Public Assessment Report for paediatric studies submitted in ...

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Six and 7 subjects reported an increase in glucose values in the VENTOLIN HFA 180mcg and 360mcg groups respectively. None of these glucose values were considered clinically significant by the respective study investigators. Symptoms of Adrenergic Stimulation: At the end of treatment (which occurred at assessment 10 or premature discontinuation) the heart rate decreased for both treatments and the decrease ranged between -9.6 and -1.8 bpm. Symptoms of adrenergic stimulation Five subjects in the VENTOLIN HFA 180mcg and 9 subjects in the VENTOLIN HFA 360mcg group had at least one post-baseline pulse rate of ≥20% over baseline. One subject each (#102 and 159) in both the treatment groups had this increase at 0 min pre-dose therefore a baseline condition. Two subjects in the VENTOLIN HFA 180mcg (#311 and 451) group and 4 subjects in the VENTOLIN HFA 360mcg (#102, 426, 453, 459) group were either agitated or crying during the procedure. For the other subjects the respective study site investigator did not consider the increase in pulse rates to be significant. None of the subjects with a HR increase of >20% over baseline were considered by the respective investigator as significant to be recorded as an AE. The overall incidence of AEs possibly related to adrenergic stimulation was very low and occurred in a single subject each in the VENTOLIN HFA 180mcg (ventricular extrasystole) and 360mcg (tachycardia) groups. The subject (#385) presented with this condition in an ECG prior to the administration of investigational product. Both these subjects had within threshold values for serum potassium for both screening and end of treatment visits. These AEs resolved the same day and did not lead to subject withdrawal from the study. Pulse oxymetrie Pulse oximetry at the begin of the study was greater than 88%, but the end of study the mean baseline pulse oximetry values were increased and were comparable between the two treatments (94.9% (SD=2.84) for VENTOLIN HFA 180mcg group and 95.7% (SD=3.01) for VENTOLIN HFA 360mcg group). Assessor's comment: The results obtained from this study showed that treatment with salbutamol inhalation aerosol decreased percentage and also the absolute values of Modified Tal Asthma Symptoms Score from baseline. The mean dose for rescue albuterol use during treatment was considerably higher in the VENTOLIN HFA 360 mcg group (1340mcg) when compared to the VENTOLIN HFA 180mcg group (288mcg) was very similar for both groups. However, in terms of effectiveness , no significant differences have been found between the two treatment doses (VENTOLIN HFA 180mcg and VENTOLIN HFA 360 mcg, respectively) administered. The current study conducted in children younger than 24 months old and administered cumulative doses of VENTOLIN HFA MDI 180mcg or 360mcg with valved holding chamber and attached facemask demonstrated that it has been well tolerated by this population. The safety profile of VENTOLIN HFA 180mcg and VENTOLIN HFA 360 mcg was similar compared to placebo. Significant adverse effects such as hypokalemia, increased heart rate, adrenergic stimulation or abnormalities in heart rate or QT prolongation difference were not between the two treatment groups. Assessor’s discussion and conclusion Ventolin inhaled formulations is registered for use in adult and children of all ages for the asthma treatment. There is no lower age range limit established by GlaxoSmithKline for Ventolin inhaled formulations. Salbutamol Final Public Assessment Report RO/W/0001/pdWS/001 Page 36/76
Three studies regarding the clinical efficacy and safety of salbutamol in younger children less than 4 years were submitted. The results obtained in these submitted studies did not support the efficacy of VENTOLIN HFA given to children under 4 years during episodes of bronchospasm in asthma or obstructive airway disease. In terms of effectiveness, differences were not statistically significant. These sudies could not determine the minimum efficacy dose of salbutamol inhaled administered ; the maximum daily dose can be administered to this age group. These data are absolutely required to be mentioned in section indication and in dosage and manner of administration when VENTOLIN HFA is recommended to be administered to children less 4 years. The dosage of salbutamol administered in these studies were well tolerated and had a similar safety profile compared to placebo. The applicant mentioned that in September 2008, FDA granted VENTOLIN HFA paediatric exclusivity following submission of the above 3 studies. However, they found the information to be inadequate to support the use in patients under 4 years of age but did agree to incorporate information from the paediatric exclusivity studies in the Clinical Trials Experience and Use In Specific Populations sections of the US labelling. We consider that the FDA proposed resolution was good and we propose the same approach for EU. 2.1.3 NEBULES Study RID/CT/69, study D37/A24 Studies RID/CT/69 and D37/A24, using the same protocol, were conducted by GSK UK in the mid 1980s for comparing of salbutamol and sodium cromoglycate in exercise – induced asthma in children. � Objective These 2 studies were designed to compare the relative efficacy of salbutamol and sodium cromoglicate (SCG), using both nebulised and dry-powder formulations in the prophilaxis of exercise-induced asthma (EIA) in moderately asthmatic children � Study design - duble-blind placebo controlled cross-over assessed the relative efficacy of the treatment with salbutamol alone and in combination with cromoglycate sodium (SCG), using both nebulised and dry-powder salbutamol in prophilaxis of exercise – induced asthma (EIA) in 16 children with a history of chronic perennial asthma � Study population - 16 children (males and females) with a history of chronic perennial asthma, with a reproductible post-exercise fall in peak expiratory flow rate of greater than 20% had been demonstrated and lung function on the 4 test days was greater than 50% of the predicted normal value � Treatments – was administered on 4 consecutive days, 30 minutes before a standard treadmill exercise test. � Outcomes - Lung function was assessed during the study, recording the best of 3 readings obtained using a Wright peak flow meter. PEFR was measured pre - treatment and 30 minutes post treatment, during wich time the patient was instructed to rest quietly. The exercise test was then carried out and PEFR mesurements taken immediately after exercise (time 0) and at 1, 3, 5, 7, 10 şi 15 minutes post-exercise. � Statistical methods Not specified Results The results were calculated as the absolute fall in PEFR post -exercise from the baseline PEFR (L/minute) measured after the treatment was administered, and the mean value at each time point after Salbutamol Final Public Assessment Report RO/W/0001/pdWS/001 Page 37/76
Page 1 and 2: Public Assessment Report for paedia
Page 3 and 4: Pharmacovigilance and PSUR Name: Da
Page 5 and 6: Rapid-acting inhaled β 2 -agonists
Page 7 and 8: The MAHs are requested to submit a
Page 9 and 10: Neonatal onset of symptoms (associa
Page 11 and 12: Study Code: RID/CT/84 (D140/B16); D
Page 13 and 14: of predicted FEV1 to be 12%, the re
Page 15 and 16: central laboratory where this clini
Page 17 and 18: DISKUS 200 mcg compared to albutero
Page 19 and 20: Study period 25 Nov 1996 - 28 May 1
Page 21 and 22: Investigational products for this s
Page 23 and 24: 180mcg 1 inhalation of 90mcg (Can B
Page 25 and 26: Efficacy results Primary efficacy v
Page 27 and 28: At Week 4, mean changes from baseli
Page 29 and 30: In the ITT population the daytime a
Page 31 and 32: This study demonstrated similar saf
Page 33 and 34: Protocol deviations were summarised
Page 35: The overall (based on all evaluable
Page 39 and 40: The improvment in PEF was 51 L. min
Page 41 and 42: eported by the ≤ 6 year age group
Page 43 and 44: suitable for this age because young
Page 45 and 46: In the group treated with salbutamo
Page 47 and 48: common complaints associated with h
Page 49 and 50: although being gradually replaced b
Page 51 and 52: Based on the data submitted, the MA
Page 53 and 54: Inhaled Table 1 Key Differences bet
Page 55 and 56: GDS wording National SmPCs with sig
Page 57 and 58: GDS wording National SmPCs with sig
Page 59 and 60: Question 4 (Rapporteur): With regar
Page 61 and 62: Question 3 In case of divergences b
Page 63 and 64: United Kingdom: Salbulin MDPI Novol
Page 65 and 66: 2. Completely depress the coloured
Page 67 and 68: The harmonised SmPC as outcome of t
Page 69 and 70: Assessment of the Applicant’s res
Page 71 and 72: SALBUTAMOL WZF POLFA 2 mg SALBUTAMO
Page 73 and 74: symptoms. Increased consumption of
Page 75 and 76: sympathomimetic amines. High doses

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