natgillin/translations-raw huggingface dataset:
Kommittén drog slutsatsen att nytta-riskförhållandet för Levothyroxine Alapis därför inte anses vara gynnsamt. 
• The Committee concluded that the risk-benefit balance of Levothyroxine Alapis is therefore not considered to be favourable.
Med anledning av att sökanden inte lämnade in svar på CHMP:s frågelista under hänskjutningen enligt artikel 29.4, utfördes bedömningen med de data som gjordes tillgängliga under det decentraliserade förfarandet och CMDh:s hänskjutningsförfarande. 
In light of the Applicant's failure to provide responses to the CHMP list of questions during the Article 29(4) referral procedure, the assessment was carried out on the data made available during the decentralised procedure and the CMDh referral procedure.
Skäl till avslag 
Grounds for refusal
Den aktiva substansen levotyroxin är en erkänd aktiv substans som beskrivs i Europeiska farmakopén. 
The active substance levothyroxine, is an established active substance described in the European Pharmacopoeia.
som inleddes av Storbritannien enligt artikel 29.4 i direktiv 2001/83/EG. 
• The Committee considered the notification of the referral triggered by the United Kingdom under Article 29(4) of l Directive 2001/83/EC.
inträffade med den högre dosen av propylenglykol, där 33 procent av spädbarnen drabbades av anfall, mot bara 14 procent av spädbarnen 
More seizures occurred with the higher dose of propylene glycol, where 33% of the infants had seizures, vs only 14% of infants who received the lower dose of propylene glycol.
till följd av droppanordningen diskuterades av CHMP: 
The possible medication errors caused by the dropper insert were discussed by the CHMP:
Levothyroxine Alapis är en oral dropplösning som innehåller levotyroxinnatrium som aktiv substans (100 μg/ml). 
Levothyroxine Alapis is an oral drop solution containing levothyroxine sodium as active substance (100 mcg/ml).
Eftersom det finns begränsad information om säkra etanolkoncentrationer i pediatriska beredningar avsedda för stadigvarande användning finns det farhågor över stadigvarande användning av Levothyroxine Alapis hos nyfödda/barn, eftersom etanol utgör ännu en attack på en hjärnutveckling som redan är nedsatt 
As there is limited information on safe ethanol concentrations in paediatric formulations intended for chronic use, there are concerns with regard to chronic use of Levothyroxine Alapis in neonates/children, as ethanol represents an additional insult to brain development that is already compromised by congenital hypothyroidism.
Medicineringsfel orsakade av administreringsenheten (droppanordning) Först föreslog sökanden två olika droppanordningar med olika droppstorlekar vilka skulle räkna upp till 40 droppar. 
Medication errors caused by the administration device (dropper insert) Initially two different dropper inserts resulting in different drop sizes that would count up to 40 drops was proposed by the Applicant.
De föreslagna patientpopulationerna är vuxna, barn över 12 år (vid behandling av diffus atoxisk struma), samt nyfödda och spädbarn (med medfödd hypotyreos). 
The proposed patient populations are: adults, children over 12 years (in the treatment of diffuse non-toxic goitre), and neonates and infants (with congenital hypothyroidism).
Till följd av bristen på robusta användartester med representativa personer ur allmänheten kan det inte med säkerhet förväntas att denna droppanordning visar 
The absence of robust user testing with representative members of the general public provides no reassurance that this dropper device will prove manageable and accurate in practice.
Levothyroxine Alapis är en lågviskös lösning som ger en hög dropphastighet. 
Levothyroxine Alapis is a solution with low viscosity, which gives a fast drop rate.
Eftersom etanol används för att göra levotyroxin lösligt, anses dess användning vara avgörande i denna beredning, baserat på levotyroxins relativt låga löslighetsgrad i etanol vid jämförelse med propylenglykol. 
As ethanol is used to solubilise levothyroxine, its use is not considered to be essential in this formulation, based on the relatively poor solubility of levothyroxine in ethanol when compared to propylene glycol.
stora antalet administrerade droppar bidrar även till risken för medicineringsfel. 
Inaccuracy due to the miscounting of the large number of drops administered also contributes to the risk of medication error.
Trots att propylenglykol har en omfattande användning som hjälpämne i orala och injicerbara läkemedel, finns det bara sparsamma litteraturuppgifter om dess säkerhet för barn vid stadigvarande administrering. 
Although propylene glycol is widely used as an excipient in oral and injectable medicines, literature data on its safety in children when administered chronically is sparse.
Kombination av etanol och propylenglykol 
Combination of ethanol and propylene glycol
Därför kan samtidig administrering av etanol och propylenglykol leda till förhöjda och potentiellt 
Therefore, co-administration of ethanol and propylene glycol can lead to raised and potentially toxic levels of the latter.
Felaktigheter till följd av felräkning 
Inaccuracies due to miscounting
De föreslagna indikationerna för Levothyroxine Alapis är för behandling av hypotyreos (medfödd eller förvärvad, däribland diffus atoxisk struma), hypotyreosformer av Hashimotos tyreoidit och sköldkörtelcarcinom. 
The proposed indications for Levothyroxine Alapis are for: the treatment of hypothyroidism (congenital or acquired, including diffuse non-toxic goiter), hypothyroidism forms of Hashimoto's thyroiditis and thyroid carcinoma.
Felaktigheter till följd av olämplig dropporientering 
Inaccuracies due to improper dropper orientation
Det noteras även att den föreslagna bipacksedeln rekommenderar att dropparna inte administreras direkt 
It is also noted that the proposed package leaflet (PL) recommends that the drops are not administered directly to the patient, but should first be delivered to a spoon.
Dessutom finns det farhågor för utsatta vuxna patienter, t.ex. de som lider av alkoholism, liksom för patienter med leverinsufficiens och epilepsi. 
In addition there are concerns in vulnerable adults such as those suffering from alcoholism, as well as in patients with hepatic impairment and epilepsy.
(1) An assessment of dose-uniformity of samples delivered from paediatric oral droppers, A.J. Nunn et al; Journal of Clinical Pharmacy and Therapeutics (2004) 29, 521-529 
Nunn et al; Journal of Clinical Pharmacy and Therapeutics (2004) 29, 521-529
Kommittén anser att droppanordningen gav upphov till en oacceptabel risk för medicineringsfel, där droppanordningens olämpliga orientering skulle leda till en felaktig och varierande droppvolym. Felaktigheter till följd av felräkningen av det 
• The Committee was of the opinion that there was an unacceptable risk of medication error due to the dropper insert, where the inappropriate orientation of the dropper insert would result in inaccurate and variable drop volume.
patienten/vårdaren försöker påverka/sakta ner dropphastigheten för att möjliggöra räkningen av ett relativt stort antal droppar. 
Deviation from a vertical position is more likely in situations where the patient / carer is attempting to manage / slow the drop rate to enable a relatively high number of drops to be counted.
stora säkerhetsproblem vid stadigvarande användning av kombinationen etanol och propylenglykol hos nyfödda/barn. 
Therefore there are major safety concerns due to the chronic use of the combination of ethanol and propylene glycol in neonates/children.
Hjälpämnena är glycerol, propylenglykol, etanol och renat vatten, vilket uppfyller kraven i respektive monografier i Europeiska farmakopén. 
The excipients are glycerol, propylene glycol, ethanol and purified water, which comply with the respective Ph.Eur monographs.
som gäller flera tablettberedningar och lösningar av levotyroxin, varför ingen hänvisning görs till en enda unik beredning. 
This is a bibliographic application that refers to literature concerning several levothyroxin tablet formulations and solutions and thus no reference is made to a single unique formulation.
Levothyroxine Alapis, som är en högkoncentrerad lösning av ett mycket potent läkemedel, är förknippat med oönskade händelser med stadigvarande överdosering - särskilt kardiovaskulära sådana. 
Levothyroxine Alapis, which is a highly concentrated solution of a highly potent medicinal product, is associated with adverse events with chronic over-dosing - particularly cardiovascular events.
genom medfödd hypotyreos. Dessutom finns det farhågor för patienter med leverinsufficiens, epilepsi och utsatta vuxna, t.ex. de som lider av alkoholism. 
In addition there are also concerns in patients with hepatic impairment, epilepsy and in vulnerable adults such as those suffering from alcoholism.
Levothyroxine Alapis, som har beretts som en högkoncentrerad lösning av en mycket potent aktiv substans, är förknippat med oönskade händelser vid stadigvarande överdosering - särskilt kardiovaskulära sådana. 
Levothyroxine Alapis, which is formulated as a highly concentrated solution of a very potent active substance, is associated with adverse events with chronic over-dosing - particularly cardiovascular.
som är förknippade med Levothyroxine Alapis och som togs upp under det decentraliserade förfarandet och CMDh:s hänskjutningsförfarande inte är tillräckligt utredda. 
Based on the above, the CHMP considers that the safety concerns relating to Levothyroxine Alapis that were raised during the decentralised procedure and the CMDh referral procedure have not been sufficiently addressed.
Sökanden föreslog då användning av - en droppanordning för doser mellan 12,5 µg och 50 µg (5 till 20 droppar) och - en 3 ml oral 
The applicant then proposed to use: - a dropper insert for doses between 12.5 µg and 50 µg (5 to 20 drops) and - a 3 mL oral syringe for doses between 50 µg and 200 µg (0.5 to 2 mL) According to the proposed Summary of Product Characteristics (SmPC), the dropper insert will be mainly used for administration to paediatric patients as well as for initial dosing of adults and children over 12 years.
som vuxna, varför de kan löpa högre risk för både akuta och kroniska alkoholrelaterade förgiftningar. 
Newborn infants, and children are not able to metabolize ethanol as efficiently as adults; as a consequence, they may be at higher risk of both acute and chronic alcohol-related toxicities.
Som tidigare nämnts metaboliseras initialt både etanol och propylenglykol av alkoholdehydrogenas. Alkoholdehydrogenas metaboliserar företrädesvis etanol 
As mentioned previously, both ethanol and propylene glycol are initially metabolised by alcohol dehydrogenase.
”Detta läkemedel innehåller < > vol% etanol (alkohol), dvs. upp till < > mg per dos, motsvarande < > ml öl, < > ml vin per dos. 
The guidance “Guideline on the excipients in the label and the package leaflet of medicinal products for human use” states that if the content of ethanol is 100 mg - 3g per dose, the following should be stated in the PL: ‘This medicinal product contains < > vol % ethanol (alcohol), i.e. up to < > mg per dose, equivalent to < > ml beer, < > ml wine per dose.
i en av studiearmarna studerades dagliga doser av propylenglykol liknande vad som kan förväntas av Levothyroxine Alapis. Två spädbarnsgrupper behandlades med två doser propylenglykol på 0,3 g/dag respektive 3 g/dag i en intravenös multivitaminlösning under 
Two groups of infants were treated with two doses of propylene glycol; 0.3 g/day and 3 g/day in an IV multivitamin solution, during two consecutive 19month periods in a retrospective design.
Sammanfattningsvis anses det, då Levothyroxine Alapis är en högkoncentrerad lösning innehållande 100 μg/ml, att droppanordningen är olämplig till följd av felaktigheter som uppstår 
In conclusion given that Levothyroxine Alapis is a highly concentrated solution containing 100 mcg/ml the dropper device is considered to be unsuitable due to inaccuracies resulting from improper dropper orientation and miscounting, especially for paediatric initial doses less than 25 mcg.
Både etanol och propylenglykol metaboliseras initialt av alkoholdehydrogenas. Alkoholdehydrogenas metaboliserar företrädesvis etanol 
Both ethanol and propylene glycol are initially metabolised by alcohol dehydrogenase.
tillgängliga informationen vara tillräcklig för att hantera säkerhetsproblemen vid stadigvarande användning av etanol och propylenglykol, särskilt i den pediatriska populationen. 
In light of the failure to provide responses to the CHMP list of questions, , the available information was not considered to be sufficient to address the safety concerns of the chronic use of ethanol and the propylene glycol, in particular in the paediatric population.
Därför kommer alla avvikelser från en vertikal orientering, såsom ett försök att få droppet att gå långsammare, att ge en felaktig droppvolym. I den publicerade litteraturen betonas potentialen för betydande variationer i både dropphastigheten och -volymen för lågviskösa lösningar 
Therefore any deviation from vertical orientation, such as an attempt to slow the drop rate will result in inaccurate drop volume.
samma metaboliska väg är kombinationen av etanol och propylenglykol problematisk. 
Since both propylene glycol and ethanol share a common metabolic pathway the combination of ethanol and propylene glycol is a concern.
Kommittén ansåg att en stadigvarande samtidig administrering av de föreslagna mängderna av hjälpämnena etanol och propylenglykol 
• The Committee was of the opinion that the chronic co-administration of the proposed quantities of the excipients ethanol and propylene glycol in children remains a safety concern.
som används i Levothyroxine Alapis är etanol, propylenglykol, glycerol och vatten, vilket uppfyller kraven i monografierna i Europeiska farmakopén. 
Safety of excipients (ethanol / propylene glycol) in paediatric population The excipients used in Levothyroxine Alapis are ethanol, propylene glycol, glycerol and water and comply with the Ph. Eur monographs.
Propylenglykol 
Propylene glycol
så är tillämpligt för Levothyroxine Alapis och associerade namn (se bilaga I). 
And therefore the CHMP recommended the refusal of the granting of the marketing authorisation for Levothyroxine Alapis and associated names (see Annex I).
Levothyroxine Alapis innehåller 200 mg/ml etanol per dos. Enligt vägledningen ”Guideline on the excipients in the label and the package leaflet of medicinal products for human use” 
Levothyroxine Alapis contains 200mg/ml of ethanol per dose.
samförstånd uppnåddes kring frågorna som gällde medicineringsfel till följd av sättet på vilket de orala dropparna administrerades och säkerheten för hjälpämnena etanol och propylenglykol 
Since no consensus could be reached on the issues relating to medication errors due to the method of administration of the oral drops and the safety of excipients ethanol and propylene glycol in the paediatric population, the CMDh referred the matter to the CHMP under Article 29(4) of Directive
innan andra alkoholer metaboliseras, inräknat propylenglykol. 
Alcohol dehydrogenase preferentially metabolises ethanol prior to metabolising other alcohols, including propylene glycol.
Националните компетентни органи, координирани от референтната държава членка, ако е приложимо, гарантират, че притежателите на разрешения за употреба (ПРУ) са изпълнили следните условия: 
The national competent authorities, coordinated by the reference Member State, if applicable, shall ensure that the following conditions are fulfilled by the marketing authorisation holders:
ПРУ трябва да разпространят пряко съобщение до медицинските специалисти (DHPC) в съответствие с договорените основни послания. 
The MAHs should circulate a DHPC in accordance with the agreed key messages.
Определя се от държавите членки, след като бъде взето решение от ЕК. 
To be determined by Member States following EC decision
0,5ml (1mg/ml) 
0.5ml (1mg/ml) 14 Vials
Наименование (свободно избрано) 
Invented name Strength
Тези констатации са проверени. 
These findings have since been verified.
Необходими са специални среда и атмосфера и инкубационният период е дълъг (7-10 дни). 
Special media and atmosphere are required and the incubation period is long (7-10 days).
Времето за анализ е намалено до часове, за разлика от почти две седмици, необходими за конвенционалното културелно изследване. 
The assay time has been reduced to hours as opposed to almost two weeks needed for the conventional culture.
tech. Off. int. Epiz. 
Rev. sci. tech. Off. int. Epiz.
Клиничните признаци варират, но загубата на мляко обикновено е значителна. 
The clinical signs vary but the milk loss is usually significant.
Настоящите технологии, като например полимеразна верижна реакция (PCR), са позволили значително по-бързо идентифициране на M.bovis. 
Current technologies such as Polymerase Chain Reaction (PCR) have enabled significantly quicker identification of M. bovis.
Често засегната е повече от една четвърт и има значителен спад в производството на мляко. 
Often more than one quarter is affected and there is a marked drop in milk production.
Подробностите за опитите за лечение са оскъдни, но като цяло той описва резултатите като неудовлетворителни. 
Details of the treatment experiments are scarce, but altogether he described the results as unrewarding.
В случай на стари продукти, при които данните са оскъдни, показанията трябва да бъдат прегледани и ревизирани, въз основа на съвременните научните знания, когато е уместно. 
In case of old products where data are sparse indications should be reviewed and revised, based on the current scientific knowledge, where appropriate.
Проследяването на липсата на ефикасност е част от системата за ветеринарна фармакологична бдителност. 
Monitoring the lack of efficacy is a part of the veterinary pharmacovigilance system.
В 29 % от композитните проби (81/280) и в 43 % от пробите от млечните четвъртини (433/1008) не е установен растеж на Mycoplasma. 
29% of the composite samples (81/280) and 43% of the quarter milk samples (433/1008) did not yield growth of Mycoplasma.
Ефективен е срещу Enterobacteriaceae. 
It is ineffective against Enterobacteriaceae.
Заразените крави могат да останат външно нормални с няколко клинични признака, дори и в тежките случаи. 
Infected cows may remain externally normal with few clinical signs, even in severe cases.
Освен това, показанието не трябва да се разрешава за подадените заявления за издаване на лиценз за употреба (вж. Приложение I). 
Furthermore, this indication should not be granted for the pending marketing authorisation applications (see Annex I).
28108 Alcobendas (Madrid) 
28108 Alcobendas (Madrid) Spain
Авторите стигат до заключението, че рискът от погрешна диагноза се повишава, ако не са изследвани множество проби от мляко. 
The authors concluded that the risk of misdiagnosis is increased if multiple milk samples are not tested.
Оттогава се е разпространил сред добитъка в целия свят и се знае, че причинява тежки икономически загуби в засегнатите стада. 
Since then it has spread to cattle worldwide and is known to cause severe economic losses in the herds affected.
Микоплазмите не растат в конвенционалната хранителна среда; това затруднява диагностиката. 
Mycoplasmas do not grow on conventional media; this hampers the diagnosis.
Заразеното мляко може да изглежда нормално, но може също така да бъде гнойно и/или да съдържа необичайни и обезцветени секрети. 
Affected milk may seem normal but it may also be purulent and/or have abnormal and discoloured secretions.
Комитетът стига до заключението, че показанията за употреба за предпочитане трябва да бъдат ограничени до тези, за които е доказана ефикасност, и общите показания, без солидна клинична база, трябва да се избягват. 
The Committee concluded that indications for use should preferably be restricted to those for which efficacy has been proven and general indications without a solid clinical basis should be avoided.
VETOQUINOL ESPECIALIDADES VETERINARIAS, S.A. A. Fuencarral Alcobendas km 15 700 Edificio Europa I Portal 3 2º5 
ESPECIALIDADES VETERINARIAS, S.A. A. Fuencarral Alcobendas km 15 700 Edificio Europa I Portal 3 2º5
Отрицателен резултат от културелно изследване след лечение преди би могъл да бъде погрешно интерпретиран като бактериологично излекуване, въпреки че понастоящем се знае, че е само характеристика на инфекцията. 
A negative cultivation result after treatment could, before, have been falsely interpreted as bacteriological cure although at present it is known merely to be a characteristic of the infection.
Патогенът е силно заразен и причинява тежки икономически загуби. 
The pathogen is highly contagious and causes severe economic losses.
Това е основен проблем за производството на мляко и хуманното отношение към животните в засегнатите стада, и причинява тежки икономически загуби. 
It is a major problem for milk production and animal welfare in the herds affected, and causes severe economic losses.
Тези ветеринарномедицински продукти също са показани за лечение на няколко заболявания, включително респираторни и стомашно-чревни инфекции, но тези показания попадат извън обхвата на процедурата по сезиране. 
These veterinary medicinal products are also indicated for the treatment of several other diseases including respiratory and gastrointestinal infections, but these indications fall outside the scope of this referral procedure.
Международно призната методология за изследване на чувствителността не е налична по времето, когато тилозин е бил разрешен за първи път за ветеринарна употреба, и липсва към днешна дата. 
Internationally agreed methodology on sensitivity testing was not available at the time when tylosin was first authorised for veterinary use and there is none to date.
Приложение I), за да се изменят кратката характеристика на продукта, етикета и листовката в съответствие с препоръчаните промени в продуктовата информация, както е посочено в Приложение III. 
(see Annex I) in order to amend the summary of product characteristics, labelling and package leaflet in line with recommended changes in the product information as set out in Annex III.
Тилозин и неговите фосфатни и тартаратни соли се използват в лекарства за ветеринарна употреба за лечение на заболявания, причинени от чувствителни организми. 
Tylosin and its phosphate and tartrate salts are used in veterinary medicines for the treatment of conditions caused by sensitive organisms.
Говеда Прасета Кучета 
Cattle Pigs Dogs
Основният патоген сред рода е Mycoplasma bovis, който е изолиран за първи път от говеда с мастит в САЩ през 1960 г. 
The major pathogen among the genera is Mycoplasma bovis that was first isolated from bovine mastitis in the USA in the 1960s.
Той съобщава за изследването на различни антимикробни средства, включително тилозин. 
He reported testing various antimicrobials, including tylosin.
Общоприето е, че всяко използване на антимикробни средства повишава риска от антимикробна резистентност и по този начин, за да се намали рискът от предаване на тази резистентност на обществото и животните всяко ненужно приложение трябва внимателно да се избягва. 
It is generally accepted that all use of antimicrobials increases the risk of antimicrobial resistance and thus to minimise the risk of transmission of those resistance to the public and animals all unnecessary use should be carefully avoided.
Списък на наименованията, фармацевтичните форми, концентрациите на ветеринарномедицинските продукти, животинските видове, начините на приложение и заявителите/притежателите на лиценз за употреба в държавите членки 
List of the names, pharmaceutical forms, strengths of the veterinary medicinal products, animal species, routes of administration and applicants/marketing authorisation holders in the Member States
Притежателят на лиценз за употреба на референтния лекарствен продукт „Tylan 200 mg/ml“, Elanco Animal Health, се съгласява с повдигнатите опасения и стига до заключението, че е налице липса на надеждни предклинични и клинични данни в подкрепа на съответното показание. 
The marketing authorisation holder for the reference medicinal product ‘Tylan 200 mg/ml', Elanco Animal Health, agreed with the concerns raised and concluded that there is a lack of reliable pre-clinical and clinical data in support of the respective indication.