REVATIO - REVATIO - CT 11431 & 12241 - English version

REVATIO - REVATIO - CT 11431 & 12241 - English version

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Introduction REVATIO 20 mg, film-coated tablet B/90 (CIP code: 370 240-6) REVATIO 10 mg/ml, powder for oral suspension 1 bottle (CIP code: 222 776-5) Posted on Mar 19 2013 Active substance (DCI) sildenafil Pas d’avantage clinique démontré dans l’hypertension artérielle pulmonaire chez l'enfant Les spécialités REVATIO en comprimé et en suspension buvable ont l’AMM dans le traitement de l’HTAP idiopathique associée à une cardiopathie congénitale chez les enfants de 1 à 17 ans.L’efficacité du sildénafil chez l’enfant est mal établie. Les données disponibles ne font que suggérer que la survie à 3 ans est plus élevée avec le sildénafil que celle observée avec l’époprosténol (utilisé hors AMM).Le profil de tolérance observé chez l’enfant semble proche de celui de l’adulte.Les doses prescrites ne doivent pas dépasser celles précisées dans le RCP, car des doses élevées ont été associées à une mortalité accrue chez l’enfant. Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous. ATC Code G04BE03 Laboratory / Manufacturer PFIZER REVATIO 20 mg, film-coated tablet B/90 (CIP code: 370 240-6) REVATIO 10 mg/ml, powder for oral suspension 1 bottle (CIP code: 222 776-5) Posted on Mar 19 2013

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Published 06 June 2012
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  The legally binding text is the original French version  TRANSPARENCY COMMITTEE  OPINION
 6 June 2012    REVATIO 20 mg, film-coated tablet B/90 (CIP code: 370 240-6)  REVATIO 10 mg/ml, powder for oral suspension 1 bottle (CIP code: 222 776-5)   Applicant: PFIZER  sildenafil ATC code: G04BE03  List I Medicine for hospital prescription only, with prescription restricted to specialists and/or hospital departments specialising in respiratory medicine, cardiology or internal medicine.  Orphan medicinal product (date of designation: 12 December 2003 for sildenafil in the treatment of PAH)   Reason for request:   REVATIO 20 mg, film-coated tablet: · Inclusion on the list of medicines approved for hospital use in the following extension of indication: “Treatment of pulmonary arterial hypertension in children and adolescents aged from 1 year to 17 years”  Date of the initial Marketing Authorisation (centralised procedure): 28 October 2005 Amended on 2 May 2011 (obtained extension of indication)   · 10 mg/ml, powder for oral suspension: REVATIO Inclusion on the list for hospital use Date of Marketing Authorisation (centralised procedure): 21 March 2012     Medical, Economic and Public Health Assessment Division
  
 
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1 CHARACTERISTICS OF THE MEDICINAL PRODUCT   1.1. Active ingredient  sildenafil   1.2. Therapeutic indications (common to both proprietary medicinal products)  “Adults Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III1, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.  Paediatric population(extension of indication to the tablet form) Treatment of pulmonary arterial hypertension in children and adolescents aged from 1 year to 17 years old” Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease.”   1.3. Dosage (see SPC)  “Treatment should only be initiated and monitored by a doctor experienced in the treatment of pulmonary arterial hypertension. In case of clinical deterioration in spite of REVATIO treatment, alternative therapies should be considered.  Adults The recommended dose is 20 mg three times a day. Physicians should advise patients who forget to take REVATIO to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.  Paediatric population (1 year to 17 years) In children under the age of 1 year, the efficacy and safety of REVATIO have not been established. No data are available.  In children and adolescents aged from 1 year to 17 years, the recommended dose is: · weight body20 kg: 10 mg (1 ml of compounded suspension) three times a day · weight > 20 kg: 20 mg (2 ml of compounded suspension or 1 tablet) three times a body day. Higher than recommended doses should not be used in paediatric patients in the treatment of PAH (see also sections 4.4 and 5.1 of the SPC)[...].    
 1 The NYHA (New York Heart Association Functional Classification) is based on the patient’s functional capacity. Patients are broken down into 4 classes: - Class I: No limitation of physical activities. No dyspnoea and no fatigue during everyday activities - Class II: Moderate limitation of physical activities. Discomfort during strenuous physical activities. No discomfort at rest. - Class III: Marked limitation of physical activities. Discomfort during even moderate everyday activities. No discomfort at rest. - Class IV: Unable to undertake most everyday activities without considerable discomfort. Discomfort at rest.   2/19
Discontinuation of treatment Limited data suggest that the abrupt discontinuation of REVATIO is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, the dose should be reduced gradually. Intensified monitoring is recommended during the discontinuation period.  Method of administration REVATIO is for oral use only. Tablets should be taken approximately 6 to 8 hours apart with or without food. The compounded oral suspension should be shaken well for not less than 10 seconds before withdrawing the required dose from the bottle. The compounded oral suspension (a white, grape-flavoured oral suspension) should be taken approximately 6 to 8 hours apart with or without food. The compounded oral suspension should be shaken well for not less than 10 seconds before withdrawing the required dose from the bottle. For instructions on reconstituting the oral suspension before administration, see section 6.6 of the SPC.”   
  
 
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2 SIMILAR MEDICINAL PRODUCTS   2.1. ATC Classification (2012)  G: Genitourinary system and sex hormones G04: Urologicals G04B: Other urologicals, including antispasmodics G04BE: Drugs used in erectile dysfunction G04BE03: sildenafil   2.2. Medicines in the same therapeutic category  None  ADCIRCA 20 mg (tadalafil), film-coated tablet, another phosphodiesterase inhibitor indicated “in the treatment of pulmonary arterial hypertension (PAH) in patients classified as WHO functional class II and III, in order to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease” does not have a paediatric indication. Its SPC states that “the safety and efficacy of ADCIRCA in individuals below 18 years of age has not yet been established. No data are available.”   2.3. Medicines with a similar therapeutic aim  · of  Analoguesprostacyclin, FLOLAN (epoprostenol sodium) administered by I.V. infusion, VENTAVIS (iloprost) nebuliser solution, REMODULIN (treprostinil sodium) administered by continuous subcutaneous injection, are not recommended in patients under 18 years of age. The SPC for FLOLAN does state, however, that: “in the absence of sufficient data relating to the treatment of PAH in children, the Marketing Authorisation for epoprostenol advises the doctor to weigh up the expected benefits for the child against the risk incurred in the absence of this treatment. From the clinical studies available it is impossible to determine whether the efficacy and safety of the dosage regimen recommended in adults can be extrapolated to children and adolescents."   · regards endothelin receptor antagonists: As - VOLIBRIS 5 mg and 10 mg (ambrisentan), film-coated tablets, is not recommended in children under the age of 18 years. - The product TRACLEER (bosentan), indicated in the treatment of primary (idiopathic and heritable) PAH, PAH secondary to scleroderma without significant interstitial pulmonary disease, PAH associated with congenital left-right shunts and Eisenmenger’s physiology, in patients in WHO functional class II and III, has a 32 mg presentation in the form of dispersible tablets intended in particular for children (Opinion re-evaluating all treatments for PAH of 5 January 2011: moderate AB).   
  
 
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3 ANALYSIS OF AVAILABLE DATA   The paediatric clinical development of sildenafil in the treatment of PAH is based on four clinical trials: · A1481131 and its open-label extension phase (study A1481156), which evaluated the study efficacy and safety of sildenafil administered orally; ·which evaluated sildenafil by the intravenous route in paediatric patients A1481134,  study with PAH following heart surgery; · study A1481157, which evaluated sildenafil administered intravenously in newborns with persistent PAH. These last two studies will not be described because they evaluated a route of administration different from the one forming the subject of this application and which, moreover, is not recommended in children and adolescents with PAH. Besides, they were stopped prematurely on account of difficulties with recruitment.   3.1. Efficacy  3.1.1. Study A1481131  Aims and methods: 16-week, double-blind, randomised, phase III study to evaluate increasing doses of sildenafil versus placebo in patients aged from 1 to 17 years with primary PAH or PAH resulting from congenital heart disease or connective tissue disease. Randomisation was stratified by the patients’ weight and their ability (dependent on their level of physical development) to perform a Cardiopulmonary Exercise test.  Inclusion criteria: · aged from 1 to 17 years, weight Patients8 kg · defined  PAHaccording to the following criteria: mean pulmonary arterial pressure (mPAP)  mmHg at rest, pulmonary capillary pressure (PCP) 25 15 mmHg, pulmonary vascular resistance index3 Wood units/m2.(2) ·Clinically symptomatic PAH due to one of the following aetiologies:  o primary PAH o PAH due to a congenital shunt o PAH due to connective tissue disease.3  Principal non-inclusion criteria: · Pulmonary hypertension due to other diseases ·with endothelin-A receptor antagonists, prostacyclins or prostacyclin analogues  Treatment during the 30 days prior to randomisation · Currently ongoing treatment with parenteral inotropic agents · during the 3 months prior to inclusion with parenteral vasodilators, alpha-lockers Treatment or cytochrome P450 (CYP) 3A4 inhibitors.  Dosing regimen:  Actual doses administered were dependent on the patient's body weight in order to obtain steady-state target concentrations of sildenafil, determined on the basis of thein vitrodata for phosphodiesterase type 5 inhibition. The target concentrations were 47 ng/ml for low sildenafil doses, 140 ng/ml for medium doses and 373 ng/ml for high doses.   2 the pulmonary capillary pressure was not available, it was then necessary to have a left atrial pressure (LAP) If mm )15 mmHg in the absence of mitral stenosis. 3it wtsentipao  NgHo  r1  5entricula left-vtsaiciloe rad dn(Le DPVEre purssthe  in y.stud erew HAdedulcni tisthh  Pofe yp   5/19
Patients who weighed more than 20 kg were randomised 1:1:1:1 to receive three times a day:  sildenafil at a dose of 10 mg (small-dose group) either a dose of 10, 20 or 40 mg (medium-dose group) sildenafil at  or  or sildenafil at a dose of 20, 40 or 80 mg (high-dose group)  or a placebo. All the patients randomised into one of the sildenafil groups initially received 10 mg of sildenafil three times a day for one week.  In the case of patients weighing less than 20 kg, the randomisation was 1:1:2, either in the 4 placebo group, or in the medium-dose sildenafil group or in the high-dose sildenafil group.  Primary efficacy endpoint: The percentage variation in the peak volume of oxygen consumed VO2max (adjusted for body weight) between the initial value and the value measured in week 16.  The VO2evaluated with a Cardiopulmonary Exercise (CPX) test performed on an was  max ergometric bicycle in subjects capable of carrying out the test (patients over 7 years of age). Children unable to carry out this test were evaluated on the basis of secondary criteria.  The protocol envisaged a combined analysis of the three sildenafil dose groups versus placebo. It was not proposed to carry out a comparison between each of the three sildenafil treatment groups and placebo.  Main secondary endpoints: · Variation in week 16 compared to baseline in the mean Pulmonary Arterial Pressure (mPAP), Cardiac Index (CI) and the Pulmonary Vascular Resistance Index (PVRI) measured after right heart catheterisation · to VO time2max · Variation in the WHO functional class
 4 pharmacokinetic data (modelling of target plasma concentrations) suggest a similarity in these The patients between low and medium doses of sildenafil.    
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Results  Table 1: demographic characteristics of the included patients
  Sildenafil group Placebo Number of randomised Low Medium High 3 doses group patients (%) dose dose dose combined 42 56 77 175 60 ITT1 (100) 42 (99.4) 174 (100) 60 (98.2) 55 (100) 77 Age 1 - 4 years 0 9 (16.4) 19 (24.7) 28 (16.1) 7 (11.7) 5 - 12 years 25 (59.5) 28 (50.9) 36 (46.8) 89 (51.1) 37 (61.7) 13 - 17 years 17 (40.5) 18 (32.7) 22 (28.6) 57 (32.8) 16 (26.7) Mean weight 38.2 32.1 25.8 30.8 29.3 (interval) (20.0-105) (8.6-106.0) (8.2-61.0) (8.2-106.0) (9.1-60.0) Aetiology Primary PAH 12 (28.6) 19 (34.5) 26 (33.8) 57 (32.8) 21 (35.0) PAH following surgical repair 14 (33.3) 16 (29.1) 25 (32.5) 55 (31.6) 16 (26.7) PAH following congenital shunt 16 (38.1) 20 (36.4) 26 (33.8) 62 (35.6) 23 (38.3) WHO functional class n (%) I (37.0) 219 (22.5) 20 (29.4) 25 (27.6) 50 (41.7) II (52.9) 29 (48.3) (46.3) 43 (56.6) 9022 (55.0) 25 III (10.0) 29 (15.8) 6 (17.1) 89 (22.5) 12 (14.8) IV0 1 (1.9) 0 1 (0.6) 0 Age and ability to perform exercise test < 7 years 2 ( 4.8) 17 (30.9) 28 (36.4) 47 (27.0) 16 (26.7) 7 years incapable 12 (28.6) 10 (18.2) 20 42 (26.0) 14 (24.1) (23.3)  287 years capable 28 (66.7) 29 (50.9) (48.9) 30 (37.7) 85 (50.0) 1Randomised subjects having received at least 1 dose of treatment.  On inclusion, the PAH was primary in around 33% of the patients on sildenafil, 35% of the patients on placebo and secondary to a congenital heart disease in 67% of the patients on sildenafil and 65% of the patients on placebo. Twenty-seven percent (27%) of the patients included (63/234) were aged less than 7 years, i.e. 171 of the patients were aged 7 years or more. The majority of the patients were in functional class I (75/234, 32%) or II (119/234, 51%), few of the patients were in class III (35/234, 15%) or IV (1/234, 0.4%); in the case of 3/234 patients, the functional class was unknown.
  
 
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Table 2: Baseline values of the efficacy criteria   Sildenafil group Placebo  Low Medium High 3 doses group dose dose dose combined Numobremr  tohf ep eatxieernctiss ea btlees tto 24 26 27 77 29 perf mMle/kagn/ (mSinD) VO2 max 18.03 (4.36) 17.43 (4.70) 17.37 (3.80) (3.70) 17.61 (4.22) 20.02  Time to VO2 max 452.27 433.81 434.04 466.43(SD) 414.54  seconds (123.13) (141.88) (108.69) (124.44) (139.14) (TShDe)or%etical mean VO2 max43.15 (10.46) 51.16 (12.18) 44.91 (11.15) 46.07 (10.84) 45.32 (12.25)  mPAP (SD) mmHg 66.3 (22.2) 61.9 (18.1) 61.6 (23.9) 62.8 (21.7) 59.4 (21.6) MWeoaond  PunVitRsI/ (mS2 (12.0) 20.9 (13.8) 19.0 (15.2) 16.1 (16.6) 20.9 (19.0)D) 23.5 LM/emainn uCtea/rmdi2 3.44 (1.84) 4.08 (2.31)ac Index (SD) 2.95 (1.16) 3.40 (1.85) 3.73 (2.09) SD = standard deviation, PVRI = Pulmonary Vascular Resistance Index, mPAP = mean Pulmonary Arterial   Pressure  The starting mean VO2 maxwas comparable between the sildenafil treatment groups (17.37 to 18.03 ml/kg/min) and slightly higher in the placebo group (20.02 ml/kg/min).  Primary efficacy endpoint:  One hundred and fifteen patients were capable of performing the exercise test. Of these, 106 were included in the analysis.  Table 3: Variation in VO2max in week 16 – ITT population  
 Treatment group Sildenafil group Placebo Low Medium High 3 doses group dose dose dose combined Number of patients 24 26 27 77 29 mean VO2max (SD) ml/kg/min Starting level 17.37 (4.36) 18.03 (4.70) 17.43 (3.70) 17.61 (4.22) 20.02 (3.80) Week 16 18.40 (5.61) 20.39 (6.16) 19.00 (3.59) 19.28 (5.21) 20.01 (4.44) Variation/starting level % 6.44 (20.16) 13.40 (19.5) 10.58 (15.51) 10.24 (18.39) 0.53 (15.91)  NA Mean variation vs. 3.81 (5.0) 11.33 (4.84) 7.98 (4.85) 7.71 (3.98) placebo (SD)    15.6] NA 17.6] [-0.19; 20.94] [-1.64; 13.73] [1.72; [-6.11; CI 95%  NA NA p NA NS NA  No difference was observed between the sildenafil group, all doses combined, and the placebo group.  Secondary endpoints:  No difference was observed between the sildenafil group, all doses combined, and the placebo group as regards the mean PAP criteria and the time to VO2max. The cardiac index increased by 0.74 l/min/m2(95% CI [0.14; 1.34], p = 0.015) in the sildenafil group, all doses combined, compared to the placebo group. A difference of -4.1 Wood/m2 the PVRI (95% CI [-8,0; -0,2], p = 0.041) in favour of the in sildenafil group with respect to the placebo was observed. In patients in functional class II, III or IV on inclusion, there was no change in functional class in 84 patients in the sildenafil group (n = 120) and 31 patients in the placebo group (n = 35).
  
 
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An improvement of one functional class was observed in 32 patients on sildenafil and 4 on placebo.  3.1.2. Study A1481156 (results of the interim analysis on 15 May 2009)  
ary objective: To evaluate the long-term safety of the sildenafil treatment in children with Prim PAH.  Secondary objectives: to evaluate the long-term efficacy. A Cardiopulmonary Exercise test was performed in physically fit patients in Week 36 (i.e. 1 year after randomisation into the initial study A1481131). Other parameters were evaluated, such as change in functional class. A survival analysis was also performed.  This study included patients who had completed study A1481131.  Patients included in this extension phase received one of three doses of sildenafil (low, medium or high), with the exception of the patients randomised on placebo in study A1481131, who were randomised in one of the three sildenafil treatment groups according to their weight.5   In all, 229 patients received sildenafil during this extension phase: 55 patients at a low dose, 74 at a medium dose, 100 at a high dose. Two hundred and six patients were treated with sildenafil at year 1, 129 at year 2 and 88 at year 3.  Results for the endpoints V02max At 1 year, the VO2max had increased by 1.67 ml/kg/min in the low-dose group (mean starting value of 18.30 ml/kg/min, n = 33), by 0.58 ml/kg/min in the medium-dose group (mean starting value of 18.11 ml/kg/min, n 32), and by 0.15 ml/kg/min in the high-dose group (mean starting =   value of 17.78 ml/kg/min, n = 35).  WHO functional class At 1 year, the majority of the patients had not changed their functional class (60% in the low-dose group, n = 55; 63.5% of the patients in the medium-dose group, n = 74, and 65% of the patients in the high-dose group, n = 100). An improvement of one functional class was observed in 3 patients in the low-dose group, 9 in the medium-dose group and 6 in the high-dose group. A deterioration by one class was noted in 12 patients in the low and medium-dose groups and in 15 patients in the high-dose group.  At 3 years, there had not been any change in functional class in 32.3% of the patients on a low dose (n = 31), 43.9% of the patients on a medium dose (n = 41) and 41.4% of the patients on a high dose (n = 58). An improvement of one functional class was observed in 5 patients on a low dose and on a high dose, and 1 in the medium-dose group. A deterioration by one class was noted in 5 patients in the low dose group and in 9 patients in the medium and high-dose groups.  Overall survival At 1 year, the survival rate was 100% in the low and medium-dose groups, and 99% in the high-dose group.
 58-20 kg: medium or high dose of sildenafil in a ratio of 1:2.   > 20-45 kg and > 45 kg: low, medium or high dose of sildenafil in a ratio of 1:1:1. 55 of the 60 patients who had received placebo in study A1481131 were randomised into the sildenafil groups.    9/19
At 2 years, the survival rate was 98.2% in the low-dose group, 97.3% in the medium-dose group, and 93% in the high-dose group. At 3 years, the survival rate was 96.4% in the low-dose group, 93.2% in the medium-dose group, and 91% in the high-dose group.  These data should be interpreted with caution, given that patients lost to follow-up can lead to survival rates being overestimated.   3.2. Tolerance
 3.2.1. Study A1481131  In the sildenafil group (all doses combined), 174 patients had one adverse event (42 in the low-dose group, 55 in the medium-dose group, and 77 in the high-dose group); this figure was 60 in the placebo group. 46/174 patients in the sildenafil group and 14/60 patients in the placebo group experienced treatment-related adverse effects. Discontinuation of treatment because of an adverse event (from all causes or related to treatment) was noted in 4 patients in the sildenafil group and none in the placebo group.  The main adverse events recorded were:  in  headache22.9% of the patients in the sildenafil group, all doses combined (40/174) and 25% in the placebo group (15/60). In the case of 17 patients in the sildenafil group and 7 in the placebo group, the headache was considered to be treatment-related.  vomiting in 16.1% of the patients in the sildenafil group, all doses combined (28/174) and 5 patients in the placebo group. In the case of 9 patients in the sildenafil group and 1 in the placebo group, the vomiting was considered to be treatment-related.  pyrexia in 13.2% of the patients in the sildenafil group, all doses combined (23/174) and 1 patient in the placebo group. In the case of 3 patients in the sildenafil group, the pyrexia was considered to be treatment-related.  respiratory tract infection upper6 11.5% of the patients in the sildenafil group, all doses in combined (20/174) and 6.7% in the placebo group (4/60).  diarrhoea8% of the patients in the sildenafil group, all doses combined (14/174) and in 6 patients in the placebo group. In the case of 2 patients in the sildenafil group and 1 in the placebo group, the diarrhoea was considered to be treatment-related.  In the majority of cases, these adverse events were of a low or moderate intensity. Nine patients had an adverse event of severe intensity (including 7 in the sildenafil group).  Eighteen serious adverse events occurred in 11 patients. The following were reported:  cyanosis, syncope and rectal haemorrhage in a patient treated with sildenafil at dyspnoea, a low dose,  pneumonia and upper respiratory tract infection in a patient treated with a medium dose of sildenafil,   gastroenteritis, pyrexia, upper respiratory tract infection, stridor, bronchospasm, bradycardia, pneumonia, ventricular arrhythmia and congestive heart failure in 7 patients treated with sildenafil at a high dose; the stridor and ventricular arrhythmia were considered to be treatment-related,  diarrhoea and pneumonia in 2 patients who had received placebo.    
 6Nasopharyngitis, pharyngitis, rhinitis, laryngitis, sinusitis, tonsillitis, viral sinusitis and viral infection    10/19
3.2.2. Study A1481156  Adverse events were observed in 52/55 patients in the low-dose group, 71/74 patients in the medium-dose group and 85/100 patients in the high-dose group. Treatment-related adverse effects occurred in 21 patients in the low-dose group, 26 in the medium-dose group and 35 in the high-dose group. In 9 patients these events were of severe intensity. Six patients each reported one serious adverse effect considered to be treatment-related. In the medium-dose group there was one case of convulsions and in the high-dose group there was one case each of hypersensitivity, stridor, hypoxia, ventricular arrhythmia and upper respiratory tract infection.  For the most part, the adverse events were of low or moderate intensity; severe adverse events were observed in 55/229 patients (24.0%) who had received sildenafil, of whom 9 had a severe effect which was regarded as treatment-related.  The most commonly occurring adverse events were: upper respiratory tract infections (58/229 patients, 25.3%), headache (53/229 patients, 23.1%) and vomiting (52/229 patients, 22.7%).  The adverse effects considered to be treatment-related and most frequently observed were: headache (30/229 patients, 13.1%) and vomiting (15/229 patients, 6.6%).  Treatment discontinuation due to adverse events related to 2 patients in the low-dose group and 5 patients each in the other two groups.  Twenty-three deaths were reported on 15 May 2009 (13/100 patients (13%) in the high-dose group, 7/74 patients (9%) in the medium-dose group and 3/55 patients (5%) in the low-dose group. None of these deaths were considered by the investigator to be treatment-related.  3.2.3. Data on exposure to sildenafil  According to IMS data, between the 2nd quarter of 2005 and the 1st quarter of 2009, 61,728 patients with PAH, of whom 14,644 were aged under 18 years, were exposed to sildenafil.  A cumulative review of spontaneous reports up to 30 October 2009 identified 816 cases (including 1681 events) of sildenafil use in the paediatric population. As in the adult population, adverse events that could be attributed to the patient’s PAH (e.g. dyspnoea, hypoxia, signs and symptoms of heart failure) were for the most part identified. Similar events associated with the vasodilator effect of sildenafil (e.g. headache, flushing) were among the most frequently reported. Cases of impaired or sudden loss of hearing have been reported after marketing and during clinical trials in a small number of patients with all PDE5 inhibitors, including sildenafil. Another adverse event – rash – has also been reported.  3.2.4. Plan for minimising the specific risk to the paediatric population  In order to strengthen postmarketing surveillance, the EMA has decided that: ·pharmacovigilance activities will be reinforced when adverse events are reported in the  paediatric population during clinical studies or reported spontaneously  the SPC for the product should be updated to include paragraphs devoted to the paediatric · population: recommendations for use, adverse effects · analysis will be carried out of the  ancharacteristics of patients in study A1481131 who have developed an infection of the upper airways, bronchitis, pneumonia or any adverse event suggesting the presence of a respiratory infection
  
 
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