5% Mean variations in the NIS-LL score in M6: 1.26 M6: 2.08 relation to different inclusion time points M12: 1.35 M12: 4.72 M18: 2.81 M18: 5.83 Mean variations in the scores of the sub- Muscle power: 0.8 Muscle power: 3.4 scales of the NIS-LL score in comparison Sensations: 1.3 Sensations: 1.6 with inclusion at M18 Reflexes: 0.5 Reflexes: 0.8   Mean variations in the TQOL score in M6: 1.2 M6: 0.2 relation to different inclusion time points M12: 1.5 M12: 4.5 M18: 2.7 M18: 7.8 Mean variations in the modified BMI in M6: +17.1 M6: -30.5 relation to different inclusion time points M12: +19.4 M12: -30.7 M18: +39.3 M18: -33.8
 
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- Percentages of responders: analysis of treatment response according to the NIS-LL score over time suggests that patients in the tafamidis group experienced a more pronounced slowing down in the progression of the disease between inclusion and Month 6 as well as between inclusion and Month 12, compared with the patients in the placebo group, but this difference was only statistically significant at 12 months. - Mean variations in the NIS-LL score: exacerbation of the neuropathy measured by a relative increase in the NIS-LL score at Month 12 and Month 18 by comparison with the score on inclusion was less marked in the tafamidis group than in the placebo group. - Variations in the sub-scales of the NIS-LL score between inclusion and Month 18: Muscle power was better preserved in patients treated with tafamidis than in those receiving placebo. Loss of reflex activity and sensitivity was similar in both groups. - From Month 6, the modified BMI of patients in the tafamidis group rose, while that of patients in the placebo group fell.  Analyses in sub-groups planned fora priori: - The sub-group analyses of the primary efficacy endpoints (NIS-LL and QOL-DN) at Month 18 according to age (</65 years), the age at which the symptoms started (</50 years) and sex showed a similarity in terms of clinical efficacy among the various groups tested. - The results of a further analysis suggest that patients in the tafamidis group progressed better than those in the placebo group, regardless of whether their status showed them to be responders or non-responders; the NIS-LL, quality of life, and modified BMI scores of non-responder” patients in the tafamidis group fared better than those of patients who received a placebo.   Open extension study Fx-006 Eighty-six (86) of the 91 patients who completed the 18 months of treatment in Study Fx-005 went on to receive 20 mg/day of tafamidis for an additional 12 months. It should be noted that for some patients there was a break in the administration of tafamidis (patients included in South America and Portugal). Patients who had had a liver transplant or suffered liver damage (especially if the AST and/or ALT values were higher than twice the normal value) and those receiving an NSAID at least 3 to 4 times a month, were not involved in this extension phase.  Table 5: Number of patients according to the analysis population – open Study Fx-006 Tafamidis Placebo Total patients
n = 45 n = 41 n = 86   n(%) n(%) n(%)  Tolerance* 44 (97.8) 41 (100) 85 (98.8) ITT 38 (84.4) 33 (80.5) 71 (82.6) Efficacy evaluable 30 (66.7) 30 (73.2) 60 (69.8) Treatment discontinuations: 6 (13.3) 8 (19.5) 14 (16.3) * One patient was included but did not receive any treatment due to having a liver transplant. This patient was therefore not included in any of the study analyses   Efficacy results The primary objective was to gather data relating to the adverse effects of tafamidis. In view of the low prevalence of the disease, the efficacy results from the extension phase are presented simply for information (see Appendix 2).
 
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These data suggest that the effect of tafamidis lasts for up to 12 additional months of treatment. In addition, the percentage change in the NIS-LL score during the 12 months of treatment was similar to that observed in the patients who were randomised and treated with tafamidis during the previous 18-month period in double-blind mode.  3.2. Adverse effects  3.2.1. Data from the clinical studies The tolerance data were obtained from clinical trials that had evaluated the efficacy of tafamidis, including studies Fx-005, Fx-006 and Fx1A-201. In the comparative study (Fx-005), 65 patients were exposed to tafamidis and 63 to a placebo. At the end of 18 months of treatment and as part of the extension phase (Fx-006), 44 patients continued their treatment with tafamidis and 41 patients from the placebo group received tafamidis for the first time. In Study Fx1A-201, 21 new patients with a mutation other than the V30M mutation were exposed to tafamidis. In total, 127 patients received at least one dose of tafamidis, with an exposure of 175 patient-years.  Study Fx-005 (pivotal study) The mean exposure to treatment was similar in the tafamidis group and in the placebo group (15.5 months). The number of patients who had had at least one adverse event was 60/65 (92.3%) in the tafamidis group and 61/63 (96.8%) in the placebo group. Six (9.2%) patients in the tafamidis group and 9 (14.3%) patients in the placebo group had had a “severe" event. Treatment was discontinued due to an adverse event in 4/65 patients who had been receiving tafamidis and 3/63 patients receiving the placebo. The adverse events were regarded as treatment-related in 39 (60.0%) patients in the tafamidis group and 43 (68.3%) patients in the placebo group. The most commonly observed adverse events were urinary infections (10.8%) of the patients in the tafamidis versus vs. none in the placebo group), pains in the extremities (7.7% vs. 4.8%), headache (7.7% vs. 15.9%), diarrhoea (9.2% vs. 11.1%), abdominal pains (7.7% vs. 3.2%), nausea (6.2% vs. 9.5%), vomiting (4.6% vs. 7.9%) and constipation (1.5% vs. 6.3%). Of the adverse events, vaginal infections were more common in the tafamidis group (18.2%) than in the placebo group (8.1%), although the investigators were unable to identify these events as being treatment-related. An increase in liver enzymes (gamma-GT, ALT and/or AST) greater than 3 times the typical normal values was observed in 2 patients in the tafamidis group and one patient in the placebo group.  Study Fx-006 (extension study) The total mean exposure (FX-005 and Fx-006) to the treatment was around 31.0 months in patients in the tafamidis-tafamidis (TT) group and 12.0 months in the placebo-tafamidis group (PT). Adverse events were most commonly observed in patients who had not received tafamidis during the pivotal study: 37/44 patients (84.1%) in the TT group and 40/41 patients (97.6%) in the PT group. A case of nasopharyngitis was the only event reported more frequently in the TT group than in the PT group (11.4% vs. 7.3%). Six patients in the TT group and 4 patients in the PT group had an event of “severe” ni tensity. No treatment discontinuations due to an adverse event was observed in this study. The adverse events were regarded as treatment-related in 14 (31.8%) patients in the TT group and 18 (43.9%) patients in the PT group. Six patients had an increase in their gamma-GT levels to 3 times the normal value.  
 
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Study Fx1A-201 (study in patients with a non-V30M mutation) The mean exposure to treatment was 11.2 months. Seventeen of the 21 (81%) patients reported a total of 137 adverse events, the most common being: a fall (5/21), diarrhoea (5/21), pains in the extremities (4/21), dizzy spells, dyspnoea, vomiting and constipation (3/21 for each). Most of the events were of mild to moderate severity. Of the 21 patients, 8 (38%) presented an adverse event considered to be at least potentially treatment-related: diarrhoea, vomiting, neuralgia and paraesthesia (each event reported twice). The large number of falls reported in the study was considered to probably be connected with the patients’ considerable age (a median of 64.3 years).  According to the SPC “On the basis of the clinical data from the exposure of 127 TTR amyloid polyneuropathy patients treated with 20 mg of tafamidis once daily for an average of 538 days (ranging from 15 to 994 days), the very common (1/10) and common (1/10) adverse effects were: Infections: very common: urinary tract infections, common: vaginal infection Gastrointestinal disorders: very common: diarrhoea, common: upper abdominal pains.”   3.2.2. Data from TUAs
VYNDAQEL was the subject of a Cohort TUA started in September 2011 in the marketing authorisation indication. TUAs have been granted for named patients too, as well as in the treatment of stage 2 transthyretin amyloid polyneuropathy. Currently there are 43 patients being treated in the marketing authorisation indication and 16 in stage 2 polyneuropathies. The efficacy and tolerance data are currently under analysis.   3.3. Other information  Risk management plan The VYNDAQEL marketing authorisation is conditional upon a risk management plan designed to monitor and minimise three types of risk: major risks: urinary tract infections, diarrhoea, upper abdominal pains,Identified  vaginal infections.  Potential major risks: hepatotoxicity10, hypersensitivity reactions, reproduction toxicity, modification of thyroid function, especially in pregnant women.  Important missing data: tolerance and efficacy in elderly subjects, long-term tolerance.  
                                            10 Tafamidis was observed to be hepatotoxic in 3 animal species during preclinical studies. Elevated enzyme levels were reported in patients treated with tafamidis in the course of clinical trials.  11/19