Public Assessment Report for paediatric studies submitted in ...

Public Assessment Report 

for paediatric studies submitted in accordance 

with Article 45 of Regulation (EC) No1901/2006, as amended 

SALBUTAMOL 

Ventolin (Evohaler, Diskus, Nebules and Rotadisk, Injection solution for infusion, 

Tablets, Controlled release tablets, Suppositories), 

Respigen, Gerivent, 100 microgram per metered dose pressurised inhalation 

suspension 

Buventol Easyhaler, 100 microg/dose 

Salbulin MDPI Novolizer 100 micrograms/dose inhalation powder 

Salbubronch Fertiginhalat (nebuliser solution in unit dose vials), 

Salbubronch Inhalationslösung (nebuliser solution) 

Salbutamol POLFA, tablets 

Salbutamol 

Rapporteur: Romania 

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Finalisation procedure (day 120): 25 June 2011 

Date of finalisation of PAR 27 March 2012 

Salbutamol Final Public Assessment Report 

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ADMINISTRATIVE INFORMATION 

Invented name of the medicinal 

product(s): 

INN (or common name) of the active 

substance(s): 

MAH (s): 

Pharmaco-therapeutic group 

(ATC Code): 

Pharmaceutical form(s) and strength(s): 

Rapporteur’s contact person: 

Name of the assessor(s) 

See section VII 

Ventolin (Evohaler, Diskus, Nebules and Rotadisk, 

Solution for injection/infusion, Tablets, Controlled release 

tablets, Suppositories), 

Respigen, 

Buventol Easyhaler, 

Salbutamol POLFA, 

Salbutamol MEDA PHARMA GmbH, 

Salbutamol, InfectoPharm Arzneimittel GmbH 

Salbutamol 

GlaxoSmithKline Research & Development Ltd (UK), 

Generics [UK] Ltd, 

Orion Pharma, 

Menarini, Finland, 

Warsaw Pharmaceutical Works Polfa SA, Poland 

MEDA PHARMA GmbH, MEDA AB 

InfectoPharm Arzneimittel GmbH, Germany 

Ivax, 

Lannacher and 

McDermott Laboratories Ltd. 

R03AC02 

GlaxoSmithKline Research & Development Ltd (UK), 

Diskus, 

Evohaler 

Nebules, 

Nebules and RotadiskSolution for injection/infusion, 

Tablets, 

Controlled release tablets. 

Suppositories 

Orion Pharma, Menarini, Finland, 

Inhalation powder 

Pressurised inhalation suspension 

Generics [UK] Ltd., McDermott Laboratories Ltd. 

Evohaler 

Name Dana Gabriela Marin, MD 

Tel: Phone: +40 21.317.11.02/317.11.15 

Fax: +40 21.316.34.97/031.805.74.54 

Email: dana.marin@anm.ro 

Name: Dana Gabriela Marin, MD 

Email: dana.marin@anm.ro 


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Pharmacovigilance and PSUR 

Name: Daniela Pomponiu, MD 

Email: daniela.pomponiu@anm.ro 


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I. EXECUTIVE SUMMARY 

SmPC and PL changes are proposed in sections 4.1 and 4.2. 

The rapporteur considered that the SmPC/PIL in sections 4.1 and 4.2 should be updated with specific 

wording regarding the use in paediatric population (if not already included). 

Based on the submitted data the Rapporteur concludes that no wording can be proposed, but that the 

MAHs should commit to reviewing all available paediatric data and adjusting their text as appropriate 

through submission of variations to the relevant national competent authorities. 

It is suggested that following amendments should be implemented in the countries where the 

respective wordings have not already been included in the SmPCs using variation procedures. 

PROPOSED CHANGES IN THE SmPC 

Section 4.1: it is the Rapporteur's opinion that the SmPCs should be amended including a specific 

paediatric indication for all inhaled and non-inhaled salbutamol formulations and the lower age limit 

should be mentioned accordingly. 

Section 4.2: If no lower age limit is specified, the lower age limit should be mentioned depending on the 

suitability with the different formulations of salbutamol. 

Summary of outcome 

No change 

Change 

New study data: 

New safety information: 

Paediatric information clarified: section(s) 4.1, 4.2. 

New indication: 

Note: i) A new paediatric indication as reflected in section 4.1 of the current SmPC guideline 

and/or ii) addition of a paediatric dose recommendation in section 4.2 for an indication already 

granted in adult or in one or more subsets or for a new indication. Other relevant sections with 

regard to the change should be mentioned. 

EXECUTIVE SUMMARY 

Salbutamol belongs to drug groups called “relievers”, which are medicinal products used on an 

as-needed basis to reverse bronchoconstriction. Reliever medicinal products act quickly to relieve 

bronchoconstriction and its accompanying acute symptoms. 

Rapid-acting inhaled agonists of the adrenergic β 2 -receptor are the medicinal products of 

choice for relief of bronchospasm during acute exacerbations of asthma and for the pretreatment 

of exercise-induced bronchoconstriction. 


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Rapid-acting inhaled β 2 -agonists should be used only on an as-needed basis at the lowest 

required dose and frequency. Increased use, especially daily use, is a warning of deterioration of 

asthma control and indicates the need to reassess treatment. Similarly, failure to achieve a quick 

and sustained response to β 2 -agonist treatment, during an exacerbation, mandates medical attention 

and may indicate the need for short-term treatment with oral glucocorticosteroids. 

Several MAH (s) have provided a short description of its recommended indications and 

posology in children. Some variations in the indications and dosage recommendations are noted compared 

to the currently approved RO SmPCs in accordance with the specific devices (Diskus/Easyhaler, Evohaler, 

Nebulizer), but separate texts from each MS were not submitted. There is no lower age range by 

GlaxoSmithKline for Ventolin inhaled formulation. 

The data package submitted by the MAH (s) under article 45 of the Paediatric Regulation 

comprises 24 safety and efficacy clinical studies conducted both in children - adolescents and adults, 

together with a clinical overview report. All of these studies have been performed by several MAH (s). 

The MAH (s) have also conducted a literature search for publications relevant to paediatric population and 

has included some published articles as supporting data. 

The Companies’s view is that no change is necessary as a consequence of the data presented. 

II. RECOMMENDATION 

Based on the review of the paediatric data on safety and efficacy, the Rapporteur considers that 

the paediatric indication for Salbutamol in the symptomatic treatment of conditions with associated 

reversible airway obstruction, e.g. asthma or chronic obstructive pulmonary disease with a substantial 

component of reversibility and prevention of asthma attacks induced by exercise or exposure to allergens 

is confirmed. 

Although the recommended indication of salbutamol covers both adults and paediatrics (except 

COPD) the age range limits are not explicitly mentioned in paediatric population for all different 

formulations of salbutamol. Thus, an explicit wording in section 4.1, respective 4.2 for paediatric 

population is considered necessary. 

The specific sub-section of “paediatric population” should always be included and the 

information given should cover all subsets of the paediatric population depending on the suitability of 

different formulation of salbutamol. 

It is the Rapporteur’s opinion that the amendments proposed in section VI of this report should 

be implemented in the SmPCs, (if not already included). 

A Type IB variation on the proposed changes to the SmPC/PL should be submitted by the 

MAH, within 60 days after finalisation of the procedure for medicinal products included in the 

worksharing, if not already included. 

For medicinal products with the same active substance and pharmaceutical form, the submission 

of a type IB variation is requested within 90 days of publication of the public assessment report. 

The aim of the “EU worksharing project assessment of paediatric data” is to make the paediatric 

data available for all European health professionals. Based on the review of the presented paediatric data 

on pharmadynamics, efficacy and safety, it is agreed with the MAH (s) that the data from the submitted 

studies do not specifically indicate any need of major change of the current paediatric information in the 

SmPCs. However, the Rapporteur considers that a harmonisation of the SmPCs and PILs throughout 

Europe in view of the paediatric information would be recommended for consistency between all 

salbutamol-containing products across the EU. An update of the SmPCs and PILs regarding paediatric 

population for all formulations which contain salbutamol is needed in order to be in line with the revised 

SmPC guideline (September 2009) and QRD template. 


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It is acknowledge that the paediatric indication for salbutamol in the treatment of asthma is 

confirmed, but it is the Rapporteur’s opinion that some changes to the SmPC might be advisable in section 

4.1 and 4.2 in order to specify the age range limits of paediatric population for different formulations of 

salbutamol. 

The Rapporteur acknowledges that the aim of the paediatric worksharing is not to harmonise the 

SmPC and PIL as a whole but a harmonisation of the paediatric data throughout Europe taking into 

account the national Marketing authorisations should be possible and should be achieved. 

However a harmonisation procedure across the European Union, under Article 30 of Directive 

2001/83/EC, as amended would be recommended. 

I.1 Scope of the variation 

None proposed by the MAH(s). 

III. INTRODUCTION 

Ten MAH(s) submitted completed paediatric studies for salbutamol in accordance with Article 

45 of Regulation (EC) No 1901/2006, as amended, conducted on medicinal products for paediatric use. 

This is in response to the CMD(h) and the EMEA requirement that paediatric studies of authorised 

medicinal products not previously submitted should be submitted for assessment to European Health 

Agencies. 

In accordance with Article 45 of Regulation (EC) No. 1901/2006, studies assessed in this 

procedure are paediatric studies completed before 26 January 2008, which have not been submitted yet to 

the National Competent Authorities. It is intended to describe and summarise the outcome of the presented 

studies and to draw conclusions and suggestions with regards to the impact on the marketing 

authorisations. 

Ten MAH(s) are involved in this European Work-sharing of paediatric data on salbutamol. Only 

GlaxoSmithKline submitted a dossier including 18 clinical studies conducted in children, which have been 

performed by the MAH and an extensive review of the literature clinical overview. MEDA and 

MENARINI submitted a list of published clinical studies and ORION submitted a list of the same 

references. Ivax, Lannacher and McDermott did not submit any data. 

Generics [UK] Ltd. submitted one clinical study conducted on children, which has been carried 

out by Generics [UK] Ltd., with the product Respigen. 

Orion Pharm has carried out 4 clinical trials with the product Buventol Easyhaler DPI, which 

included children. To date, no other clinical trials with Buventol Easyhaler in children have been carried 

out by Orion Pharma or independent investigator. 

The first 3 studies have been included and evaluated for marketing authorisation applications (MAA) in 

EU countries. The most recent study has not been included in previous MAAs and a brief synopsis of all 

these studies is given in the submitted documentation. 

A short critical expert overview has also been provided. 

The aim of this EU Work-sharing project is the proper assessment of paediatric data on 

salbutamol and the update the summary of product characteristics accordingly. 

The MAHs stated that the submitted paediatric studies do not influence the benefit risk balance 

for medicinal products which contain salbutamol as active substance and that there is no consequential 

regulatory action. 

No additional documentation has been included. 

A line listing and annex II, including SmPC wording of sections 4.1 and 4.2 related to the 

paediatric use of the medicinal products have to be submitted for all concerned MAH (s). 


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The MAHs are requested to submit a brief description of the products including the current 

marketing authorisation status in EU/EEA and the currently approved SmPCs (translated into English) 

from the European countries. 

The Rapporteur assessed the data submitted by GlaxoSmithKline, MEDA, MENARINI and 

ORION and also performed his own research of the literature. 

The MAH (s) submitted a review of the clinically relevant information on efficacy and safety 

related to salbutamol in children. The supportive documentation available for this purpose was the 

following: 

- The own clinical paediatric studies and 

- Literature searches on standard medical databases (i.e. Embase, Medline and Cochrane). A short clinical 

expert overview has also been provided. 

GlaxoSmithKline has reviewed the results of all these studies and has concluded that no changes 

to the Ventolin (salbutamol) SmPCs are required. 

Also the others MAH(s) did not propose any change to the approved SmPC in conjunction with 

these studies and stated that the submitted paediatric studies do not influence the benefit risk for their 

products and that there is no consequential regulatory action. 

IV. SCIENTIFIC DISCUSSION 

Product background 

Salbutamol (INN) or albuterol (USAN) is a Beta-2 adrenoceptor agonist with a selective action 

on bronchial smooth muscle and no significant action on cardiac beta1-receptors. 

It is marketed by GlaxoSmithKline as Ventolin, Aerolin or Ventorlin depending on the market. 

Salbutamol (as salbutamol sulfate) is usually given by the inhalation route for direct effect on 

bronchial smooth muscle. This is usually achieved through a metered dose inhaler (MDI), nebuliser or 

other proprietary delivery devices (e.g. Rotahaler or Autohaler). In these delivery forms, the maximal 

effect of Salbutamol can occur within five to twenty minutes of dosing, although some relief is 

immediately seen. Salbutamol can also be administered orally as an inhalant or intravenously. 

Salbutamol became available in the United Kingdom in 1969 and in the United States in 1980 

under the trade name Ventolin. 

Ventolin/Volmax has been approved for marketing in the EU via national procedure(s). 

The efficacy of salbutamol (albuterol) has been well established by extensive clinical use for 

more that 20 years and it is now an accepted standard of comparison for newer bronchodilator agents. 

Since its initial release in a metered-dose inhaler (MDI) formulation (VENTOLIN (albuterol, 

USP) Inhalation Aerosol) in Europe in 1969, followed rapidly by other dosage forms, albuterol has been 

studied in hundreds of clinical trials for the prevention and relief of bronchospasm in patients four years of 

age and older with reversible obstructive airway disease and for the prevention of exercise-induced 

bronchospasm in subjects four years of age and older. 

The first powder form of albuterol, VENTOLIN ROTACAPS (albuterol sulfate, USP) for 

Inhalation, delivered via the ROTAHALER device was approved for marketing outside the U.S. in 1977 

and in the U.S. in 1988. The powder form of albuterol was also marketed outside the U.S. in a new 

delivery system known as VENTOLIN ROTADISK (albuterol sulfate, USP) with the DISKHALER 

device in 1987. The most recent powder delivery system, DISKUS, was approved for marketing with 

albuterol outside the U.S. in 1995. 

Condition to be treated - Asthma 

Asthma is a serious worldwide public health problem, affecting people of all ages. When 

uncontrolled, asthma can place severe limitations on daily life, and is sometimes fatal. 


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Asthma is defined as a clinical syndrome characterised by airway inflammation, variable lung 

function and airways responsiveness (1). Asthma severity is categorised in accordance with the Global 

Initiative for Asthma (GINA) classification system or with the National Asthma Education and Prevention 

Program guidelines. 

There are four categories based on clinical and functional features; mild intermittent, mild 

persistent, moderate persistent and severe persistent. 

In the recently revised GINA guideline (2010), classification of asthma by level of control has 

also been proposed as it is considered more relevant and useful. 

Current management of asthma in children 

The standard of care for patients with mild intermittent and mild persistent asthma in the past 

was intermittent and the regular use of inhaled short-acting b2-agonist respectively. 

Current guidelines no longer recommend this for the mild persistent group due to reports of 

increased risk of death as well as deterioration of overall asthma control. 

Recent trials have been performed to investigate the benefits of inhaled corticosteroids 

(ICS) for patients with mild persistent asthma. Other therapeutic options such as the addition of 

leukotriene antagonist, xanthines and long-acting b2-agonists (LABA) have also been studied. 

Inhaled corticosteroids (ICS) remain the main treatment for patients with mild persistent asthma. 

Early intervention with ICS decreases the risk of severe exacerbations and improves asthma control in 

patients with mild persistent asthma of recent onset. 

Inhaled corticosteroids are superior to leukotriene receptor antagonists and xanthines for control of asthma 

and in the improvement of lung functions. 

The addition of LABA may be considered in those with moderately persistent asthma or whom 

asthma is not well controlled with low doses of inhaled corticosteroids. Evidence-based treatment for mild 

intermittent asthma is scant and guidelines recommend short-acting bronchodilator treatment as required 

in this stage. 

The long-term implications of a treatment strategy that uses an inhaled corticosteroid on an asneeded 

basis in addition to an inhaled rapid-acting b2-agonist are unknown. 

Lastly, there is paucity of evidence which shows the benefits/ risks of long-term ICS as a regular 

treatment for patients with mild intermittent asthma. 

Although evidence-based treatment for mild intermittent asthma is scant, guidelines recommend 

short-acting bronchodilator treatment as required in this stage. Early intervention with ICS decreases the 

risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent 

onset. 

The differential diagnosis in patients with suspected asthma differs among different age groups: 

infants, children, young adults, and the elderly. 

The diagnosis of asthma in early childhood is challenging and has to be based largely on clinical 

judgment and an assessment of symptoms and physical findings. Since the use of the label “asthma” for 

wheezing in children has important clinical consequences, it must be distinguished from other causes 

persistent and recurrent wheeze. 

Episodic wheezing and cough is very common even in children who do not have asthma, 

particularly in those under the age of 3. The following categories of symptoms are highly suggestive of a 

diagnosis of asthma: frequent episodes of wheeze (more than once a month), activity-induced cough or 

wheeze, nocturnal cough in periods without viral infections, absence of seasonal variation in wheeze, and 

symptoms that persist after the age of 3. A simple clinical index based on the presence of a wheeze before 

the age of 3 and the presence of one major risk factor (parental history of asthma or eczema) or two of 

three minor risk factors (eosinophilia, wheezing without colds and allergic rhinitis) has been shown to 

predict the presence of asthma in later childhood. 


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Neonatal onset of symptoms (associated with failure to thrive), vomiting-associated symptoms, 

or focal lung or cardiovascular signs suggest an alternative diagnosis and indicate the need for further 

investigations. 

A useful method for confirming the diagnosis of asthma in children 5 years and younger is a trial 

of treatment with short-acting bronchodilators and inhaled glucocorticosteroids. 

Marked clinical improvement during the treatment and deterioration when treatment is stopped 

supports a diagnosis of asthma. Use of spirometry and other measures recommended for older children 

and adults such as airway responsiveness and markers of airway inflammation is difficult and several 

require complex equipment, making them unsuitable for routine use. 

However, children 4 to 5 years old can be taught to use a PEF meter, but the ensurance of 

reliability parental supervision is required. 

A thorough history and physical examination, together with the demonstration of reversible and 

variable airflow obstruction (preferably by spirometry), will in most instances confirm the diagnosis in 

older children. 

IV.1 Information on the pharmaceutical formulation used in clinical studies 

Salbutamol is a selective ß2-adrenergic receptor agonist providing short-acting bronchodilatation in 

reversible airway obstruction. It was originally developed by GlaxoSmithKline and is available in several 

pharmaceutical forms and dosage. 

Salbutamol belongs to the drug group called “relievers”, which are medicinal products used on 

an as-needed basis in order to reverse bronchoconstriction. Reliever medications act quickly to 

relieve bronchoconstriction and its accompanying acute symptoms. 

Rapid-acting inhaled agonists of the adrenergic β 2 -receptor are the medicinal products of 

choice used for bronchospasm relief during acute exacerbations of asthma and in the pretreatment 


Rapid-acting inhaled β 2 -agonists should only be used on an as-needed basis at the lowest 

dose and frequency required. Increased use, especially daily use, is a warning of deterioration of 

asthma control indicating the need to reassess treatment. Similarly, failure to achieve a quick and 

sustained response to β 2 -agonist treatment during exacerbation mandates medical attention and 

may indicate the need for short-term treatment with oral glucocorticosteroids. 

The following salbutamol pharmaceutical forms are indicated in the treatment of airways 

obstruction in paediatric population: respirator solution for Nebulizer, aerosols for Evohaler, powder for 

Diskus/Easyhaler, syrup and tablets. 

Aerosol for Evohaler is a pressurised metered-dose inhaler delivering 100 micrograms of 

salbutamol (as Salbutamol Sulphate BP) per actuation. Ventolin Evohaler contains a new CFC-free 

propellant (HFA 134a). An inhaler comprising an aluminium alloy can be sealed with a metering valve, 

actuator and dust cap. Each canister contains 200 metered actuations providing 100 micrograms of 

salbutamol (as Salbutamol Sulphate BP). After shaking the inhaler, the mouthpiece is placed inside the 

mouth and the lips closed around it. The actuator is depressed to release a spray, which must coincide with 

inspiration of breath. 

Solution for inhalation via nebuliser - the nebuliser solution may be inhaled through a face 

mask, T-piece or endotracheal tube. Intermittent positive pressure ventilation (IPPV) may be used but is 

rarely necessary. When there is a risk of anoxia through hypoventilation, oxygen should be added to the 

inspired air. As many nebulisers operate on a continuous flow basis, it is likely that some nebulised drug 

will be released into the local environment. Ventolin Nebules should therefore be administered in a wellventilated 

room, particularly in hospitals when several patients may be using nebulisers simultaneously. 


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Ventolin Nebules may be diluted with sterile normal saline. Solutions in nebulisers should be 

replaced on a daily basis. 

Easyhaler Salbutamol Sulphate 100 micrograms and 200 micrograms per actuation 

inhalation powder 

The multidose powder inhaler (Easyhaler) consists of seven plastic parts and a stainless steel 

spring. 

The starting package contains an inhaler and a protective cover. The maintenance pack contains 

the dry powder inhaler only. Pack size: 200 actuations. With the powder inhalers the patient first 

actuates the device and the dose is ready to be inhaled with forced and prolonged inspiration. 

Diskus/Accuhaler is a multi-dose dry powder inhalation device plastic inhaler containing a foil 

strip with 60 regularly spaced blisters, each containing a mixture of 200 micrograms of microfine 

salbutamol (as sulphate) and larger lactose particles. The powder mix of salbutamol (as sulphate) and 

lactose is filled into a blister strip consisting of a formed base foil with a peelable foil laminate lid. The 

foil strip is contained within the Accuhaler device. The powdered medicinal product is inhaled through the 

mouth into the lungs. The Accuhaler device contains the medicinal product in individual blisters which are 

open as the device is handled. 

IV.2 Non-clinical aspects 

Non-clinical studies have not been provided or summarized by the MAHs on salbutamol 

sulphate. It is noted that no literature review has been conducted by the MAHs to identify preclinical 

studies relevant for the paediatric use of this active substance. 

IV.3 Clinical aspects 

A) Summary of clinical program sponsored by GSK 

1. Introduction 

The MAH submitted reports for the following 18 completed paediatric studies: 

Study Code: SALA3008; SALA2003 

Study Title: Ventolin Diskus Safety/Efficacy studies in 4-11 year olds 

GSK Study Report Number: Report Nos. RM1997/00754/00 and RM1998/00055/00 

Study Code: SALA3006; SB030003; 

Study Title: Ventolin Evohaler studies in over 4 year olds 

GSK Study Report Number: Report Nos. RM1997/00818/00 and RM2004/00133/00 

Study Code: SB020001; SB030001, SB030002 

Study Title: Ventolin Evohaler studies in under 4 year olds 

GSK Study Report Number: Report Nos. RM2003/00584/00; RM2004/00507/00; 

RM2006/00188/00; 

Study Code: SBM40122(Neb02); SBM40140 (505/250) 

Study Title: Ventolin Nebules studies 

GSK Study Report Number: Report Nos. Publications only 

Study Code: RID/CT/69; D137/A25 

Study Title: Ventolin Nebules and Rotadisk exercise-induced asthma study 

GSK Study Report Number: Report Nos. GPM/84/001 


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Study Code: RID/CT/84 (D140/B16); D78/B24 

Study Title: Ventolin Injection/Intravenous studies 

GSK Study Report Number: Report Nos. GPM/84/024; GPM/85/008 

Study Code: SCR4/85/CPI; STC388; SBM40056; SBM40107 

Study Title: Ventolin/Volmax Tablets studies 

GSK Study Report Number: Report Nos. GMR/86/008; GRP/88/013; Publication only 

Study Code: BIO/75/09 

Study Title: Ventolin Suppository study 

GSK Study Report Number: Report No. BIO/75/09 

2. Clinical studies 

2.1 Oral Inhalation 

A separation was made between Salbutamol pMDI (Ventolin Evohaler (CFC-Free Inhaler, 

Ventolin HFA inhalation aerosol) and Salbutamol DPI (Rotadisks/Rotacaps Accuhaler/Diskus, 

Pulmicort Turbuhaler) and Salbutamol nebuliser suspension (Ventolin Nebules). The three types will be 

completely discussed separately at once. 

device. 

9 clinical studies were submitted. An overview is presented in the part concerning the specific 

2.1.1 Inhalation powder 

The first powder form of albuterol, VENTOLIN ROTACAPS (albuterol sulfate, USP) for 

Inhalation, delivered via the ROTAHALER device was approved for marketing outside the U.S. in 1977 

and in the U.S. in 1988. The powder form of albuterol was also marketed outside the U.S. in a new 

delivery system known as VENTOLIN ROTADISK (albuterol sulfate, USP) with the DISKHALER 

device in 1987. The most recent powder delivery system, DISKUS, was approved for marketing with 

albuterol outside the U.S. in 1995. 

Two studies which had not been previously submitted regarding the clinical efficacy and safety of 

salbutamol Diskus in paediatric patients are assessed (SALA3008 and SALA2003): 

Study Code: SALA3008 

Study Title: A Randomized, Double-blind, Double-Dummy, Parallel-Group, Clinical Trial 

Assessing the Safety and Efficacy of Albuterol Powder 200 mcg QID via the DISKUS versus 

Albuterol Aerosol 200mcg (180 mcg Ex-Actuator) versus Placebo in Paediatric Subjects Aged 4-11 

years with Asthma. 

Study period: 20 Jan 1997 - 06 Sep 1997. 

GSK Study Report Number: Report Nos. RM1997/00754/00. 

Methods 

• Objective 

To compare the safety and efficacy of albuterol powder 200 mcg QID via DISKUS versus albuterol 

aerosol 200 mcg QID (180 mcg ex/actuator) via the MDI versus placebo QID over a 4-week treatment 

period in paediatric subjects age 4-11 years with asthma. 

Thus, the purpose of this study was to determine the safety and efficacy of albuterol powder 200 mcg via 

the DISKUS over a 4-week treatment period in paediatric patients aged 4-11. 

• Study design 


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Multicenter, Randomized, Double-blind, Double-Dummy, Parallel-Group, Active/Active 

Comparator/placebo study. 

Phase III. 

Location: 13 centers in the Unites States and one in Mexico. 

• Study population /Sample size 

Male or premenarchal females, 4-11 years of age, with asthma (ATS definition) requiring 

chronic pharmacotherapy for at least 6 months prior to screening. Patients had to demonstrate a baseline 

FEV1 (or PEFR for 4-5 years olds who could not adequately perform spirometry) of 50-80% of predicted 

normal value and show reversibility (≥15% increase in FEV1 (or PEFR if patients qualified on PEFR) 

following inhalation of 2 actuations of VENTOLIN MDI. 

142 patients were blindly randomized into 3 groups: 45 patients in the Placebo group, 49 

patients in the albuterol DISKUS group and 48 patients in the albuterol MDI group. 

There were no statistically significant differences between all groups regarding age, sex, 

duration of chronic renal failure, post transplant periods. 

• Treatments 

During the treatment period, patients were randomized to albuterol DISKUS, albuterol MDI, or 

placebo given four times daily. 

The treatment per age group was as follows: 

2 capsules (500mg) daily up to 1 year of age 

3 capsules (750mg) daily from 1 year to 5 years of age 

3-6 capsules (750-1500 mg) daily over 5 years of age 

Total duration of the study: 4 weeks. 

Outcomes/endpoints 

The primary measures of efficacy were the peak within 30 min. of dosing of percent of predicted 

PEFR and FEV1 measured by change from baseline. Secondary measures of efficacy consisted of serial 

PEFR and FEV1 measurements. Other measurements of efficacy included patient-conducted 

determinations of morning peak expiratory flow rates (PEFR), use of back-up medication (VENTOLIN 

MDI), patient-rated asthma symptoms (including night time awakenings). 

Safety assessments included clinical adverse events, clinical laboratory tests, vital signs, 12-lead 

electrocardiograms, and physical examinations. 

FEV1 and PEFR measurements were recorded at each visit as the primary assessments of 

efficacy. 

FEV1 is defined as forced expiratory volume in one second. 

PEFR is defined as peak expiratory flow rate. 

• Statistical Methods 

Enrollment was planned for 120 patients (40 per treatment group). Data from previous studies 

have suggested that a reasonable assumption for the standard deviation of percent of predicted FEV1 

measured in paediatric patients is 12%. Use a two-sample t-test and a significance level of 0.05, 40 

patients per treatment group would provide at least 80% power in detecting a difference of 7.5% in 

percent of predicted FEV1 for any pairwise treatment comparison. This sample size would also provide at 

least 80% power to show a difference of 11% in percent of predicted PEFR (based on a standard deviation 

of 18%). It was anticipated that up to 10% of patients enrolled in the study would be aged 4 or 5 years, 

and therefore would not perform serial FEV1 measurements. Assuming the standard deviation of percent 


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of predicted FEV1 to be 12%, the resulting sample size of 36 6-11 year-old patients per treatment group 

would provide al least 80% power of detecting a difference of 7.9% in percent of predicted FEV1. 

The primary efficacy endpoints were the peak effect, measured as the change from baseline in 

maximum percent of predicted FEV1 value (for patients aged 6-11) and percent of predicted PEFR value 

(for patients aged 4-11) observed within 30 minutes of dosing. Other measures of efficacy included FEV1 

and PEFR at each of the time points on Day 1 and Week 4 and summary measures for 6-hour serial 

measurements (repeat measures, area under the curve and weighted average); functions of FEV1 and 

PEFR; diary card results, including morning PEFR, back-up VENTOLIN use, night time awakenings, 

asthma symptom scores and asthma exacerbations. The primary efficacy measures were analyzed using 

analysis of covariance with the percent of predicted same-day baseline as the covariate. The model 

included terms for treatment, investigator and baseline covariate. 

Results 

Safety results: 

Overall, both albuterol DISKUS and albuterol MDI were well tolerated and showed comparable 

effects to placebo with QID dosing over 4 weeks. There were no deaths reported during the study. There 

was one serious status asthmaticus adverse event (patient on albuterol DISKUS) which was not considered 

related to the study drug.No statistically significant differences were observed among the three treatment 

groups for the incidence of adverse events. The four adverse events that were thought by the investigator 

to be possibly, probably or almost certainly drug related were in the placebo group. None of the 

laboratory, vital sign, EKG, or physical examination results demonstrated a safety concern. 

Efficacy results 

Albuterol DISKUS and albuterol MDI, administered QID, were significantly more effective than 

placebo with QID dosing over 4-week treatment period in paediatric patients aged 4-11 years. At 

treatment Day 1 and Treatment week 4, albuterol DISKUS and albuterol MDI exhibited a significantly 

(p≤0.006) higher mean peak effect within 30 min of dosing compared to placebo as measured by the 

change from same-day baseline in percent of predicted PEFR and FEV1. 

Albuterol DISKUS and albuterol MDI demonstrated comparable efficacy over the 4-week 

treatment period. This was demonstrated by comparable increases in both of the primary efficacy 

endpoints, peak within 30 min, of dosing measured as a change from baseline of percent of predicted 

PEFR for patients aged 4-11 and FEV1 for patients aged 6-11. Both albuterol DISKUS and albuterol MDI 

demonstrated efficacy through the 2-3 hour interval based on PEFR and FEV1. The subgroup analysis of 

the 4-8 and 9-11 year olds demonstrated similar results as the total age group analysis. 

Albuterol DISKUS and albuterol MDI were numerically greater than placebo for all endpoints 

comprising the analysis of functions of 6-hour serial PEFR and FEV1, with the exception of time to 

maximum effect. Overall statistical significance was achieved for onset of effect, duration of effect, onset 

of maximum effect and WAVE ≥15% at Treatment Day 1 and for subjects achieving response, onset of 

effect, offset of effect and maximum effect at Treatment Week 4. Where overall significance was 

achieved, pairwise comparison showed both albuterol groups were significantly better than placebo at 

Treatment Day 1 and Treatment Week 4 (p≤0,044). Albuterol DISKUS and albuterol MDI were similar at 

Treatment Day 1 and Treatment Week 4 except onset of effect and duration of effect at Treatment Week 4 

(p=0,028 and p=0,049, respectively) favoring albuterol DISKUS. In general there was agreement between 

the PEFR results and the FEV1 results. 

There was no overall significance demonstrated between the three treatment groups as measured 

by morning PEFR values, use of back-up VENTOLIN, asthma symptoms, and night time awakenings 

requiring treatment with back-up VENTOLIN. 

A great number of patients who received albuterol MDI experienced exacerbations (25% total 

number and 17% out of clinic) during the study compared to those who received albuterol DISKUS (14% 


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total number and 10% out of clinic) or placebo (13% total number and 9% out of clinic). The incidence of 

patients having two or more exacerbations was very low and comparable among treatment groups (2-4%). 

Conclusions: 

Albuterol DISKUS and albuterol MDI significantly improve bronchodilation compared to 

placebo in paediatric patients aged 4-11 years with asthma. 

Albuterol DISKUS and albuterol MDI are well tolerated and show comparable safety to placebo 

throughout a 4-week treatment period in paediatric patients aged 4-11 years with asthma. 

Albuterol DISKUS and albuterol MDI produce comparable improvements in lung function in 

paediatric patients. 

In the responder subset, albuterol DISKUS and albuterol MDI produce clinically significant 

onset of improvement (≥15% over baseline) in pulmonary function between 3 to 4 minutes after dosing 

and maintain this improvement for 2-4 hours. 

Study Code: SALA2003 

Study Title: A Randomized, Double-blind, Double-Dummy, Single-Dose, Six-Way 

Crossover Study to Compare the Safety and Efficacy of Single Dose of 200 and 400 mcg Albuterol 

Powder Via DISKUS With Single Dose of 100, 200 and 400 mcg (90, 180 and 360 mcg Ex-Actuator) 

Albuterol Aerosol Via MDI and Placebo in Subjects, Aged 4-11 Years, With Asthma. 

Study period: 08 Mar 1997 – 12 Aug 1997. 

GSK Study Report Number: Report Nos. RM1998/0055/00. 

Methods 

Protocol SALA2003 was designed to assess the safety and efficacy of both 200 and 400 mcg 

doses of albuterol powder via DISKUS, as well as comparability with 100, 200 and 400 mcg doses of 

albuterol via MDI and placebo in asthma patients, 4 to 11 years of age. 

• Objective 

1. to compare the safety and efficacy of single doses of 200 and 400 mcg albuterol powder via 

DISKUS with single doses of 100, 200 and 400 mcg (90, 180 and 360 mcg ex-actuator) albuterol aerosol 

via MDI and placebo in paediatric patients (ages 4-11 years) with asthma; 

2. to demonstrate dose-response characteristics of both albuterol formulations. 

• Study design 

Multicenter, Randomized, Double-blind, Double-Dummy, single-dose, placebo-controlled, sixway 

crossover, multicenter in paediatric patients with asthma. 

The study included a screening visit conducted 3-14 days before the Treatment Visit 1, followed 

by six treatment visits, each separated by 1-14 days. 

This study included a concurrent placebo treatment with an additional active control comparator 

treatment (MDI). The study drug was supplied in identical MDI devices and identical DISKUS devices in 

blind treatments. 

Phase II. 

Location: 5 centers in the Unites States. 

The clinical trial, including study medication management, was monitored by Glaxo Wellcome 

personnel with one contract monitor from Research Scientists, Inc (Los Angeles, CA). Site visits were 

scheduled every 4 to 8 weeks depending on site enrollment. Covance, Inc (Indianapolis, IN) was the 


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central laboratory where this clinical trial has been performed. Pulmonary function data was transferred to 

Pulmonary Data Services (Louisville, CO) for processing. Case Report Form data was collected in an 

electronic case report form designed by Technilogix Inc. (Ridgefield, NJ). Statistical data analyses were 

performed by the Glaxo Wellcome Clinical Statistics Department. 

• Study population /Sample size 

Enrollment was planned for 60 evaluable patients. The following selection criteria were chosen 

to ensure the appropriate patient population (mild-to-moderate paediatric asthma patients with no 

significant concomitant diseases who were responsive to beta-agonists and used similar concurrent 

medications)was enrolled. Concurrent medications which could affect the efficacy analysis were either 

discontinued during the study period or withheld for an appropriate period of time prior to pulmonary 

function testing. 

Using a paired t-test and a significance level of 0.05, 60 patients would provide at least 80% 

power in detecting a difference of 6.1 % in percent of predicted FEV1 for any pairwise treatment 

comparison. This sample size would also provide at least 80% power to show a difference of 9.2% in 

percent of predicted PERF (based on a standard deviation of 18%). 

It was anticipated that up to 17% of patients enrolled in the study would be aged 4 to 5 years, 

and therefore would not perform serial FEV1 measurements. Assuming the standard deviation of percent 

of predicted FEV1 to be 12%, the resulting sample size of 50 6 to 11-year old patients would provide at 

least 80% power of detecting a difference of 6.7 % in percent of predicted FEV1. 

Inclusion Criteria: 

Males and premenarchal females 4 to 11 with a 6 month history of asthma, FEV1 50 to 80% 

Outcomes/endpoints 

The primary efficacy endpoints were: 

� the peak effect within 30 min of dosing, measured as the change from baseline in percent 

of predicted PEFR (for subjects aged 4-11) and 

� the peak effect within 30 min of dosing, measured as the change from baseline in percent 

of predicted FEV1 (for subjects aged 6-11). 

Peak effect was defined as the maximum above-baseline change in percent of predicted FEV1 

and PEFR observed within 30 minutes of dosing. 


efficacy. 

The safety of each patient was assessed by monitoring vital signs and clinical adverse events. 

Medical history, complete physical examination, clinical laboratory tests and 12-lead electrocardiograms 

were performed only at the screening visit. 

Descriptive statistics were calculated for all patients and responders. Inferential statistics were 

calculated for the entire patient population only. 

The definition of responder was a patients who achieved a 15% or more increase from baseline in 

FEV1 or PEFR within 30 minutes of dosing. 

• Statistical Methods 

Enrollment was planned for 60 (male or female) patients, 4-11 years of age, who demonstrated a 

baseline FEV1 of 50-80% of the Polgar predicted normal value and airways reversibility (≥15% increase 

in FEV1 following 2 actuations of Ventolin). 


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Due to the inability of 4 and 5-year olds to always perform the spirometry maneuver adequately, 

FEV1 data, if collected, was not analysed in these patients. PERF data was analysed for all patients 4-11 

years old and FEV1 data was analyzed for all patients 6-11 years old. 

Using a paired t-test and a significance level of 0.05, 60 patients would provide at least 80% 

power in detecting a difference of 6.1% predicted FEV1 for any pairwise treatment comparison. This 

sample size would also provide at least 80% power to show a difference of 9,2% in percent of predicted 

PERF. 

The primary efficacy endpoints represented the peak effect, measured as a change from baseline 

in maximum above-baseline percent predicted FEV1 value (for patients aged 6-11) and percent of 

predicted PEFR value (for patients aged 4-11) observed within 30 minutes of dosing. Other measures of 

efficacy included some summary measures of serial FEV1 and PEFR (area under the curve, repeated 

measures [average of 6-hour serial measurements] and weighted average), functions of serial FEV1 and 

PEFR, and frequency of asthma exacerbations. 

The primary efficacy measures were assessed via covariance analysis with the percent of 

predicted same-day baseline as a covariate. The model included terms for treatment, patients within 

investigator, period, previous treatment, baseline covariate and patient. 

Results 

Safety results: 

Overall, both albuterol DISKUS and albuterol MDI were well tolerated. 

Adverse events occurred in < 5% of patients having undergone all treatments; no significant 

differences between doses or formulations or placebo were observed. None of the adverse events were 

thought by the investigator to be likely, probably, or almost certainly drug-related. None of the vital sign 

results demonstrated a safety concern. 

There were no deaths reported during the study. There was one serious adverse event, which was 

an asthma exacerbation requiring hospitalisation, but was consideredunrelated to study drug. 


All albuterol treatments were significantly greater than placebo (p≤0.001) based on the peak 

effect within 30 minutes of dosing of change from same-day baseline in percent predicted PEFR. The peak 

within 30 minutes of dosing of change from baseline in percent predicted PEFR was similar for albuterol 

DISKUS (16,0 and 16,1 percent predicted for 200 mcg and 400 mcg doses, respectively) and showed 

slight improvement for albuterol MDI 400 mcg (17.9 percent predicted) compared to 100 mcg and 200 

mcg doses (14.5 and 13.8 percent predicted, respectively). 

A significant difference was seen in both percent predicted and change from baseline in percent 

predicted PEFR for albuterol MDI 400 mcg versus 100 mcg (p=0.002 and 0.015 respectively) and 400 

mcg versus 200 mcg (p≤0.001 and p=0.003, respectively). Albuterol DISKUS 200 mcg and 400 mcg were 

not significantly different from each other. 

All albuterol treatments were significantly greater than placebo (p≤0.001) based on the peak 

effect within 30 minutes of dosing of change from same-day baseline in percent predicted FEV1. The peak 

within 30 minutes of dosing of change from baseline in percent predicted PEFR was similar for albuterol 

DISKUS (15,3 and 15,9 percent predicted for 200 mcg and 400 mcg doses, respectively) and showed 

slight improvement for albuterol MDI 400 mcg (18.8 percent predicted) compared to 100 mcg and 200 

mcg doses (16.7 and 17.1 percent predicted, respectively). 

There was no significant difference between albuterol MDI 400 mcg and 100 mcg, therefore no 

other comparisons were considered. 

Treatment with albuterol DISKUS 200 mcg and albuterol MDI 200 mcg were comparable with 

respect to the peak within 30 minutes and change from baseline in percent predicted PEFR and FEV1. The 

percent predicted PEFR change from baseline was slightly greater for albuterol DISKUS 200 mcg 

compared to albuterol MDI 200 mcg (16.0 and 13.8% predicted, respectively) with a difference of 2.2 % 

predicted while the change from baseline in percent predicted FEV1 was slightly less for albuterol 


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DISKUS 200 mcg compared to albuterol MDI 200 mcg (15.3 and 17.1% predicted, respectively) with a 

difference of -1.8% predicted. 

Efficacy results with the 400 mcg doses of albuterol DISKUS and albuterol MDI were relatively 

similar with respect to the peak effect within 30 minutes and change from baseline in percent of predicted 

PEFR and FEV1. However, in contrast to results with the 200 mcg doses, where efficacy results favored 

the DISKUS for PEFR and the MDI for FEV1, results observed with the 400 mcg doses favored the MDI 

for both PEFR and FEV1. 

The peak within 30 minutes of dosing of percent change from baseline in PEFR was similar for 

albuterol DISKUS for 200 mcg and 400 mcg doses and showed slightly greater improvements for 

albuterol MDI 400 mcg compared to 100 mcg and 200 mcg doses. 

A higher percentage of patients achieved a ≥ 15% increase from baseline in PEFR in the 

albuterol treatments compared to placebo throughout the entire 6-hour evaluation. The percent of patients 

who exhibited a ≥ 15% increase was similar for both doses of albuterol DISKUS. The percent of patients 

who exhibited a ≥ 15% increase was generally similar for albuterol MDI 100 mcg and 200 mcg doses and 

higher for albuterol MDI 400 mcg. 

As we have seen in the case of PEFR, a higher percentage of patients achieved a ≥ 15% increase 

from baseline in FEV1 with albuterol treatments compared to placebo throughout the entire 6-hour 

evaluation. The percent of patients who exhibited ≥ 15% increase from baseline in FEV1 was similar for 

both doses of albuterol DISKUS at most timepoints. A greater percentage of patients achieved ≥ 15% 

increase with albuterol MDI 400 mcg compared to 100 mcg or 200 mcg doses at most timepoints. 

For all functions of serial PEFR, the albuterol DISKUS and MDI 200 mcg doses were 

comparable, including the percent of responders. For FEV1, both devices showed similar median onset of 

effect, maximum effect and time to maximum effect at the 200 mcg. A greater proportion of patients 

responded to albuterol MDI compared to albuterol DISKUS at the 200 mcg dose (66 versus 56% 

respectively), and albuterol MDI 200 mcg appeared slightly better than albuterol DISKUS for offset of 

effect, duration of effect and AUC (bl). 

At the 400 mcg dose, a greater proportion of patients were responders with albuterol MDI 

compared to albuterol DISKUS for both PEFR and FEV1. For functions of PEFR, results with both 

devices at the 400 mcg dose were relatively similar, although the duration of effect with the DISKUS was 

slightly longer compared to the MDI (5.8 hours versus 5.18 hours, respectively. Comparison of FEV1 

results indicate that albuterol MDI provided a longer duration of effect and median maximum effect 

compared to albuterol DISKUS, with the other results being comparable. 

The peak effect within 30 minutes of dosing in percent predicted PEFR or FEV1 for albuterol 

DISKUS 200 and 400 mcg were comparable without clear evidence of dose response. 

A dose-response was observed for the peak effect within 30 minutes of dosing for percent 

predicted PEFR among the three doses of albuterol MDI. Statistically significant differences were seen for 

the 400 versus 200 mcg ( p

were fewer significant differences between the 200 mcg and 400 mcg doses of albuterol MDI and no 

significant differences between 200 mcg and 400 mcg doses of albuterol DISKUS. The albuterol DISKUS 

200 mcg and albuterol MDI 200 mcg comparisons were generally similar for PEFR. There were 

occasional differences favoring albuterol MDI 200 mcg for FEV1. 

Assessor’s Comment 

This report contains an adequate efficacy and safety review of albuterol DISKUS 200 mcg and 400 mcg. 

Patients were aged between 4 and 11 years. However, no sub-analysis for the paediatric population was 

provided for patients between 4 and 6 years of age. Therefore this study is of limited value for indication 

of salbutamol DISKUS for children aged 4-6 years. It is acknowledged that the lower limit for this device 

(DISKUS) for paediatric use is 6 years. 

No recommendation for inclusion the age 4-6 years for albuterol DISKUS will be made. 

Single dose of albuterol DISKUS 200 mcg and 400 mcg induced significant bronchodilatation measured 

by peak effect within 30 minutes of dosing in change from same-day baseline in percent predicted PEFR 

and FEV1. There were no significant differences in efficacy between the two doses. 

No clinically relevant difference in efficacy was observed for treatment with albuterol DISKUS 200 mcg 

compared to that of albuterol MDI 200 mcg. 

The occurrence of in-clinic asthma exacerbations was similar across all albuterol treatments. 

All doses of albuterol MDI also induced significant bronchodilation when compared to placebo. For 

FEV1, a trend towards dose-response was observed among the doses of albuterol MDI. Albuterol 

DISKUS 200 mcg induced slightly better bronchodilation to that of albuterol MDI 200 mcg, as assessed 

by peak effect within 30 minutes in change from baseline in percent predicted PEFR whereas for FEV1, 

albuterol MDI appeared to provide a slightly greater benefit. 

Peak change in PEFR within 30 minutes of dosing observed with albuterol DISKUS 200 was slightly 

greater than that for albuterol MDI 200 mcg, but no statistically significant. Since measurement of PEFR 

included 4 and 5-year old children, this difference may reflect a more efficient use of the DISKUS than of 

MDI in younger children. 

Similar findings for secondary and other efficacy measures have also supported the efficacy of albuterol 

DISKUS and MDI. All albuterol treatment periods demonstrated efficacy versus placebo through 6 hours 

following treatment, with the exception of albuterol MDI 100 mcg for which the efficacy was 

demonstrated for only 4 hours following treatment. 

Albuterol DISKUS and albuterol MDI treatments were well tolerated during this single-dose study. The 

safety profile (adverse events and serial vital signs) of the albuterol treatments was comparable to that of 

placebo. 

2.1.2 Pressurized metered dose inhaler (pMDI) 

Ventolin Evohaler studies in children aged 4 years and over: 

Study/Protocol Number: SALA 3006 

Study title: A Randomized, Double Blind, Parallel Group, Clinical Trial Assessing the 

Safety and Efficacy of Albuterol 200 mcg (180 mcg ex-actuator) QID in CFC Propellant 11/12 

Versus Albuterol 200 mcg (180 mcg ex-actuator) QID in GR 106642X Propellant versus Placebo 

(GR 106642X) in Paediatric Subjects Aged 4-11 Years with Asthma 


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Study period 25 Nov 1996 - 28 May 1997 

GSK Study Report Number: Report No. RM1997/00818/00. 

Methods 

• Objective – To compare the efficacy and safety of Albuterol 200 mcg in CFC Propellant 11 

and 12 (P11/12) given QID to Albuterol 200 mcg in GR106642X Propellant given QID with placebo 

(GR106642X) via the MDI when administered for 2 weeks in paediatric subjects with asthma. 

• Study design - Multicenter Study, 10 centres in the USA and 1 centre in Puerto Rico, Phase III 

• Study population /Sample size – 135 male or premenarchal female patients 4 to 11 years of 

age, with asthma (ATS definition) requiring chronic pharmacotherapy for at least 6 months prior to 

screening. Patients have demonstrated a baseline FEV1 of 50 - 80% of predicted normal value and showed 

reversibility (>15% increase in FEV1 following inhalation of VENTOLIN MDI). 

• Treatments - During the treatment period, patients were randomized to receive albuterol GR 

106642X, 200 mcg via inhalation, albuterol P11/12, 200 mcg via inhalation and placebo GR106642X via 

inhalation 

The treatment per age group was as follows: 

- for 4 – 8 year group – 25 subjects received placebo GR106642X 

- 26 subjects received albuterol GR106642X 

- 23 subjects received albuterol P 11/12 

- for 9 – 11 year group – 18 subjects received placebo GR106642X 

- 20 subjects received albuterol GR106642X 

- 23 subjects received albuterol P 11/12 

� Outcomes/endpoints - The primary measures of efficacy were serial measurements of 

FEV1 (for 6 – 11 years old and those 4-5 years old patient capable of performing spirometry) and PEFR 

(using the Mini the Wright Peak Flow Metter) for all patients. 

Secondary measures of efficacy were AM and PM assessment of PEFR, subject rated asthma 

symptom scores, frequency of night time awakening, use of back-up albuterol and frequency of asthma 

exacerbation. 

Safety assessments included clinical adverse events, clinical laboratory tests, vital signs, 12-lead 

electrocardiograms and physical examinations. 


efficacy. 

� Statistical Methods 

Enrollment was planned for 90 evaluable patients (30 completed patients per treatment 

group).Data from previous studies have suggested that a reasonable assumption for the standard deviation 

of FEV1 percent of predicted is 12.23%. Using a significance level of 0.05, 30 patients per treatment group 

provided at least 80% power in detecting a difference of 10% in percent of predicted FEV1 between any 

treatment groups. 

Serial PEFR and FEV1 were summarized descriptively by treatment groups at both visits where 

serial PFTs were performed (Treatment day 1 and Treatment week 2). Change from baseline (either same 

day baseline or Treatment Day 1 baseline) was calculated for each patient as the PTF at each time point 

minus the baseline PFT. Percent change was the increase in the PTF as a percentage of the baseline PFT. 

Predicted PFT was based on the patient’s age, height and sex (Polgar). 

Repeated Measure Analysis of Variance was used to analyse PEFR for each post-randomization 

visit where serial PFTs were performed. Repeated measures analysis includes both the equally and 

unequally weight averages of all measurements. Repeated measures analysis and the individual timepoint 

analysis, based on percent of predicted PEFR used an Analysis of Covariance F-test with baseline percent 

of predicted PEFR used an Analysis of Covariance F-test with baseline percent of predicted PEFR as the 

covariate. Repeated Measures Analysis and the individual timepoint analysis was also based on the change 

from same day baseline using an Analysis of Variance F-test. 

Serial FEV1 was analyzed in the same manner. 


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Results 

The subjects included in the study met the inclusion and exclusion criteria. The number of the 

subjects is considered adequate, the three therapeutic group where relative homogenous and the number of 

subjects between 4 and 8 years old was slightly smaller than in the 9-11 year old group. 

Eligible patients had a history of asthma of at least 6 months duration that had required 

physician-prescribed chronic pharmacotherapy with at least one asthma medication for the 6 months 

preceding the screening visit. 

A baseline FEV1 or PEFR of 50-80% of their Polgar predicted normal value during the 

screening visit and treatment day 1 after withholding anti-asthma medications for the appropriate time 

intervals. 

If a 4 or 5-year old subject produced an FEV1 value which was not within ± 10% (based on the 

highest of the two values) or otherwise could not adequately perform the spirometry maneuver (could not 

maintain the effort for at least 3 seconds), then the baseline PEFR (using the study issued Mini-Wright 

Peak Flow Meter) had to be 50-80% of their Polgar predicted value. 

In addition, a corrector factor of 0.88 was used in African-Americans with regard to Polgar 

predicted values of FEV1 and PEFR. 

Reversibility Component: Each subject demonstrated an increase in FEV1 or PEFR (for 4 and 5 

years old only) of >15% following inhalation of VENTOLIN Inhalation Aerosol (in P11/12 propellant 

during the screening visit). 

Compared to placebo, both albuterol 200 mcg in propellant GR 106642X QID and albuterol 200 

mcg CFC propellant P11/12 QID produce significant improvements in pulmonary function. 

Both albuterol in propellant GR 106642X QID and albuterol 200 mcg CFC propellant P11/12 

QID produce clinically comparable improvements in pulmonary function of paediatric patients 4-11 years 

old with asthma. 

Treatment with albuterol 200 mcg in propellant GR 106642X QID is safe and well tolerated. 

Assessor’s comments Since salbutamol is acting as reliever medication, the design and duration of the 

efficacy clinical trial is adequately chosen. The emphasis is placed on the measurement of airway 

obstruction. Both FEV1 and Peak Expiratory Flow (PEP) reflect airway obstruction and are accepted as 

spirometric evaluation of the effect of anti-asthma drugs. 

The statistical analyses were well performed and have shown the following results: albuterol in 

propellants GR 106642X and P11/12 significantly improved lung function and decreased the need for use 

of back-up rescue albuterol. Albuterol GR 106642X improved symptoms compared to placebo GR 

106642X following two weeks of treatment in the paediatric asthma population. Albuterol GR 106642X 

was shown to have a similar efficacy profile to albuterol P11/12. 

Study/Protocol number: SB030003 

Study title: An Open-Label, Multi-Center Study to Evaluate the Performance and Patient 

Satisfaction of Albuterol HFA with Counter in Asthma or COPD Subjects at Least 4 Years of Age. 

Multicenter study, 37 sites in the United States enrolled and treated subjects. 

Phase III study: Since this is an open-label, single arm study, no statistical hypotheses will be 

tested. 

Sponsor: The GlaxoSmithKline Group of Companies Five Moore Drive Research Triangle Park, 

NC 27709 

Initiation Date: 16 May 2003 - Completion Date: 02 Dec 2003 

Objective - to evaluate the performance of Albuterol HFA with Counter 90 mcg in subjects with 

asthma or COPD. Additionally, patient satisfaction with the MDI device was evaluated. 

Number of subjects: 250 subjects on an outpatient basis to ensure about 200 subjects will 

complete the study. About 25% of the enrolled subjects (n=63) are aged between 4-11 years; in subjects ≥ 

12 years of age, about half (n=94) have asthma, while the others (n=94) have COPD. About 25% of the 

subjects (n=63) are ≥ 65 years of age. 


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Investigational products for this study: VENTOLIN HFA 90 mcg during the 7-21 day screening 

period, Albuterol HFA with Counter 90 mcg during the 50-day Open-label Treatment period. In addition, 

a separate VENTOLIN HFA will be provided for rescue use throughout the study period. Since this is a 

single arm study, there are no treatment comparisons of interest. 

No efficacy endpoints will be collected throughout this study. 

Dose counter evaluation measures include: 

• Diary card recorded actuations 

• Diary card recorded MDI counter readings 

• Canister weight (including MDI canister, actuator, and dose counter) before subject use 

and at the end of study 

• Results of any investigations into subject-reported problems with the MDI counter. 

Since this is an open-label, single arm study, no statistical hypotheses will be tested. No 

interim analyses will be performed. The diary data will comprise the primary data set of interest. 

Results 

The concordance between MDI with Counter readings and the diary card recorded actuations 

were assessed. Additionally, patient satisfaction with the MDI device was assessed. 

Ninety percent of the subjects (241 of 268) enrolled completed the study. In the subjects who 

completed the study, a total of 333 discrepancies between the diary card and MDI with Counter readings 

occurred in 43.865 MDI actuations, constituting a discrepancy rate of 0.76 discrepancies per 100 

actuations. 

Of the 333 discrepancies between the subject reported diary value and the subject reported MDI 

with Counter reading, the majority (88%) represented a discrepancy size of 1 or 2 actuations. The number 

of reports of the MDI firing without a change in the counter reading was very low (0.09 per 100 

actuations). 

The differences in subject-reported actuations ranged from a mean of 2.8 actuations lower to 1.3 

actuations higher than the Counter reading. At end of device use the mean number of actuations captured 

by the MDI with Counter was 200, and the mean number of actuations based on the patient reported diary 

card was 200. MDI with Counter endpoints for the ITT Population were similar to those of the Complete 

Population. 

This study confirmed the reliability of the Metered Dose Inhaler (MDI) with counter in actual 

patient use, including children over 4 years. 

Safety assessments indicated the study drug was well tolerated. 

Assessor’s comments: The concordance between MDI with Counter readings and the diary card recorded 

actuations confirmed the reliability of the Metered Dose Inhaler (MDI) with counter in actual patient use, 

including children over 4 years. Device robustness was good, but the dose counter did not reliably 

indicate the number of doses left in the device. Safety assessments indicated the fact that the study drug 

was well tolerated. 

Ventolin Evohaler studies in children aged 4 years and under: 

To support the efficacy and safety use of salbutamol inhaled formulations in the treatment of 

children younger than 4 yeras, the applicant submitted three clinical trials. These studies were identified 

(SB020001; SB030001, SB030002) and submitted to the FDA under FDA Paediatric Written Request in 

September 2007. These studies were also submitted to the FDA to amend the Indications and Usage 

section of the VENTOLIN HFA US labelling to provide for use in patients under 4 years of age. 

1. STUDY NUMBER: SB020001 

A Four-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-group, Multi-Center 

Study of VENTOLIN HFA MDI delivered with facemask and two different holding chambers in 


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Subjects aged 24 to

180mcg 

1 inhalation of 90mcg 

(Can B) 

Placebo 1 inhalation of placebo 

(Can A) 

1 inhalation of placebo 

(Can B) 


(Can B) 


(Can A) 


(Can B) 


(Can B) 


(Can A) 


(Can B) 

Treatments were randomly stratified by age: 24 to

Safety variable including assessment of: 

� Adverse events 

� Signs and symptoms of adrenergic stimulation as resulted from the physician’s 

assessment of tremor and the diary card and the FSII(R) questionnaire, 

� clinical laboratory assessment 

� ECG monitoring 

� vital signs 

� physical examination 

� peak expiratory flow in subjects who were capable of performing this maneuver. 

Statistical methods and determination of sample size: 

Considering a 10% dropout rate, approximately 75 subjects (25 per treatment group) were 

planned for enrollment in this study so that a minimum of 22 completed subjects per treatment group 

could be achieved per regulatory requirement. However the sample size of 22 subjects per treatment arm 

was not expected to provide enough statistical power to detect any difference between any two-treatment 

arms. 

All statistical tests performed assessed similar two-sided hypotheses between treatment groups. 

The nominal significance level was 0.05. 

Analysis of daily 24-hour asthma symptom scores, daytime asthma symptom scores, and 

FSII(R) total scores was performed using ANCOVA. 

Analysis of the percentage of symptom-free 24-hour days and 24-hour rescue albuterol use was 

performed using the van Elteren modification of the Wilcoxon rank-sum test. 

Analysis sets: 

Total Population - all subjects screened for inclusion in the study. Summaries of subject 

disposition and reasons for withdrawal prior to randomization were summarized for this population 

(n=97). 

Intent-to-Treat (ITT) Population - all subjects who were randomized and received at least one 

dose of study medication. Analyses of all safety and efficacy data were based on this population (n=77) 

Screen Failure Population - all subjects screened for inclusion in the study who were 

discontinued from the study prior to randomization who were not administered study drugs 

(n=20) 

Assessor's comment: 

The patients included in this study are paediatric subjects aged 24 to


Primary efficacy variable 

Analysis of daily 24-hour asthma symptom scores by holding chamber (Aerochamber Plus or 

Optichamber) showed similar improvements from baseline in all treatment groups over 4 weeks of 

treatment. Results were comparable between the holding chambers. 

Similarly, the analysis of daily 24-hour asthma symptom scores for subjects using concomitant 

ICS or no concurrent therapy demonstrated similar improvements from baseline in all treatment groups 

over 4 weeks of treatment 

Secondary efficacy 

In the ITT population the daytime asthma symptom scores were similar across the treatment 

groups at baseline. At endpoint, subjects in the VENTOLIN HFA treated groups experienced fewer 

daytime asthma symptoms than subjects in the placebo group, however the differences were not 

significant. 

At Baseline, the percentage of symptom-free 24-hour days was greater for the placebo group 

and comparable with the VENTOLIN HFA treated groups. The mean change over the four week 

treatment period and evaluation at endpoint in percent of symptom-free 24 hour days was greater, 

although not significant in the two VENTOLIN HFA treated groups. When the weekly percentage of 

symptom-free 24-hour days was analysed throughout the four weeks of treatment, subjects in the 

VENTOLIN HFA treated groups demonstrated a greater change from baseline although not significant 

when compared to placebo 

At baseline, 24-hour rescue albuterol use was comparable across the treatment groups except 

for a slightly higher use in the VENTOLIN HFA 180mcg group. At endpoint, subjects in both 

VENTOLIN HFA groups experienced a slightly greater mean reduction in 24-hour albuterol use; this 

difference between placebo was greater for subjects in the VENTOLIN HFA 90mcg group, albeit did not 

achieve statistical significance. The maximum decrease in 24-hour rescue albuterol use ranged between – 

1.2 and –2.1 puffs in week 3. Although not significant this decrease was greater in the VENTOLIN HFA 

treated groups. 

Other efficacy endpoints 

In the ITT population, night time asthma symptom scores were similar across the treatment 

groups at baseline. Subjects in the active groups experienced a reduction in night time asthma symptom 

scores mostly during the first three weeks of treatment with the maximal decrease in night time symptoms 

at week 3 (–35.7% change from baseline) for the VENTOLIN HFA 90 mcg group. At endpoint, subjects 

in all three groups had similar night time symptom scores. 

The percentage of nights with no awakenings due to asthma for subjects in the VENTOLIN 

180mcg group at baseline were slightly lower than the other two groups. Both the VENTOLIN HFA 

treated groups experienced a greater percentage of nights with no awakenings due to asthma than placebo, 

which did not change from baseline at endpoint during the 4 weeks of treatment 

Three subjects using rescue systemic and inhaled corticosteroids during the treatment 

period, one in the placebo and two in the VENTOLIN HFA 90 mcg group. The subject in the placebo 

group received systemic corticosteroids and the subjects in the VENTOLIN HFA group received inhaled 

corticosteroids to treat their exacerbations. 

Treatment failure was defined as premature discontinuation from the study due to lack of 

efficacy. The mean time to asthma exacerbation was doubled in the active group. The subject in the 

placebo group had an exacerbation during the first week of treatment. In the VENTOLIN HFA 90mcg 

group, one subject had an exacerbation during the second week of treatment while the other experienced 

an exacerbation during the final week of treatment. Too few subjects had asthma exacerbations to draw 

any meaningful conclusions regarding time to exacerbation. 


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Peak expiratory flow 

Mean Baseline AM and PM PEF were slightly lower in the VENTOLIN HFA 90mcg group 

than in the other two treatment groups. Small mean increases in AM and PM PEF was noted in both of the 

VENTOLIN HFA treated groups over 4 weeks of treatment, however these increases were slightly less in 

the VENTOLIN HFA 90mcg group. At baseline and endpoint the mean AM and PM PEF were 

comparable in VENTOLIN HFA treated groups 

Safety results 

Adverse events 

The overall incidence of adverse events occurring both pre-treatment and during treatment were 

similar among the treatment groups and the adverse events that occurred most frequently in this study 

were as expected in a population of children 243% of subjects and greater than placebo. A total of 33 subjects (43%) 

reported at least one AE during treatment: 11 subjects (42%) in the placebo group, 9 subjects (35%) in the 

VENTOLIN HFA 90mcg group, and 13 subjects (52%) in the VENTOLIN HFA 180mcg group. 

System organ classes with the highest incidence of AEs were infections and infestations (2 

subjects in the placebo group, 3 subjects in the VENTOLIN HFA 90mcg group, and 5 subjects in the 

VENTOLIN HFA 180mcg group) and investigations (e.g., ECG and laboratory findings-no subjects in 

the placebo group, 3 subjects in the VENTOLIN HFA 90mcg group, and 4 subjects in the VENTOLIN 

HFA 180mcg group). 

A total of 3 subjects had one AE each considered by the investigator to be potentially drug 

related (2 subjects in the VENTOLIN HFA 90mcg group and 1 subject in the VENTOLIN HFA 180mcg 

group). In the VENTOLIN HFA 90mcg group, drug-related AEs were “Blood alkaline phosphatase 

increase” and “Electrocardiogram QT corrected interval prolonged.” In the VENTOLIN HFA 180 mcg 

group, the drug-related AE was psychomotor hyperactivity. These AEs did not lead to subject withdrawal 

from the study 

Signs and symptoms of adrenergic stimulation 

At all on-treatment assessments, most subjects (91-100%) had no tremor present. No moderate or 

severe tremor was reported at any time during the study. At the post treatment assessment on Day 1, mild 

tremor was reported for two subjects (one each) in the VENTOLIN HFA 90 and 180mcgs group. 

However the subject in the VENTOLIN HFA 180mcg did not have any further episodes of tremor after 

week 1, during the study. Mild tremor was reported for ≤2 subjects at each subsequent treatment 

assessment. At Week 4, mild tremor was reported in 1-2 subjects in the VENTOLIN HFA treatment 

groups and in no subjects in the placebo treated group. 

FSII(R) questionnaire 

Functional Status II (R) was assessed by the parent/guardian-for the study site administered 

FSII(R) questionnaire for each subjects. Mean Baseline scores ranged from 82.6 to 85.6 and indicated a 

high pre-treatment functioning. There was improvement in scores over the treatment period in all 

treatment groups (adjusted mean Endpoint scores ranged from 88.1 to 92.0). However no significant 

differences were observed between the VENTOLIN HFA treatment groups and the placebo treatment 

group 

Clinical laboratory assessment 

No AEs of hypokalemia were reported 

Blood glucose values remained fairly consistent across the treatment groups over the course of 

the study. 

Hyperglycemia was reported for one subject in the placebo group. 

ECG monitoring 

Most subjects had normal cardiovascular assessments and results were comparable in the 

treatment groups. There were no clinically relevant differences in the mean change from baseline in the 

QT interval between treatment groups. 


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At Week 4, mean changes from baseline in heart rate was small. Mean changes from baseline in 

heart rates for the subjects in the VENTOLIN HFA 90 mcg group were slightly higher (9-13bpm) when 

compared to VENTOLIN HFA 180mcg (1.4-8.9bpm) or placebo (0.9-1.6bpm). 

Vital signs 

Mean values for systolic and diastolic blood pressure during Week 4 were comparable to those 

observed at Baseline. Mean changes from baseline were very small, ranging from -0.1 to 1.2 mmHg for 

systolic blood pressure and -1.1 to -1.6mmHg for diastolic blood pressure. Mean values for heart rate, 

body temperature, and respiratory rate at Week 4 were also comparable to those observed at baseline. 

Physical examination 

At Screening, there were 7-11 subjects across treatment groups (11 in placebo, 8 in VENTOLIN 

HFA 90mcg and 7 subjects in the VENTOLIN HFA 180mcg group) with abnormal physical findings. 

The body system with the most frequent physical abnormalities were ear, nose and throat (ENT: 7-10 

subjects) and eyes (1-4 subjects). 

A slightly higher incidence of hair and skin changes were noted in the VENTOLIN HFA 

treatment groups (1 subject each) compared to the placebo group (no subjects) and respiratory changes 

were noted in the placebo and VENTOLIN HFA 90 mcg group (1 subject each) alone. 


The results of the primary efficacy parameter showed similar improvements from baseline in all treatment 

groups over 4 weeks of treatment. An improved trend was demonstrated in daytime and nighttime asthma 

symptom scores, percentage of symptom free 24 hour days, nighttime awakenings and AM/PM peak 

expiratory flow compared to placebo. These differences were not statistically significant at endpoint. 

This study demonstrated similar safety profile of VENTOLIN HFA 90 mcg or 180 mcg when compared to 

placebo and included adverse events, adrenergic stimulation, ECG monitoring, serum potassium and 

blood glucose levels. The overall safety profiles were similar across the treatment groups. 

In conclusion, the efficacy of VENTOLIN HFA 90 mcg or 180 mcg administered three times daily to 

relieve asthma symptoms in younger children aged 24 to

A total of 118 male and female subjects between the ages of birth to 81%). Twenty-two subjects below 

1 year of age were included. 

Inclusion criteria: 

� Outpatient in an acute care setting. 

� Birth to 23 months old at visit 2) 

� Male or female 

� documented history of asthma symptoms 

� Subjects had least 1 episodes of increased symptoms of asthma requiring medical attention and asthma 

pharmacotherapy within the preceding 12 months prior to Visit 1 

� Subjects had received a maintenance asthma medication other than systemic corticosteroids on a 

regular basis for the preceding 4 weeks 

� Subjects received treatment with a short-acting beta-agonist for the relief of asthma symptoms at least 

three times per week over the preceding 4 weeks prior to visit 1. 

� Subjects and parents/guardians had to have demonstrated the ability to comply with the use of the 

MDI and the holding chamber with facemask using the demonstration kit provided to the site. 

The primary objective of this study was to evaluate the safety and efficacy of VENTOLIN 

HFA MDI 90mcg and 180mcg TID delivered with facemask and a holding chamber versus HFA placebo 

supplemented with the use of rescue VENTOLIN HFA or albuterol nebules over a 4 week (minimum 29 

days) treatment period in subjects between the ages of birth to

In the ITT population the daytime asthma symptom scores were similar across the treatment 

groups at baseline. At endpoint, the daytime asthma symptoms were also similar across treatment groups. 

At Baseline, the percentage of symptom-free 24-hour days was greater for the placebo (16.3) 

group and VENTOLIN HFA 180mcg group (14.7) than for the VENTOLIN HFA 90mcg (9.0) treated 

group. 

The mean change over the four week treatment period, the evaluation at endpoint in the percent 

of symptom-free 24 hour days, was similar. When the weekly percentage of symptom-free 24 hour days 

was analyzed over the four weeks of treatment, subjects in all three groups demonstrated that the 

percentage of symptom free days increased. 

Other efficacy endpoints 

At baseline, 24-hour rescue albuterol use was comparable across the treatment groups except 

for a slightly lower use in the VENTOLIN HFA 180mcg group. At endpoint, subjects in the VENTOLIN 

HFA 90 mcg group experienced a slightly greater mean reduction in 24-hour albuterol use. 

The maximum decrease in 24 hour rescue albuterol use was between –1.5 and –1.8 puffs at week 

1 with the greatest decrease in the VENTOLIN HFA 90mcg group. 

The mean time to asthma exacerbation for the active group was approximately 5-8 days 

greater than that for the placebo group. The subjects in the placebo group had an exacerbation ranging 

between the first week and 41 days post treatment of investigational product administration. 

In the VENTOLIN HFA 90mcg group, one subject reported an exacerbation more than once and 

was withdrawn. Another subject from the same group reported an exacerbation after 24 days of treatment 

that resolved. 

In the VENTOLIN HFA 180 mcg group 3 subjects reported an exacerbation between 17-28 days 

during the treatment period and one reported an exacerbation at 36 days during the post treatment period. 

The primary cause of these asthma exacerbations were either respiratory infections or infections due to 

unknown etiology. 

In the ITT population, night time asthma symptom scores were similar across the treatment 

groups at baseline. At endpoint, subjects in all three groups had similar night time symptom scores. 

The percentage of nights with no awakenings due to asthma for subjects in the VENTOLIN 

90mcg group at baseline were slightly lower than the other two groups. Both the VENTOLIN HFA 

180mcg and placebo treated groups experienced a similar change from baseline to endpoint (the average 

of the 4-week treatment period) in percentage of nights with no awakenings due to asthma which was 

lower than the change from baseline to endpoint in the VENTOLIN HFA 90mcg group 



A total of 59 subjects (53%) reported at least one AE during treatment: 20 subjects (71%) in the 

placebo group, 17 subjects (59%) in the VENTOLIN HFA 90mcg group, and 22 subjects (76%) in the 

VENTOLIN HFA 180mcg group. 

The most frequently reported event was pyrexia which was higher in the VENTOLIN HFA 

180mcg group (7 subjects) than the VENTOLIN HFA 90mcg (2 subjects) and placebo (3 subjects). The 

next frequently reported adverse events were nasopharyngitis (3 subjects in the placebo group, and 2 and 4 

subjects respectively in the Ventolin 90 and 180mcg groups), upper respiratory tract infection (5 subjects 

in the VENTOLIN HFA 180mcg group and 3 in the placebo group), sinus tachycardia (5 subjects in the 

VENTOLIN HFA 180mcg group and 2 subjects each in the VENTOLIN HFA 90mcg and placebo 

groups), nasopharyngitis (3 subjects in the placebo group and 2 and 4 subjects in the VENTOLIN HFA 90 

and 180mcg groups respectively), teething (3 subjects in the placebo, 4 in the VENTOLIN HFA 90mcg 

and 1 subject in the VENTOLIN HFA 180mcg group), rhinorrhoea (3 subjects in the placebo and 2 


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subjects in the VENTOLIN HFA 180mcg group), and sinus arrhythmia (1 subject in the VENTOLIN 

90mcg group only). Other adverse events were reported in one or less subjects per treatment group. 

Symptoms of adrenergic stimulation 

At all on-treatment assessments, all subjects had no tremor present. 

The mean change from baseline in the heart rates for the week 4 pre and post dose were 

consistent in terms of a drop in all three treatment groups (i.e. range of -1.6 to - 5.4 for the week 4 predose 

and -2.9 to 3.0 for the week 4 post dose group) except for the post-dose VENTOLIN 180mcg group 

where the heart rate increased by 3 beats/minute. 

FSII(R) questionnaire 

Functional Status II (R) was assessed by the parent/guardian-for the study site administered 

FSII(R) questionnaire for each subjects. Mean scores were similar across the treatment groups at Baseline 

and at Endpoint except for the sleep well and unusually irritable scores at baseline that were slightly lower 

in the placebo group. 

Clinical laboratory assessment 

No AEs of hypokalemia were reported. 

Blood glucose values remained fairly consistent across the treatment groups over the course of 

the study. 

No AEs of hyperglycemia were reported. Six subjects, (2 in the placebo group and 3 and 1 

subject in the VENTOLIN 90mcg and VENTOLIN 180mcg groups respectively) had laboratory errors at 

the study termination visit either due to hemolysis, failed blood draw attempts and/or parent refusal to 

blood draw 


At Week 4, mean changes from baseline in heart rate, and QT interval were small. Mean 

changes from baseline in heart rates for the subjects in the VENTOLIN HFA 90 mcg group were slightly 

higher (-5.4 to -2.9 bpm) when compared to VENTOLIN HFA 180mcg (-1.6 to 3.0 bpm) or placebo (-4.5 

to -2.0 bpm). No subject had a QT or QTc (Fridericia’s formula) interval >460msec. 

Vital sings 

Mean values for systolic and diastolic blood pressure at Week 4 were comparable to those 

observed at baseline except for systolic pressure in the VENTOLIN 90 mcg group which was slightly 

higher (5.5mmHg) at Week 4. Mean changes from baseline were very small, ranging from 0.4 to 

5.5mmHg for systolic blood pressure and -0.9 to 3.4mmHg for diastolic blood pressure. 

Mean values for heart rate, body temperature, and respiratory rate at Week 4 were also 

comparable to those observed at baseline. 

Physical examinations 

At the end of the study, there was a higher incidence of unfavorable changes in the VENTOLIN 

HFA 180 mcg treatment group (7 subjects) compared to the VENTOLIN HFA 90mcg (2 subjects) and 

placebo (3 subjects) treatment group. These changes were primarily ENT (ear, nose and throat), 5 subjects 

in the VENTOLIN HFA 180 mcg group vs. 2 and 1 subject in the placebo and VENTOLIN HFA 90mcg 

groups respectively. A slightly higher incidence of ENT, hair and skin, and respiratory changes were 

noted in the placebo and VENTOLIN HFA 180 mcg treatment groups (2 and 5 subjects respectively) 

compared to the placebo group (1 and 2 subjects, respectively) and the VENTOLIN 90mcg group (0 

subjects in each body system). An unfavourable change in the urogenital body system was noted in the 

VENTOLIN HFA 90 mcg group (1 subject) only. 


The results of the primary, secondary and other efficacy parameters showed similar improvements from 

baseline in all treatment groups over 4 weeks of treatment. 


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This study demonstrated similar safety profile for VENTOLIN HFA 90 mcg and 180 mcg when compared 

to placebo and included adverse events, adrenergic stimulation, ECG monitoring, serum potassium and 

blood glucose levels. The overall safety profiles were similar across the treatment groups. 

In conclusion,in this study were not demonstrated efficacy of VENTOLIN HFA 90 mcg or 180 mcg 

administered three times daily to relieve of asthma symptoms in children less than 2 years of age but 

Ventolin HFA inhalation aerosol had a similar safety profile to placebo in this age group. 

3. STUDY NUMBER: SB030002 

A Randomized, Double-Blind, Parallel-group, Multi-Center Study of Albuterol Sulfate HFA 

Inhalation Aerosol Delivered Cumulatively with a Valved Holding Chamber and an Attached 

Facemask in Subjects Between Birth to 23 Months of Age with Acute Wheezing Due to Obstructive 

Airways Disease 

Study SB030002 was a multicenter double-blind, randomized, parallel-group, cumulative dose 

study of albuterol sulfate HFA inhalation aerosol in an acute care clinical setting where subjects were seen 

in the emergency department (ED) or clinic. This study was a Phase III study conducted at 20 sites in the 

United States (US). A total of 16 sites enrolled subjects. 

The study was initiated on 10, September 2004 (date first subject screened) and completed on 

26, February 2006 (date of last observation for last subject). 

This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline 

Standard Operating Procedures for all processes involved, including the archiving of essential documents. 

A total of 110 subjects were screened for this study, 23 of these subjects discontinued prior to 

randomization, and 87 male and female subjects with acute wheezing due to obstructive airways disease 

were randomized and enrolled in the study. A minimum of 30 completed subjects per treatment group 

complete the study. Enrolment was monitored to ensure that approximately 15 total subjects below one 

year of age, including neonates, completed the study. 

Inclusion criteria: 

� Outpatient in an acute care setting. 

� Birth to 23 months of age (subject was less than 24 months of age at Randomization). 

� Male or female 

� Acute wheezing consistent with reversible obstructive airway disease 

� Asthma symptoms score between 4 and 9 based on the Modified Tal Asthma Symptoms 

Score (a Modified Tal Asthma Symptoms Score (range, 0 to 12) was calculated by adding 

the scores for each of the four variables: components of respiratory rate, wheezing, 

cyanosis, and accessory respiratory muscle utilization) 

� Pulse oximetry greater than 88% taken at screening while the subjects was breathing room 

air 

� Written informed consent was obtained from the subject's legally acceptable 

representative prior to study participation 

Exclusion criteria: 

� Experienced an exacerbation of obstructive airways disease or a history of intubation or 

respiratory distress 

� Presented with known pulmonary or cardiac congenital malformations 

� Had clinically significant medical conditions, including: chronic pulmonary disease (e.g., 

cystic fibrosis, bronchiestasis, or bronchopulmonary dysplasia), cardiovascular disease, 


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endocrine disorders, hepatic and renal disease, glaucoma, respiratory infection within two 

weeks prior to screening, and a history of immediate or delayed hypersensitivity reaction 

to any sympathomimetic drug or corticosteroid therapy 

� Had used methotrexate, gold, cyclosporine, and other immunosuppressive agents 

� Presented with a fever (defined as a rectal temperature ≥100.5°F (38°C). 

� Born prior to 34 weeks of gestation and/or had an episode of mechanical ventilation 

� Had clinically significant abnormalities of clinical laboratory tests at screening 

� Had received an investigational drug for any indication within 30 days of screening or 

within 10 half-lives (whichever was the longer of the two) 

The primary objective of this study was to evaluate the safety and efficacy of cumulative dose 

administration of VENTOLIN HFA 180mcg and 360mcg both in propellant 1, 1, 1, 2-tetrafluoroethane 

(GlaxoSmithKline code GR106642X) MDI inhalation aerosol delivered with a valved holding chamber 

(AeroChamber Plus) with attached facemask in an acute care clinical setting. Subjects were between the 

ages of birth to

Protocol deviations were summarised by each treatment group and haven’t had a significant impact on 

the safety or integrity of the study results. 

Criteria for evaluation: 

Primary efficacy variable 

The mean percent change from baseline over the entire treatment period in the Modified Tal 

Asthma Symptom Score assessed by the investigator. 

Secondary efficacy variable including 

The change from baseline over the entire treatment period in absolute Modified Tal Asthma 

Symptoms Score, and rescue salbutamol use. 

groups. 

Safety variable including assessment of: 

� Continuous ECG monitoring 

� Adverse events 

� Pulse oximetry 

� Vital signs 

� Physical examination 

� Clinical laboratory tests for blood glucose and serum potassium, 

� Symptom of adrenergic stimulation. 

Statistical methods and determination of sample size: 

All statistical tests performed tested two-sided hypotheses of no difference between treatment 

The nominal significance level was 0.05. 

Analysis of Modified Tal Asthma Symptom Score data was performed using analysis of 

covariance (ANCOVA) adjusting for baseline Modified Tal Asthma Symptoms Score, investigative site, 

age, and gender. 

All programming was performed using SAS version 8, in a UNIX environment. 

The sample size of 30 subjects per treatment group would provide at least 90% power to detect a 

difference of 23% between the two treatment groups in mean percent change from baseline in Modified 

Tal Asthma Symptom Score over the entire 3-hour treatment period 

Analysis sets: 

Intent-to-Treat (ITT) Population - all subjects who were randomized and received at least one 

dose of study medication. Analyses of all safety and efficacy data were based on this population (n=87) 

Fulfilled Regulatory Criteria (FRC) Population - subjects in the ITT Population who also 

received a minimum of 3 study treatment doses and provided Holter monitoring data, was a supporting 

population used for analysis of safety and efficacy data (n=66) 

The subset of the ITT Population, the Fulfilled Regulatory Criteria (FRC) population was 

evaluated based on the FDA Written Request and this population included subjects that required a 

minimum of three study treatment dosings during the treatment period. 


In general, the efficacy of bronhodilatator therapy in infants is often difficult demonstrated. According to 

CHPM/EWP/4151/00, Rev 1 “in children 5 years of age and younger, spirometry is feasible in children 

over 3 years, although either FEV0.5 or FEV0.75 may be a better measure than FEV1 ( literature should 


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e reviewed particularly with regard to criteria for accepting data, data reporting and repeatability), 

however the diagnosis of asthma is challenging in this younger age group and may need to be based on 

clinical judgment, assessment of symptoms and physical findings”. Since the children included in the study 

were younger than 24 months of age, we consider that the efficacy parameters tested in this study have 

been well chosen and could demonstrate the effectiveness of salbutamol inhalation aerosol in treatment of 

acute wheezing. The efficacy evaluation was performed by the physician and not by the caregiver (parent 

or guardian) 

The safety variables measured during the study are accepted. Moreover, the statistical methodology used 

is accepted. 


Primary efficacy variable, mean percent change Modified Tal Asthma Symptom Score over 

the entire treatment period compared to baseline. 

The primary efficacy measure, mean percent change from baseline over the entire treatment 

period in the Modified Tal Asthma Symptom Score decreased indicating improvement in the overall 

analysis for each of the 2 treatment groups and two populations (VENTOLIN HFA 180mcg:-49.8% (ITT), 

-47.2 % (FRC); VENTOLIN HFA 360mcg:-48.4% (ITT), -47.9% (FRC)). 

No significant differences were noted between the two treatment groups in the entire treatment 

period or at any particular assessment. 

Secondary efficacy results 

The overall adjusted mean change from baseline in Modified Tal Asthma Symptom Score 

decreased by 2.7 and 2.9 in the VENTOLIN HFA 180mcg and 360mcg groups respectively, showing 

improvement in both treatment groups and populations, however no statistically significant difference 

between the two treatment groups were observed at any specific assessment (Baseline value was score 5.7 

(SE=0.19) and 5.8 (SE=0.19) for the VENTOLIN HFA 180mcg and 360mcg groups respectively). 

The mean dose for rescue albuterol use during treatment was considerably higher in the 

VENTOLIN HFA 360 mcg group when compared to the VENTOLIN HFA 180mcg group, although the 

number of subjects using rescue albuterol use was very similar across treatment groups. 



Overall the incidence of adverse events was low across both treatment groups. Pyrexia was the 

only AE reported during treatment in 1(2%) subject each in both treatment groups. No subjects withdrew 

due to this condition or any other AE. 

A total of 2 subjects, one in each VENTOLIN HFA 180mcg and 360 mcg groups had an AE 

considered by the investigator to be potentially investigational product related. A subject in the 

VENTOLIN HFA 180mcg group had ventricular extrasystoles and a subject in the VENTOLIN HFA 

360mcg group experienced tachycardia. These AEs resolved the same day and did not cause subject 

withdrawal from the study. 

Two subjects in the VENTOLIN HFA 360 mcg group experienced a SAE one subject had 

worsening of wheezing and the other subject experienced bronchial hyperactivity, and respiratory 

syncytial virus infection. Each investigator considered the respective events having no causal relationship 

to study medication. Both subjects completed the study. 

Holter monitoring 

There were no significant Holter abnormalities. For both the ITT and FRC Population 7 subjects 

(17%) in the VENTOLIN HFA 180mcg group and 2 subjects (5%) in the VENTOLIN HFA 360mcg 

group had abnormal not significant Holter abnormalities. 


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The overall (based on all evaluable data which may include more or less than 3 hours) mean 

cardiac rates showed a 0.7 decrease from baseline in the VENTOLIN HFA 180mcg group whereas an 

increase of 5.5 from baseline for the VENTOLIN HFA 360mcg group. 

The number of subjects with single VEs (ventricular ectopic events) in each treatment group was 

3 subjects in the VENTOLIN HFA 180mcg group and a single subject in the VENTOLIN HFA 360mcg 

group. 

The number of subjects with SVEs (supraventricular ectopic events) was higher in the 

VENTOLIN HFA 180mcg (9 and 8 subjects in the ITT and FRC Populations respectively) group 

compared to the VENTOLIN HFA 360mcg group (4 and 3 subjects in the ITT and FRC Populations 

respectively). 


Seven subjects in each treatment group had abnormal significant ECGs at end of treatment. In 

the VENTOLIN HFA 180mcg group majority of these subjects had tachycardia for age event (based on 

protocol defined age specific heart rates for tachycardia) and five of the subjects had this abnormality at 

baseline. In the VENTOLIN HFA 360mcg group 6 out of the 7 subjects with abnormal significant ECGs 

had tachycardia and the remaining subject had sinus rhythm and prolonged QT or QT-U fusion. 

The mean change from baseline in ECG recorded heart rates was similar at end of treatment for 

the VENTOLIN HFA 180mcg group (decrease of -1.8/ITT or - 2.6bpm/FRC) for both populations. 

However there was an increase in heart rate for the VENTOLIN HFA 360mcg group (3.3/ITT or 

8.2bpm/FRC) for both the populations. 

At end of treatment the mean QT values were similar, however the change from baseline for the 

VENTOLIN HFA 180mcg group increased to 0.7 (ITT)/2.8msec (FRC) for QT and 0.4 (ITT) /2.9msec 

(FRC) for QTc and for the VENTOLIN HFA 360mcg group it decreased to -5.3 (ITT)/-8.0 msec (FRC) 

for QT and -5.2 (ITT) /-4.8msec (FRC) for QTc for both the populations. None of the individual 

QT or QTc (Fridericia’s formula) values were >440msec. 

Vital Signs 

Blood Pressure (BP): Mean changes from baseline at end of treatment were very small, ranging 

from -1.0 to 2.2mmHg for systolic blood pressure and -1.9 to 0.9mmHg for diastolic blood pressure. 

Mean values for body temperature, and pulse oximetry at end of treatment were also comparable 

to those observed at baseline. 

The mean respiratory rates decreased at end of treatment by almost 10 breaths/min for both 

treatment groups. 

Physical examination 

Physical abnormalities induced of treatment at Screening and at end of the study are presented. 

At Screening, there were 17 (40%) subject in VENTOLIN HFA 180mcg group and 16 (36%) 

subjects in the VENTOLIN HFA 360 mcg with abnormal physical findings. The body system with the 

most frequent physical abnormalities was ear, nose and throat. The other abnormalities were in the eyes (1 

[2%] and 4 [9%] subjects respectively in the VENTOLIN HFA 180mcg and 360 mcg groups), respiratory 

(3 [7%] subjects in the VENTOLIN HFA 180mcg and 1 [2%] subject in the VENTOLIN 

HFA 360mcg group), hair and skin (1 [2%] subject in the VENTOLIN HFA 180mcg and 3 [7%] 

subjects in the VENTOLIN HFA 360mcg group) abdomen (1 [2%] subject in each treatment group) and 

lymph nodes in 1 (2%) subject in the VENTOLIN HFA 180mcg group body systems. 

At the end of the study, there was a higher incidence of abnormalities (i.e. unfavorable changes) 

in the VENTOLIN HFA 180mcg treatment group (2 [5%] subjects) compared to the VENTOLIN HFA 

360mcg (0 subjects) group. This unfavorable change occurred in the ear nose and throat body system. 

There were no unfavorable changes noted for the other body systems. 

Clinical laboratory tests 

No subjects reported hypokalemia. 


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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). 


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. 


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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 


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exercise were plotted. The maximum absolute fall and maximum percentage fell in PEFR on each 

treatment and for each subjects was calculated and the mean values recorded. 

In both studies was observed a typical pattern of EIA following placebo. PEFR fell rapidly 

during the first minute post exercise and continued to fall for 5 minutes before slowly starting to increase 

back to baseline. 

All treatments were more effective than placebo regarding the inhibition of EIA. 

In study 1 both nebulised salbutamol and SCG administered individually were highly 

significantly more effective than placebo (p < 0.001), but salbutamol was seen to provide a significantly 

greater protection than SCG (p0,1). 

In study 2 the dry powder SCG was significantly better than placebo (p< 0.01) and significantly 

less effective than salbutamol dry powder (p

The improvment in PEF was 51 L. min.-1 for JN and 27 L.min -1 for PMDi at 30 minutes (p= 

0.0007) and 57 L. min .-1 for JN and 31,5 L.min -1 for PMDi at 60 minutes (p= 0.001). 

Conclusion was that the administration of salbutamol by PMDi with a large volume spacer 

device provides effective relief in the management of acute asthma in children, but to a lesser extent than a 

jet nebuliser. The difference may represent a dose response effect. 

Study SBM 40140 (505/250) 

Duble-blind, randomized, controlled is a subset of a large trial carried out in 275 children aged 3 

to 17 years entitled „A randomized controlled trial using objective assessment of airway obstruction in the 

treatment of acute asthma in preschool children” (Ducharme F.M., Davis G.M., Montreal, Canda, 1998). 

Objective - to compare the efficacy of salbutamol deliverded by JN vs. salbutamol delivered by 

PMDi with a large volume spacer (Volumatic) for managment of acute asthma in children. 

In this study were compared 4 different nebulised inhaled salbutamol in 112 children aged 3 to 

6 years with acute asthma. 

Treatments - following an initial inhalation of salbutamol patients were randomised to one of 

these 4 treatment schedules: 

- salbutamol high dose every hour, 

- salbutamol low dose every 30 minutes, 

- salbutamol high dose every hour + a single dose of ipatropium bromide 

- salbutamol low dose every 30 minutes + a single dose of ipatropium bromide. 

Results 

On arrival the mean % predicted resistence by forced oscillation (Rfo) was 76 (102, 255) and 

SaO2 was 95% (88, 100) 

Rfo improved significantly between baseline and at 90 minutes for all treatments (p < 0.001) and 

SaO2 improved in the 45 patients with an initially low SaO2 (p= 0.001). 

There was no difference among the 4 treatments: salbutamol frequent low dose (SFLD) vs. SH (p= 

0,28), IB vs. SH (p= 0,41). There was no synergy between SFLD + IB (p= 0,94). 

Salbutamol in frequent low dose was associted with increasd vomiting. 

Conclusion was that in preschool children with mild and moderate asthma more frequent low 

dose of salbutamol did not results in greater improvment in Rfo and SO2 than hourly high dose of 

salbutamol. 

The results do not support the use of frequent low dose of nebulised salbutamol or the addition 

of ipratropium bromide compared to hourly high dose of salbutamol in children with mild and moderate 

asthma. 

Assessor’s comment: The findings of small studies RID/CT/69 and D37/A24 conducted approximately 20 

years ago in the mid 1980s do not provide sufficient evidence to justify change to the product information. 

The results of studies SBM 40140 (505/250) and SBM 40122 (Neb 02) conducted in the mid 1990s have no 

impact on product information 

2.2 Oral Administration 

2.2.1 Controlled–release tablets and tablets 

SCR4/85/CPI Study Report GMR/86/008 

Double blind parallel group comparison of controlled–release Salbutamol tablets 4mg bd with 

standard Salbutamol tablets 2mg qd in the management of reversible airways obstruction in children“ 

Objective - to investigate the efficacy of controlled-release Salbutamol 4mg twice daily with 

standard Salbutamol tablets 2mg four times a day in children aged 3 to 16 years. 

Study design - randomized controlled, double blind, parallel group trial, carried out in 16 

hospital centres. 


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Study population/ sample size - children with a clinical history of reversible airway obstruction 

(RAO), stratified into 2 age groups: 6 years or less - 74 children (31%) and 7 years or greater and less than 

17 years- 163 (69%). 

Treatments - 120 patients received salbutamol CR 4 mg and 117 patients received Salbutamol 

standard tablets 2mg. Treatment allocation was randomized in balanced blocks within each of these age 

groups. Patients were entered into a 2-week pre trial run-in period and thereafter randomly allocated to 

receive one of the treatment regimens for a period of six weeks. 

- Group A: Controlled release salbutamol tablets (4 mg salbutamol controlled tablet twice daily 

plus one placebo standard 2 mg tablet four times daily) 

- Group B: Standard Salbutamol tablets (one placebo controlled tablet twice daily plus one 

standard 2 mg salbutamol tablet four times daily) 

Endpoints - primary endpoints: 

- peak expiratory flow rate (PEER), forced expiratory volume in one second (FEV1) and forced 

vital capacity (FVC) were made in those children who were able to perform the spirometry tests reliably. 

- second endpoints - vital capacity (VC) and mid expiratory flow rate (FEV50) were 

additional optional assessments. 

Statistical methods 

For respiratory function measurements was applied the standard statistics methods for 

evaluation the means values (student’s, t distributions). Clinic lung function measurements were analysed 

using regression analysis adjusting for the pre-treatment value and centre. 

The mean of the symptom scores for each treatment group were compared following subtraction 

of the baseline values, using the non-parametric Mann-Whitney test. The proportion of days with no 

symptoms was transformed using the arc-sin transformation (Snedcor and Cochran) and the difference 

from baseline values were compared for each treatment group using the standard student’s t test 

Safety Assessment - Adverse events were tabulated for the total population as were abnormal 

biochemistry measurements. Clinical relevant changes in biochemistry between the start and end of trial 

were identified 

Results 

Efficacy 

Baseline lung function and percentage reversibility of the two treatments group at the start of the 

study were seen to be similar within each age group for the efficacy population. The CR tablets and 

standard tablets were similarly efficacious in maintaining lung function in the 2, 4, 6 week population 

(p>0.05). 

No clinically significant differences between the treatments were identified with respect to 

effects on lung function parameters (FEV1, FVC, PEFR, FE50, VC) for both age groups. In both young 

children and the older children compliance was better in the salbutamol CR group. 

No significant difference was identified between treatment in the change of symptoms scores 

and symptom free days over the study period. (p>0.05). 

For the children of 6 years or less 79% of the parents in the salbutamol CR group assessed the 

treatment to be effective or very effective as compared to 67% of the parents in the standard tablets group. 

For the children of 7 years and over 75% of the parents in the salbutamol CR group assessed the treatment 

to be effective or very effective, as compared to 61% of the parents in the standard tablet group 

Safety 

Adverse events were determined from the total population receiving treatment within each age 

group. 

No difference between the two treatments were identified either in total numbers of adverse 

events or in their severity. 

Adverse events are divided into recognized pharmacological effects of salbutamol (tremor, 

palpitation, muscle cramps) and non – specific but possibly drug related (headache, hyper-activity and 

sleep disturbance) and the remainder which probably not drug related. About 50% of the adverse events 


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eported by the ≤ 6 year age group and 40% of those reported by 7 year age group during administration 

of salbutamol CR appeared unlikely to be related to the study drug. 

Biochemical profiles before and after treatment evaluated for those children cooperative and 

show that neither the CR nor standard formulation caused clinically significant change in any of the 

parameters measured. 

Assessor ’s comments 

This study showed that 4 mg salbutamol CR tablet, twice day regimen, are as effective as standard 2 mg 

salbutamol tablets, four times daily, in controlling the symptom of reversible airways obstruction in 

children. 

As regards the ability of administering tablets to children under 6 years, the pharmaceutical form is not 

suitable for this age because the young children have difficulty swallowing. 

STC 388 Study report GRP/88/013 

An open crossover comparison of salbutamol controlled release (CR) tablets (4 mg bd) with 

individually titrated slow release theophilline (Theodur) in the management of chronic reversible airways 

obstruction in children 

Objective - to compare the efficacy and acceptability of 4 mg salbutamol CR tablets taken twice 

daily, with Theodur tablets taken, in children with reversible airways obstruction. 

Study design - open crossover study carried out in 11 hospital centers. 

Study population - 224 children aged 3 to 16 years, who had their daily doses of Theodur titrated 

to produce plasma concentration of 10-20 µg/ml, and 198 who tolerated this dose to be randomized into 

the 2 x 3 week (including 1 week wash-out period) 

Treatments - the study had a run-in period in which each patient received theophylline treatment. 

The optimal dose was determined by titration of plasma theophylline levels, either during this period or 

during the 3 months prior to the study. 

Each patient was randomly allocated to receive one treatment for a period of 3 week and then to 

cross-over to the alternative for a further 3 week. 

Either: 

1 x 4 mg CR salbutamol bd, at 12 hourly intervals, for 3 week followed by individually titrated 

dose of Theodur bd at 12 hourly intervals (after a standard build-up dosage regimen during days 1-3) for 

the second 3 week period 

Or: 

Individually titrated dose of Theodur bd at 12 hourly intervals (after a standard build-up dosage 

regimen during days 1-3) for 3 week, followed bd 1.4 mg Salbutamol CR bd at 12 hourly intervals for the 

second 3 week period. 

If the optimum dose of Theodur was not known, a dose titration was required. Theodur is 

currently recommended in children at an average dose of 200 mg bd ( if body weight is greater than 35 kg) 

or 100 mg bd ( if body weight is less than 35 kg). However, it is widely accepted that a 10-15 mg/kg dose 

of theophylline is required per day, in order for the theophylline to attain a therapeutic level in the plasma, 

and that increments of 20 mg/kg are effective, without producing toxic plasma levels. Each patient 

theophylline level was titrated to achieve a plasma concentration of 10-20µ/ml 

During the 6-week study period, patients were to take no other regular form or bronchodilator 

therapy apart from the study medication (with exception on additional symptomatic bronchodilator 

therapy, taken as required basis only). All other non bronchodilator asthma therapy was continued at a 

constant dose throughout the study period. 

Endpoints 

Primary endpoints: 

- Clinic lung function measurements assessment by functional parameters: peak expiratory flow 

rate (PEER), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were made 


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in those children who were able to perform the spirometry tests reliably. The second parameters vital 

capacity (VC) and mid expiratory flow rate (FEV50) were additional optional assessments. 

- A daily record card was issued for evaluation of the clinical status. The daily record card 

assessment of the symptoms by a nominal score of 0-3 scale of intensity, for following symptoms: cough 

and wheeze at night, daytime cough, daytime wheeze, breathlessness on exercise, sputum production. 

- Additional inhaled bronchodilator requirements were also recorded on the daily record card. 

This primary endpoints were assessed at a 4 clinical visits scheduled a run-in period, after first 3 

week and end of trial. 

Safety Assessment - adverse events were tabulated for the total population as were abnormal 

biochemistry measurements. Clinical relevant changes in biochemistry between the start and end of trial 

were identified 

Statistical Methods 

Clinic lung function measurements were analysed using parametric methods for the two period 

cross-over trial. If a treatment by period interaction was present, analysis was based on the first period 

only. When the treatment by period interaction was not significant, the difference between the treatments 

was calculated following Hills and Armitage and significance tests and 95% confidence intervals were 

contracted. 

For the five symptoms recorded, 8-20 of each treatment for each patient were summarized by the 

mean symptom score and the proportion of days with no symptoms. The mean symptom scores were 

analysed using non-parametric methods. 

Additional bronchodilator usage was analyses by standard analysis 

Results 

Efficacy 

There were no significant differences in clinic lung measurements between Salbutamol CR or 

theophyline SR and no treatment order effect was apparent. Clinic lung function measurements as a 

percentages of predicted normal, indicated that the children were generally well controlled during both 

treatment periods with no difference between the 2 therapies. 

The mean morning and evening peak flow measurements, recorded for each patient during both 

3 week study period, were calculated over days 8-20 of each treatment. 

Salbutamol CR was seen to produce statistically significantly higher PEER values than 

theophylline SR, both in patients who received salbutamol CR during the first study period and patients 

who received theophylline SR during the first study period for morning PEER (p=0.0158) and evening 

PEER (p= 0.0023). Although these difference in morning and evening PEER were very small. 

The overall frequency distribution of diary card symptom scores for cough and wheeze at night, 

daytime wheeze, phlegm production, breathlessness on exercise and daytime cough was similar during the 

2 study period, and indicated that patients' symptoms were generally well controlled on both treatments. 


Salbutamol CR was better tolerated than Theodur SR, 16% of patients reporting adverse events 

during SCR treatment vs 33% during theodur. 

5 patients withdrew from the study due to drug related adverse reaction during treatment with 

Theodur as compared to 2 patients while on salbutamol CR. 

51% of patients preferred treatment with SCR tablets compared to 28% of patients who preferred 

Theodur. 

Assessor ’s comments 

This study shows that Salbutamol CR tablets given twice daily are equally effective in the control of 

asthma as individually titrated Theodur twice daily but the lower incidence of adverse events after 

administration Salbutamol may offer advantages over methyl xantines in the treatment of chronic asthma. 

However actually guidelines for the management of bronchial asthma in children recommend as 

treatment of first intention on stage 2-5 of disease, the use of combination corticosteroids + B2 agonists 

inhaler. 

Concerning the ability to administer tablets to children under 6 years, the pharmaceutical form is not 


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suitable for this age because young children have difficulty swallowing. Salbutamol syrup may be used in 

this population. 

GlaxoSmithKline submitted two publication regarding the efficacy of salbutamol controlled 

release tablets. The first abstract (SBM40056), contained results of a very small clinical trial (N=9) which 

had evaluated the effect of salbutamol to improve the quality of sleep to children with asthma (S Zeitlen, 

D.Foulkes, C Rolles, Southampton General Hospital, UK)) 

The results of the study showed that oral long acting anti-asthmatic medication appeared to 

improve sleep quality, when assessed objectively with EEGs. 

Regarding the second publication, there was an comparative efficacy study (SBM40107) 

between salbutamol CR and ketotifen. This abstract does not confirm the ages of the subjects. The study 

showed that salbutamol contolled-release tablet provides an superior control of airways obstruction 

comparative with ketotifen. 

2.2.2 Syrup 

GSK did not submit any data. 

2.3 Intravenous Administration 

Study RID/CT/84 (D140/B16) 

Intramuscular or subcutaneous salbutamol in management of acute exacerbation of asthma in 

children. 

Objective – to investigate the clinical response and monitor side effects of intramuscular or 

subcutaneous salbutamol administrated in a dose of 8 µg/kg to children with an acute exacerbation of 

asthma. 

Study population/Sample size - 17 children (11 males, 6 females) with an acute exacerbation of 

asthma who required parenteral bronchodilators and who had not received bronchodilators within 3 hours 

of admission; mean age 7 years (ranged 5-9). 

The average duration of children’s attacks was 21 hours (range 3-72 hours), excluding one 

patient whose apparent duration was one week prior to receiving the salbutamol injection. The mean 

number of exacerbations of their asthma was 19 attacks (range 3-52) throughout the previous year. 

Treatment - each child received a single injection of salbutamol in a dose of 8 µg/kg, 

administrated either subcutaneously or intramuscularly, in a random fashion. 9 patients received 

salbutamol intramuscularly in one dose of 8 µg/kg and 8 patients received salbutamol subcutaneously in 

one dose of 8 µg/kg. 

Results 

Only 9 children (5 sc, 4 im) cooperated sufficient to obtain good peak flow measurements, the 

others being too young or too ill. After 5 minutes an improvement in peak expiratory flow was seen in 6 of 

these children (4 sc, 2 im) and after 30 minutes in 8 of these children (5 sc, 3 im) the increases ranging 

from 22% to 400% of pretreatment values. One receiving im salbutamol showed no change. 

Pulmonary auscultation 5 minutes after the injection showed marked improvement in 2 children 

(sc), slight improvement in 4 (3 sc, 1 im) and no change in 10. This increased after 30 minutes to marked 

improvement in 4 (3 sc), slight improvement in 6 (3 im, 3 sc) and no change in 10. None of the children 

deteriorated throughout the study period. 

Adverse effects 

The pulse rate increased significantly 5 minutes after intramuscular injection (p

Assessor’s comment 

The sample size is small and 8 subjects could not be assessed by peak expiratory flow. The study 

design was poor as the assessment of clinical status was not assessed as accurately as other 

measurements. These facts limit the significance of the findings. 

The study was very old (1984) and the latest paediatric guidelines (2009) do not provide any 

information about these routes of administration in acute exacerbation of asthma. These routes of 

administration of salbutamol might be of little clinical importance in such cases. 

The reported adverse events are known to be associated with the use of salbutamol (increase of 

heart rate and blood pressure) and not very well investigated (eg ECG); there was no report of a new 

one. 

There isn’t any document to certify that the study has been conducted in accordance with GCP. 

In conclusion, this study does not provide robust evidence on the efficacy and safety of 

intramuscular or subcutaneous salbutamol administrated in a dose of 8 µg/kg to children with an acute 

exacerbation of asthma. 

Study D78/B24 

A comparison of intravenous salbutamol, aminophyline and the combination in the treatment of 

acute severe asthma in children 

Objective - to compare the effectiveness of continuous intravenous infusion of either salbutamol, 

amonophylline or the combination of both drugs in the treatment of acute severe asthma in children. 

Study population - 64 children (44 males), aged 3.9-14.8 (mean 8.1 years), with acute severe 

asthma. 

Study design - the patients were randomly allocated to one of 3 treatment groups: salbutamol, 

aminophylline or a combination of salbutamol plus aminophylline. 

All patients had basic details recorded and were examined. Before starting treatment, their 

clinical status was assessed using a scoring system, 0-3 for normal, mild, moderate and severe respectively 

for each of four signs: rib recession, breath sound intensity, rhonchi and rales. 

A sample of arterial blood was taken for measurement of pH, pO2 and pCO2. Venous blood was 

taken for serum potassium and, in some, plasma salbutamol. 

Heart rate was measured from was measured from electrocardiographic (ECG) trace and peak 

expiratory flow rate (PEFR) with a Wright peak flow meter. 

Clinical score and PEFR were reassessed at 1, 2, 4, 6, 12 and 18h after the start of infusion. 

Arterial pH and blood gases were repeated at 6 and 18h. Theophylline concentration was measured at 6h 

or if therapy was to be changed on clinical grounds. 

Treatments - the dosage of aminophylline consisted of a loading dose of 5.6 mg/kg infused over 

15 to 30 minutes followed by a continuous infusion of 1 mg/kg/min. 

The proposed salbutamol dosage consisted of increasing the flow rates up to 1.6 µg/kg/min or 

until relief was seen or heart rate reached 160-180 beats/min. 

At 4 hours, when patients were reassessed, intravenous hydrocortisone could be added if 

response was regarded as sluggish. The dosage consisted of a 4 mg/kg loading dose followed by 3 mg/kg 

every 3 hours. If response was satisfactory at 4h but not at 6h or subsequently, hydrocortisone could be 

started at those times. 

If after hydrocortisone had been added, response was still not regarded as satisfactory at a 

subsequent assessment either salbutamol or aminophylline could be added so that all three drugs were 

used. All intravenous drugs were given using a constant rate infusion pump. 

Statistical methods 

The chi square test was used whenever appropriate for dichotomous data, but Fisher’s exact test 

was used for small expected frequencies. The probability values were those for the two tailed tests. 

Results 

There was a preponderance of males, 44 (69%). The distribution of patients between the 3 

treatment groups was the following: 19 patients were treated with salbutamol, 25 patients were treated 

with aminophylline and 20 patients were treated with the combination. 


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In the group treated with salbutamol, 4 patients (21%) had to be given hydrocortisone at 4, 5 or 6 

h and one also had aminophylline (at 6 h). 

In the aminophylline group, 14 patients (56%) had hydrocortisone between 4 and 18h after the 

start of infusion and 2 had to have salbutamol as well. 

In combination group, 3 patients (15%) had hydrocortisone, at 4 or 6h. 

The difference between the 3 groups was statistically significant (p< 0.01; chi-square) as were 

the differences between aminophylline and salbutamol (p

2.4 Rectal Administration 

Study BIO 75/9 „A comparison in children of the rectal absorption of salbutamol from Sultanol 

suppositories and the oral absorption of salbutamol from Sultanol aerosol“. The study was carried out in 

1975. 

Study design - randomized, crossover, with 2 period/2 treatments, separate to wash-out period of 

24 hours. 

Study population - 10 healthy children. 

Treatment - in the first day a blood sample was taken from the children as control. 

- in the second day of the study, at 8,00 hour, was administered 1 suppository containing 2 mg 

salbutamol and the blood samples were taken at 1, 4, 7 and 10 hours after dosing. 

- in the third day, at 8,00 hour, 2 puffs ( 100µg/puf) of sulbutamol aerosol were given to the 

cildren and a blood samples was taken 1 hour later. 

Peak plasma concentration of salbutamol after puffs and suppositories administration was 

measured by Gas cromatography – Mass Spectroscopy method. 

Results 

After administration of a suppository containing 2mg salbutamol, the peak plasma concentration 

ranged from 4.0 to 12.3ng/ml was reached within 4 hours after treatment administration. 

The plasma levels of salbutamol at 10 hours after dosing were from 0.8 to 3.2ng/ml. 

The plasma salbutamol concentrations at one hour after treatment with 2 puffs of aerosol 

containing 0.1mg salbutamol/puff were ranged from

common complaints associated with high doses of β 2 -agonists in children. These complaints are more 

common after systemic administration and disappear with continued treatment. 

The current guidelines (4, 5) recommend a stepwise approach aiming to abolish symptoms as 

soon as possible and to optimise peak flow by starting treatment a the level most likely to achieve this. 

Patients should start treatment at the step most appropriate to the initial severity of their asthma. The aim 

is to achieve early control and to maintain control by stepping up treatment as necessary and stepping 

down when contrl is good. For children aged 5 to 12 years and adults, Step 1 is inhaled short acting 

β 2 agonist as required for mild intermittent asthma. Step 2 involves addition of inhaled steroid as regular 

preventer therapy. 

When choosing the inhaler device for children older than 6 years, the GINA guideline (4) 

recommends using DPI, or breath-actuated pMDI, or pMDI with spacer and mouthpiece. 

According to the British National Formulary for Children (BNFC), salbutamol doses when 

administered by inhalation of powder are as follows: 

• Child 5–12 years 200 μg; for persistent symptoms up to 4 times daily 

• Child 12–18 years 200–400 μg; for persistent symptoms up to 4 times daily 

Many drugs used in treatment of asthma can be delivered to the airways via pressurised metered 

dose inhalers (pMDIs), dry powder inhalers (DPI) or jet nebulisers. The pMDIs have been increasingly 

replaced by various types of DPIs. However, there are differences between countries in the use of DPIs. 

In Nordic countries more than 90% of inhalation therapy for asthma is delivered by DPIs. DPIs have 

proved to be effective, safe and easy to handle in all age groups. With the powder inhalers the patient first 

actuates the device and the dose is ready to be inhaled with forced and prolonged inspiration. Easyhaler 

multidose DPI is registered in many EU countries and also countries outside EU for the administration of 

salbutamol, beclometasone, formoterol and budesonide. 

2. Clinical studies 

Orion Pharma has carried out 4 clinical trials with the product Buventol Easyhaler DPI, that 

have included children. To date, no other clinical trials with Buventol Easyhaler in children have been 

carried out by Orion Pharma or independent investigator. 

The first 3 studies have been included and evaluated in marketing authorisation applications 

(MAA) in EU countries. The most recent study has not been included in previous MAAs. A brief synopsis 

of these studies is given here. 

- The study of Malmström and co-workers evaluated the suitability of the Easyhaler device 

for children with asthma. The study was an open, non-randomised trial. A total of 120 asthmatic children 

(mean age 9.1 years, range 4-16) were enrolled in the study. The peak inspiratory flow through the 

Easyhaler (PIF EH ) was evaluated versus age, height, and peak expiratory flow (PEF). A correlation was 

observed between PIF EH and age, height and PEF. Only 4 children (aged 5, 6, 10 and 16 years) had PIF EH 

values below 28 l/min, which was considered the threshold for effective use of the Easyhaler device. Most 

children aged 6-16 years produced PIF values sufficient for the use of the Easyhaler. The bronchodilatory 

effect of salbutamol (200 μg) inhaled from Easyhaler was compared to salbutamol inhaled from an MDI 

with a spacer (Ventoline with Volumatic) in 15 children with PEF < 85% of the predicted. In these 

children the bronchodilatory effect of salbutamol inhaled from Easyhaler and from the MDI with spacer 

was equal. This study confirmed that the Easyhaler inhaler device performed well in children aged 6 years 

and above, and it can be used also in patients with low inspiratory flow. 

- The second study by Koskela and coworkers (7) compared the bronchodilating effect of 

salbutamol (100 μg) inhaled with low inspiratory flow (targeted flow 30 l/min) from Easyhaler with that 

of salbutamol inhaled optimally from a MDI with spacer (Ventoline with Volumatic). The follow up 

period after drug inhalation was 60 minutes. In addition, the acceptability of the inhalers was evaluated. 

Twenty-one patients with asthma and reversibility in lung function (15%) completed this double-blind, 

randomised, crossover study. The mean age of the patients was 19 years (range 7-65). The results showed 


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that the bronchodilating effect of 100 μg dose of salbutamol from Easyhaler with low inspiratory flow 

was eual to that of 100 μg dose of salbutamol from the MDI with spacer when optimal inhalation 

technique was applied. This result was achieved despite the equivalence criterion for AUC of FEV 1 was 

not completely met due to the low number of patents in the analysis. Easyhaler and the MDI with spacer 

were equally safe and well accepted. 

- The third study (8) was designed to compare the efficacy, safety and acceptability of the 

Easyhaler device with those of a pMDI (Glaxo&Wellcome, UK) and a spacer in asthmatic children 

(n=40, mean age 11, range 6 - 16 years). The children were treated with inhaled beclometasone 

(400 μg/day) and salbutamol (100 μg/day). The primary efficacy variable was morning PEF. Secondary 

efficacy variables were evening PEF, the number of sympathomimetic inhalations, daily symptom scores, 

and spirometry performed at follow-up visits. Both types of inhalers, Easyhaler and the pMDIs with a 

spacer, gave similar bronchodilating effect suggesting equal clinical efficacy. The children had moderate 

or severe asthma, but were well controlled before entering the study. This left not much room for 

improvement in either of the study treatments. However, the patients were well documented asthmatics 

who needed regular anti-inflammatory treatment with inhaled glucocorticoids. t would have been 

unethical to first withdraw the steroid treatment to test the reversibility of the children’s bronchial 

obsruction. The study was open, but randomised and of crossover design. One of the primary outcome 

measures was the acceptability of the devices. The majority of the children rated the Easyhaler device 

easier to handle and use compared to the pMDIs with spacer. 

-The fourth study (9) was a 4 week, open, randomised multicenter parallel group trial 

evaluating correct use and acceptability of Diskus, Turbuhaler, and Easyhaler DPIs among inhaler 

naive asthmatics or patients with asthma symptoms. The study population consisted of 326 

subjects aged 13 years or older (mean age 44, SD 15.4). The subjects were asked to read the 

instruction leaflet before taking one dose at the first visit. The correct use was evaluated when 

the subject took the dose. The subjects were subsequently instructed in correct use of the devices. 

At the first visit, the proportions of subjects who used the devices correctly were as follows: 

Easyhaler, 45%; Diskus, 43%; and Turbuhaler, 51%. The corresponding figures at the last visit were 

84%, 89%, and 81%. The differences at any visit were not statistically significant. Acceptability was 

greater for Easyhaler and Diskus for 3 of 8 assessment items in the study, all pertaining to receiving 

the powder from the device and control of the inhalation of the powder. 

An additional study by Malinen and co-workers (10) has also been included in the line listing, 

but this study does not involve patients less than 19 years of age and is thus not dealt with here. 

The SPC texts of Buventol Easyhaler products reflect adequately the current knowledge about 

salbutamol use in children older than 4 years. Based on the mentioned studies no changes in SPCs of 

Buventol Easyhaler are thus needed. 

The current posology for Buventol Easyhaler (both 100 and 200 μg/dose strengths) is the 

following: 

The lowest effective doses of inhaled salbutamol are recommended to be used in the treatment of 

asthma. In the long term treatment it is recommended, instead of regular use, to use inhaled 

salbutamol as needed. 

Adults and children (4 years and older): 

For the treatment of acute periods of reversible bronchoconstriction or prior to exercise usually: 

100–200 micrograms 1-4 times daily. 

Patients have to be instructed to perform a strong and deep inhalation through the Easyhaler 

device. Patients have to be instructed not to exhale into the device. 

There is wide consensus that inhaled short acting β 2 agonists are the most effective reliever 

therapy, and are therefore the recommended treatment for asthma for children of all ages. Salbutamol, 


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although being gradually replaced by newer β 2 agonists, is still very useful in treatment of adult and 

paediatric asthma. 

C) Summary of clinical program sponsored by Generics [UK] Ltd. 

One equivalence clinical trial involving children has been carried out by Generics [UK] Ltd. 

with the product Respigen, the new generic HFA-salbutamol 100 µg inhaler comparative to the reference 

Salbutamol – HFA 134a100 µg formulation (Ventolin Evohaler). 

Study Code: 03-SAL-01/BS520 

Study Title: A placebo controlled trial to investigate the protective effect in a histamine 

challenge test of a new Salbutamol HFA 134a 100 µg formulation compared to a reference 

Salbutamol-HFA 134 a 100 µg formulation in paediatric patients aged 4-12 years with asthma. 

03-SAL-01/BS520 reports a placebo controlled, randomized study from 2004-2005 with a total of 24 male 

and female asthmatic paediatric patients between the ages of 4 and 12 years with a history of bronchial 

asthma and a proven hypersensitivity for histamine. The primary objective of the study was to assess the 

effect of a new Salbutamol-HFA 134a 100 µg formulation (Respigen) in a histamine challenge test 

compared to a reference Salbutamol-HFA 134a 100 µg formulation (Vetolin Evolaher). The secondary 

objective was to assess the safety and tolerability of new Salbutamol-HFA 134a 100 µg formulation 

(Respigen). Patients were randomized and given all three treatments (200 mcg of salbutamol) with the aid 

of a Nebuhaler (Astra-Zeneca Pharmaceuticals). The dose was administered to the patients 15 minutes 

before the histamine challenge on each of the three trial days. It was shown that Respigen was equally as 

effective in providing protection against histamine-induced bronchoconstriction as the reference 

formulation, Ventolin Evolaher, therefore, it can be said to be therapeutically equivalent and 

interchangeable. In addition Respigen was clinically and statistically superior to Placebo (HFA-134a 

propellant). No serious adverse events were observed. Few adverse events were reported during the trial 

and most of these adverse events were related to trial procedures. No clinically relevant changes in vital 

signs or laboratory parameters were observed. It was concluded from safety parameters that both active 

treatments were safe and well tolerated. 

D) Summary of clinical program sponsored by MEDA PHARMA GmbH, MEDA AB 

MEDA Pharma (resp. MEDA AB) use the active substance Salbutamol in a inhalation device 

called 'Novolizer' for patients with asthma and COPD, and is Applicant/MAH for this product using a 

hybrid generic dossier with regard to module 4 and 5. 

MEDA never conducted own clinical studies in children with the 'Salbutamol Novolizer'. 

The only clinical studies in children had been studies to examine the ability of asthmatic children 

to use the Novolizer device correctly - without using an active substance (handling studies). 

As mentioned in our submission to the national authorities with regard to Art 45/46 in January 

2008, the reports to the above mentioned 'handling studies' have been already submitted to the national 

authorities in the frame of several MR/DC procedures (MRP DE/H/0333/001, DCP DE/H/0864/001, DCP 

DE/H/0865/001 and DCP DE/H/1027/001). The DC procedure DE/H/1027/001 is just running, including 

also the national authority of Romania as concerned member state. 

Therefore, there are no clinical studies with the active substance Salbutamol in children 

conducted by MEDA company, which can be submitted for this worksharing procedure. 

It was enclosed a list of the same references of published clinical studies as MENARINI and 

ORION. 

Assessor’s comments 

The articles refer to a review of salbutamol. 

No new information on salbutamol is concerned. 


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E) Summary of clinical program sponsored by InfectoPharm Arzneimittel GmbH, 

Germania 

InfectoPharm Arzneimittel GmbH has confirmed that dispose only bibliographic data, 

concerning the active substance salbutamol, which has not yet been submitted. This data is based on freely 

accessible literature. It has been assumed that all kind of literature open to the public was already 

submitted and it was not submitted the same documents once again. 


Publications only. Its can not be considered a relevant clinical change. 

F) Summary of clinical program sponsored by Warsaw Pharmaceutical Works Polfa SA, 

Poland 

Oral administration: tablets and syrup 

Warsaw Pharmaceutical Works Polfa SA has submitted a copy of the study “Clinical 

Evaluation of the Preparation Salbutamol Tablets and Syrup" with the participation of the paediatric 

population, carried out in 1973, in Department of Internal Disease, Medical Academy, Warszawa. 

The patients included were 30 women and 26 men aged 16 to 72 years. 


It is noted that the study is performed in 1973 and according to the current guidelines it suffered from 

some deficiencies. As only a summary of this study was submitted, no appropriate information could be 

identified on inclusion and exclusion criteria as well as on the primary clinical endpoint. Therefore 

clinical relevance of the outcomes of this study is questionable. 

The analysis of the PSUR(s) submitted by the concerned Marketing Authorisation Holders 

revealed no new safety information requiring the amendements to the SPC. 

IV. RAPPORTEUR’S OVERALL CONCLUSION 

AND RECOMMENDATION ON DAY 89 

� Overall conclusion 

In general, it is agreed with the MAH (s) that the data from the submitted studies do not 

specifically indicate any need of major change of the current paediatric information in the SmPCs. 

However, the precise wording of all European national SmPCs was not provided by the MAH (s), and in 

the review provided by the MAH (s), it is unclear whether all European countries where salbutamol is 

approved do have similar recommendations for dosage in paediatric patients. Furthermore, according to 

the CMD(h) best practice guide on article 45-Paediatric regulation (September 2008), “the aim of Article 

45 procedure is to make the information on the use of medicines in the paediatric population available for 

all healthcare professionals and patients (or parents). After finalisation of the assessment of the data 

recommendations for the text to be included in the SmPC and PL will be published on the CMD(h) 

website. This information should be included in all SmPCs/PLs of products with the same active substance 

and pharmaceutical form within 90 days of publication of Public assessment report.” 

The Applicants should review the national SmPC and previously submitted studies and all other 

available data which should form a basis for a proposed harmonised SmPC text regarding paediatric 

indications and dosage recommendation. 

� Recommendation 


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Based on the data submitted, the MAH (s) was/were asked to provide clarifications requested per 

studies as part of this worksharing procedure (see section “Request for supplementary information”). 

REQUEST FOR SUPPLEMENTARY INFORMATION 

List of questions at day 89 

Based on the data submitted, the MAH(s) should provide the following information as part of 

this procedure according to article 45: 

- The Marketing Authorisation Holders are requested to submit the lines listing and for all 

medicinal products with paediatric use, the respective wordings of sections 4.1 and/or 4.2 of the SmPC 

(Annex II), as per the procedural guidance. 

- MAH(s) should review the information on paediatric use included in the national SmPCs from 

all MS in which salbutamol is an approved medical compound for paediatric use and identify the 

differences regarding paediatric indications and dosage recommendations. 

- In case of divergences between MS, the MAH (s) should provide a proposal for a harmonised 

SmPC text in sections 4.1, 4.2, and 4.4 regarding paediatric use. The proposal should be justified by 

supporting data from the MAH database and relevant published data. 

Following the circulation of the draft preliminary paediatric assessment report for Salbutamol 

paediatric EU worksharing procedure, we received comments from UK and Sweden, who both fully 

endorsed the conclusions and recommendations of the Rapporteur. No comments were received from the 

other Member States. 

Based on the assessment report and the data submitted, the MAH(s) are requested to provide the 

additional clarifications as outlined in section IV of the report. The clock was stopped for this procedure 

and the company response was requested by 09 th February 2011. Subsequently the clock stop period was 

extended with 3 months, until 10 May 2011, following the request from the GSK company for responding 

to the questions raised. 

V. ASSESSMENT OF MAH(s)’ RESPONSES TO THE DAY 89 PRELIMINARY PDAR 

A) The GlaxoSmithKline’s responses to the questions raised 

Question 1(Rapporteur): 

The Marketing Authorisation Holders are requested to submit the lines listing and for all medicinal 

products with paediatric use, the respective wordings of sections 4.1 and/or 4.2 of the Summary of 

Product Characteristics (SmPC) (Annex II), as per the procedural guidance. 

The MAH’s Response: 

A list of salbutamol licences held by GlaxoSmithKline in EU is provided in Appendix 1. Salbutamol has 

been registered in the EU since the late 1960s and is available in numerous dosage forms, most of which 

are indicated for the use of paediatrics. 

The inhaled formulations of salbutamol are: 

• Evohaler (CFC-free metered dose inhaler) 

• Accuhaler/Diskus (Multi-Dose Powder Inhaler) 

• Rotadisk, Rotacaps (Dry powder inhalers) 

• Nebules 

• Respirator Solution 

The non-inhaled formulations of salbutamol are: 

• Injection* 

• Solution for Intravenous infusion* 

• Tablets including controlled-release tablets and Spandets** 


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• Syrup 

• Suppositories*** 

* Not registered for use in paediatrics as there is insufficient evidence to recommend a dosage 

regimen for routine use in children. 

** No Spandets licences in Europe. 

*** Suppositories are only registered in France for an obstetrical indication in the management of 

premature labour. 

GlaxoSmithKline (GSK) has submitted two excel documents (Appendices 2 and 3) which provide 

translations of the Sections 4.1 and 4.2 wording in the EU national Summary of Product Characteristics 

(SmPCs) for inhaled (Appendix 2) and non-inhaled (Appendix 3) salbutamol and the differences from 

GSK’s Global Data Sheets (GDS) for these products have been highlighted as follows: 

- Additional text in local national SmPCs that is not in the GDS is shown as bold red 

italics. 

- Text in the GDS that is missing from the local national SmPCs is shown as bold 

blue strikethrough text. 

- Text in the local SmPCs that belongs to a different section from that of the GDS is shown 

as green text, followed by a note to say in which section of the SmPC is included. 

The following key is used in the spreadsheets: 

Cell Colour 

Significantly different to GDS 

Consistent with GDS 

Product not registered 

Definitions: 

• Significantly Different: The text in the local SmPC contains meaningful deviations from the content of Core 

Safety Information (CSI) and non-CSI text in the GDS, e.g. SmPC is missing the text from the GDS, is missing 

dosing regimens or indications, or contains dosing regimens or indications not supported by the GDS. 

• Consistent with GDS: Text in the local SmPC represents that contained in the GDS. The wording may not be 

identical between the two, but the information contained in the SmPC is an accurate reflection of that intended by the 

GDS 

Assessment of the Applicant’s response 

The requested data has been submitted. 

Question 2 (Rapporteur) 

MAH(s) should review the information on paediatric use included in the national SmPCs from all 

MS in which salbutamol is an approved medical compound for paediatric use and identify the 



GlaxoSmithKline (GSK) has reviewed the information on paediatric use included in the national 

salbutamol SmPCs regarding paediatric indications and dosage recommendations and considers that the 

SmPC indication and posology information for the majority of the European countries are consistent with 

the Company’s Global Data Sheets (GDSs) for inhaled and non-inhaled salbutamol. 

For a complete list of all differences see the excel spreadsheets in Appendices 2 and 3. 

A summary of the key differences with respect to indications and dosage recommendations are 

highlighted in Table 1(Inhaled) and Table 2 (Non-Inhaled). 


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Inhaled 

Table 1 Key Differences between GDS and National SmPCs in relation to Indications and Dosage 

Recommendations – Inhaled Salbutamol 

GDS wording National SmPCs with significant differences to 

GDS 

Therapeutic indications 

Evohaler, Accuhaler/Diskus, Rotadisks, 

Rotacaps: 

Salbutamol is a selective beta-2 adrenoceptor 

agonist. At therapeutic doses it acts on the beta-2 

adrenoceptors of bronchial muscle, with little or no 

action on the beta-1 adrenoceptors of the heart. 

With its fast onset of action, it is particularly 

suitable for the management and prevention of 

attack in mild asthma and for the treatment of acute 

exacerbations in moderate and severe asthma. 


Rotacaps: 

With this primary background corticosteroid 

treatment, salbutamol provides essential rescue 

medication for a severe asthmatic in treating acute 

exacerbations. Failure to respond promptly or fully 

to such rescue medication, signals a need for urgent 

medical advice and treatment. 


Rotacaps: 

Salbutamol provides short-acting (four hours) 

bronchodilation with fast onset (within five 

minutes) in reversible airways obstruction due to 

asthma, chronic bronchitis and emphysema. It is 

suitable for long-term use in the relief and 

prevention of asthmatic symptoms. 


Rotacaps: 

Salbutamol should be used to relieve symptoms 

when they occur and to prevent them in those 

circumstances recognised by the patient to 

precipitate an asthmatic attack (e.g. before exercise 

or unavoidable allergen exposure). 

Nebules, Respirator Solution: 

Routine management of chronic bronchospasm - 

unresponsive to conventional therapy. 

Nebules, Respirator Solution: 

Treatment of acute severe asthma (status 

asthmaticus). 

Austria, Bulgaria, Estonia, France, Lithuania, 

Sweden; additional indication for COPD 

Denmark, Norway; a shorter statement referring to 

the pharmacology but not the indication of 

salbutamol is present in another section 

Greece, Portugal; this text is not included in 

SmPCs. 

Romania; text is in section 5.1 of national SmPC 

Austria, Bulgaria, Cyprus, Denmark, Estonia, 

Finland, France, Germany, Greece, Netherlands, 

Norway, Poland, Portugal, Sweden, UK; this text 

not included in SmPCs 

Lithuania; text in section 4.4 of national SmPC 

Bulgaria, Denmark, Estonia, Finland, France, 

Norway; this text is not included in SmPCs 

Italy; text is in sections 4.4 and 5.1 of national 

SmPCs. Following GDS indications not included in 

national SmPCs: chronic bronchitis and 

emphysema. 

Lithuania; in section 5.1 of national SmPC 

Bulgaria, Estonia, Finland, France, Germany, 

Italy, Netherlands, Sweden, UK; this text is not 

included in SmPCs 

Lithuania; text in section 5.1 of national SmPC 

Belgium, Denmark, Estonia, Finland, France, 

Netherlands, Spain, Sweden, UK; this text is not 

included in SmPCs 

Belgium, Denmark, Estonia, Finland, Greece, 

Spain, Sweden, UK; this text is not included in 

SmPCs 


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GDS 

Posology and method of administration 

RELIEF OF ACUTE BRONCHOSPASM 

Populations 

• Children 

Evohaler 

100 micrograms, the dose may be increased to 200 

micrograms if required 

Accuhaler/Diskus 

200 micrograms as required 

Rotadisks, Rotacaps 

200 micrograms. 

PREVENTION OF ALLERGEN OR 

EXERCISEINDUCED 

BRONCHOSPASM 

Populations 

• Children 

Evohaler: 

100 micrograms before challenge or exertion, the 

dose may be increased to 200 micrograms if 

required. 

Accuhaler/Diskus: 

200 micrograms before challenge or exertion. 

. Rotadisks, Rotacaps: 

200 micrograms before challenge or exertion 

CHRONIC THERAPY 

Populations 

• Children 

Evohaler: 

Up to 200 micrograms four times daily 

Accuhaler/Diskus 

200 micrograms four times daily. 

Rotadisks, Rotacaps 

200 micrograms three or four times daily 

ROUTINE MANAGEMENT OF CHRONIC 

BRONCHOSPASM (UNRESPONSIVE TO 

CONVENTIONAL THERAPY) AND 

TREATMENT 

OF ACUTE SEVERE ASTHMA (STATUS 

France, Norway, Poland; dosage for this 

indication in children is not included in SmPCs 

Netherlands; maximum dose is 400micrograms 

Norway; 200 – 400 micrograms when needed 

Poland; no dosage stated for this formulation and 

indication in children 

None 

Denmark; 200 micrograms 10-15 minutes before 

exercise 

Italy, Poland, Sweden; no dose specified for this 

formulation and indication in children 

Netherlands; maximum daily dose 400 

micrograms 

Italy, Poland, Sweden; no dose specified for this 


None 

France; no dose specified for this formulation and 

indication in children 

France, Poland, Sweden; no dose specified for this 


None 

Norway, Poland; no dose specified for this 



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GDS 

ASTHMATICUS) 

Populations 

• Adults and Children 

Nebules: 

A suitable starting dose of salbutamol by wet 

inhalation is 2.5 mg. 

Respirator Solution: 

1. By intermittent administration: 

Intermittent treatment may be repeated four times 

daily. 

• Adults 

Salbutamol Respirator Solution 0.5 to 1.0 ml (2.5 to 

5.0 mg of salbutamol) should be diluted to a final 

volume of 2.0 or 2.5 ml using sterile normal saline 

as 

a diluent. The resulting solution is inhaled from a 

suitably driven nebuliser until aerosol generation 

ceases. Using a correctly matched nebuliser and 

driving source this should take about ten minutes 

Respirator Solution: 

By continuous administration: 

Salbutamol Respirator Solution is diluted using 

sterile normal saline to contain 50 to 100 

micrograms of salbutamol per ml, (1 to 2 ml 

solution 

made up to 100 ml with diluent). The diluted 

solution 

is administered as an aerosol by a suitably driven 

nebuliser. The usual rate of administration is 1 to 2 

mg per h. 

Austria; 0.25mL up to four times a day 

Finland; dosing information not present 

Sweden; dose is based on weight 

Denmark, Estonia; no dose specified for this 


Sweden; dose is based on weight 

Non-Inhaled 

Table 2 Key Differences between GDS and National SmPCs in relation to Indications and Dosage 

Recommendations – Non-Inhaled Salbutamol 


GDS 

Therapeutic indications 

Tablets, Controlled release tablets, Spandets, 

Syrup, Suppositories: 

Relief of bronchospasm in bronchial asthma of all 

types, chronic bronchitis and emphysema. 

Bulgaria; chronic bronchitis and emphysema 

indications not included. 

Cyprus; emphysema indication is not included 

Denmark; emphysema indication is not included 

Controlled release tablets, Spandets Austria, Estonia; not included in section 4.1, but is 


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GDS 

Salbutamol controlled-release tablets/Spandets are 

particularly suitable for nocturnal asthma 

None 

Syrup 

Salbutamol syrup is a suitable oral therapy for 

children or those adults who prefer liquid 

medicines. 

Posology and method of administration 

Tablets: 

2 to 6 years: 1 to 2 mg (½ to 1 tablet of 2 mg) three 

or four times daily 

Tablets 

6 to 12 years: 2 mg (1 tablet of 2 mg) three or four 

times daily 

Tablets 

Over 12 years: 2 to 4 mg (1 tablet of 2 mg or 1 

tablet 

of 4 mg) three or four times daily. 

Tablets 

Controlled release tablets: 

One 4 mg tablet twice daily 

Spandets 

Over 12 years: 4 mg (½ Spandet) every 12 h. 

Syrup 

2 to 6 years: 2.5 to 5 ml of syrup (1 to 2 mg 

salbutamol) three or four times daily. 

Syrup 

6 to 12 years: 5 ml of syrup (2 mg salbutamol) three 

or four times daily 

Syrup 

Over 12 years: 5 to 10 ml of syrup (2 to 4 mg 

salbutamol) three or four times daily. 

Suppositories: 

2 to 12 years: One 2 mg suppository morning and 

night 

Suppositories: 

If necessary, the dose may be increased to one 2 

mg suppository, four times a day (8 mg). 

in section 4.2 of national SmPC. 

Belgium, Denmark, Finland, Ireland, Latvia, 

Luxembourg, Norway, Sweden; not included 

Denmark; not included 

Sweden; up to 6 years rather than 2 to 6 years. 

None 

Denmark; no dose for this age range stated 

None 

None 

Latvia; no dose for this age range stated 

Sweden; paediatric dosing for syrup based on 

weight rather than age 







None 

None 


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GDS 

Rapporteur’s comment 


This is a helpful review of differences with respect to indications and dosage recommendations of inhaled 

and non-inhaled formulations of salbutamol. Because the products are nationally approved across Europe, 

there is no harmonized SmPC. 

For most of these formulations a separate indication in paediatric population with defined age range limits 

is not included in the SmPCs. Also for some of these formulations no dose is stated for the specific age 

range groups. 

A harmonisation of the paediatric data throughout Europe taking into account the national Marketing 

authorization is recommended. 

Because of the lack of a homogeneous European SmPC the Core data sheet has been assessed as a basis 

for the wording of the SmPC. 

The age limit for all inhaled and non-inhaled salbutamol formulations should be specified in section 4.1 

and 4.2. 

Taking into account that the very young children are not able to use powder inhalers properly and due to 

the limited data for the youngest children the age limit for dry powder inhalers should be - children over 6 

years as noted in the current guidelines. 

Due to the risk of inadvertent aspiration, non-inhaled formulations as tablets and control release tablets 

should normally be contra-indicated in children under 6 years of age. A more appropriate and suitable oral 

formulations for this paediatric population should be taken into consideration. 

Clinical efficacy of nebulised salbutamol in infants under 18 months is uncertain. As transient hypoxaemia 

may occur, supplemental oxygen therapy should be considered. 

Question 3 (Rapporteur) 

In case of divergences between MS, the MAH (s) should provide a proposal for a harmonised SmPC 

text in sections 4.1, 4.2, and 4.4 regarding paediatric use. The proposal should be justified by 



The Summary of Product Characteristics (SmPC) paediatric indications and dosage recommendations for 

the majority of the European countries are consistent with GlaxoSmithKline’s (GSK’s) Global Data 

Sheets (GDSs) for inhaled and non-inhaled salbutamol. However, some countries do not have “Routine 

management of chronic bronchospasm - unresponsive to conventional therapy” and “Treatment of acute 

severe asthma (status asthmaticus)” in their salbutamol Nebules and Respirator Solution SmPCs. 

The main differences between the national SmPCs and the GDSs with regards to dosage recommendations 

relate to the fact that some national salbutamol products SmPCs do not have a dose specified for children. 

As the national SmPC paediatric indications and dosage recommendations for the majority of the 

European countries are consistent with GSK’s GDSs for inhaled and non-inhaled salbutamol, GSK 

would propose any national SmPCs which are not consistent should ensure that they have as a 

minimum the same or similar paediatric indications and dosage recommendations as per their 

GDSs. This will also include the addition of GDS text relating to the spacer use to be added to Section 4.2 

and 


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eference to three Ventolin Evohaler paediatric exclusivity studies in Section 5.1 of the salbutamol 

Evohaler national SmPCs (see response to Question 4). With regards to Section 4.4, GSK has reviewed 

the Company’s inhaled and non-inhaled salbutamol GDSs and there are no paediatric-specific warnings 

and precautions. This is due to the pharmacology of the drug being the same in all age groups and 

therefore the side effects profile and warnings and precautions are the same for paediatrics as for adults. 

We have also reviewed the national SmPCs and the only warnings are information which appears in other 

sections of the GDSs (eg dosage and administration) (see Table 3 for details of national SmPCs which 

contain a warning relating to paediatrics in Section 4.4). Therefore, GSK do not propose any specific 

paediatric text for Section 4.4 of the EU national salbutamol SmPCs. 

Table 3 National SmPCs which contain a warning relating to paediatrics in Section 4.4 

National SmPC Section 4.4 Paediatric Warning 

Ireland A responsible adult should supervise the use of the 

inhaler in children. 

Lithuania Ventolin solution for injection does not suit to treat 

children 

Netherlands For babies and young children if Ventolin Inhaler 

and Babyhaler are not effective a physician must be 

consulted. 

Sweden The SmPCs for Nebules 1mg/ml and 2mg/ml and 

Respirator Solution 5mg/ml include the following 

statement in section 4.4 regarding paediatrics: 

'When treating children under 18 months of age a 

good therapeutic response cannot always be 

expected'. 

In summary, as the paediatric indications and dosage recommendations in the national SmPCs for the 

majority of the European countries are consistent with GSK’s GDSs for inhaled and non-inhaled 

salbutamol, GSK’s recommendation is that any national SmPCs which are not consistent should ensure 

that they have as a minimum the same or similar paediatric indications and dosage recommendations as 

per GSK’s GDSs. We also do not recommend any paediatric specific warnings for Section 4.4 of the 

national SmPCs as the pharmacology of the drug is the same in all age groups and therefore the side 

effects profile and warnings and precautions are the same for paediatrics as for adults. 

Rapporteus’s comment 

Following the rapporteur’s request, the MAH conducted a review of all Salbutamol national SmPCs in the 

EU and has compiled the texts related to paediatric use of the drug from sections 4.1, 4.2 and 4.4. 

Reviewing the approved SmPCs, the MAH acknowledged that there are variations in the national texts 

across the EU. There appears to be variability of the information on paediatric use for sections 4.1 and 4.2 

of the SmPC 

GSK proposes that any national SmPCs which are not consistent should ensure that they have as a 

minimum the same or similar paediatric indications and dosage recommendations as per their 

GDSs. 

The company’s proposal is agreed, but it is the Rapporteur’s opinion that the sections 4.1 and 4.2 for all 

inhaled and non-inhaled salbutamol formulations of the GDSs should be updated with information about 

age range limits for paediatric population. 


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Question 4 (Rapporteur): 

With regard to the Assessor’s comment on the three Ventolin HFA paediatric exclusivity studies 

(SB020001, SB030001, SB030002) in younger children less than 4 years. GlaxoSmithKline (GSK) stated 

that the Global Data Sheet (GDS) was updated to include non-core safety wording in the “Dosage and 

Administration” section concerning spacer devices, and reference to the paediatric studies in the “Clinical 

Studies” section with a statement to say that the Evohaler has a safety profile comparable to that in 

children aged ≥ 4 years, adolescents and adults. This update was classified as a change to existing 

information so it was the decision of GSK affiliates in the EU member states whether to add this 

information to their salbutamol Evohaler SmPC. 

A copy of the Clinical Overview that supported this GDS update is included in Appendix 6. Of the three 

paediatric studies conducted in the < 4 years age group, the acute-care setting study (SB030002) in 

subjects between birth to 2 years of age provides evidence of the effectiveness of salbutamol HFA in the 

treatment of acute bronchospasm, as demonstrated by approximately 48% improvement in the Modified 

TAL asthma symptom score (Pavon 1999; a Modified Tal Asthma Symptoms Score (range, 0 to 12) 

was calculated by adding the scores for each of the four variables: components of respiratory rate, 

wheezing, cyanosis, and accessory respiratory muscle utilization). 

Additionally, and in line with literature, the majority of children in this age group did not require a full 

three hours of treatment or six treatment doses. From the published literature (Delgado 2003, Leversha 

2000, Mandelberg 2000, Rubilar 2000, and Yuksel 1994 – full citations provided in Appendix 6), the 

majority of children presenting with mild or moderate asthma exacerbations had improvement of their 

respiratory symptoms with salbutamol with the mean or median number of salbutamol treatments ranging 

from 1.9 to 4 doses. Improvement was generally achieved within one hour of treatment, which is 

consistent with study SB030002, where the majority of subjects did not need more than an hour or four 

doses of treatment. The two other paediatric studies (SB020001 and SB030001) were primarily safety 

studies, and although efficacy parameters were evaluated, the studies were not powered to demonstrate 

efficacy. 

The efficacy from study SALA3006 in 4-11 year olds in conjunction with published literature in this 

younger age group, are considered to be consistent in demonstrating efficacy similar to that of study 

SB030002 conducted in patients from birth to < 2 year olds. 

Therefore, GSK’s proposed approach in the EU is to ensure that the following wording is added to 

all EU national Salbutamol Evohaler (Non-CFC inhaler) Summaries of Product Characteristics by 

the submission of a national variation: 

Section 4.2 

Paediatric population 

Babies and young children using the may benefit from the use of a 

paediatric spacer device with a face mask (for example the BABYHALER) (see Section 5.1). 

(Recommended statement “for example the BABYHALER” is for use only in those markets 

where the Babyhaler spacer device is available) 

Section 5.1 

Paediatric population 

Paediatric clinical studies conducted at the recommended dose (SB020001, SB030001, 

SB030002), in patients < 4 years with bronchospasm associated with reversible obstructive 

airways disease, show that the Evohaler has a safety profile comparable to that in children ≥ 4 

years, adolescents and adults. 

Rapporteus’s comment 

For Salbutamol Evohaler (Non-CFC inhaler) formulation, the MAH had updated the CDS with noncore 

safety wording in the “Dosage and Administration” section concerning spacer devices, and reference 


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to the paediatric studies in the “Clinical Studies” section with a statement to say that the Evohaler has a 

safety profile comparable to that in children aged ≥ 4 years, adolescents and adults, following the three 

Ventolin HFA paediatric exclusivity studies (SB020001, SB030001, SB030002), in younger children less 

than 4 years carried out by GSK. 

However, the GSK stated that the implementation of these proposed changes has varied across the 

member states, being the decision of GSK affiliates in the EU member states whether to add this 

information to their salbutamol. 

The Company’s proposal is to ensure that wording in sections 4.1 and 5.1 for Salbutamol Evohaler 

(Non-CFC inhaler) formulation in Summaries of Product Characteristics by the submission of national 

variation. 

The company’s proposal is agreed. 

B) The Orion Corporation (Orion Pharma, Menarini)’s responses to the questions raised 

Orion Corporation Buventol Easyhaler 100 microg/dose and 200 microg/dose inhalation powder 

Question 1: 


products with paediatric use, the respective wordings of sections 4.1 and/or 4.2 of the SmPC (Annex 

II), as per the procedural guidance. 


The line listing with current approved wordings of sections 4.1 and 4.2 of the SmPC was enclosed in 

separate attachment. This line listing contains all medicinal products where the Orion Corporation is 

either Marketing Authorization Holder (MAH) or licensor. 


The requested data has been submitted. Point resolved. 

Question 2 





Symptomatic treatment of asthma attacks is an indication in all the Buventol Easyhaler national SmPCs, 

although there are differences in the wordings of this indication. In addition to this, prevention of exercise- 

or allergen induced bronchospasm is an indication in Buventol Easyhaler SmPCs of Germany, United 

Kingdom, Czech Republic, Hungary, Latvia and Poland, and prevention of exercise-induced 

bronchospasm is an indication in the Buventol SmPC of Finland. 

The age limit of Buventol Easyhaler has been increased from 4 years to 6 years recently. It has been 

changed already into the SmPCs in Finland, Denmark and Latvia. Age limit is still 4 years in Germany, 

Hungary, Poland and Estonia. Age limit is missing from the SmPCs in United Kingdom, Czech Republic, 

Sweden and Norway. 

The recommended single dose for children is 100-200 micrograms in all countries with the exception of 

Finland, Czech Republic, Sweden and Estonia, where is 100-400 micrograms. The recommended 

maximum daily dose for children is 800 micrograms except for Germany (400 micrograms), Norway 

(1200 micrograms) and Sweden (missing). 

Rapporteur’s comments 



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Question 3 





The Orion’s proposal for a harmonised SmPC text is as follow: 

4.1 Therapeutic indications 

- Symptomatic treatment of asthma attacks and exacerbations of asthma 

- Prevention of exercise-induced bronchospasm or before exposure to a known unavoidable allergen 

challenge 

4.2 Posology and method of administration 

Children over 6 years: 100-200 micrograms 1-4 times daily. 

4.4 Special warnings and precautions for use 

No specific warnings for the children. 

The proposed text is already included in the current Company Core Data Sheet (CCDS) for Buventol 

Easyhaler and the variations to the Summary of Product Characteristics (SmPC) texts are on-going. The 

variation has been approved by the authorities in Finland, Denmark and Latvia. As a generic product, 

Buventol Easyhaler has limited amount of clinical studies especially regarding paediatric patients. 

Therefore, Orion’s proposal is based on the current treatment guidelines, the Global Initiative for Asthma 

(GINA) and the British Guideline on the management of asthma (1, 2) and is in line with the dosing 

instructions of the originator, Ventoline SmPC (3). 

The proposed therapeutic indications are the same as for adults excluding treatment of chronic obstructive 

pulmonary disease (COPD). The role of salbutamol in the treatment of asthma is well-established and 

salbutamol is commonly used for the bronchospasm during acute exacerbations of asthma and for the pretreatment 


Buventol Easyhaler is not recommended for children under 6 years. The age limit has recently been 

increased from 4 years to 6 years according to current recommendations (1, 2). The Global Initiative for 

Asthma (GINA) report recommends that dry powder inhalers (DPIs) should be used for children over 6 

years (1). The British Guideline on the management of asthma states that there are no data to make 

recommendations for DPIs in children under 5 years (2). 

Orion proposes that the dosage for adults and children over 6 years would be 100-200 micrograms 1-4 

times daily, which is in line with the current national guidelines. It is also in line with the current posology 

of the originator, Ventoline SmPC (1-3). The British National Formulary for Children (BNFC) suggests 

the following usual doses administered by dry powder inhalers: 

Orion Corporation Buventol Easyhaler: 100 microg/dose and 200 microg/dose inhalation powder 

ORION PHARMA Paediatric review, article 45 2010-11-09. 3 - 5 to 12 years of age: 200 micrograms up 

to 4 times daily - 12 to 18 years of age: doses as for adults (200-400 micrograms up to 4 times daily) 

(4). 


The Orion’s proposal for the harmonised SmPC text is agreed, but in the rapporteur’s opinion the section 

4.1 should be updated with “….in adults and children over 6 years of age”. 

It is also important to ensure that the patients receive detailed instructions for correct use and children 

should always have adult supervision when using the device. 

C) The Generics [UK] Ltd’s responses to the questions raised 

Responses to the Preliminary Assessment Report issued on 9th November 2010 via email for 

salbutamol were received from the MAHs Generics [UK] Ltd. (previously Merck Generics Ltd. UK) and 

McDermott Laboratories Limited, Ireland (both companies are part of the Mylan group): Line listings 


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were provided for Respigen 100 micrograms per actuation pressurised suspension and Gerivent CFC-Free 

100 micrograms per metered dose pressurised inhalation suspension. Moreover the MAH committed to 

harmonise section 4.2 of the SmPC to specify the posology and the mode of administration according to 

the age range. 

The responses to the Preliminary Assessment Report issued on 9th November 2010 via email, for 

salbutamol, on behalf of Generics [UK] Ltd. (previously Merck Generics Ltd. UK) and McDermott 

Laboratories Limited, Ireland (both companies are part of the Mylan group) are as follows: 

D) On behalf of MEDA Pharma GmbH and Co. KG and MEDA AB and all associated 

companies responses to the questions raised 

The responses to the LoQ are on behalf of MEDA Pharma GmbH and Co. KG and MEDA AB 

and all associated companies (named in the PrAR as MAHs MEDA PHARMA GmbH and MEDA AB). 

Question 1: 





The following products are authorised in the following countries: 

Country: Product name: 

Austria: Novolizer Salbutamol Meda 100 µg Pulver zur Inhalation 

Belgium: Novolizer Salbutamol 100 microgrammes, poudre pour inhalation 

Bulgaria: Вентиластин Новолайзер 100 микрограма / за доза прах за инхалация 

Czech Republic: Ventilastin Novolizer 100 mikrogramů, prášek k inhalaci 

Denmark: Ventilastin Novolizer 

Estonia: Ventilastin Novolizer 

Finland: Ventilastin Novolizer 100 mikrog/annos inhalaatiojauhe 

France: Ventilastin Novolizer 100 microgrammes/dose, poudre pour inhalation 

Germany: 

Inhalation, 

Ventilastin Novolizer, 

Salbutamol MDPI Novolizer 100 Mikrogramm/Dosis Pulver zur 

Salbutamol Novolizer 100 Mikrogramm/Dosis Pulver zur Inhalation, 

Salbutamol 100 Novolizer 100 Mikrogramm/Dosis Pulver zur Inhalation 

Greece: Ventilastin Novolizer 100 micrograms / Κόνις γιa eιspνοή 

Ireland: Novolizer Salbutamol 100 micrograms inhalation powder 

Latvia: Ventilastin Novolizer 

Lithuania: Ventilastin Novolizer 100 mikrogramų/dozėje milteliai inhaliacijai 

Luxembourg: Novolizer Salbutamol 100 microgrammes, poudre pour inhalation 

Netherlands: Salbutamol Novolizer 100 µg, inhalatiepoeder 

Norway: Vivoret 100 mikrogram/dose, inhalasjonspulver 

Poland: Ventilastin Novolizer 

Portugal: Salbutamol Novolizer 100 µg pó para inalação 

Romania: Ventilastin Novolizer 100 micrograme / doza pulberede inhalat 

Slovakia: Ventilastin Novolizer 

Slovenia: Ventilastin Novolizer 100 mikrogramov /odmerek prasek za inhaliranje 

Spain: Ventilastin Novolizer 100 MCG/dosis, polvo para inhalación 

Sweden: Ventilastin Novolizer 100 mikrogram/dos inhalationspulver 


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United Kingdom: Salbulin MDPI Novolizer 100 micrograms/dose inhalation powder 

The MAHs stated that these products had been assessed in the scope of 4 European procedures, each with 

Germany as Reference Member State (MRP DE/H/0333/001, DCP DE/H/0864/001, DCP DE/H/0865/001 

and DCP DE/H/1027/001). DCP DE/H/1027/001 has been the newest European procedure, concluded in 

June 2009. Therefore the harmonised SmPC as outcome of that procedure represents the company’s recent 

SmPC for the products with Salbutamol Novolizer, considering the at that time newest QRD templates 

and including recommendations for the paediatric population (e.g., the SmPC for the first procedure MRP 

DE/H/0333/001, will be adapted to the recent version in the scope of a renewal procedure). 



Q2: MAH(s) should review the information on paediatric use included in the national SmPCs from 

all MS in which salbutamol is an approved medical compound for paediatric use and identify the 



The respective wording of sections 4.1, 4.2 and 4.4 of this recent SmPC was enclosed as English version: 

4.1 Therapeutic indications 

Symptomatic treatment of conditions with associated reversible airway obstruction, e.g. asthma or chronic 

obstructive pulmonary disease with a substantial component of reversibility. 

Prevention of asthma attacks induced by exercise or exposure to allergens. 

4.2 Posology and method of administration 

Posology 

The dose depends on the type, severity, and course of the disorder. 

Asthma 

Adults (including the elderly and adolescents) 

For the relief of acute symptoms including bronchospasm a starting dose of one inhalation (100 

micrograms) is recommended for adults. 

For prevention of exercise-induced or allergen induced symptoms two inhalations (200 micrograms) 

should be taken 10-15 minutes prior to challenge. 

The maximum on-demand use in any 24 hours should not exceed 8 inhalations (equivalent to 800 

micrograms). 

Children (aged 6 to 12 years) 


micrograms) is recommended for children aged 6 years and above. 

For prevention of exercise-induced or allergen induced symptoms one inhalation (100 micrograms) should 

be taken 10-15 minutes prior to challenge and a further inhalation (to a total of 200 micrograms), if 

necessary. 


micrograms). 

Children below 6 years of age 

Salbutamol 100 Novolizer is not recommended for use in children below age 6 due to insufficient data on 

safety and efficacy. 

COPD 

Adults (including the elderly and adolescents) 


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micrograms) is recommended for adults. 


micrograms). 

For all patients 

When other salbutamol inhalers are replaced by Salbutamol 100 Novolizer 100 micrograms inhalation 

powder the amount of salbutamol delivered to the lung may vary between different inhalers and therefore 

the posology may have to be adjusted. 

Method of administration 

There should be an interval of at least 1 minute between 2 inhalations. 

Inhalation use 

Usage and handling of the Powder inhaler (= Novolizer) 

Figure 

Refilling 

1. Lightly press together the ribbed surfaces on both sides of the lid, move the lid forwards and lift off. 

2. Remove the protective aluminium foil from the cartridge container and take out the new cartridge. 

3. Insert the cartridge into the Powder inhaler (= Novolizer) with the dosage counter facing the 

mouthpiece. 

4. Replace the lid into the side guides from above and push down flat towards the button until it snaps 

into place. The cartridge can be left in the Powder inhaler (= Novolizer) until it has been used up, or 

for up to 6 months after insertion. 

Note: Salbutamol 100 Novolizer 100 micrograms cartridges may only be used in the Novolizer powder 

inhaler 

Usage 

1. When using the Powder inhaler (= Novolizer) always keep it horizontal. First remove the protective 

cap. 


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2. Completely depress the coloured dosage button. A loud double click will be heard and the colour of 

the control window (lower) will change from red to green. Then release the coloured dosage button. 

The colour green in the window indicates that the Powder inhaler (= Novolizer) is ready for use. 

3. Exhale (but not into the Powder inhaler (= Novolizer)). 

4. Put the lips around the mouthpiece. Inhale the powder with a deep breath. During this breath a loud 

click should be heard, indicating correct inhalation. Hold the breath for a few seconds and then 

continue with normal breathing. 

Note: If the patient needs to take more than 1 inhalation at a time, steps 2 - 4 should be 

repeated. 

5. Replace the protective cap on the mouth piece - the dosing procedure is now complete. 

6. The number in the top window indicates the number of inhalations left. 

Note: The coloured dosage button should only be pressed immediately before inhalation. 

A double inhalation in error is not possible with the Powder inhaler (= Novolizer). The click sound 

and the change of colour in the control window indicate that inhalation has been performed 

correctly. If the colour of the control window does not change then inhalation should be repeated. If 

inhalation is not completed correctly after several attempts, then the patient should consult the 

doctor/physician. 

Cleaning 

The Powder inhaler (= Novolizer) should be cleaned at regular intervals, but at least every time the 

cartridge is changed. Instructions on how to clean the Powder inhaler (= Novolizer) can be found in 

the ‘Instructions for use’ which is part of package leaflet. 

Note: In order to ensure correct use of the Powder inhaler (= Novolizer), patients should receive 

thorough instructions on how to use the Powder inhaler (= Novolizer). Children should only use this 

product under the supervision of an adult. 

4.4 Special warnings and precautions for use 

Treatment should be carried out stepwise according to the severity. 

Bronchodilators should not be the only or main treatment in patients with persistent asthma. Severe 

asthma requires regular medical assessment as patients are at risk of severe attacks and even death. 

For patients with asthma, use of Salbutamol 100 Novolizer 100 micrograms inhalation powder should not 

delay the introduction and regular use of inhaled corticosteroid therapy. 

In the following cases, salbutamol should only be used with caution and if strictly indicated: 

- serious cardiac disorders, in particular recent myocardial infarction 

- coronary heart disease, hypertrophic obstructive cardiomyopathy and tachyarrhythmia 

- severe and untreated hypertension 

- aneurysm 

- hyperthyroidism 

- diabetes which is difficult to control 

- pheochromocytoma 

There is some evidence from post-marketing data and published literature of rare occurrences of 

myocardial ischaemia associated with salbutamol. Patients with underlying severe heart disease (e.g. 

ischaemic heart disease, tachyarrhythmia or severe heart failure) who are receiving salbutamol for 

respiratory disease, should be warned to seek medical advice if they experience chest pain or other 

symptoms of worsening heart disease. 


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Daily self assessment of asthma control following instructions regarding the use of Salbutamol 100 

Novolizer 100 micrograms and any other drugs required for the management of asthma is important in 

order that the course of the disease can be followed and the success of both bronchodilator and antiinflammatory 

therapy monitored. The patient should be instructed in the regular measurement of peak 

expiratory flow rate (PEFR) using a portable peak flow meter. 

If disease control does not improve satisfactorily or deteriorates, or if the short-acting relief bronchodilator 

treatment becomes less effective, or more inhalations than usual are required, medical advice must be 

sought in order that the clinical condition can be re-assessed and therapeutic management revised 

appropriately. 

In this situation, for patients with asthma anti-inflammatory therapy may be required, the dose of antiinflammatory 

therapy may need to be increased or a short course of oral glucocorticoids may be needed. 

For patients with chronic obstructive pulmonary disease regular treatment of one or more long-acting 

bronchodilators may be required, rehabilitation, use of inhaled corticosteroids or long term oxygen may be 

needed. 

Increasing use of bronchodilators and in particular short-acting inhaled beta2 adrenergic agonists to 

relieve symptoms indicates deterioration of disease control. 

A sudden and increasing deterioration of symptoms can be life-threatening. Therefore, medical assistance 

must be sought immediately. 

The dose and frequency of inhalation of short-acting beta2 agonists should only be increased following 

medical advice and if a previously effective dose fails to give the expected relief the patient should be 

advised to seek medical advice. Exceeding the prescribed dose can be dangerous (see section 4.9). If acute 

asthma symptoms are not relieved or gets even worse following a second inhalation, or if patients are 

unable to trigger the Powder inhaler (= Novolizer) during an acute asthma attack, medical assistance 

should be sought immediately. 

Potentially serious hypokalaemia may result from beta2 agonist therapy, mainly from parenteral and 

nebulised administration. Particular caution is advised in acute severe asthma as this effect may be 

potentiated by hypoxia. 

Inhaled salbutamol preparations are not appropriate for the management of premature labour and should 

not be used for threatened abortion. 

Lactose may contain milk protein. The amount of lactose contained in Salbutamol 100 Novolizer does not 

normally cause problems in lactose intolerant people. 

However, in patients with profound enzyme deficiency, lactose intolerance has been reported very rarely 

following inhalation of powder containing lactose. 

Patients should be instructed in the proper use of the Powder inhaler (= Novolizer). The patient’s inhaler 

technique should be checked to ensure that the patient is able to use the Powder inhaler (= Novolizer) 

correctly. 

Rapporteur’s comments: 

The company has only one authorised medicinal product which contains salbutamol – Salbutamol 

Novolizer (Powder inhaler) 100 micrograms/dose inhalation powder, with different brand name in 

different countries. This medicinal product was subject for 4 European procedures, each with Germany as 

Reference Member State (MRP DE/H/0333/001, DCP DE/H/0864/001, DCP DE/H/0865/001 and DCP 

DE/H/1027/001). DCP DE/H/1027/001 has been the newest European procedure and was concluded in 

June 2009. 


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The harmonised SmPC as outcome of that procedure represents the company’s recent SmPC for the 

products with Salbutamol Novolizer. The other SmPCs for the first procedure MRP DE/H/0333/001, will 

be adapted to the recent version in the scope of a renewal procedure 

Q3: In case of divergences between MS, the MAH (s) should provide a proposal for a harmonised 

SmPC text in sections 4.1, 4.2, and 4.4 regarding paediatric use. The proposal should be justified by 



The wording mentioned above represents the company’s proposal as a basis for a harmonised SmPC text 

in sections 4.1, 4.2 and 4.4 as requested in the Rapporteur’s Preliminary Assessment Report / VI. Request 

for supplementary information. However, the company wanted to point out that only the text in section 4.2 

gives own information for paediatric use. 


The proposed changes regarding paediatric use for powder inhaler in section 4.2 by the MAH are endorsed 

by the rapporteur. However supplementary minor changes are requested in section 4.1 in order to be in 

line with the revised SPC guideline (September 2009) and QRD template. The proposal of the rapporteur 

is that the age limit for children to be also specified in section 4.1. 

E) The InfectoPharm Arzneimittel GmbH’s responses to the questions raised 

Question 1: 





The company has two authorized medicinal products which contain salbutamol: Salbubronch 

Fertiginhalat (nebuliser solution in unit dose vials) and Salbubronch Inhalationslösung (nebuliser 

solution). 

The translated wording of sections 4.1 and 4.2 of the SmPC for Salbubronch Fertiginhalat 

(nebuliser solution in unit dose vials) and Salbubronch Inhalationslösung (nebuliser solution) has 

been attached, as requested in the Preliminary Assessment Report. 


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Since the company only holds national registrations in Germany, a further review of the 

information on paediatric use in national SmPC has not been carried out. 


This is acceptable.No issue is raised. 





N/A ( see above question). 

F) The Warsaw Pharmaceutical Works Polfa SA’s responses to the questions raised 

Question 1: 





The Polfa’s salbutamol products are 2 and/or 4 mg tablets registered via national procedures in 

Poland, Slovakia, Lithuania, Bulgaria, Hungary and Czech Republic. The company stated that their 

product is a generic to Ventolin. 

A line listing with the respective wording of sections 4.1 and/or 4.2 of the SmPC in all countries 

has been submitted. 








A comparison of the SmPC sections 4.1, 4.2, 4.4 of Polfa’s salbutamol (2 and/or 4 mg tablets) 

products registered via national procedures in Poland, Slovakia, Lithuania, Bulgaria, Hungary and Czech 

Republic has been carried out. The company stated that this product is a generic of Ventolin and the 

product information in Slovakia and in Hungary will be soon updated to the Polish version. There are no 

differences regarding paediatric indications (emphysema generally refers to adults) and dosage 

recommendations. 


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SALBUTAMOL 

WZF POLFA 2 mg 

SALBUTAMOL 

WZF POLFA 4 mg 

Poland 

-Salbutamol WZF 2 

mg 

(MA No R/1303) 


mg 

(MA No R/2771 

4.1. Therapeutic 

indications 

Salbutamol is a 

selective βadrenomimetic 

agent 

acting on β2 

receptors. 

Salbutamol WZF 

POLFA is used in the 

treatment of asthma, 

bronchospasm and/or 

reversible airway 

obstruction 

conditions. 

4.2. Posology and 

method of 

administration 

Adults and children 

over 12 years of age: 

The dosage is usually 

initiated from 2 mg 

to 4 mg, up to three 

to four times a day. 

Doses can be taken at 

intervals not shorter 

than 6 hours. If the 

action of these doses 

is insufficient, they 

can be up-titrated, 

but a dose higher 

than 8 mg four times 

a day should not be 

used. 

Caution should be 

exercised when 

increasing the doses 

(if adverse effects 

occur, product 


should be 

discontinued). 

Single doses higher 

than 4 mg can be 

used only if there is 

no reaction to 

smaller doses. 

In elderly patients 

with increased 

SALBUTAMOL 2 

mg tabletta 

SALBUTAMOL 

WZF POLFA 

SALBUTAMOL 

WZF Polfa 2 mg 

SALBUTAMOL 

WZF Polfa 4 mg 

САЛБУТАМОЛ 

WZF 2 mg 

САЛБУТАМОЛ 

WZF 4 mg 

SALBUTAMOL 

WZF POLFA 2 

SALBUTAMOL 

WZF POLFA 4 

Hungary 1 Slovakia 2 Lithuania Bulgaria Czech Republic 

-Salbutamol 2 mg 

(MA No OGYI – T – 

0991/01) 



Relief of 

bronchospasm in 

asthma bronchiale, 

chronic obstructive 

bronchitis and 

emphysema. 


method of 



over 12 years: 

Conforming to the 

Polish version 

Children from 6-12 

years: 

2 and 4 mg 

(MA No 14/0199/87- 

C/S) 



Spastic status of the 

smooth muscles 

during episodes of 

bronchial asthma, 


bronchitis, lung 

emphysema. 


method of 



over 12 years: 



Children from 6-12 

years: 


mg 

(MA No 

LT/1/94/1671/001) 


mg 

(MA No 

LT/1/94/1671/002) 



Relieve spastic 

conditions of smooth 

muscles in the course 

of bronchial asthma 

or chronic 

obstructive 

bronchitis. 


method of 



above 12 years of 

age: 



Children 6 – 12 years 

of age: 


mg 

(MA No 

9900343/28.12.2005) 


mg 

(MA No 

9900344/28.12.2005) 



Spastic conditions of 

the smooth muscles 

of respiratory tract in 

case of bronchial 

asthma, chronic 

obstructive 

bronchitis and 

emphysema. 


method of 







of age: 


mg 

(MA No 14/199/87- 

A/C) 


mg 

(MA No 14/199/87- 

B/C) 



The product is 

indicated for the 

treatment and 

prevention of 

bronchospasm in 

bronchial asthma and 


pulmonary disease. 


method of 







of age: 

1 

Summary of Products Characteristics and Patients Information Leaflet of Salbutamol in Hungary will be modified this year (2011), the 

variation procedure is ongoing. 

2 

Summary of Products Characteristics and Patients Information Leaflet of Salbutamol in Slovakia will be modified this year (2011), the 

variation procedure starts next month. 


RO/W/0001/pdWS/001 

Page 71/76

sensitivity to 

sympathomimetic 

amines, the initial 

dose of 2 mg up to 

four times a day 

should be used. 

The maximum daily 

dose of salbutamol is 

32 mg. 

Children aged 6 to 12 

years 

The initial dose is 

usually 2 mg up to 

three to four times a 

day. Doses can be 

taken at intervals not 

shorter than 6 hours. 

If the action of these 

doses is insufficient, 

they can be uptitrated, 

but a dose 

higher than 6 mg 

four times a day (24 

mg) should not be 

used. Caution should 

be exercised when 

using high doses (if 

adverse effects 

occur, product 


should be 

discontinued). 

4.4 Special 

warnings and 

precautions for use 

Bronchodilators 

should not be the 

only or main 

treatment in patients 

with severe or 

unstable asthma. 

Such patients 

requires regular 

medical assessment 

including lung 

function testing as 

the patients are at 

risk of severe asthma 

attacks and even 

death. In the case of 

this group of 

patients, the 

physician should 

consider using oral 

corticosteroid 

therapy and/or the 

maximum dose of 

inhaled 

corticosteroids. 

Patients taking 

salbutamol in the 

form of tablets may 

also use short-acting 

bronchodilators to 

alleviate their 



4.4 Special 

warnings and 

precautions for use 

Salbutamol, 

similarly to other �adrenomimetics 

can 

induce a significant 

stimulation of the 

sympathetic nervous 

system, manifesting 

as: heart palpitations, 

elevation of arterial 

blood pressure, 

accelerated heart rate 

and ECG 

abnormalities 

(flattening of T 

waves, prolongation 

of QTc interval, 

shortening of ST 

interval). 

Due to a possibility 

of excessive 



system, salbutamol 

should be used with 

caution in patients 

with cardiovascular 

system diseases, 

especially with 

ischaemic heart 

disease, cardiac 



4.4. Special 

warnings 

Similarly to other 

beta-adrenomimetics, 

salbutamol can 

induce significant 


vegetative nervous 

system which can be 

indicated by the 

following symptoms: 

palpitations, 

increased arterial 


tachycardia, 

abnormal ECG. Rare 

occasions of an 

allergy caused by 

salbutamol can be 

expressed by 

urticaria, 

angioedema, rash, 

brochospasm, 

anaphylactic 

symptoms and 

swollen vocal 

chords. 

In relation to the 

possibility of 

excessive stimulation 

of the vegetative 

nervous system, 

salbutamol should be 

used with increased 



4.4. Special warning 

and precautions for 

use 







Severe asthma 





patients are at risk of 

severe attacks and 

even death. 

Physicians should 




maximum 

recommended dose 

of inhaled 

corticosteroid in 

these patients. 


salbutamol tablets 

may also be 

receiving shortacting 



relieve symptoms. 





use 

Products dilating 

smooth muscles in 

the bronchi should 

not be used as 

monotherapy in 

patients with severe 

or unstable asthma. 

Such patients require 

regular control, 

including the 

execution of lung 

function tests, 

because they are at 

risk of development 

of severe asthma 

attack or even death. 

In this group of 

patients, a doctor 

should consider the 

administration of oral 

corticosteroids and 

(or) the maximum 

dose of inhaled 



salbutamol in a form 

of tablets can also 

use short-acting 

bronchodilators in 

order to control the 

symptoms. Increased 





use 







Severe asthma 





patients are at risk of 

severe attacks and 

even death. 

Physicians should 




maximum 



corticosteroid in 

these patients. 









RO/W/0001/pdWS/001 

Page 72/76


consumption of 

bronchodilators, 

including shortacting 

β-adrenergic 

receptor agonists is a 

sign of asthma 

aggravation. In such 

circumstances, the 

patient’s condition 

should be reassessed 

and an increase of 

the dose of inhaled 

corticosteroids used 

so far or the use of 

oral corticosteroids 

should be 

considered. 

Similarly as after the 

use of other drugs of 

the group of βadrenergic 

receptor 

agonists, salbutamol 

may cause transient 

metabolism changes 

such as increased 

blood glucose. On 

patients with 

diabetes, metabolic 

acidosis has been 

noted, because their 

bodies are unable to 

compensate 

increased blood 

glucose. 

Concomitant use of 

these drugs and 

corticosteroids may 

potentiate this effect. 

Similarly as other βadrenomimetics, 

salbutamol may 

cause stimulation of 

the sympathetic 

system, manifested, 

for example, as 

palpitations, elevated 

blood pressure, rapid 

pulse rate and ECG 

changes (flattening 

of T-wave, 

prolonged QTc, 

shortened ST). 

In view of the 



of the sympathetic 



caution in persons 


disorders, especially 

with ischaemic heart 

disease, arrhythmia 

and arterial 

hypertension. 



cardiovascular side 

arrhythmias and 

hypertension. 

Because of potential 

risks to the 

circulatory system, 

increased demand for 

�-adrenomimetics in 

the course of 

bronchial asthma 

should prompt the 

physician towards 

revision of the 

current therapeutic 

management, and 

possibly to 

replacement of �adrenomimetics 

with 

other medicinal 

products. 

Rare cases of 

hypersensitivity to 


manifest with 

urticaria, 


bronchospasm and 

glottis oedema. The 

treatment with 


discontinued if 

bronchospasm 

develops. After oral 

administration of 

salbutamol to 

children rare case of 

erythema multiforme 

and Stevens–Johnson 

syndrome were 

observed. 

Caution is also 

necessary when 

salbutamol is used in 

patients with 

hyperthyroidism, 

epilepsy, diabetes 

mellitus and 

excessive response to 


amines. 

High doses of 


inhibit the uterine 

contractions. This 

fact should be taken 

into consideration, 

when the medicinal 

product is used 

during labour. 

The patient should be 

advised that the dose 

of the medicinal 

product or dosage 

frequency must not 

be increased without 

doctor’s consultation, 

because it could 

create a serious 

care in patients with 

diseases of the 

cardiovascular 

system, mainly 

ischemic heart 

disease, heart 

arrhythmias and high 

blood pressure. Care 

is also necessary 

during treatment 

using salbutamol in 

patients suffering 

from 



mellitus and 

glaucoma. 

High doses of 

salbutamol could 

inhibit uterus 


fact can be taken into 

account when using 

this drug during 

labour. 

A patient should be 

warned that 

increased doses of 

the drug or frequency 

of doses in 

comparison with the 


can cause serious 

risk of cardiovascular 

disease. Individual 

doses or frequency of 

dosing must not be 

increased without 

consulting a treating 

doctor. 

Due to the existence 

of possible risks of 

circulation system 

disorders, when there 

is increased 

consumption of betaadrenomimetics 

for 

bronchial asthma, 

treating doctors 

should re-evaluate 

the current treatment 

and possible replace 

beta-adrenomimetics 

with another drug. 

Cases of erythema 

multiforme or 

Stevens-Johnson 

syndrome were noted 

rarely after oral 


salbutamol to 

children. 

Patients with rare 

hereditary problems 

of galactose 

intolerance, the Lapp 

lactase deficiency or 

glucose-galactose 

malabsorption should 

Increasing use of 

bronchodilators, in 

particular shortacting 

inhaled Beta2agonists 

to relieve 

symptoms, indicates 

deterioration of 

asthma control. In 

these situations, 

patients should be 

reassessed and 

consideration given 

to the need for 

increased antiinflammatory 

therapy (e.g. higher 

doses of inhaled 

corticosteroids or a 

course of oral 

corticosteroids). 

In common with 

other β-adrenoceptor 


can induce reversible 

metabolic changes 


blood glucose levels. 

Diabetic patients 

may be unable to 

compensate for the 

increase in blood 

glucose and the 

development of 

ketoacidoses has 

been reported. 

Concurrent 


corticosteroids can 

exaggerate this 

effect. 

Salbutamol, similarly 

to other �adrenomimetics 

can 

induce a significant 



system, manifesting 

as: heart palpitations, 

elevation of arterial 


accelerated heart rate 

and ECG 

abnormalities 

(flattening of T 

waves, prolongation 

of QTc interval, 

shortening of ST 

interval). 

Due to a possibility 

of excessive 





caution in patients 


system diseases, 

especially with 




β-adrenergic 

receptors agonists, 

indicates the 

worsening of asthma. 

In such situation the 

patient's condition 

should be reevaluated 

and 

increase of the dose 


corticosteroids or 

administration of oral 

corticosteroids 

should be 

considered. 

Similarly as after 


other β-adrenergic 

receptors agonists 


produce transitory 

metabolic changes 

such as elevated 

blood glucose level. 

There are reports in 

patients with diabetes 

developed metabolic 

acidosis because 

their body cannot 

compensate the 

elevated blood 

glucose level. 

Concomitant use 

with corticosteroids 

can enhance this 

effect. 

Salbutamol as other 

β-adrenomimrthics 

can cause stimulation 

of sympathetic 

nervous system 

which occur with 

cardiac palpitations, 


pressure, accelerated 

pulse, also with ECG 

- disturbances 

(decrease in the 

amplitude of the Twaves, 

prolongation 

of QT – interval and 

shortness of STinterval). 

Taking into 

consideration the 

potential risk for 

cardio-vascular 

system and the 

increased need of βadrenomimethics 

in 

case of bronchial 

asthma the attention 

of the doctor should 

be turn to revision of 

the treatment and 

eventual replacement 

of βadrenomimethics 




β-adrenergic 












should be 

considered. 




receptor 






patients with 





compensate 


glucose. 





Similarly as other βadrenomimetics, 


cause stimulation of 

the sympathetic 

system, manifested, 

for example, as 

palpitations, elevated 

blood pressure, rapid 

pulse rate and ECG 

changes (flattening 

of T-wave, 

prolonged QTc, 

shortened ST). 




of the sympathetic 



caution in persons 


disorders, especially 

with ischaemic heart 


and arterial 

hypertension. 



cardiovascular side 

effects, in the case of 


RO/W/0001/pdWS/001 

Page 73/76

effects, in the case of 

increased 

requirements for βadrenomimetics 


the course of 

bronchial asthma, the 

existing treatment 

regimen should be 

analysed and 

potentially βadrenomimetics 

should be replaced 

by other drugs. 

In postmarketing 

studies and published 

literature, rare cases 

of ischaemic heart 

disease related to 

salbutamol use were 

reported. Patients 

with coexisting 

severe heart disorder 

(e.g. ischaemic heart 

disease, with cardiac 

arrhythmia or severe 

heart failure), who 

receive salbutamol 

for respiratory 

indications, should 

be cautioned about 

the need to consult a 

doctor in the case of 

chest pain or other 

symptoms which 

may be a 

manifestation of 

heart disease 

deterioration. 

In rare cases of 

salbutamol 

hypersensitivity, 

urticaria, 



glottis oedema may 

occur. If 

bronchospasm 

occurs, treatment 

with salbutamol 

should be 

discontinued. Cases 

of erythema 






salbutamol to 

children. 

Caution is necessary 

when using 

salbutamol in 

persons with 

hyperthyroidism, in 

patients with 

epilepsy or diabetes 

and in patients with 

excessive reaction to 

threat of 


system disorders. 


also advised about 

the necessity 

of physician’s 

consultation if 

administration of the 

recommended doses 

brings no relief. 

not take this 

medicine because it 

contains lactose. 




persons with 


patients with 












Such patients 





the patients are at 

risk of severe asthma 

attacks and even 

death. In the case of 

this group of 

patients, the 

physician should 




maximum dose of 













β-adrenergic 












should be 

considered. 




receptor 



disease, cardiac 

arrhythmias and 

hypertension. 

Because of potential 

risks to the 

circulatory system, 

increased demand for 

�-adrenomimetics in 

the course of 

bronchial asthma 

should prompt the 

physician towards 

revision of the 

current therapeutic 

management, and 

possibly to 

replacement of �adrenomimetics 

with 

other medicinal 

products. 

Cardiovascular 

effects may be seen 

with 


drugs, including 

SALBUTAMOL 

WZF Polfa. 

There is some 

evidence from postmarketing 

data and 

published literature 

of rare occurrences 

of myocardial 

ischaemia associated 

with beta agonists 

(salbutamol). 

Patients with 

underlying severe 

heart disease (e.g. 



or severe heart 

failure) who are 

receiving 

SALBUTAMOL 

WZF Polfa should be 

warned to seek 

medical advice if 

they experience chest 

pain or other 

symptoms of 

worsening heart 

disease. Attention 

should be paid to 

assessment of 

symptoms such as 

dyspnoea and chest 

pain, as they may be 

of either respiratory 

or cardiac origin. 

Rare cases of allergy 

to salbutamol can 

manifest with 

urticaria, 


bronchospasm, 

anaphylactoid 

symptoms and glottis 

with other product. 

Cardiovascular 

effects may be 

observed with 


including salbutamol. 

There are records 

from post-marketing 

surveillances and 

publications about 

myocardial 

ischaemia associated 

with beta-agonists 

administration. 

Tocolysis 

The product should 

be used with caution 

in tocolysis and 

cardiac and 

respiratory functions 

should be monitored, 

including ECG 

monitoring. 

Treatment should be 

discontinued if signs 

of myocardial 

ischaemic (such as 

chest pain or ECG 

changes) occur. The 

product should not 

be used as a tocolytic 

agent in patients with 

significant risk 

factors for or preexisting 

heart disease 

(see section 4.3). 

Respiratory 


Patients with 

underlying severe 

heart disease (e.g. 



or heart failure) who 

are receiving the 

product should be 

advised to seek for a 

medical assistance if 

they experience chest 

pain or other 

symptoms of 

worsening heart 

disease. Special 

attention should be 

paid to assessment of 

symptoms such as 

dyspnoea and chest 

pain as they may be 

of either respiratory 

or cardiac origin. 


hypersensitivity to 

salbutamol urticaria, 



glottis oedema can 

develop. If 

bronchospasm occurs 

the salbutamol 

treatments should be 

discontinued. Rare 

increased 

requirements for βadrenomimetics 


the course of 

bronchial asthma, the 

existing treatment 

regimen should be 

analysed and 

potentially βadrenomimetics 

should be replaced 

by other drugs. 


salbutamol 

hypersensitivity, 

urticaria, 



glottis oedema may 

occur. If 

bronchospasm 

occurs, treatment 

with salbutamol 

should be 

discontinued. Cases 

of erythema 






salbutamol to 

children. 




persons with 


patients with 






High doses of 


inhibit uterine 


should be taken into 

account when the 

drug is used during 

delivery. 

Patients should be 

instructed that if their 

reaction to the 

current dose of the 

drug or the duration 

of drug action 

decreased, they 

should not increase 

the drug doses or 

frequency of their 

intake without first 

consulting their 

doctor. This may 

cause severe 



RO/W/0001/pdWS/001 

Page 74/76



High doses of 





account when the 

drug is used during 

delivery. 

Patients should be 

instructed that if their 

reaction to the 

current dose of the 

drug or the duration 

of drug action 

decreased, they 


the drug doses or 

frequency of their 

intake without first 

consulting their 

doctor. This may 

cause severe 


disorders. 

Furthermore, the 


informed on the need 

to consult a doctor if 

the use of the 


does not bring any 

improvement. 



of galactose 





not take this 







patients with 





compensate 


glucose. 





oedema. The 

treatment with 


discontinued if 

bronchospasm 

develops. After oral 


salbutamol to 

children rare cases of 

erythema multiforme 

and Stevens–Johnson 

syndrome were 

observed. 

Caution is also 

necessary when 

salbutamol is used in 

patients with 



mellitus, glaucoma 

and excessive 

response to 



High doses of 




fact should be taken 

into consideration, 

when the medicinal 

product is used 

during labour. 


advised that the dose 

of the medicinal 

product or dosage 

frequency must not 

be increased without 

doctor’s consultation, 

because it could 

create a serious 

threat of 


system disorders. 


also advised about 

the necessity of 

physician’s 

consultation if 



brings no relief. 

Because of the 

lactose content, 

product should not 

be used to treat 

patients with rare 

inherited galactose 

intolerance, Lapp 



malabsorption. 

cases of erythema 

multiforme and 


syndrome were 

recorded after oral 


salbutamol to 

children. 

Salbutamol should be 

used carefully in 

patients with 


case of epilepsy, 

diabetes and also in 

patients with 

sensitivity to 

sympathomimetics. 

High doses of 

Salbutamol can 

suppress uterus 



account in case the 

product is issued 

during delivery. 


informed that if the 

dose response or the 

duration of product 

effect reduces they 


the dose or frequency 

of administration 

without consulting 

with the doctor - this 

can cause 


disorders. It is also 

necessary to inform 

the patient about the 

necessity to consult 

the doctor if the 



is without effect. 

Because of the 

presence of lactose 

this product should 

not be used in 

patients with a rare 

inherited galactose 

intolerance, lactase 

deficiency (Lapp 

type) or glucosegalactose 

malabsorption 

syndrome 

disorders. 

Furthermore, the 


informed on the need 

to consult a doctor if 

the use of the 


does not bring any 

improvement. 



of galactose 





not take this 



In postmarketing 

studies and published 

literature, rare cases 

of ischaemic heart 

disease related to 

salbutamol use were 

reported. Patients 

with coexisting 

severe heart disorder 

(e.g. ischaemic heart 

disease, with cardiac 

arrhythmia or severe 

heart failure), who 

receive salbutamol 

for respiratory 

indications, should 

be cautioned about 

the need to consult a 

doctor in the case of 

chest pain or other 

symptoms which 

may be a 

manifestation of 

heart disease 

deterioration. 


RO/W/0001/pdWS/001 

Page 75/76



The company SmPC for salbutamol tablets is acceptable. 





N/A ( see above question). 

VI. OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT 

As a result of the submitted paediatric studies, the MAH (s) did not propose any change to the 

approved SmPC of all inhaled and non-inhaled salbutamol formulations. 

Salbutamol has a well-established medicinal use, with recognised efficacy and an acceptable level of 

safety. The benefit-risk balance is considered positive in the symptomatic treatment of conditions with 

associated reversible airway obstruction, e.g. asthma or chronic obstructive pulmonary disease with a 

substantial component of reversibility and in the prevention of asthma attacks induced by exercise or 

exposure to allergens. 

In general, it is agreed with the MAH (s) that the data from the submitted studies do not 

specifically indicate any need of major change of the current paediatric information in the SmPCs. 

However, in the Rapporteur’s opinion a harmonisation of the paediatric data throughout Europe taking 

into account all the national Marketing authorizations for salbutamol is needed. 

It is suggested that following amendments should be implemented in the countries where the 

respective wordings have not already been included in the SmPCs using variation procedures. 

PROPOSED CHANGES IN THE SmPC 

Section 4.1: it is the Rapporteur's opinion that the SmPCs should be amended including a specific 

paediatric indication for all inhaled and non-inhaled salbutamol formulations and the lower age limit 

should be mentioned accordingly. 

Section 4.2: If no lower age limit is specified, the lower age limit should be mentioned depending on the 

suitability with the different formulations of salbutamol. 

None 

VII. ADDITIONAL CLARIFICATIONS REQUESTED 


RO/W/0001/pdWS/001 

Page 76/76

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