qanastek/EMEA-V3 huggingface dataset:
The indication sought is “ Symptomatic treatment of bronchoconstriction due to bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD) and emphysema.
L- indikazzjoni mfittxija hija “ Trattament sintomatiku ta ’ bronkokostrizzjoni minn ażma tal- bronki, bronkite kronika, marda pulmonari ostruttiva kronika (COPD) u enfisema.
Prophylaxis of exercise and allergen induced asthma .” The Applicant submitted pharmaceutical and clinical efficacy and safety documentation, but a number of Member States did not consider the product to be approvable based on the submitted in vitro data only.
L- applikant ippreżenta dokumentazzjoni tal- effikaċja u sigurtà farmaċewtika u klinika, iżda numru ta ’ Stati Membri ma kkunsidrawx li l - prodott huwa approvat abbażi tad- dejta in vitro ppreżentata.
Major objections were raised and because the main issues on quality (in vitro equivalence to the reference product) and the insufficiency of the clinical studies could not be resolved, the procedure was referred to CHMP by a number of objecting concerned member states.
Tqajmu oġġezzjonijiet maġġuri u minħabba l- kwistjonijiet ewlenin dwar il- kwalità (l- ekwivalenza in vitro għall- prodott ta ’ referenza) u minħabba li l- insuffiċjenza tal- istudji kliniċi ma setgħux jiġu solvuti, il- proċedura ġiet irreferuta lis - CHMP minn għadd ta ’ Stati Membri konċernati li oġġezzjonaw.
Critical Evaluation
Evalwazzjoni kritika
The CHMP adopted a List of Questions summarising a number of unresolved issues to be addressed and substantiated by the Applicant.
Is- CHMP adotta Lista ta ’ Mistoqsijiet li jagħtu fil- qosor numru ta ’ kwistjonijiet mhux solvuti li kellhom jiġu indirizzati u ssostanzjati mill- Applikant.
Following the assessment of the Applicants response to the CHMP List of Questions, the CHMP considered that the presented answers did not support the comparability of the Applicant’ s product to the reference product.
Wara l- valutazzjoni tar- reazzjoni tal- Applikanti għal- Lista ta ’ Mistoqsijiet tas- CHMP, is- CHMP ikkunsidra li t- tweġibiet ppreżentati ma appoġġjawx il- komparabilità tal- prodott tal- Applikant mal- prodott ta ’ referenza.
The supplied data on particle size distribution did not allow the prediction of the lung deposition pattern affecting clinical efficacy and safety and the aerodynamic particle size distribution differed significantly between the two products.
Id- dejta fornuta dwar id - distribuzzjoni tad- daqs tal- partiċella ma ppermettitx li jsir it- tbassir tal- mod ta ’ depożizzjoni fil - pulmun u dan affettwa l- effikaċja u s- sigurtà klinika u d- distribuzzjoni ajrudinamika tad- daqs tal - partiċella varjat ferm bejn iż- żewġ prodotti.
The CHMP concluded that the applied product had not shown enough similarity to the reference product to establish therapeutic equivalence with regards to efficacy and safety and therefore adopted a list of seven Outstanding Issues to be addressed by the Applicant.
Is- CHMP ikkonkluda li l- prodott li saret applikazzjoni għalih ma weriex biżżejjed xebh mal- prodott ta ’ referenza biex jistabbilixxi ekwivalenza terapewtika fir- rigward tal- effikaċja u sigurtà u għaldaqstant adotta lista ta ’ seba ’ Kwistjonijiet Pendenti biex ikunu indirizzati mill- Applikant.
Question 1- The Applicant should provide the protocol of the in vitro comparisons of the particle size distributions in dry conditions, humid conditions and with spacer where all the relevant information should have been pre-specified, e. g. objective, sample size required to demonstrate equivalence in the predefined pools of stages within a pre-specified acceptance range, the pre-specified batches and the pre-specified statistical methods.
Mistoqsija 1 - L- Applikant għandu jipprovdi l- protokoll tat- tqabbil in vitro tad- distribuzzjonijiet tad - daqs tal- partiċelli f’ kundizzjonijiet xotti, kundizzjonijiet umdi u bi spejser fejn l- informazzjoni relevanti kollha kellha tkun speċifikata minn qabel, ngħidu aħna, daqs ta ’ kampjun oġġettiv meħtieġ biex juri ekwivalenza fil- ġabriet ta ’ stadji definiti minn qabel fi ħdan medda ta ’ approvazzjoni speċifikat minn qabel, il- lottijiet speċifikati minn qabel u l- metodi statistiċi speċifikati minn qabel.
Similarly, the final report of the three comparisons should be provided indicating the study dates, the raw data and the study results with its corresponding QA certificate.
Bl - istess mod, għandu jkun ipprovdut rapport finali tat- tliet tqabbiliet li jindika d- dati tal- istudju, id- dejta mhux ipproċessata u r- riżultati tal- istudju biċ- ċertifikat QA korrespondenti.
The Applicant stated that no protocol was established before the in vitro comparison but that in house documents with pre-specified criteria were used and that test product batches were subjected to release and stability testing according to protocols from the quality control department.
L- Applikant iddikjara li ma kien stabbilit l- ebda protokoll qabel it- tqabbil in vitro iżda li ntużaw dokumenti interni bi kriterji speċifikati minn qabel u li l- lottijiet tal- prodott tat- test kienu soġġetti għall- ittestjar ta ’ rilaxx u stabbilità skont protokolli mid- dipartiment tal- kontroll tal- kwalità.
The Applicant provided single issue specific protocols for test and generic products, demonstrating that the approach for demonstration of in vitro equivalence followed a planned and sound concept.
L - Applikant ipprovda protokolli speċifiċi ta ’ kwistjonijiet singoli għall- prodotti tat- test u dawk ġeneriċi, li wrew li l- approċċ għall- wiri ta ’ ekwivalenza in vitro mexa ma ’ kunċett ippjanat u sod.
In addition, the Applicant provided a consolidated final protocol consisting of all single protocols retrospectively combined and a retrospectively combined report from all the corresponding study reports including the raw data and study results.
Barra minn hekk, l- Applikant ipprovda protokoll finali kkonsolidat li jikkonsisti mill- protokolli singoli kollha kkumbinati retrospettivament u rapport ikkumbinat retrospettivament mir- rapporti tal- istudji korrespondenti kollha inkluż dejta mhux ipproċessata u riżultati tal- istudju.
The CHMP noted the Applicant response, but considered that the data was not analysed according to the methodological requirements for clinical comparison.
Is- CHMP innota r- rispons tal- Applikant, iżda kkunsidra li d- dejta ma ġietx analizzata skont ir - rekwiżiti metodoloġiċi għat- tqabbil kliniku.
The new formal protocol of the performed retrospective analysis and the new final report on the in vitro data indicated that the 90% CI remained outside the 15% or 20% acceptance range for stage 0, stage 1 and stage 2 and within the 20% CI but outside the 15% CI for stage 3 the 90% CI.
Il- protokoll formali l- ġdid tal- analiżi retrospettiva magħmula u r- rapport finali l- ġdid dwar id- dejta in vitro indika lis- CI ta ’ 90% baqa ’ barra mill- medda ta ’ aċċettabilità ta ’ 15% jew 20% għall- istadju 0, stadju 1 u stadju 2 u fi ħdan is- CI ta ’ 20% iżda barra
The CHMP did not agree that this amount of drug is too small to be relevant and could furthermore not support the Applicant claim that stage 1 is related only to safety.
Is- CHMP ma qabilx li dan l- ammont ta ’ mediċina huwa żgħir wisq biex ikun rilevanti u barra dan ma setax jappoġġja l- affermazzjoni tal- Applikant li stadju 1 huwa relatat biss mas- sigurtà.
The pooling method used and the addition of the spacer is likely to mask differences in quality between the two products.
Il- metodu ta ’ raggruppament użat u ż- żieda tal- ispejser x’ aktarx jgħatti d- differenzi fil- kwalità bejn iż- żewġ prodotti.
Therefore the CHMP considered in vivo data to be necessary to confirm therapeutic equivalence.
Għaldaqstant, is- CHMP ikkunsidra li hija meħtieġa dejta in vivo biex tikkonferma l- ekwivalenza terapewtika.
6 Question 2 - The Applicant´s justification of the selected pooling of stages is not acceptable.
Mistoqsija 2 - Il- ġustifikazzjoni tal- Applikant tar- raggruppament tal- istadji magħżula mhijiex aċċettabbli.
The Applicant should justify:
L- Applikant għandu jiġġustifika:
Why the comparison of all the individual stages is not more discriminative to detect differences between formulations that may have clinical relevance b.
Għaliex it- tqabbil tal- istadji kollha individwali mhuwiex iktar diskriminattiv biex jinkixfu differenzi bejn il- formulazzjonijiet li jista ’ jkollhom relevanza klinika. b.
Why the particles of 6 µm or up to 8 µm, which are deposited in stage 1, are considered with regards to safety only. c.
Għaliex il- partiċelli ta ’ 6 µm jew sa 8 µm, li huma ddepożitati fi stadju 1, huma meqjusin fir - rigward tas- sigurtà biss. c.
The Applicant should discuss why the ranges of particles that are deposited in the large conducting intrathoracic airways are pooled instead of investigating them with the highest accuracy and precision in the large possible number of categories (stages).
L- Applikant għandu jiddiskuti għaliex il- medda ta ’ partiċelli li huma ddepożitati fil- passaġġi l- kbar li jittrażmettu l- arja jiġu raggruppati flok ma investigahom bl- iktar eżattezza u preċiżjoni fin- numru possibbilment kbir ta ’ kategoriji (stadji).
The Applicant provided in vitro data to demonstrate the in vitro equivalence between the test product and the reference product and presented justifications for the pooling of the data including a second pooling using the following grouped stages:
L- Applikant ipprovda dejta in vitro biex juri l- ekwivalenza bejn il- prodott tat- test u l- prodott ta ’ referenza u ppreżenta ġustifikazzjonijiet għar- raggruppament tad- dejta inkluż t- tieni raggruppament bl- użu tal- istadji raggruppati li ġejjin:
Throat separately (oropharyngeal deposition and hence swallowed dose), Pooling 1:
Gerżuma separatament (depożizzjoni orofarinġeali u għaldaqstant id- doża miblugħa), Raggruppament 1:
Stage 0, 1, and 2 (large non respirable particles deposited in upper airway, which can be ignored as clinically insignificant), Pooling 2:
Stadju 0, 1, u 2 (partiċelli kbar mhux respirabbli depożitati fil- passaġġ tal- arja ta ’ fuq, li jistgħu ma jitqisux bħala klinikament mhux sinifikanti), Raggruppament 2:
Stage 3, 4 and 5 (fine particle dose (FPD) between 1.1 and 4.5 µm, deposited on bronchi and predictive of the in vivo bronchodilator efficacy and of Cmax (early lung bioavailability)) and Pooling 3:
Stadju 3, 4 u 5 (doża ta ’ partiċella fina (FPD) bejn 1. 1 u 4. 5 µm, iddepożitati fuq il- bronki u ta ’ tbassir tal- effikaċja bronkodilatorja in vivo u s- Cmax (bijodisponibbiltà bikrija fil - pulmun)) u Raggruppament 3:
Stage 6, 7, and Filter (reflects extra fine particles deposited in alveoli).
Stadju 6, 7, u Filtru (jirrifletti partiċelli ekstrafini ddepożitati fl - alveoli).
Particles > 4.5 µm are swallowed and contribute by negligible amount to the early systemic bioavailability (as Cmax) and peak adverse events of inhaled salbutamol.
Il- partiċelli > 4. 5 µm jinbelgħu u jikkontribbwixxu b’ ammont negliġibbli għall - bijodisponabbilità sistemika bikrija (bħala Cmax) u episodji avversi massimi ta ’ salbutamol inalat.
The Applicant stated that the presented in vitro data can be predictive of pharmacokinetic bioequivalence for Cmax and for peak airway and systemic beta-2 adrenoceptor mediated responses, which are mainly determined by lung bioavailability.
L - Applikant iddikjara li d- dejta ppreżentata in vitro tista ’ tkun ta ’ tbassir għall- bijoekwivalenza farmakokinetika għas- Cmax u għar- risponsi massimi tal- passaġġi tal- arja u sistemiċi medjati minn riċettur beta- 2 adrenerġiku (adrenoceptor), li huma prinċiplament iddeterminati mill- bijodisponibbiltà tal- pulmun.
a) The Applicant quoted the EMEA draft guideline on orally inhaled products (OIP) which offers the possibility to pool different stages of the Andersen Cascade Impactor.
a) L- Applikant ikkwota l- abbozz tal- linja gwida tal- EMEA fuq prodotti inalati oralment (OIP) li joffri l- possibilità li stadji differenti tal- Andersen Cascade Impactor jiġu raggrupati.
The particle size is considered to be one of the most significant characteristic influencing deposition in the respiratory tract and can be determined using Cascade Impactor measurements although the in vitro comparison should be performed per impactor stage or justified grouped stages which are relevant to efficacy and safety.
Id- daqs tal- partiċella huwa meqjus li huwa l- iktar karatteristika sinifikanti li tinfluwenza d- depożitu fil- passaġġ respiratorju u tista ’ tkun iddeterminata permezz tal- użu tal- kejl tal- Cascade Impactor għalkemm it- tqabbil in vitro għadu jsir għal kull stadju impactor jew stadji raggruppati ġġustifikati li huma relevanti għall- effikaċja u s- sigurtà.
The reason for stage pooling is to become discriminative in terms of lung deposition and the measurement of particle size with an instrument such as an impactor is a way to obtain information on particle size of the aerosolized medication and the particle size distribution.
Ir- raġuni għar- raggruppament tal- istadju hija li jsir diskriminattiv f’ termini ta ’ depożizzjoni fil- pulmun u l- kejl tad- daqs tal- partiċella bi strument bħalma huwa impactor huwa mezz kif tikseb l- informazzjoni fuq id- daqs tal- partiċella tal- medikazzjoni ajrosolizzata u d- distribuzzjoni tad- daqs tal- partiċella.
The amount of salbutamol depositing in the lung or in certain regions of the lung has clinical relevance and therefore single stages of the impactor represent a certain particle size or a size-range which correlates to the site of deposition.
L- ammont ta ’ salbutamol li jiddepożita fil- pulmun jew f’ ċerti reġjuni tal - pulmun għandu relevanza klinika u għaldaqstant stadji singoli tal- impactor jirrappreżentaw ċertu daqs ta ’ partiċella jew medda ta ’ qisien li tikkorrelata mas- sit ta ’ depożizzjoni.
However, for some substances, clinical efficacy and safety is not represented by a specific stage but a range of stages and therefore, comparison of individual stages cannot detect differences between formulations that may have clinical relevance.
Madankollu, għal xi sustanzi, l- effikaċja u s- sigurtà klinika mhijiex irrappreżentata minn stadju speċifiku iżda minn medda ta ’ stadji u għaldaqstant, tqabbil ta ’ stadji individwali ma jistax isib differenzi bejn formulazzjonijiet li jistgħu jkollhom relevanza klinika.
b) The Applicant indeed considered that it is the amount of respirable particles < 4.7 µm that will ultimately determine bronchodilator efficacy, particularly for stages 3/ 4/ 5 (i. e. particle size 1.1-4.7 µm) which correspond to bronchial deposition where the airway smooth muscle beta-2 adrenoceptors are located.
b) L- Applikant tabilħaqq ikkunsidra li l- ammont ta ’ partiċelli respirabbli < 4. 7 µm li fl- aħħar mill - aħħar jiddeterminaw l- effikaċja bronkodilatorja, b’ mod partikolari għall- istadji 3/ 4/ 5 (jiġifieri daqs ta ’ partiċella 1. 1 - 4. 7 µm) li tikkorrespondi ma ’ depożizzjoni bronkjali fejn jinsabu r- riċetturi beta- 2 adrenerġiċi tal- muskolatura lixxa tal- passaġġ tal- arja.
The amount of salbutamol impacted on stages comprising throat/ 0/ 1/ 2 are non respirable (i. e. > 4.7 µm) and will correspond to larger particles deposited on the oropharynx (throat stage) and upper airway (stages 0/ 1/ 2).
L- ammont ta ’ salbutamol li kellu impatt fuq l - istadji inkluż il- gerżuma / 0/ 1/ 2 mhumiex respirabbli (jiġifieri > 4. 7 µm) u jikkorrispondu għal partiċelli ikbar iddepożitati fl- orofarinġi (stadju tal- gerżuma) u l- passaġġ tal- arja tan- naħa ta ’ fuq (stadji 0/ 1/ 2).
Pharmacokinetic and pharmacodynamic studies have shown that the swallowed fraction from oropharyngeal depositions contributes a negligible amount to the early systemic bioavailability and peak adverse effects of inhaled salbutamol and that there is only negligible direct absorption from the oropharynx.
Studji farmakokinetiċi u farmakodinamiċi wrew li l- frazzjoni miblugħa minn depożizzjonijiet orofarinġeali tikkontribbwixxi ammont negliġibbli għall- bijodisponibbiltà sistemika bikrija u effetti avversi massimi ta ’ salbutamol inalat u li hemm biss assorbiment dirett negliġibbli mill- orofarinġi.
c) Pooling of stages is justified based on safety and efficacy, taking into account the particularities of salbutamol and its site of action.
7 c) Ir- raggruppament tal- istadji huwa ġġustifikat abbażi tas- sigurtà u l- effikaċja, bit- teħid f’ kunsiderazzjoni tal- partikolaritajiet ta ’ salbutamol u s- sit tal- azzjoni tiegħu.
According to the Applicant, a comparison of the results for the different approaches (individual stages 3, 4 and 5 versus pooled stages 3/ 4/ 5) demonstrates that except for stage 3 (below the -15% limit), both approaches lead to comparable results.
Skont l- Applikant, tqabbil tar- riżultati għall- approċċi differenti (stadji individwali 3, 4 u 5 meta mqabbla ma ’ stadji raggruppati 3/ 4/ 5) juri li għajr għall- istadju 3 (taħt il- limitu - 15%), iż- żewġ approċċi jwasslu għal riżultati komparabbli.
38.17 µg) of the pooled fine particle dose for stages 3/ 4/ 5.
Id- differenza għall- istadju 3 tammonta għal differenza medja ta ’ 3. 27% (jiġifieri 38. 17 µg) biss tad- doża ta ’ partiċelli fini raggruppati għall- istadji 3/ 4/ 5.
This difference is not expected to be of clinical relevance and the two products are therefore considered to exhibit
Din id- differenza mhijiex mistennija li tkun ta ’ relevanza klinika u ż- żewġ prodotti huma għaldaqstant ikkunsidrati li jeżibixxu rispons bronkodilatur ekwivalenti.
The Applicant concluded that the in vitro data and the negligible clinical relevance of the differences detected were supported by the provided in vivo study.
L- Applikant ikkonkluda li d- dejta in vitro u r- relevanza klinika negliġibbli tad- differenzi kienet appoġġjata mill- istudju in vivo pprovdut.
The CHMP noted the position of the Applicant but considered that this oversimplifies the effect of all generated particles on the respiratory and alimentary tract and that it is difficult to define the role of the individual stages in terms of safety and efficacy, effects such as differences in breathing patterns, aerosol velocity in entering the airways and the shape of the plume must be taken into account.
Is- CHMP innota l- pożizzjoni tal- Applikant iżda kkunsidra li din tissimplifika żżejjed l- effett tal - partiċelli kollha ġġenerati fuq il- passaġġ respiratorju u alimentari u li huwa diffiċli biex wieħed jiddefinixxi r- rwol tal- istadji individwali f’ termini ta ’ sigurtà u effikaċja, ta ’ effetti bħalma huma differenzi fil- patterns tat- teħid tan- nifs, veloċità tal- aerosol waqt id- dħul fil- passaġġi tal- arja u l- forma tas- sħaba għandhom jiġu kkunsidrati.
Furthermore, the CHMP did not agree that particles larger then 6 µm are not relevant for the demonstration of efficacy, as even such large particles may penetrate to the peripheral airways.
Barra minn hekk, is- CHMP ma qabilx li partiċelli ikbar minn 6 µm mhumiex rilevanti għall- wiri tal- effikaċja, peress li anke partiċelli kbar bħal dawn jistgħu jippenetraw il- passaġġi tal- arja periferiċi.
The in-vitro data without spacer suggests inferiority in stages 0, 1, 2 and 3 and similarity for stages 4, 5, 6, 7 and the filter stage, which suggests a similar Cmax and a superior AUC or similar AUC if the small amount in stages 0/ 1/ 2 were negligible.
Id- dejta in- vitro mingħajr spejser tissuġġerixxi inferjorità fi stadji 0, 1, 2 u 3 u xebh fl- istadji 4, 5, 6, 7 u l- istadju tal- filtru, li jissuġġerixxi Cmax simili u AUC superjori jew AUC simili jekk l- ammont żgħir fl- istadji 0/ 1/ 2 kellu jkun negliġibbli.
The in vivo bioequivalence study shows an equivalent but statistically significant superiority for the test product for Cmax and a shorter Tmax, indicating that the test product has a slightly higher peripheral deposition.
L- istudju ta ’ bijoekwivalenza in vivo juri superjorità ekwivalenti iżda statistikament sinifikattiva għall- prodott tat - test għal Cmax u Tmax iqsar, li jindika li l- prodott tat- test għandu depożizzjoni periferiku xi ftit ogħla.
Therefore, the different cloud size/ shape or the humid environment that exists in the respiratory tree may be relevant.
Għaldaqstant, id- daqs/ forma tas- sħaba differenti jew l- ambjent umdu li jeżisti fis- siġra respiratorja jista ’ jkun rilevanti.
The in vitro tests performed in humid environment show non- equivalence due to superiority in the stages with the finest particles both separately and after pooling.
It- testijiet in vitro li saru f’ ambjent umidu wrew nuqqas ta ’ ekwivalenza minħabba s- superjorità fl- istadji bl- ifjen partiċelli kemm separatament kif ukoll wara r- raggruppament.
Question 3 - The Applicant´s justification to widen the acceptance range taken from the draft guideline is not acceptable.
Mistoqsija 3 - Il- ġustifikazzjoni tal- Applikant li jwessa ’ l- medda ta ’ aċċettabilità meħuda mill- abbozz tal- linja gwida mhijiex aċċettabbli.
The Applicant should provide evidence based on sensitive clinical studies (preferably studies investigating the relative potency) that a 20% difference lacks of clinical relevance.
L- Applikant għandu jipprovdi evidenza bbażata fuq studji kliniċi sensittivi (preferabbilment studji li jinvestigaw il- qawwa relattiva) li differenza ta ’ 20% fiha nuqqas ta ’ relevanza klinika.
The Applicant stated that for pharmacokinetic studies, equivalence is conventionally demonstrated by applying a +/ - 20% limit for the 90% CI and therefore applied these limits to the FDP comparison, despite the recent EMEA guidance recommending +/ - 15% limits for in vitro equivalence and +/ - 20% limits for in vivo pharmacokinetic equivalence.
L- Applikant iddikjara li għall- istudji farmakokinetiċi, l- ekwivalenza tintwera konvenzjonalment bl - applikazzjoni ta ’ limitu ta ’ + / - 20% għal CI ta ’ 90% u għaldaqstant applika dawn il- limiti għat- tqabbil FDP, minkejja l- gwida reċenti tal- EMEA li tirrakkomanda limiti ta ’ + / - 15% għal ekwivalenza in vitro u limiti ta ’ + / - 20% għal ekwivalenza farmakokinetika in vivo.
The Applicant considered that the widening of the limits to +/ - 20% is justifiable and demonstrated that the results obtained fall within the +/ - 15% range, except for stage 3.
L- Applikant ikkunsidra li t - twessigħ tal- limiti għal + / - 20% huwa ġustifikabbli u wera li r- riżultati miksubin jaqgħu fil- medda ta ’ + / - 15%, ħlief għall- istadju 3.
For stages representing extra fine particles (< 1.1µm), equivalence was also shown, with the exception of deposition in the filter stage (outside +15% but within +20%).
Għall- istadji li jirrappreżentaw partiċelli ekstrafini (< 1. 1µm), intweriet ukoll l- ekwivalenza, bl- eċċezzjoni ta ’ depożizzjoni fl- istadju tal- filtru (barra +15% iżda fi +20%).
In absolute terms, the values outside the +/ - 20% limit represent a negligible mean difference which is clinically irrelevant in the context of any overall potential increase in systemic exposure.
F’ termini assoluti, il- valuri barra l- limitu + / - 20% jirrappreżentaw differenza medja negliġibbli li hija klinikament irrelevanti fil- kuntest ta ’ xi żieda potenzjali totali fl- esponiment sistemiku.
Based on the draft OIP guideline, the Applicant initiated two parmacokinetic studies, both with a single dose administration of 800 µg salbutamol in healthy volunteers: studies 2007-59-DOS-5 (systemic safety study) and 2007-76-DOS-6 (pulmonary deposition study).
Abbażi tal - abbozz tal- linja gwida OIP, l- Applikant beda żewġ studji farmakokinetiċi, it- tnejn b’ għoti ta ’ doża singola ta ’ 800 µg salbutamol f’ voluntiera f’ saħħithom: studji 2007- 59- DOS- 5 (studju ta ’ sigurtà sistemika) u 2007- 76- DOS- 6 (studju ta ’ depożizzjoni pulmonari).
As seen in the interim analysis, the intra-subject variability for the pulmonary deposition study is about twice as high as for the systemic safety study, demonstrating that variability increases when only pulmonary deposition is assessed.
Kif jidher fl- analiżi, il- varjabilità fis- suġġett għall- istudju ta ’ depożizzjoni pulmonari hija madwar darbtejn ogħla minn dik għall- istudju ta ’ sigurtà sistemika, li turi li l- varjabilità tiżdied biss meta d- depożizzjoni pulmonari tkun ivvalutata.
The Applicant considered that the results from study 2007-59-DOS-5 demonstrate bioequivalence in terms of rate and extent of the total systemic absorption of inhaled salbutamol.
L- Applikant ikkunsidra li r- riżultati mill- istudju 2007- 59- DOS- 5 juru bijoekwivalenza f’ termini tar - rata u l- medda tal- assorbiment sistemiku totali ta ’ salbutamol inalat.
Based on the submitted expert report from study 2007-76-DOS-6, the Applicant concluded that “ the presented in vitro data for fine particle dose and the in vivo data for lung bioavailability as Cmax clearly point to the presence of therapeutic equivalence within the 20% limits for both airway and systemic beta-2 adrenoceptor mediated peak effects.
Abbażi tar- rapport espert sottomess mill- istudju 2007- 76- DOS- 6, l- Applikant ikkonkluda li “ d- dejta in vitro ppreżentata għad - doża ta ’ partiċelli fini u d- dejta in vivo għall- bijodisponibilità għall- pulmun minħabba li Cmax jipponta b’ mod ċar lejn il- preżenza ta ’ ekwivalenza terapewtika fi ħdan il- limiti 20% kemm għall - effetti massimi tal- passaġġi tal- arja kif ukoll għall- effetti massimi sistemiċi medjati minn riċetturi beta- 2 adrenerġiċi.
Moreover, the in vitro data for larger particle deposition together with the total (lung +gut) systemic bioavailability as AUC show evidence of overall systemic equivalence.
Barra minn hekk, id- dejta in vitro għad- depożizzjoni ta ’ partiċelli ikbar flimkien ma ’ bijodisponibilità sistemika totali (pulmun u musrana) bħala AUC juru evidenza ta ’ ekwivalenza sistemika totali.
On the basis of these data the two formulations are considered to exhibit an equivalent therapeutic ratio and to be clinically interchangeable”.
Fuq il- bażi ta ’ dawn id- dejta iż- żewġ formulazzjonijiet huma kkunsidrati li jesibixxu proporzjon terapewtiku ekwivalenti u li huma jistgħu jinbidlu klinikament ma ’ xulxin ”.
The CHMP stated that the draft guideline proposed a more conservative approach to the applied acceptance range mainly due to lack of experience in this filed and the fact that pooling may mask the differences in the evaluated products, as is the case for the current product.
8 Is- CHMP iddikjara li l- abbozz tal- linja gwida ppropona approċċ iktar konservattiv għall- medda ta ’ approvazzjoni applikata prinċiplament minħabba nuqqas ta ’ esperjenza f’ dan ippreżentata u l- fatt li raggruppament jista ’ jgħatti d- differenzi fil- prodotti evalwati, kif inhu l- każ għall- prodott attwali.
The CHMP was of the opinion that the bioequivalence study (2207-59-DOS-5) demonstrated equivalency in safety profile when used without a spacer, as well as similar Cmax and Tmax values.
Is - CHMP kien tal- opinjoni li l- istudju ta ’ bijoekwivalenza (2207- 59- DOS- 5) wera ekwivalenza fil- profil ta ’ sigurtà meta użat mingħajr spejser, kif ukoll bħala valuri Cmax u Tmax simili.
Question 4 - Raw data of the comparison with spacer have not been provided and neither the raw data nor results in humid conditions have been provided and discussed.
Mistoqsija 4 - Dejta mhux ipproċessata tat- tqabbil bi spejser ma ġietx provduta u la d- dejta mhux ipproċessata u lanqas ir- riżultati f’ kundizzjonijiet umdi ma ġew ipprovduti jew diskussi.
8 The Applicant provided raw data obtained under humid condition clearly demonstrating that the aerodynamic characteristic of salbutamol sulphate particles do not change under humid conditions.
L- Applikant ipprovda dejta mhux ipproċessata miksuba f’ kundizzjonijiet umdi li turi b’ mod ċar li l - karatteristika ajrudinamika ta ’ partiċelli ta ’ salbutamol sulfat ma tinbidilx f’ kundizzjonijiet umdi.
In addition, because two clinical studies are submitted for demonstration of in vivo equivalence and for confirming the in vitro data, the in vitro results obtained under humid condition become less important.
Barra minn hekk, minħabba li żewġ studji kliniċi huma sottomessi għall- wiri ta ’ ekwivalenza in vivo u biex jikkonfermaw dejta in vitro, ir- riżultati in vitro miksubin f’ kundizzjonijiet umdi jsiru inqas importanti.
The Applicant also decided to generate additional spacer data in order to obtain more reliable information on the particle size distribution when the compared inhalers are fitted with their respective spacer devices.
L- Applikant iddeċieda ukoll li jiġġenera dejta addizjonali tal- ispejser sabiex jikseb informazzjoni iktar kredibbli fuq id- distribuzzjoni tal- qies tal- partiċella meta l- inalaturi mqabbla jintramalhom l- apparat spejser rispettiv tagħhom.
The data clearly shows that the spacer induces a significant depletion of large particles in the throat and an increase in fine particle dose (< 5 µm particles), with the confidence intervals for the single impactor stages within the +/ - 20% limit, except for stage 0.
Id- dejta turi b’ mod ċar li l- ispejser jinduċi tnaqqis sinifikanti ta ’ partiċelli kbar fil- gerżuma u żieda fid- doża ta ’ partiċelli fini (partiċelli < 5 µm), bl - intervalli ta ’ kunfidenza għall- istadji ta ’ impactor singolu fi ħdan il- limitu ta ’ + / - 20%, ħlief għall - istadju 0.
The Applicant considered that the overall data demonstrate that spacer use results in the same high extent of in vitro equivalence as inhaler testing without this device.
L- Applikant ikkunsidra li d- dejta ġenerali turi li l- użu tal- ispejser jirriżulta fl- istess medda għolja ta ’ ekwivalenza in vitro bħal ittestjar tal- inalatur mingħajr dan l- apparat.
The CHMP noted the inclusion of the requested raw data but considered that the results did not demonstrate similarity in all stages and that it was therefore difficult to conclude on therapeutic equivalence.
Is- CHMP innota l - inklużjoni tad- dejta mhux ipproċessata mitluba iżda kkunsidra li r- riżultati ma wrewx xebh fl- istadji kollha u li għaldaqstant huwa diffiċli li tinġibed konklużjoni fuq l- ekwivalenza terapewtika.
The CHMP requested the Applicant to provide data from a PK study with concomitant use of a spacer.
Is- CHMP talab lill- Applikant biex jipprovdi dejta minn studju farmakokinetiku bl- użu konkomittanti ta ’ spejser.
Question 5 - The Applicant should justify why the product is considered equivalent when the particle size comparison with spacer is not able to demonstrate equivalence in the pool of throat + stage 0 + stage 1, pooled as desired by the Applicant with the 20% acceptance range and pool of stages 2 + 3, as desired by the Applicant, with the 15% acceptance range, mainly because the sample size of this comparison has not been calculated appropriately.
Mistoqsija 5 - L- Applikant għandu jiġġustifika għaliex il- prodott huwa kkunsidrat ekwivalenti meta t - tqabbil tad- daqs tal- partiċella bl- ispejser mhuwiex kapaċi juri ekwivalenza fir- raggruppament ta ’ gerżuma + stadju 0 + stadju 1, raggruppat kif mixtieq mill- Applikant bil- medda ta ’ approvazzjoni ta ’ 20% u raggruppament ta ’ stadji 2 + 3, kif mixtiqin mill- Applikant, bil- medda ta ’ approvazzjoni ta ’ 15%, prinċiplament peress li d- daqs tal- kampjun ta ’ dan it- tqabbil ma ġiex ikkalkulat b’ mod xieraq.
Following an additional request for clinical spacer studies, the Applicant decided to extend the previously submitted in vitro equivalence study with spacer use, including 7 generic and 10 reference batches (compared to 2 and 3 previously).
Wara talba addizzjonali għall- istudji kliniċi tal- ispejser, l- Applikant iddeċieda li jestendi l- istudju ta ’ ekwivalenza bl- użu tal- ispejser in vitro li kien diġà ġie ppreżentat, inklużi 7 lottijiet ġeneriċi u 10 ta ’ referenza (mqabblin ma ’ 2 u 3 ta ’ qabel).
The equivalence limits were set at 80 - 125%.
Il- limiti tal- ekwivalenza ġew stabbiliti għal 80 - 125%.
For stages with a small deposition of particles and a relatively high standard deviation it is particularly critical to reach a confidence interval within the defined limits.
Għall- istadji b’ depożizzjoni żgħira ta ’ partiċelli u b’ devjazzjoni standard relattivament għolja huwa partikolarment kritiku li jintlaħaq intervall ta ’ kunfidenza fi ħdan il- limiti definiti.
Single stage comparison revealed that most of the values are within the ± 15% range (except from stage 0, 1 and filter) and after pooling, all values were within the ± 15% range.
It- tqabbil ta ’ stadju singolu wera li l- parti l- kbira mill- valuri huma fil- medda ta ’ ± 15% (ħlief mill- istadju 0, 1 u l- filtru) u wara r- raggruppament, il- valuri kollha kienu fi ħdan il- medda ta ’ ± 15%.
The fine particle dose ratio was 1.01 and the corresponding confidence interval was 0.97 – 1.04 and the data therefore clearly demonstrate that the expected spacer effect is identical for test and reference product.
Il- proporzjon ta ’ doża ta ’ partiċelli fini kien 1. 01 u l- intervall ta ’ kunfidenza korrispondenti kien 0. 97 – 1. 04 u għaldaqstant, id - dejta turi b’ mod ċar li l- effett mistenni tal- spejser huwa identiku għall- prodott tat- test u tar- referenza.
The Applicant also included results from a comparative pharmacokinetic study evaluating systemic safety, which demonstrates equivalence and considered that the equivalence of the Cmax values as identified from the systemic safety study supports the prediction of equivalent lung bioavailability and equivalent lung deposition.
L- Applikant inkluda wkoll riżultati minn studju farmakokinetiku ta ’ tqabbil li evalwa s- sigurtà sistemika, li juri l- ekwivalenza u kkunsidra li l- ekwivalenza tal- valuri Cmax kif identifikati mill- istudju ta ’ sigurtà sistemika jappoġġjaw it- tbassir ta ’ bijodisponibilità tal- pulmun ekwivalenti u depożizzjoni fil- pulmun ekwivalenti.
The CHMP noted the additional data but remained of the opinion that the pooling method masked the differences between the test products and that in addition, the used spacer decreased the amount of the larger particles and increased the amount of fine particles.
Is- CHMP innota d- dejta addizzjonali iżda baqa ’ tal- opinjoni li l- metodu raggruppat għatta d- differenzi bejn il- prodotti tat- test u li barra minn hekk, l- ispejser użat naqqas l - ammont ta ’ partiċelli ikbar u żied l- ammont ta ’ partiċelli fini.
Although the claim of the Applicant that the PK bioequivalence study demonstrated equivalence without spacer was endorsed, the CHMP did not support the assumption that the data with the use of a spacer would provide the same evidence of equivalence and therefore considered that a PK study with a spacer is mandatory.
Għalkemm il- klejm tal- Applikant li l - ekwivalenza tal- istudju tal- bijoekwivalenza tal- farmakokinetika ntweriet mingħajr l- ispejser ġiet approvata, is- CHMP ma appoġġjax is- suppożizzjoni li d- dejta bl- użu ta ’ spejser tipprovdi l- istess evidenza ta ’ ekwivalenza u għaldaqstant li studju farmakokinetiku bi spejser huwa obbligatorju.
Question 6 - The first part of question 5 of the LoQ, “ The Applicant should discuss the storage stability of the product, in light of studies demonstrating that the inverted and lying orientations of the device are the most stable” has not been fully answered, since only discussions about upright and lying position, but not about inverted orientation has been submitted.
Mistoqsija 6 - L- ewwel parti ta ’ mistoqsija 5 tal- LoQ, “ L- Applikant għandu jiddiskuti l- istabbilità tal - ħażna tal- prodott, fid- dawl ta ’ studji li wrew li huwa iktar stabbli jekk maħżun rasu ‘ l isfel u mimdud ” ma ġietx imwieġba b’ mod komplut, minħabba li ġew sottomessi biss diskussjonijiet dwar pożizzjoni wieqfa u mimduda, iżda mhux l- pożizzjoni tal- prodott rasu ‘ l isfel.
The Applicant is required to present this discussion.
L- Applikant huwa meħtieġ li jippreżenta din id- diskussjoni.
Regarding the storage stability, the Applicant complemented the already submitted repriming study with comparative data from inverted storage and found that all investigated shots for the generic product comply with the specified delivered dose up to a storage period of 7 days.
9 Rigward l- istabbilità waqt il- ħażna, l- Applikant ikkumplimenta l- istudju ta ’ riattivazzjoni (repriming) diġà sottomess ma ’ dejta ta ’ tqabbil minn ħażna bil- prodott rasu ‘ l isfel u sab li s- shots kollha investigati għall- prodott ġeneriku jikkonformaw mad- doża speċifikata mwassla sa perjodu ta ’ ħażna ta ’ 7 ijiem.
The undesirable reflow from suspension formulation into the canister does not occur if the cans are stored in an inverted or lying position but may occur if the inhaler is stored in an upright position.
Il- fluss lura mhux mixtieq mill- formulazzjoni ta ’ sospensjoni fiċ- ċilindru ma sseħħx jekk il- bottijiet jinħażnu f’ pożizzjoni rashom ‘ l isfel jew mimdudin iżda tista ’ sseħħ jekk l- inalatur jinħażen f’ pożizzjoni wieqfa.
The results provided as a whole clearly indicate the non inferiority of the generic product to the reference product and the Applicant considered both products to be fully interchangeable.
B’ mod ġenerali, ir- riżultati pprovduti jindikaw b’ mod ċar in- nuqqas ta ’ inferjorità tal- prodott ġeneriku u l- Applikant ikkunsidra ż- żewġ prodotti li jistgħu jinbidlu kompletament ma ’ xulxin.
The functionality of the applicator is not affected and therefore the aerosol cloud and the
Waqt l- iżvilupp tal- prodott tal- mediċina, l- Applikant ottimizza l- applikatur, immodifika l - forma tal- apparat biex jagħmilha possibbli li l- applikatur jinħażen fiż- żewġ pożizzjonijiet ta ’ ħażna meħtieġa identifikati.
9 aerodynamic particle size distribution remain the same.
Il- funzjonalità tal- applikatur mhijiex affettwata u għaldaqstant is- sħaba tal - aerosol u d- distribuzzjoni ajrudinamika tad- daqs tal- partiċelli jibqgħu l- istess.
The CHMP acknowledged the improved device design and agreed with the Applicant response, the issue was considered resolved.
Is- CHMP għaraf forma imtejba tal- apparat u qabel mar- reazzjoni tal- Applikant, il- kwistjoni tqieset bħala waħda solvuta.
Question 7 - In order to complete the comparative study between the reference and the test products, a comparative repriming study after storage at lying position (0°C) (initial stage of can life and partially emptied can) should be carried out to confirm their similarity of behaviour.
Mistoqsija 7 - Sabiex jintemm l- istudju ta ’ tqabbil bejn il- prodotti ta ’ referenza u tat- test, għandu jsir studju ta ’ riattivazzjoni (repriming) ta ’ tqabbil wara ħażna fil- pożizzjoni mimduda (0°C) (stadju inizjali tal- ħajja tal- bott u tal- bott parzjalment żvujtat) biex jikkonferma x- xebh tal- imġiba tagħhom.
As stated earlier, the Applicant provided initial repriming studies on the test product which were complemented with a repriming study with the reference product and the CHMP considered that while the data demonstrate the effect of the position of the MDI on the deposited dose, this effect is observed in both the test and the reference product.
Kif iddikjarat qabel, l- Applikant ipprovda studji ta ’ riattivazzjoni (repriming) inizjali fuq il- prodott tat - test li kienu kkumplimentati bi studju ta ’ riattivazzjoni (repriming) bil- prodott ta ’ referenza u s- CHMP kkunsidra li waqt li d- dejta turi l- effett tal- pożizzjoni tal- MDI fuq id- doża ddepożitata, dan l- effett kien osservat kemm fil- prodott tat- test kif ukoll f’ dak ta ’ referenza.
Therefore, the CHMP concluded that the products should be considered as interchangeable.
Għaldaqstant, is- CHMP ikkonkluda li l- prodotti għandhom jiġu kkunsidrati bħala li jistgħu jinbidlu ma ’ xulxin.
Conclusion of the assessment of the Applicant response to the List of Outstanding Issues
Konklużjoni tal- valutazzjoni tar- rispons tal- Applikant għal- Lista ta ’ Kwistjonijiet Pendenti
In conclusion, the CHMP considered that the Applicant responses to the List of Outstanding Issues did allow the committee to conclude that the test and the reference product are similar when used without a spacer, with regards to safety aspects.
Bħala konklużjoni, is- CHMP ikkunsidra li r- reazzjonijiet tal- Applikant għal- Lista ta ’ Kwistjonijiet Pendenti ħallew lill- kumitat jikkonkludi li l- prodott tat- test u tar- referenza huma simili meta użati mingħajr spejser, fir- rigward tal- aspetti tas- sigurtà.
However, equivalence between the test and reference products has still not been fully demonstrated although this may be addressed by submitting an analysis of the data from the ongoing study 2007-76-DOS-6, the CHMP addressed two outstanding issues to be discussed by the Applicant during an oral explanation:
Madankollu, l- ekwivalenza bejn il- prodotti tat- test u ta ’ referenza għadha ma ntwerietx għal kollox għalkemm din tista ’ tkun indirizzata billi tiġi ppreżentata analiżi tad- dejta mill- istudju 2007- 76- DOS- 6 li għadu għaddej, is- CHMP indirizza żewġ kwistjonijiet pendenti biex ikunu diskussi mill- Applikant waqt spjegazzjoni orali:
The Applicant should provide in vivo equivalence when the products are used with and their spacers 2.
L- Applikant għandu jipprovdi ekwivalenza in vivo meta l- prodotti jintużaw bi u mingħajr l - ispejsers tagħhom 2.
A comparison between reference and test products pulmonary deposition should be addressed (Study 2007-76-DOS-6)
Għandu jkun indirizzat tqabbil bejn id- depożizzjoni pulmonari tal- prodott ta ’ referenza u tat- test (Studju 2007- 76- DOS- 6)
The Applicant responded to the outstanding issues during an Oral Explanation held during the November CHMP meeting.
L- Applikant irrisponda għall- kwistjonijiet pendenti waqt Spjegazzjoni Orali li saret waqt il- laqgħa tas - CHMP ta ’ Novembru.
The Applicant was able to present data from the pulmonary deposition study (Study 2007- 76-DOS-6) were presented and interpreted and this new in vitro data (without spacer in a normal and humid environment and with spacer in a normal environment) suggested a similar particle size distribution between the test and the reference product.
L- Applikant kien kapaċi jippreżenta dejta mill- istudju ta ’ depożizzjoni pulmonari (2007- 76- DOS- 6) li ġiet ippreżentata u interpretata u din id- dejta ġdida in vitro (mingħajr spejser f’ ambjent normali u umdu u bi spejser f’ ambjent normali) issuġġeriet distribuzzjoni simili ta ’ daqs ta ’ partiċella bejn il- prodott tat- test u ta ’ referenza.
The pharmacokinetic bioequivalence study also confirmed that both products possess the same systemic safety profile since bioequivalence in systemic levels (AUC and Cmax) have been shown.
L- istudju ta ’ bijoekwivalenza farmakokinetika kkonferma wkoll li ż- żewġ prodotti għandhom l- istess profil ta ’ sigurtà sistemika minħabba li ntweriet il- bijoekwivalenza fil- livelli sistemiċi (AUC u Cmax).
In addition, the study demonstrated indirectly the same lung deposition with a trend to a deeper lung deposition based on a higher ratio in Cmax and a shorter Tmax.
Barra minn hekk, l- istudju wera indirettament l - istess depożizzjoni fil- pulmun b’ tendenza għal depożizzjoni iktar fil- fond fil- pulmun ibbażata fuq proporzjon ogħla b’ Cmax u Tmax iktar qosra.
In the opinion of the CHMP, this small difference is not expected to be clinically significant and a pharmacodynamic study does not seem to be required.
Fl- opinjoni tas- CHMP, din id- differenza żgħira mhijiex mistennija li tkun klinikament sinifikanti u ma jidhirx li huwa meħtieġ studju farmakodinamiku.
10 GROUNDS FOR POSITIVE OPINION
10 RAĠUNIJIET GĦAL OPINJONI POŻITTIVA
The CHMP was of the opinion that based on the totality of the data submitted, including the data from the pulmonary deposition study (Study 2007-76-DOS-6), a similar particle size distribution between the test and the reference product could be demonstrated.
Is- CHMP kien tal- opinjoni li abbażi tad- dejta kollha ppreżentata, inkluża d- dejta mill- istudju ta ’ depożizzjoni pulmonari (Studju 2007- 76- DOS- 6), tista ’ tintwera distribuzzjoni ta ’ daqs tal- partiċella simili bejn il- prodott tat- test u dak tar- referenza.
The pharmacokinetic bioequivalence data also confirmed that Sabumalin and the reference product possess the same systemic safety profile since bioequivalence in systemic levels (AUC and Cmax) have been shown, when used with or without a spacer.
Id- dejta ta ’ bijoekwivalenza farmakokinetika kkonfermat ukoll li Salbumalin u l- prodott ta ’ referenza għandhom l- istess profil ta ’ sigurtà sistemika minħabba li ntweriet il- bijoekwivalenza f’ livelli sistemiċi (AUC u Cmax), meta użati bi jew mingħajr spejser.
In conclusion a Potential Serious Risk to Public Health was no longer identified and the CHMP concluded that the products are bioequivalent and that the benefit-risk ratio is positive.
Bħala konklużjoni il- Periklu Gravi Potenzjali lis- Saħħa Pubblika ma kienx iktar identifikat u s- CHMP ikkonkluda li l- prodotti huma bijoekwivalenti u li l- proporzjon benefiċċju- riskju huwa wieħed pożittiv.
- the CHMP considered that a similar particle size distribution between the test and the reference product was
- is- CHMP ikkunsidra li ntweriet distribuzzjoni ta ’ daqs tal- partiċella simili bejn il- prodott tat- test u
demonstrated,
dak ta ’ referenza,
- the CHMP considered that Sabumalin and the reference product possess the same systemic safety profile,
- is- CHMP ikkunsidra li Salbumalin u l- prodott ta ’ referenza għandhom l- istess profil ta ’ sigurtà
as demonstrated by the bioequivalence in systemic levels (AUC and Cmax),
sistemika minħabba li ntweriet il- bijoekwivalenza f’ livelli sistemiċi (AUC u Cmax),
- the CHMP concluded that the products are bioequivalent and that the benefit-risk ratio is positive,
- is- CHMP ikkonkluda li l- prodotti huma bijoekwivalenti u li l- proporzjon benefiċċju- riskju huwa
the CHMP has recommended the granting of the Marketing Authorisations for which the valid Summary of Product Characteristics, labelling and package leaflet are the final versions achieved during the Coordination group procedure are set out in Annex III for Sabumalin and associated names (see Annex I).
is- CHMP irrakkomanda l- għoti ta ’ Awtorizzazzjonijiet għat- Tqegħid fis- Suq li s- Sommarju tal - Karatteristiċi tal- Prodott, tikketta u fuljett ta ’ tagħrif għalihom validi huma l- verżjonijiet finali miksubin waqt il- proċedura tal- grupp ta ’ Koordinament kif stabbiliti fl- Anness III għal Sabumalin u ismijiet assoċjati (ara l- Anness I).
12 The valid Summary of Product Characteristics, labelling and package leaflet are the final versions achieved during the Coordination group procedure.
12 Is- Sommarju tal- Karatteristiċi tal- Prodott, l- ittikkettar u l- fuljett ta ’ tagħrif fil- pakkett validi huma l - verżjonijiet finali miksuba waqt il- proċedura tal- Grupp tal- Koordinazzjoni.
London, 17 March 2009 Doc.
Londra, 17 ta ’ Marzu 2009 Dok.
EMEA/ CHMP/ 194784/ 2009 EMEA/ H/ A-29/ 990
EMEA/ CHMP/ 194622/ 2009 EMEA/ H/ A- 29/ 990
Questions and answers on the referral for Sabumalin salbutamol, metered dose aerosol inhaler, 100 μ g/ dose
Mistoqsija u tweġiba dwar ir- referenza għal Sabumalin salbutamol, inalatur ajrosol b’ doża mkejla, 100 μg/ doża
The European Medicines Agency (EMEA) has completed a referral procedure following a disagreement among Member States of the European Union regarding the authorisation of the medicine Sabumalin.
L- Aġenzija Ewropea dwar il- Mediċini (EMEA) temmet proċedura ta ’ referenza wara nuqqas ta ’ qbil fost l- Istati Membri tal- Unjoni Ewropea fir- rigward tal- awtorizzazzjoni tal- mediċina Sabumalin.
Belgium, Denmark, Estonia, Finland, Germany, Greece, Hungary, Italy, Latvia, Lithuania, the Netherlands, Norway, Poland, Portugal, Slovenia, Spain and the United Kingdom.
Il - Kumitat għall- Prodotti Mediċinali għal Użu mill- Bniedem (CHMP) tal- Aġenzija ikkonkluda li l - benefiċċji ta ’ Sabumalin huma akbar mir- riskji tiegħu, u li l- awtorizzazzjoni għat- tqegħid fis- suq tista ’ tingħata fl- Iżvezja kif ukoll fl- Istati Membri tal- Unjoni Ewropea li ġejjin: il- Belġju, id- Danimarka, l - Estonja, il- Finlandja, il- Ġermanja, il- Greċja, l- Ungerija, l- Italja, il- Latvja, il- Litwanja, l- Olanda, in - Norveġja, il- Polonja, il- Portugall, is- Slovenja, Spanja u r- Renju Unit.
The review was carried out under an ‘ Article 29’ referral 1.
Ir- reviżjoni twettqet skont referenza tal - ‘ Artikolu 29 ’ 1.
What is Sabumalin?
X’ inhu Sabumalin?
Sabumalin is a medicine in a pressurised inhaler that contains salbutamol as active substance.
Sabumalin huwa mediċina f’ inalatur taħt pressjoni li fih salbutamol bħala sustanza attiva.
Salbutamol is a beta2-adrenergic receptor agonist.
Salbutamol huwa agonista tar- riċettur ta ’ beta2- adrenerġiku.
This means that salbutamol activates the beta2- receptors in the body.
Dan ifisser li salbutamol jattiva r- riċetturi beta2 fil - ġisem.