qanastek/EMEA-V3 huggingface dataset:
There is no indication that any of the members within this class differs with respect to efficacy and safety, and Vantas seems to be no exception in that respect.
Ma hemm l- ebda indikazzjoni li xi membru ġo din il- klassi ma jaqbilx ma ’ l- effikaċja u s- sigurtà, u Vantas jidher li mhux eċċezzjoni f’ dan ir- rigward.
The data from the Long Term Extension Study 301 concerning efficacy and safety are in support for both long-term efficacy and safety for patients, receiving palliative treatment of advanced prostate cancer with histrelin implant for two or more years.
Id- dejta mill- Istudju ta ’ Estensjoni għal Tul ta ’ Żmien 301 li tikkonċerna l- effikaċja u s- sigurtà tappoġġja kemm l- effikaċja kif ukoll is- sigurtà fuq tul ta ’ żmien għal pazjenti, li qegħdin jingħataw trattament għat- tnaqqis ta ’ l- uġigħ f’ każijiet ta ’ kanċer tal- prostata avvanzat b’ impjant histrelin għal sentejn jew aktar.
The CHMP requests the inclusion, as proposed by the Applicant/ MAH, of the five pharmacovigilance safety concerns in the Risk Management Plan as mentioned above.
Is- CHMP titlob l- inklużjoni kif proposta mill- Applikant/ MAH, tal - ħames konsiderazzjonijiet dwar is- sigurtà tal- farmakoviġilanza fil- Pjan tal- Maniġment tar- Riskju kif imsemmi hawn fuq.
4 ANNEX III
4 Is- CHMP irrakkomanda l- għoti ta ’ l- Awtorizzazzjoni tat- Tqegħid fis- Suq li għalih, is- Sommarju tal - Karatteristiċi tal- Prodott, it- tikketta u l- fuljett ta ’ tagħrif tal- prodott huma l- verżjonijiet finali miksuba waqt il- proċedura ta ’ koordinazzjoni tal- grupp kif imsemmi fl- Anness III għal Vantas.
SUMMARY OF PRODUCT CHARACHTERITICS, LABELLING AND PACKAGE LEAFLET
O Resumo das Características do Medicamento, rótulo e folheto informativo válidos são as versões finais concluídas no procedimento do Grupo de Coordenação.
5 The valid Summary of Product Characteristics, labelling and package leaflet are the final versions achieved during the Coordination group procedure.
5 ANNESS III
London, 30 July 2007 EMEA/ CHMP/ 247760/ 2007
Londra, 30 ta ’ Lulju 2007 EMEA/ CHMP/ 247760/ 2007
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP)
KUMITAT GĦALL- PRODOTTI MEDIĊINALI GĦALL- UŻU MILL- BNIEDEM
OPINION FOLLOWING AN ARTICLE 29(4)1 REFERRAL FOR Vantas International Non-Proprietary Name (INN):
OPINJONI SKOND L- ARTIKOLU 29( 4) 1 REFERENZA GĦAL Vantas Denominazzjoni Komuni Internazzjonali (INN - International Non- proprietary Name):
Vantas, 50 mg, implant, is a luteinizing hormone-releasing hormone (LHRH) agonist indicated for the palliative treatment of advanced prostate cancer.
Vantas, impjant, 50 mg, huwa ormon li jirrilaxxa l- ormoni lutejinizzanti (LHRH) agonist indikat fit - trattament palljattiv ta ’ kanċer tal- prostata avvanzat.
Valera Pharmaceuticals Ltd. submitted applications for mutual recognition of Vantas, 50 mg, implant, on the basis of the marketing authorisation granted by Denmark on 17 November 2005.
Valera Pharmaceuticals Ltd. issottomettew applikazzjonijiet għar- rikonoxximent reċiproku tal- Vantas, impjant, 50 mg abbażi ta ’ l- awtorizzazzjoni għat- tqegħid fis- suq mogħtija lid- Danimarka fis- 17 ta ’ Novembru 2005.
The Mutual Recognition Procedure started on 23 August 2006.
Il- Proċedura ta ’ Rikonoxximent Reċiproku bdiet fit- 23 ta ’ Awwissu 2006.
The Reference Member State was Denmark and the Concerned Member States were Germany, Spain, Ireland, Italy and the United Kingdom.
L- Istat Membru ta ’ Referenza kien id- Danimarka u l- Istati Membri konċernati kienu l- Ġermanja, Spanja, l- Irlanda, l- Italja u r- Renju Unit.
These Member States were not able to reach an agreement in respect of the Mutual Recognition of the Marketing Authorisation granted by the Reference Member State.
Dawn l- Istati Membri ma kienux kapaċi jilħqu ftehim rigward ir- Rikonoxximent Reċiproku ta ’ l- Awtorizzazzjoni tat- Tqegħid fis- Suq mogħtoija mill- Istat Membru ta ’ referenza.
Germany, Spain, Ireland, Italy and the United Kingdom referred the reasons for disagreement to the EMEA on 1 February 2007.
Il- Ġermanja, Spanja, l - Irlanda, l- Italja u r- Renju Unit rreferew ir- raġunijiet ta ’ nuqqas ta ’ qbil lill- EMEA fl- 1 ta ’ Frar 2007.
The reasons for disagreement was that, according to some Member States, the efficacy of Vantas was not demonstrated in comparison to other approved, effective treatments and that the safety of Vantas also was not adequately demonstrated.
Ir- raġunijiet ta ’ nuqqas ta ’ qbil kienu illi, skond xi Stati Membri l- effikaċja ta ’ Vantas ma kienitx murija a paragon ma ’ trattamenti oħra appruvati u effettivi u illi s- sigurtà ta ’ Vantas ma kienitx murija b’ mod xieraq.
The arbitration procedure started on 22 February 2007 with the adoption of a list of questions.
Il- proċedura ta ’ l- arbitraġġ bdiet fit- 22 ta ’ Frar 2007 permezz ta ’ l- adozzjoni ta ’ lista ta ’ domandi.
The Rapporteur was Dr Frits Lekkerkerker and Co-Rapporteur(s) was Dr Jens Ersbøll.
Frits Lekkerkerker u l- Ko- Rapporteur( s) kien Dr Jens Ersbøll.
The Marketing Authorisation Holder provided written explanations on 7 March 2007.
Il- Pussessur ta ’ l - Awtorizzazzjoni għat- Tqegħid fis- Suq ta ’ spjegazzjonijiet bil- miktub fis- 7 ta ’ Marzu 2007.
During their May 2007 meeting, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, was of the opinion that the benefit/ risk ratio is favourable for Vantas, that the objections raised by Germany, Spain, Ireland, Italy and the United Kingdom should not prevent the granting of a Marketing Authorisation and that the Summary of Product Characteristics, labelling and package leaflet of the Reference Member State should be amended.
Matul il- laqgħa tagħhom ta ’ Mejju 2007, is- CHMP issottometta fid- dawl tad- dejta globali u d- diskussjoni xjentifika fi ħdan il- Kumitat, ikkunsidra li l- proporzjon ta ’ benefiċċju/ riskju huwa favorevoli għal Vantas, illi l- oġġezzjonijiet imqajjma mill- Ġermanja, Spanja, l- Irlanda, l- Italja u r- Renju Unit għandhom jipprevjenu l - għoti ta ’ Awtorizzazzjoni għat- Tqegħid fis- Suq u illi għandhom isiru l- emendi għas- Sommarju tal - Karatteristiċi tal- Prodott, tikketta u fuljett ta ’ tagħrif ta ’ l- Istat Membru ta ’ Referenza.
A positive opinion was adopted by consensus on 24 May 2007.
Ġiet adottata opinjoni pożittiva permezz ta ’ kunsens fl- 24 ta ’ Mejju 2007.
The final opinion was converted into a Decision by the European Commission on 30 July 2007.
L- opinjoni finali hija konvertita f’ Deċiżjoni mill- Kummissjoni Ewropea fit- 30 ta ’ Lulju 2007.
1 Article 29(4) of Directive 2001/ 83/ EC, as amended.
1 Artiklu 29( 4) tad- Direttiva 2001/ 83/ KE kif emendat.
London, 29 May 2007 Doc. Ref.
Londra 29 ta ’ Mejju 2007 Dok. Ref.
EMEA/ 144030/ 2007
EMEA/ CHMP/ 274899/ 2007
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP)
KUMITAT GĦAL PRODOTTI MEDIĊINALI GĦAL UŻU MILL- BNIEDEM (CHMP)
OPINION FOLLOWING AN ARTICLE 30 REFERRAL FOR Xefo and associated names International Non-Proprietary Name (INN): lornoxicam
OPINJONI WARA ARTIKLU 30 TA ’ REFERENZA GĦAL Xefo u ismijiet assoċjati Isem Mhux Patentat tal- Prodott (INN): lornoxicam
Xefo and associated names, 4mg and 8mg film-coated tablets, 8mg rapid film coated tablet, and 8mg powder and solvent for solution for injection, is a non-steroidal anti-inflammatory drug (NSAID), used for short-term relief of acute mild to moderate pain, symptomatic relief of pain and inflammation in osteoarthritis and symptomatic relief of pain and inflammation in rheumatoid arthritis.
Xefo u ismijiet assoċjati, pilloli miksijin b’ rita ta ’ 4mg u 8 mg, pillola rapida miksija b’ rita ta ’ 8mg, u trab u solvent għal soluzzjoni għal injezzjoni ta ’ 8mg, huwa mediċina mhux sterojde kontra l- infjammazzjoni (NSAID), użata għal serħan mill- uġigħ ħafif għal moderat akut għal perjodu ta ’ żmien qasir, serħan sintomatiku mill- uġigħ u infjammazzjoni fl- oseoartrite u serħan sintomatiku ta ’ uġigħ u ta ’ l - infjammazzjoni fl- artrite rewmatojde.
On 16 May 2006 Nycomed Denmark Aps presented to the EMEA a referral under Article 30 of Directive 2001/ 83/ EC, in order to harmonise the nationally authorised Summaries of Product Characteristics (SPC), Package Leaflets and Labelling of the medicinal product Xefo and associated names.
Fis- 16 ta ’ Mejju 2006 Nycomed Danmark Aps ippreżentat referenza lill- EMEA taħt l- Artikolu 30 tad - Direttiva 2001/ 83/ KE, sabiex tarmonizza s- Sommarji tal- Karatteristiċi tal- Prodott (SPC), Fuljetti ta ’ Tagħrif u t- Tikketti tal- prodott mediċinali Xefo u ismijiet assoċjati awtorizzati fuq livell nazzjonali.
The basis for referral was that there were divergences in the Summaries of Product Characteristics of Xefo and associated names approved across EU Member States, with respect to the short-term relief of acute mild to moderate pain, symptomatic relief of pain and inflammation in osteoarthritis and symptomatic relief of pain and inflammation in rheumatoid arthritis.
Il- bażi għal referenza kienet li kien hemm diverġenzi fis- Sommarji tal- Karatteristċi tal- Prodott ta ’ Xefo u ismijiet assoċjati approvati fost l- Istati Membri ta ’ l- UE, fir- rigward tas- serħan għal qasir żmien minn uġigħ ħafif għal moderat akut, serħan sintomatiku mill- uġigħ u infjammazzjoni fl- oseoartrite u serħan sintomatiku mill- uġigħ u infjammazzjoni fl- artrite rewmatojde.
The procedure started on 2 June 2006.
Il- proċedura bdiet fit- 2 ta ’ Ġunju 2006.
The Marketing Authorisation Holder provided supplementary information on 21 September 2006 and 12 January 2007.
Id- Detentur ta ’ l- Awtorizzazzjoni għat- Tqegħid fis- Suq ipprovda tagħrif supplimentari fil- 21 ta ’ Settembru 2006 u fit- 12 ta ’ Jannar 2007.
During its February 2007 meeting, the CHMP, in the light of the overall submitted data and the scientific discussion within the Committee, was of the opinion that the proposal for the harmonisation of the SPC, Labelling and Package leaflet was acceptable and that they should be amended.
Waqt il- laqgħa tiegħu ta ’ Frar 2007, is- CHMP, fid- dawl tat- tagħrif totali sottomess u d- diskussjoni xjentifika fi ħdan il- Kumitat, kien ta ’ l- opinjoni li l- proposta għal armonizzazzjoni ta ’ l- SPC, Tikketta u Fuljett ta ’ Tagħrif kienet aċċettabbli u li dawn għandhom jiġu emendati.
The CHMP gave a positive opinion on 22 February 2007 recommending the harmonisation of the SPC, labelling and package leaflet for Xefo and associated names.
Is- CHMP ta opinjoni pożittiva fit- 22 ta ’ Frar 2007 fejn irrikmanda l- armonizzazzjoni tal- SPC, tikketta u fuljett ta ’ tagħrif għal Xefo u ismijiet assoċjati.
The list of product names concerned is given in Annex I.
Il- lista ta ’ l- ismijiet tal- prodotti kkonċernati hija mogħtija f’ Anness I.
The scientific conclusions are provided in Annex II together with the amended SPC, labelling and package leaflet in Annex III.
Il- konklużjonijiet xjentifiċi huma pprovduti fl- Anness II flimkien mal- SPC, tikketta u fuljett ta ’ tagħrif emendati f’ Anness II.
A Decision was issued by the European Commission on 29 May 2007.
Id- Deċiżjoni nħarġet mill- Kummissjoni Ewropea fid- 29 ta ’ Mejju 2007.
LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANTS MARKETING AUTHORISATION HOLDERS IN THE MEMBER STATES
LISTA TA` L- ISMIJIET, GĦAMLA FARMAĊEWTIKA, QAWWA TAL- PRODOTT MEDIĊINALI, MNEJN JINGĦATA, SIDIEN TA` L- AWTORIZZAZZJONI TAL - KUMMERĊ TA` L- APPLIKANT F` L- ISTATI MEMBRI
Marketing Authorisation Holder
Sid ta` l- Awtorizzazzjoni tal- Kummerċ
(Invented) Name
Isem Ivvintat / Isem Qawwa
Germany
Id- Danimarka
Merz Pharmaceuticals GmbH Eckenheimer Landstraße 100 60318 Frankfurt/ Main Germany
Merz Pharmaceuticals GmbH Eckenheimer Landstraße 100 60318 Frankfurt/ Main Il- Ġermanja
Powder for solution for injection
trab għal soluzzjoni għall- injezzjoni
For intramuscular use
Għall- użu ġol - muskoli
Denmark
Il- Ġermanja
Sweden
Il- Finlandja
Austria
Il- Lussemburgu
Spain
Il- Polonja
Finland
Il- Portugall
France
In- Norveġja
Italy
Ir- Renju Unit
Luxembourg
L- Awstrija
Merz Pharmaceuticals GmbH Eckenheimer Landstraße 100 60318 Frankfurt/ Main
Merz Pharmaceuticals GmbH Eckenheimer Landstraße 100 60318 Frankfurt/ Main Il- Ġermanja
Powder for solution For intramuscular use for injection
trab għal soluzzjoni għall- injezzjoni
Poland
L- Italja
Portugal
Franza
UK
Spanja
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY(IES) OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET PRESENTED BY THE EMEA
KONKLUŻJONIJIET XJENTIFIĊI U RAĠUNIJIET GĦALL- EMENDI FIS- SOMMARJU( I) TAL- KARATTERISTIĊI TAL- PRODOTT, TIKKETTA U FIL- FULJETT TA ’ TAGĦRIF IPPREŻENTATI MILL- EMEA
4 SCIENTIFIC CONCLUSIONS
4 U Xeomin u Botox fil -
OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF XEOMIN< (see Annex I) >
14- il voluntier raġel b’ saħħtu Open label, tqabbil waqt it- trattament
- Quality issues
Tibdil fl- ikbar mewġa tas -
From a quality point of view, Xeomin is highly purified and differs from the drug substance in Botox® and Dysport® in that it is free of complexing proteins (haemagglutinins).
Studju open label bi tqabbil komparattiv, b’ għażla irregolari.
No quality aspects were the subject of disagreement during the Mutual Recognition procedure.
Studju double blind parallel bi tqabbil attiv (Botox) b’ għażla irregolari.
- Efficacy issues
Tibdil fil- punteġġ totali tal -
The clinical development program was composed by 5 studies provided in the following table:
Units
The submitted clinical trial programme consisted of: • Two Phase I studies MRZ/ BTC-9901 and MRZ/ BTC-0113, of which the latter was performed after completion of the Phase III studies • One Phase II study (MRZ/ BTC-9801) • Two Phase III studies (one study in each of the intended indication, spasmodic torticollis (MRZ/ BTC-0013) and blepharospasm (MRZ/ BTC-0003) respectively)
Il- programm ta ’ l- istudju kliniku sottomess kien jikkonsisti minn: • Żewġ studji ta ’ l- Ewwel Fażi MRZ/ BTC- 9901 u MRZ/ BTC- 0113, li minnhom it- tieni wieħed sar wara t- tlestija ta ’ l- istudji tat- Tielet Fażi • Studju wieħed tat- Tieni Fażi (MRZ/ BTC- 9801) • Żewġ studji tat- Tielet Fażi (studju wieħed f’ kull waħda mill- indikazzjonijiet intiżi, torticollis spasmodika (MRZ/ BTC- 0013) u blefarospażmu (MRZ/ BTC- 0003) rispettivament)
In addition, at present there are three ongoing clinical studies with Xeomin: • In the upper limb spasticity study (MRZ 0410) 144 patients entered the second injection cycle, in which doses up to 400 U of Xeomin are administered. • In the cervical dystonia study (MRZ 0408) in which doses up to 240 U of Xeomin are administered, 31 patients entered the second injection cycle. • In the blepharospasmus study (MRZ 0433) one patient has entered the second injection cycle.
Barra dan, bħalissa għaddejjin tliet studji kliniċi dwar Xeomin: • Fl- istudju dwar l- ispastiċità tad- driegħ (MRZ 0410) 144 pazjent daħlu fit- tieni ċiklu ta ’ injezzjoni, li fiha jingħataw dożi sa 400 U ta ’ Xeomin. • Fl- istudju dwar id- distonja ċervikali (MRZ 0408) li fih jingħataw dożi sa 240 U ta ’ Xeomin, 31 pazjent daħlu fit- tieni ċiklu ta ’ injezzjonjiet. • Fl- istudju dwar il- blefarospażmu (MRZ 0433) pazjent wieħed daħal fit- tieni ċiklu ta ’ l - injezzjonijiet.
5 Posology The applicant submitted three non-clinical, two Phase I, one Phase II and one Phase III studies to demonstrate that a safe posology has been established for Xeomin.
6 L- applikant issottometta tliet studji mhux kliniċi, żewġ studji ta ’ l- Ewwel Fażi, wieħed tat- Tieni Fażi u wieħed tat- Tielet Fażi biex juru li ġiet stabbilita pożoloġija sigura għal Xeomin.
• Non-clinical data In non-clinical studies, the pharmacological effect (i. e. degree of the paralytic activity, effect on motility, effect on paralysis over time, duration) of Xeomin was compared to Botox:
• Tagħrif mhux kliniku Fl- istudji mhux kliniċi, l- effett farmakoloġiku (jiġifieri l- livell ta ’ attività paralitika, l- effett fuq il - motilità, l- effett fuq il- paraliżi matul iż- żmien) ta ’ Xeomin tqabbel ma ’ Botox:
- The paralytic activity of Xeomin and Botox was assessed in the mouse regional paralysis test, after 3
- L- attività paralitika ta ’ Xeomin u Botox ġiet valutata fit- test tal- paraliżi reġjonali tal- ġrieden, wara
32 LDU/ kg).
tliet injezzjonijiet fil- muskoli b’ intervalli ta ’ 6 u 13- il ġimgħa sa doża ta ’ 0. 64 Unità tad- Doża Letali (LDU) għal kull annimal għal Xeomin u Botox (madwar 32 LDU/ kg).
- The influence of Xeomin and Botox on motility (static and active movements) was assessed within
- L- influwenza ta ’ Xeomin u Botox fuq il- motilità (movimenti statiċi u attivi) kienet valutata fi studju
an acute intravenous toxicity study in mice up to 68 LDU/ kg.
dwar it- tossiċità intravenuża akuta fil- ġrieden sa 68 LDU/ kg.
- The paralytic efficacy of Xeomin and Botox was analysed by electromyography (EMG) in vivo in
- L- effett paralitiku ta ’ Xeomin u Botox ġie analizzat permezz ta ’ elettromijografija (EMG) in vivo
male monkeys after a single intramuscular injection of 16 LDU/ kg in the left gluteus medius muscle.
fix- xadini rġiel wara injezzjoni waħdanija ta ’ 16 LDU/ kg fil- muskolu gluteu medju tax- xellug.
The nonclinical data clearly demonstrated that one unit of Xeomin is equipotent to one unit of Botox and a clear dose-response was shown in two species.
It- tagħrif mhux kliniku wera li unità waħda ta ’ Xeomin hija qawwija daqs unità waħda ta ’ Botox u ntwera rispons korrispondenti għad- doża f’ żewġ speċi.
Based on the results, it could be concluded that pharmacological effect of Xeomin and Botox are almost comparable in animals.
Skond ir- riżultati, jista ’ jiġi konkluż li l- effett farmakoloġiku ta ’ Xeomin u Botox huwa kważi komparabbli fl- annimali.
• Clinical data Both Phase I studies showed equal doses of Xeomin to be as effective as Botox in the EMG measurements; it was clearly demonstrated that the paralytic effects of Xeomin and Botox increased with ascending doses and a comparable trend was seen in a Phase II study.
• Tagħrif Kliniku Iż- żewġ studji ta ’ l- Ewwel Fażi wrew li dożi ndaqs ta ’ Xeomin kienu effettivi daqs Botox fil- kejl ta ’ l - EMG; intwera biċ- ċar li l- effetti paralitiċi ta ’ Xeomin u Botox żdiedu maż- żieda fid- dożi u dehret tendenza simili fl- istudju tat- Tieni Fażi.
In Phase II dose finding trial, the efficacy in patients with rotational cervical dystonia at three doses (10, 20 and 30 U) of Xeomin was compared to the optimal dose of Botox (30 U).
Fl- istudju tat- Tieni Fażi għas- sejbien tad- doża, l- effikaċja f’ pazjenti b’ distonja ċervikali rotazzjonali għal tliet dożi (10, 20 u 30 U) ta ’ Xeomin tqabblet mad- doża ottima ta ’ Botox (30 U).
The primary efficacy variable was the decrease from baseline of the most relevant (i. e. highest amplitude) surface electromyography (EMG) level in the dystonic sternocleidomastoid muscle during maximal voluntary activation 14 days post-injection.
L- effikaċja primarja kienet definita bħala t- tnaqqis mil- livell bażi ta ’ l- iktar livell relevanti (jiġifieri bl- ogħla mewġa) ta ’ elettromijografija (EMG) fil- muskolu sterncleidomastoid distoniku waqt l - attivazzjoni volontarja massima 14- il jum wara l- injezzjoni.
The study failed with respect to the determination of the optimal therapeutic dose of Xeomin in the treatment of spasmodic torticollis, as no statistically significant treatment differences (overall or pair-wise) were observed, but similar effectiveness of Xeomin and Botox in EMG measurements could be demonstrated.
L- istudju ma rnexxilux jistabbilixxi d - doża terapewtika ottimali ta ’ Xeomin fit- trattament tat- torticollis spasmodiku, għax ma kienet osservata l- ebda differenza statistikament sinjifikanti (globalment jew fi ħdan par), iżda ntweriet effettività simili ta ’ Xeomin u Botox fil- kejl ta ’ l- EMG.
Nevertheless, the mean change of surface EMG level in the sternocleidomastoid muscle, which is to be regarded as an objective parameter, showed a clear dose-trend of Xeomin.
Minkejja dan, it- tibdil medju fil- livell tas - superfiċje ta ’ l- EMG fil- muskolu sternocleidomastoid, li hu meqjus bħala parametru oġġettiv, wera tendenza ċara tad- doża ta ’ Xeomin.
Considering the data from the non-clinical studies, the early Phase I study and its conclusions, and the Phase II study - although limited conclusions could be drawn from it, the dosage of Xeomin in both Phase III studies was based on the established dose of Botox.
Meta wieħed jikkonsidra t- tagħrif mill- istudji mhux kliniċi, l- istudju bikri ta ’ l- Ewwel Fażi u l - konklużjonijiet tiegħu, u l- istudju tat- Tieni Fażi – għalkemm wieħed jista ’ jasal għal konklużjonijiet limitati minnu, id- doża ta ’ Xeomin fiż- żewġ studji tat- Tielet Fażi kienet ibbażata fuq id- doża stabbilita ta ’ Botox.
This approach is considered acceptable.
Din l- analiżi hi meqjusa aċċettabbli.
During a Scientific Advice procedure in 2000, the EMEA did not require or recommend that further Phase II studies be conducted before the Phase III studies were performed.
Waqt proċedura tas- Scientific Advice (Parir Xjentifiku) fl- 2000, l- EMEA ma kellhiex bżonn u ma rrakkomandatx li jsiru iktar studji tat- Tieni Fażi qabel ma jsiru l- istudji tat- Tielet Fażi.
The applicant presented efficacy data of Phase III study in spasmodic torticollis.
L- applikant ippreżenta t- tagħrif ta ’ l- effikaċja ta ’ l- istudju tat- Tielet Fażi fit- torticollis spasmodika.
This study showed the non-inferiority of Xeomin (70-300 U) compared to Botox (70-300 U).
Dan l- istudju wera li Xeomin (70- 300 U) ma kienx inferjuri għal Botox (70- 300 U).
A similar dose-efficacy response relationship has been demonstrated for Xeomin and Botox after one injection in spasmodic torticollis Phase III study.
Intweriet relazzjoni simili fid- doża u l- effikaċja tar- rispons għal Xeomin u Botox wara injezzjoni waħda fl - istudju tat- Tielet Fażi tat- torticollis spasmodiku.
Taken altogether, the data from the non-clinical and clinical development program, which has been designed with support of Scientific Advice, provided sufficient evidence that a 1:1 dose ratio between Xeomin and Botox with respect to efficacy and safety can be concluded and the adoption of the dosage which has been established for Botox is adequately justified.
Komplessivament, it- tagħrif mill- programm ta ’ żvilupp kliniku u mhux kliniku, li ġie ddisinjat bl - appoġġ ta ’ Scienific Advice, turi biċ- ċar li dożi ugwali ta ’ Xeomin u Botox huma effikaċji u siguri u li l- adozzjoni tad- doża stabbilita għal Botox hi ġustifikata adegwatament.
Against this background a further extensive dose-ranging program would not have been justifiable from an ethical point of view.
F’ dan l- isfond, mill- aspett etiku, ma kienx ġustifikabbli li jsir programm ieħor estensiv b’ varjetà ta ’ dożi.
6 • Safety data The numbers of adverse events in Phase II study and in Phase III dystonia Study are submitted in the following Table:
• It- tagħrif dwar is- sigurtà In- numru ta ’ avvenimenti sekondarji fl- istudju tat- Tieni Fażi u fl- istudju tad- distonja tat- Tielet Fażi jinsabu fit- Tabella ta ’ hawn taħt:
Due to the very low number in each group, results of this Phase II study were not considered to be useful from a safety point a view.
Minħabba n- numru żgħir ħafna f’ kull grupp, ir- riżultati ta ’ dan l- istudju tat- Tieni Fażi ma kinux ikkunsidrati ta ’ utilità mil- lat ta ’ sigurtà.
It should be noted that some adverse events have only been reported in patients who received Xeomin, such as dysphagia (reported in one patient in each of the Xeomin groups versus no patients in the Botox group).
Irid jiġi nnotat li xi effetti sekondarji ġew rappurtati biss f’ pazjenti li ngħataw Xeomin, bħal problemi biex wieħed jibla ’ (rappurtati f’ pazjent wieħed f’ kull wieħed mill- gruppi ta ’ Xeomin u minn ebda pazjent fil- grupp ta ’ Botox).
In addition, two adverse events have been assessed as related to study medication, versus none in the Botox group.
Barra minn hekk, ġew valutati żewġ episodji sekondarji relatati mal- medikazzjoni ta ’ l- istudji u l- ebda episodju fil- grupp ta ’ Botox.
The two related adverse events were reported in the same patient who received 30/ 60 U of Xeomin (one injection site pain and one dysphagia).
Iż- żewġ episodji sekondarji relatati kienu rappurtati fl- istess pazjent li kien ingħata 30/ 60 U ta ’ Xeomin (uġigħ fis- sit ta ’ l- injezzjoni u tbatija biex jibla ’).
The fact that the Phase III studies were performed in patients pretreated with Botox is adequately addressed in the SPC, which now states that ‘ there is limited experience in treatment-naïve patients’.
Il- fatt li l- istudji tat- Tielet Fażi saru f’ pazjenti ttrattati minn qabel b’ Botox hu indirizzat b’ mod adegwat fl- SPC, li issa jgħid li ‘ hemm esperjenza limitata fit- trattament ta ’ pazjenti li ma kinux trattati qabel (treatment- naïve patients) ’.
Lack of data on repeated administration and the need for data on immunogenicity • Non-clinical data Two non-clinical studies, LPT10929 and LPT12444 with repeated high dose administration of Xeomin (25 LDU/ animal in LPT10929 and 16-40LDU/ animal in LPT12444) at very short injection intervals were performed in rabbits:
Nuqqas ta ’ tagħrif fuq l- amministrazzjoni ripetuta u fuq il- ħtieġa ta ’ tagħrif fuq l - immunoġeneċità • Tagħrif mhux kliniku Saru żewġ studji mhux kliniċi fil- fniek, LPT10929 u LPT12444 b’ amministrazzjoni ripetuta b’ doża għolja ta ’ Xeomin (25 LDU għal kull annimal f’ LPT10929 u 16- 40LDU għal kull annimal f’ LPT12444) b’ intervalli qosra ħafna:
- In LPT10929, in study week 12, two weeks after the last administration, Botulinum neurotoxin type
- F’ LPT10929, fit- 12- il ġimgħa ta ’ l- istudju, ġimagħtejn wara l- aħħar aministrazzjoni, instabu
A neutralising antibodies were found in 4 of 8 surviving rabbits treated with Botox, but in none of the 10 surviving rabbits treated with Xeomin.
antikorpi newtralizzanti tan- newrotossin tal- Botulinum tat- tip A f’ erbgħa mit- tmint ifniek ittrattati b’ Botox li baqgħu ħajjin, iżda fl- ebda wieħed mill- għaxart ifniek li baqgħu ħajjin wara li ngħataw Xeomin.
- In LPT12444, in week 36, three weeks after the final injection, the ELISA test (indicating the
- F’ LPT12444, fis- 36 ġimgħa, tliet ġimgħat wara l- injezzjoni finali, it- test ELISA (li juri l- preżenza ta ’
presence of antibodies against Botulinum neurotoxin type A) revealed that seven of the 20 rabbits treated with Botox showed a positive response and four of these rabbits displayed BoNT/ A neutralising activity in the hemidiaphragm assay (HDA indicating if antibodies are neutralising or non-neutralising).
antikorpi ta ’ kontra newrotossin tal- Botulinium tat- Tip A) wera li sebgħa mill- għoxrin fenek ittrattati b’ Botox kellhom rispons pożittiv u erbgħa minn dawn il- fniek u erbgħa minn dawn il- fniek urew attività newtralizzanti BoNT/ A fil- hemidiaphragm assay (HDA li juri jekk l- antikorpi humiex newtralizzanti jew le).
In contrast, one animal treated with Xeomin was tested positively in the ELISA test, but no neutralising activity was detected in the HDA.
B’ kuntrast għal dan, annimal wieħed ittrattat b’ Xeomin ittestja pożittivament fit- test ELISA, iżda l- ebda attività newtralizzanti ma nstabet fl- HDA.
In the non-clinical study, Xeomin was not more or less immunogenic than Botox even at dose levels clearly exceeding the recommended human dose.
Fl- istudju mhux kliniku, Xeomin ma kienx iktar jew inqas immunoġeniku minn Botox anke f’ livelli ta ’ dożi li jaqbżu b’ mod ċar id- doża umana rakkomandata.
• Clinical data Botox and Xeomin are different drug substances in terms of clostridial protein content, although both contain the same 150 kDa neurotoxin, which is the actual active substance.
• Tagħrif kliniku Botox u Xeomin huma mediċini differenti f’ termini tal- kontenut tal- proteini klostridjali, għalkemm it - tnejn fihom l- istess newrotossin tal- 150 kDa, li hi s- sustanza attiva attwali.
Botox has a protein content of 5 ng/ 100U, i. e. the 150 kDa neurotoxin and non-effective complexing proteins, and quickly dissociates into the neurotoxin and the complexing proteins after administration.
Botox għandu kontenut tal - proteini ta ’ 5 ng/ 100U, jiġifieri n- newrotossin tal- 150 kDa u proteini komplessanti mhux effettivi.
Xeomin has a protein content of only 0,6 ng/ 100U as it only consists of the 150 kDa neurotoxin, free from complexing proteins.
Xeomin għandu kontenut tal- proteini ta ’ 0, 6 ng/ 100U biss għax jikkonsisti biss min- newrotossin tal - 150 kDa, mingħajr proteini komplessanti.
By reason of these facts it is implausible, that injection of Xeomin would lead to more frequent secondary therapeutic failures than Botox.
Minħabba dawn il- fatti, mhuwiex plawżibbli li injezzjoni ta ’ Xeomin twassal għal fallimenti terapewtiċi sekondarji iktar frekwenti minn Botox.
Xeomin has been developed with the aim of reducing the risk of formation of neutralising antibodies, which may lead to secondary therapy failure.
Xeomin ġie żviluppat bil- għan li jnaqqas ir- riskju tal- formazzjoni ta ’ antikorpi newtralizzanti, li tista ’ twassal għal falliment sekondarju tat- terapija.
Publications of clinical studies have been mentioned
Issemmew pubblikazzjonijiet (Jankovic et al, 20031,
7 (Jankovic et al, 20031, 20062, Barnes et al, 20053) to support the hypothesis that the amount of antibodies is correlated to the amount of clostridial protein load and thus, that there might be a lower risk for patients treated with Xeomin to develop secondary non-response.
8 2006 2, Barnes et al, 2005 3) li jappoġġjaw l- ipoteżi li l- ammont ta ’ antikorpi hu korrelatat ma ’ l - ammont tat- tagħbija tal- proteini klostridjali u għalhekk jista ’ jkun hemm riskju iżgħar għal pazjenti ttrattati b’ Xeomin li jiżviluppaw nuqqas ta ’ rispons sekondarju.
In 2003, Jankovic compared 130 patients treated for cervical dystonia with original Botox (25ng protein/ 100 U before 1998), 42 of whom were exposed only to the original Botox and 119 treated with the current Botox (5ng protein/ 100 U since 1998).
Fl- 2003, Jankovic qabbel 130 pazjent trattati għad- distonja ċervikali bil- Botox oriġinali (25ng ta ’ proteini kull 100 U qabel l- 1998), li 42 minnhom kienu esposti biss għall- Botox oriġinali u 119 kienu trattati bil- Botox kurrenti (5ng proteini kull 100 U mill- 1998).
Blocking antibodies were detected in 4 of 42 (9.5%) patients treated only with original Botox and in none of the patients treated with only the current Botox, despite a higher mean dose of current Botox per visit than original Botox.
Instab li kien hemm imblukkar ta ’ l - antikorpi f’ 4 minn 42 (9. 5%) tal- pazjenti ttrattati biss bil- Botox oriġinali u fl- ebda mill- pazjenti ttrattati biss bil- Botox kurrenti, minkejja doża medja ogħla ta ’ Botox kurrenti kull żjara minn dik ta ’ Botox oriġinali.
These findings must be interpreted cautiously because all patients were not systematically tested for Botulinum toxin antibodies.
Dawn is- sejbiet iridu jiġu interpretati b’ kawtela għax mhux il- pazjenti kollha kienu sistematikament ittestjati għall- antikorpi tat- tossin tal- Botulinum.
The immunological reactions on Xeomin were specifically investigated in the Phase III study MRZ- 0013 in patients with cervical dystonia.
Ir- reazzjonjiet immunoloġiċi għal Xeomin kienu speċifikament investigati fl- istudju tat- Tielet Fażi MRZ- 0013 f’ pazjenti b’ distonja ċervikali.
Data of changes in TWSTRS-Severity score in patients with hemidiaphragm assay (HAD) positive group between control visit (3 weeks after one injection) and final visit (12 weeks after one injection) were submitted.
Ġie ppreżentat tagħrif dwar it- tibdiliet fil- punteġġ ta ’ severità- TWSTRS f’ pazjenti fil- grupp pożittiv għall- hemidiaphragm assay bejn iż- żjara ta ’ kontroll (3 ġimgħat wara injezzjoni waħda) u ż- żjara finali (12- il ġimgħa wara injezzjoni waħda).
These data were divided into 3 subgroups: patients with HDA negative, patients with positive antibodies< 5 mU/mL and patients with positive antibodies> 5 mU/ mL.
Dan it- tagħrif tqassam fi 3 sottogruppi: pazjenti b’ HAD negattiv, pazjenti b’ antikorpi pożittiv < 5 mU/ mL u pazjenti b’ antikorpi pożittivi > 5 mU/ mL.
Of the Xeomin patients with a negative mouse hemidiaphragm assay (HDA) result at baseline, indicating that no neutralising antibodies are present, 2 individuals had a positive result (< 5 mU/ mL) at the final visit.
Mill- pazjenti li ngħataw Xeomin b’ riżultat bażi negattiv fil- hemidiaphragm assay (HDA) tal- ġrieden, li jindika li l- ebda antikorpi newtralizzanti ma huma preżenti, żewġ individwi kellhom riżultat pożittiv (< 5 mU/ mL) fl- aħħar żjara.
Of the Botox patients 4 individuals with a negative result at baseline had a positive result (< 5 mU/mL in 3 patients, > 5 mU/mL in 1 patient) at the final visit.
Mill- erba ’ pazjenti li ngħataw Botox, 4 individwi b’ riżultat bażi negattiv kellhom riżultat pożittiv (< 5 mU/ mL fi tliet pazjenti, > 5 mU/ mL f’ pazjent wieħed) fl- aħħar żjara.
In addition, the HDA titer increased from< 5 mU/mL to > 5 mU/mL in 2 patients in each treatment group.
Barra minn hekk, il- livell ta ’ l- HDA żdied minn < 5 mU/ mL għal > 5 mU/ mL f’ żewġ pazjenti f’ kull grupp ta ’ trattament.
In both treatment groups, 4 patients with a positive HDA result at baseline had a negative result at the final visit.
Fiż- żewġ gruppi ta ’ trattament, 4 pazjenti b’ riżultat bażi pożittiv ta ’ l- HDA kellhom riżultat negattiv fiż- żjara finali.
In the Phase III study MRZ-0003 in patients with blepharospasm, no patient in both treatment groups had a HDA antibody titer higher than 1 mU/ l at baseline or at final visit.
Fl- istudju tat- Tielet Fażi MRZ- 0003 bis- sehem ta ’ pazjenti bi blefarospażmu, l- ebda pazjent miż- żewġ gruppi ma kellu livell ta ’ antikorpi ta ’ l- HDA ogħla minn 1 mU/ l fl- analiżi inizjali jew fl- aħħar żjara.
The informational value of the Phase III studies concerning immunogenicity is limited, as the patients were pretreated with Botox, and Xeomin was administered only once.
Il- valur informattiv ta ’ l- istudji tat- Tielet Fażi dwar l- immunoġeneċità hi limitata, għax il- pazjenti kienu ttrattati minn qabel b’ Botox, u Xeomin kien amministrat darba biss.
Therefore, no valid conclusions can be drawn from the resulting data with respect to immunogenicity of Xeomin compared to Botox.
Għalhekk, wieħed ma jista ’ jasal għall- ebda konklużjoni valida mit- tagħrif li tirriżulta fir- rigward ta ’ l- immunoġeneċità ta ’ Xeomin meta mqabbel ma ’ Botox.
However, there is no indication of a higher antigenic potential of Xeomin compared to Botox.
Madankollu, ma hemm l- ebda indikazzjoni ta ’ potenzjal antiġeniku ogħla ta ’ Xeomin meta mqabbel ma ’ Botox.
At present there are three ongoing clinical studies with Xeomin (all of which have a placebo- controlled single injection main period and subsequent extension periods, in which only Xeomin is administered).
Bħalissa għaddejjin tliet studji kliniċi dwar Xeomin (li kollha għandhom perjodu ewlieni b’ injezzjoni waħdanija ikkontrollata bi plaċebo u perjodi sussegwenti ta ’ injezzjoni, li fihom ikun amministrat Xeomin biss).
In each of the ongoing studies, data are still blinded, but no secondary therapy failures due to antibody development have been reported up to now.
F’ kull wieħed mill- istudji li hemm għaddejjin, it- tagħrif għadu ma ngħatax (blinded), iżda sa issa ma ġew rappurtati l- ebda fallimenti sekondarji tat- terapija minħabba l- iżvilupp ta ’ antikorpi.
In the upper limb spasticity study (MRZ 0410) 144 patients entered the 2nd injection cycle, in which doses up to 400 U of Xeomin are administered.
Fl- istudju dwar l- ispastiċità fid- driegħ (MRZ 0410) 144 pazjent daħlu fit- tieni ċiklu ta ’ l- injezzjoni, li fih ingħataw dożi sa 400 U ta ’ Xeomin.
One hundred and ten patients are in the 3rd and 13 patients in the 4th injection cycle.
Mija u għaxar pazjenti jinsabu fit- 3 u t- 13- il pazjent fir- 4 ċiklu ta ’ injezzjonijiet.
HDA tests are performed at baseline and repeatedly during the course of the study and the results which are, amongst others, available for 107 patients after the 2nd injection cycle and for 73 patients four weeks after 3rd injection did not show any neutralising antibodies.
Isiru testijiet ta ’ l- HDA fil- bidu u ripetutament matul l- istudju u r- riżultati li huma, fost l- oħrajn, disponibbli għal 107 pazjenti wara t- 2 ċiklu ta ’ l- injezzjonijiet u għal 73 pazjent erba ’ ġimgħat wara t- 3 ċiklu ta ’ injezzjonijiet ma wrew l- ebda antikorpi newtralizzanti.
In the cervical dystonia study (MRZ 0408) in which doses up to 240 U of Xeomin are administered, 63 patients received the 2nd injection, 27 patients received the 3rd, and 6 patients received the 4th injection, respectively.
Fl- istudju dwar distonja ċervikali (MRZ 0408), li fih, ingħataw dożi sa 240 U ta ’ Xeomin, 63 pazjent irċevew t- 2 injezzjoni, 27 pazjent irċevew t- 3 injezzoni u 6 pazjenti rċevew r- 4 injezzjoni, rispettivament.
Up to now the FIA (Fluorescence Immuno Assay) screening test revealed no trend of a development of antibodies after Xeomin injection.
Sa llum, it- test ta ’ skrining tal- FIA (Assaġġ Immuno Fluworexxenti) ma kixef ebda tendenza ta ’ żvilupp ta ’ antikorpi wara injezzjoni ta ’ Xeomin.
Meanwhile the respective results
It- testijiet HDA tal- kampjuni
8 are available, showing one positive test result at baseline and before 3rd injection and two positive results four weeks after 1st injection and before 2nd injection.
Sa dan it- tant, ir- riżultati rispettivi huma disponibbli, u dawn juru riżultat ta ’ test pożittiv wieħed fil- linja bażi u qabel it- 3 injezzjoni u żewġ riżultati pożittivi erba ’ ġimgħat wara l- 1 injezzjoni u qabel it- 2 injezzjoni.
However, as one of the two positive results four weeks after 1st injection and before 2nd injection was found in a patient pretreated with Botox and the study is still blinded, no conclusions concerning immunogenicity of Xeomin can be drawn from these results.
Madankollu, minħabba li wieħed miż- żewġ riżultati pożittivi erba ’ ġimgħat wara l- 1 injezzjoni u qabel it- 2 injezzjoni instab f’ pazjent ittrattat minn qabel b’ Botox u l- istudju għadu blinded, ma tista ’ tissarraf ebda konklużjoni dwar l- immunoġeniċità ta ’ Xeomin minn dawn ir - riżultati.
The applicant is requested to submit the results of all scheduled HDA tests of the upper limb spasticity study (MRZ 0410) and the cervical dystonia study (MRZ 0408) after unblinding of the respective studies.
L- applikant huwa mitlub jissottometti r- riżultati tat- testijiet tal- HDA skedati kollha ta ’ l- istudju ta ’ l - ispastiċità tal- parti ta ’ fuq tad- driegħ (MRZ 0410) u ta ’ l- istudju tad- distonja ċervikali (MRZ 0408) wara l- kxif ta ’ l- istudji rispettivi.
In the blepharospasmus study (MRZ 0433) 6 patients received the 2nd injection.
Fl- istudju tal- blefarospażmu (MRZ 0433) 6 pazjenti rċevew t- 2 injezzjoni.
Thus, up to now no case of secondary therapy failure can be derived from the ongoing studies, in which Xeomin (or placebo) has been used repetitively in a total of 213 patients, even though Xeomin doses are partially very high (which is usually a risk factor of antibody formation).
B’ hekk, s’ issa, ebda każ ta ’ falliment ta ’ terapija sekondarja ma jista ’ joħroġ mill- istudji li huma għaddejjin il- ħin kollu, li fihom intuża Xeomin (jew plaċebo) ripetittivament f’ total ta ’ 213 pazjent, anki jekk id- dożi ta ’ Xeomin huma parzjalment għoljin ħafna (li normalment huwa fattur ta ’ riskju ta ’ formazzjoni ta ’ antikorpi).
The applicant has committed to perform a post-marketing surveillance study, in which immunogenicity of Xeomin will be further investigated after repeated administration (up to 6 injection sessions).
L- applikant impenja ruħu li jwettaq studju ta ’ sorveljanza ta ’ wara t- tqegħid fis- suq, li fih, l - immunoġeniċità ta ’ Xeomin sejra tiġi investigata aktar wara amministrazzjoni ripetuta (sa 6 sessjonijiet ta ’ injezzjonijiet).
The study proposed is an open, single arm study in which 74 patients with cervical dystonia (naïve and pre-treated) are planned.
L- istudju propost huwa studju single arm u miftuħ li fih huwa ppjanat li jieħdu sehem 74 pazjent b’ distonja ċervikali (naïve u ttrattati minn qabel).
Lastly, the proposed SPC for Xeomin does not claim a potentially lower risk of development of antibodies with the product: “ It has not been investigated whether secondary non-response due to the development of antibodies is less frequent under Xeomin therapy than under treatment with conventional preparations containing the Botulinum neurotoxin type A complex.
Fl- aħħar nett, l- SPC propost għal Xeomin ma jurix riskju potenzjalment aktar baxx ta ’ antikorpi mal - prodott: “ Għadu ma ġiex investigat jekk nuqqas ta ’ rispons sekondarju minħabba l- iżvilupp ta ’ anti - korpi huwiex inqas frekwenti taħt terapija b’ Xeomin milli taħt terapija bi preparazzjonijiet konvenzjonali li fihom il- kumpless Botulinum neurotoxin tip A.
In cases of non- response, alternative therapies should be taken into consideration .”
F’ każijiet ta ’ nuqqas ta ’ rispons, għandhom jitqiesu terapiji alternattivi. ”
Safety profile • Overall Comparison of Adverse Events in Phase I – III Studies A total of five clinical trials (BTC-9901, MRZ-0113, BTC-9801, MRZ-0013, MRZ-0003) have been completed to provide data on the safety and efficacy of Xeomin.
Profil tas- sigurtà • Tqabbil globali ta ’ l- Episodji Avversi fl- Istudji ta ’ Fażi I - III B’ kollox saru ħames provi kliniċi (BTC- 9901, MRZ- 0113, BTC- 9801, MRZ- 0013, MRZ- 0003) sabiex jipprovdu tagħrif fuq is- sigurtà u l- effikaċja ta ’ Xeomin.
Overall, safety data from 908 participants have been included in these trials, 466 subjects were treated with Xeomin and 442 subjects were treated with Botox.
B’ mod ġenerali, it- tagħrif dwar is - sigurtà minn 908 parteċipanti ġie nkluż f’ dawn il- provi kliniċi, 466 suġġett ġew trattati b’ Xeomin u 442 suġġett ġew trattati b’ Botox.
Of the 908 participants, 239 thereof experienced adverse events (AEs).
Mid- 908 parteċipanti, 239 minnhom esperjenzaw episodji avversi (AEs).
An almost identical percentage of patients in both treatment groups reported AEs (26.6% in the Xeomin group and 26.0% in the Botox group).
Perċentwal kważi identiku ta ’ pazjenti fiż- żewġ gruppi tat- trattament irrapportaw AEs (26. 6% fil- grupp ta ’ Xeomin u 26. 0% fil- grupp Botox).
The most common AEs (i. e. with an incidence of ≥ 1%) were dysphagia, ptosis, back and skeletal pain and muscle weakness, the majority of them assessed as mild or moderate.
L- aktar AEs komuni (jiġifieri b’ inċidenza ta ’ ≥1%) kienu disfaġja, ptożi, uġigħ fid- dahar u fl- għadam u dgħjufija muskolari, il- maġġoranza tagħhom ġew ivvalutati bħala ħfief jew moderati.
The only severe case of dysphagia occurred in the Botox group.
L- uniku każ sever ta ’ disfaġja seħħ fil- grupp ta ’ Botox.
The applicant has submitted the total number of adverse events with no distinction between adverse events related or not related.
L- applikant ippreżenta n- numru totali ta ’ episodji avversi mingħajr distinzjoni bejn episodji avversi relatati u mhux relatati.
The difference of the total number of adverse events related or not related between Xeomin and Botox was not statistically significant.
Id- differenza tan- numru totali ta ’ episodji avversi relatati u mhux relatati bejn Xeomin u Botox ma kinitx statistikament sinjifikanti.
• Phase III Cervical Dystonia Study (MRZ 0013) In this trial, 65 out of 231 patients (28.1%) treated with Xeomin reported a total of 110 adverse events.
• Studju ta ’ Distonja Ċervikali ta ’ Fażi III (MRZ 0013) F’ din il- prova, 65 pazjent minn 231 (28. 1%) ittrattati b’ Xeomin irrapportaw total ta ’ 110 episodju avvers.
For Botox, 57 out of 232 patients (24.6%) reported a total of 90 adverse events.
Għal Botox, 57 pazjent minn 232 patients (24. 6%) irrapportaw total ta ’ 90 episodju avvers.
Most of the adverse events were of mild or moderate severity in both groups.
Ħafna mill- episodji avversi kienu ta ’ severità ħafifa jew moderata fiż- żewġ gruppi.
The most frequently reported adverse event was dysphagia (Xeomin 10.8%; Botox 8.2%; p=0.29).
L- aktar episodju avvers irrapportat b’ mod komuni kien disfaġja (Xeomin 10. 8%; Botox 8. 2%; p=0. 29).
One case with severe dysphagia was reported in the Botox group.
Każ wieħed b’ disfaġja severa ġie rrapportat fil- grupp ta ’ Botox.
• Phase III Blepharospasm Study In this trial, 40 out of 148 patients (27.0%) treated with Xeomin reported a total of 57 adverse events.
• Studju ta ’ Blefarospażmu ta ’ Fażi III F’ din il- prova, 40 pazjent minn 148 (27. 0%) trattati b’ Xeomin irrapportaw total ta ’ 57 episodju avvers.
For Botox, 45 out of 152 patients (29.6%) reported a total of 62 adverse events.
Għal Botox, 45 pazjent minn 152 (29. 6%) irrapportaw total ta ’ 62 episodju avvers.
All adverse events were of mild or moderate severity except one case of treatment-related ptosis in the Xeomin and one case of unrelated myocardial infarction in the Botox group.
10 Xeomin u każ wieħed ta ’ infart mijokardijaku mhux relatat fil- grupp ta ’ Botox.
The most frequently reported adverse event was ptosis (Xeomin 6.1%; Botox 4.6%).
L- aktar episodju avvers irrapportat b’ mod frekwenti kien ptożi (Xeomin 6. 1%; Botox 4. 6%).
9 However, in clinical trials the related adverse events were numerically more frequent in the Xeomin group compared to the Botox group.
Madankollu, fi provi kliniċi, l- episodji avversi relatati kienu numerikament aktar frekwenti fil- grupp ta ’ Xeomin meta mqabbla mal- grupp ta ’ Botox.
Phase III study in
XEOMIN (n=231)
Phase III study in
BOTOX (n=232)
cervical dystonia (MRZ 60201-0013)
XEOMIN (n=148)
blepharospasm, (MRZ 60201-0003)
BOTOX (n=155)
Patients with related adverse
b’ effetti
effects 95% CI of differences between related adverse effect
relatati 95% CI ta ’ differenzi bejn proporzjonijiet ta ’ effett
(16.5%)
(16. 5%)
proportions (Xeomin versus Botox)
avvers relatat (Xeomin vs Botox)
Thus, related adverse effects occurred more frequently in the Xeomin group compared to Botox.
Għalhekk, effetti avversi relatati seħħew b’ mod aktar frekwenti fil- grupp ta ’ Xeomin meta mqabbla ma ’ Botox.
The rate of serious adverse events (SAEs) in all studies was 2.1% with Xeomin and 2.7% with Botox.
Ir- rata ta ’ episodji avversi serji (SAEs) fl- istudji kollha kienet ta ’ 2. 1% b’ Xeomin u 2. 7% b’ Botox.
All of the SAEs were assessed as unrelated to treatment.
L - SAEs kollha ġew ivvalutati bħala mhux relatati mat- trattament.
One death (colon carcinoma), assessed as unrelated to study treatment (Botox), was reported during the Phase II cervical dystonia study.
Mewta waħda (karċinoma tal- kolon), ivvalutata bħala mhux relatata mat- trattament użat fl- istudju (Botox), ġiet irrapportata matul l- istudju ta ’ distonja ċervikali ta ’ Fażi II.
Three patients discontinued the studies prematurely due to adverse events considered as unrelated to study drug.
Tliet pazjenti waqfu mill- istudji qabel minħabba episodji avversi meqjusin mhux relatati mal- mediċina ta ’ l- istudju.
Post-marketing experience revealed no different or new safety signals for Xeomin compared to other Botulinum toxin containing medicinal products.
L- esperjenza ta ’ wara t- tqegħid fis- suq ma tat ebda sinjal ta ’ sigurtà differenti jew ġdid għal Xeomin meta mqabbel ma ’ tossin ta ’ Botulinum ieħor li fih prodotti mediċinali.
1.3 RECOMMENDATION
1. 3 RAKKOMANDAZZJONI
The applicant has committed to perform a post-marketing study, in which immunogenicity of Xeomin is further investigated after repeated administration (up to 6 injection sessions).
L- applikant impennja ruħu li jwettaq studju ta ’ wara t- tqegħid fis- suq, li fih, l- immunoġeniċità ta ’ Xeomin hija investigata aktar fil- fond wara amministrazzjoni ripetuta (sa 6 sessjonijiet ta ’ injezzjonijiet).
The applicant is requested to submit the results of all scheduled HDA tests of the upper limb spasticity study (MRZ 0410) and the cervical dystonia study (MRZ 0408) after unblinding of the respective studies.
L- applikant huwa mitlub jippreżenta r- riżultati tat- testijiet tal- HDA skedati kollha ta ’ l- istudju ta ’ l - ispastiċità tal- parti ta ’ fuq tad- driegħ (MRZ 0410) u ta ’ l- istudju tad- distonja ċervikali (MRZ 0408) wara l- kxif ta ’ l- istudji rispettivi.
Overall, the safety data shows that the prevalence of adverse events (AEs) was nearly identical in the Xeomin and in the Botox group (26.6% vs.
B’ mod ġenerali, it- tagħrif tas- sigurtà juri li l- prevalenza ta ’ episodji avversi (AEs) kienet kważi identika fil- grupp ta ’ Xeomin u fil- grupp ta ’ Botox (26. 6% vs.
26%, respectively).
26%, rispettivament).
The most frequent at least possibly related AE was dysphagia (5.2% for Xeomin vs.
L- aktar AE frekwenti possibbilment relatat kien disfaġja (5. 2% għal Xeomin vs.