natgillin/translations-raw huggingface dataset:
Two studies, one observational and one prospective, reported less convincing evidence13 where around 26% patients had satisfactory, good or excellent outcomes.
V dveh študijah, od katerih je bila ena opazovalna, druga pa prospektivna, so zbrali manj prepričljive dokaze13, saj so zadovoljive, dobre ali odlične rezultate zabeležili pri približno 26 % bolnikov.
The indication should be restricted to patients with functional disability in whom other treatments have failed.
Indikacijo je treba omejiti na bolnike s funkcionalno nezmožnostjo, pri katerih druga zdravljenja niso bila učinkovita.
However, cases have also been reported with treatment duration up to six months, so occurrence of fibrosis with short-term treatment cannot be excluded.
Vendar pa so o primerih poročali tudi pri zdravljenju, ki je trajalo do šest mesecev, tako da pojava fibroze med kratkotrajnim zdravljenjem ni mogoče izključiti.
Regarding the risk of retroperitoneal fibrosis, there is evidence of increased risk in patients treated with methysergide (200 versus 1.3 per 100 000 patients)23,24.
Kar zadeva tveganje za retroperitonealno fibrozo, obstajajo dokazi o povečanem tveganju pri bolnikih, zdravljenih z metizergidom (200 v primerjavi z 1,3 na 100 000 bolnikov)23,24.
In addition, further trials comparing methysergide with placebo or comparators were also presented, some of which also showed efficacy of methysergide compared to placebo in this indication5,6,7.
Poleg tega so bila predložena tudi dodatna preskušanja, v katerih so metizergid primerjali s placebom ali primerjalnimi zdravili, in nekatera od teh prav tako kažejo na učinkovitost metizergida v primerjavi s placebom pri tej indikaciji5,6,7.
Methysergide is an ergot alkaloid, first described in clinical practice in 1959.
Metizergid je ergot alkaloid, ki so ga v klinični praksi prvič opisali leta 1959.
Serious intolerance or contra-indication to a first line drug is regarded as treatment failure.
Resna intoleranca in kontraindikacija za zdravilo prve izbire se štejeta za neuspešno zdravljenje.
Methysergide is to be used only following unsuccessful treatment with other standard classes of drugs after sufficient treatment duration (at least 4 months) at the maximal tolerated dose.
Metizergid se lahko uporablja samo po neuspešnem zdravljenju z drugimi standardnimi vrstami zdravil, ki je potekalo dovolj časa (najmanj 4 mesece) pri največjem tolerančnem odmerku.
In addition, development of fibrosis appears to be correlated to treatment duration, as most patients developed fibrotic events after long-term therapy (at least one year).
Poleg tega se zdi, da je razvoj fibroze povezan s trajanjem zdravljenja, saj so se pri večini bolnikov fibrozni dogodki pojavili po dolgotrajnem zdravljenju (po najmanj enem letu).
The incidence rates of valvular and pulmonary fibrosis in patients treated with methysergide was shown to be similar to those of the general population19,20,21,22.
Incidenca valvularne in pljučne fibroze pri bolnikih, zdravljenih z metizergidom, je bila podobna incidenci pri splošni populaciji19,20,21,22.
In this respect, the CHMP took note of the fact that one of the marketing authorisation holders of the products for which this indication is approved informed the CHMP of their intention to voluntarily withdraw the indication “diarrhoea caused by carcinoid syndrome”.
Ob tem je odbor CHMP upošteval dejstvo, da je eden od imetnikov dovoljenja za promet z zdravili, za katera je odobrena ta indikacija, obvestil odbor, da namerava prostovoljno umakniti indikacijo „driska, ki jo povzroča karcinoidni sindrom“.
In order to evaluate the safety of methysergide, the CHMP considered data from literature and safety database including spontaneous and literature reports.
Da bi ocenil varnost metizergida, je odbor CHMP proučil podatke iz literature in zbirke podatkov o varnosti, vključno s spontanimi poročili in poročili iz literature.
This is subject to the agreed warnings, other changes to the product information and additional risk minimisation measures.
Vse to velja pod pogojem, da se upoštevajo dogovorjena opozorila, druge spremembe informacij o zdravilu in dodatni ukrepi za zmanjšanje tveganja.
• The CHMP considered the procedure under Article 31 of Directive 2001/83/EC for methysergide containing medicinal products.
• odbor CHMP je obravnaval napotitev v skladu s členom 31 Direktive 2001/83/ES za zdravila, ki vsebujejo metizergid;
Therefore, the potential causal association between fibrotic reactions and methysergide cannot be excluded.
Morebitne vzročne povezave med fibroznimi reakcijami in metizergidom zato ni mogoče izključiti.
− Is not favourable for the treatment of diarrhoea caused by carcinoid disease.
− ni ugodno za zdravljenje driske, ki jo povzroča karcinoidna bolezen.
Since fibrotic reactions are believed to be associated with persistent agonist activation of the 5-HT2B receptor, long-term treatment with methysergide will expose patients to the potential for tissue fibrosis mediated by its principal active metabolite, methylergometrine.
Ker so fibrozne reakcije domnevno povezane z nenehno aktivacijo receptorja 5-HT2B z agonisti, bodo bolniki med dolgotrajnim zdravljenjem z metizergidom izpostavljeni tveganju za fibrozo tkiva, ki jo povzroča njegov glavni aktivni presnovek, metilergometrin.
Based on this, France considered that the benefit risk balance of methysergide containing products should be reviewed and triggered a referral under Article 31 of Directive 2001/83/EC.
Francija je zato menila, da je treba ponovno pregledati razmerje med tveganji in koristmi zdravil, ki vsebujejo metizergid, in sprožila napotitveni postopek v skladu s členom 31 Direktive 2001/83/ES.
with caution as methods of detection of fibrosis used in these studies are not sensitive enough, in particular for valvular fibrosis.
metode za odkrivanje fibroze, ki so jih uporabili v teh študijah, niso bile dovolj občutljive, še zlasti ne za odkrivanje valvularne fibroze.
These included restricted duration of treatment, optimal dose of treatment, specialist supervision and information for prescribing physicians and patients' organisation.
Ti ukrepi vključujejo omejitev trajanja zdravljenja, optimalen odmerek zdravila, nadzor specialista in informacije za zdravnike, ki predpisujejo zdravilo, ter organizacije za bolnike.
Methysergide binds with varying affinities to a range of serotonergic receptors (5-HT receptors).
Metizergid se z različno afiniteto veže na več vrst serotoninergičnih receptorjev (receptorji 5-HT).
Warnings on the risk of fibrosis should be included in the product information, alongside measures to monitor patients for development of fibrosis, and these should also be communicated to prescribers and patients using educational material.
V informacije o zdravilu je treba vključiti opozorila o tveganju za fibrozo, skupaj z ukrepi za spremljanje bolnikov glede razvoja fibroze, in o vsem tem obvestiti zdravnike in bolnike z razdelitvijo izobraževalnega gradiva.
Taking into account the number of fibrosis cases reported and the probable under reporting, the risk of fibrotic reactions associated with methysergide cannot be excluded.
Ob upoštevanju števila primerov fibroze, o katerih so poročali, in verjetnega pomanjkljivega poročanja, tveganja za fibrozne reakcije, povezane z metizergidom, ni mogoče izključiti.
The CHMP acknowledged the advice of the Scientific Advisory Group (SAG) which was convened in September 2013 during which the experts discussed, based on their clinical experience, whether it is possible to define a population for which there is a therapeutic need for oral methysergide-containing products when standard treatment for these indications have been ineffective.
Odbor CHMP je upošteval nasvet znanstveno svetovalne skupine, ki se je septembra 2013 sestala na seji, med katero so strokovnjaki na podlagi svojih kliničnih izkušenj razpravljali o tem, ali je mogoče opredeliti populacijo, pri kateri obstaja terapevtska potreba po peroralnih zdravilih, ki vsebujejo metizergid, kadar standardno zdravljenje za te indikacije ni učinkovito.
However, in view of the demonstrated risk of fibrosis, adequate risk minimisation measures should be put in place.
Vendar pa je treba zaradi dokazanega tveganja za fibrozo sprejeti ustrezne ukrepe za zmanjšanje tveganja.
Methysergide is currently indicated in the prophylaxis of migraine headache, cluster headache and also in the treatment of diarrhoea caused by carcinoid disease (specific wording of the indication may vary from product to product).
Metizergid je trenutno indiciran za preprečevanje migrenskega glavobola in glavobola v rafalih ter tudi za zdravljenje driske, ki jo povzroča karcinoidna bolezen (točno besedilo indikacije se lahko med posameznimi zdravili razlikuje).
Patients should have failed at least 2 classes of drugs before starting methysergide.
Bolniki morajo prestati neuspešno zdravljenje z vsaj 2 vrstama zdravil, preden se uvede metizergid.
The CHMP also noted that methysergide is included in the latest recommendations of migraine preventive treatments of the European Federation of Neurological Societies (EFNS; 2009)9 as drug of third choice for migraine prophylaxis for short-term use only, and in the latest French recommendations of 2013 as Grade B or C (probably effective) for migraine prophylaxis10.
Odbor CHMP je upošteval tudi, da je metizergid vključen v najnovejša priporočila v zvezi s preventivnim zdravljenjem migrene Evropske zveze nevroloških združenj (EFNS, 2009)9 kot zdravilo tretje izbire za preprečevanje migrene, ki se lahko uporablja samo kratek čas, in v najnovejša francoska priporočila iz leta 2013 kot zdravilo za preprečevanje migrene razreda B ali C (verjetno, da je učinkovito)10.
The CHMP further noted that methysergide is included as second choice treatment in the latest recommendations of cluster headache preventive treatments of the EFNS (2006)15 and is also included in the list of preventive therapies for cluster headache in recently published guidelines16,17,18.
Prav tako je odbor upošteval, da je metizergid kot zdravljenje druge izbire vključen v najnovejša priporočila v zvezi s preventivnim zdravljenjem glavobola v rafalih zveze EFNS (2006)15 ter tudi na seznam zdravil za preventivno zdravljenje glavobola v rafalih v nedavno objavljenih smernicah16,17,18.
• The Committee reviewed all available data on the efficacy and safety of methysergide containing medicinal products, in particular with regard to the risk of fibrotic reactions.
• odbor je pregledal vse razpoložljive podatke o učinkovitosti in varnosti zdravil, ki vsebujejo metizergid, zlasti podatke v zvezi s tveganjem za fibrozne reakcije;
Therefore, in accordance with Article 116 of Directive 2001/83/EC, the CHMP recommends the variation to the terms of the marketing authorisation for methysergide containing medicinal products referred to in Annex I.
Posledično je odbor CHMP v skladu s členom 116 Direktive 2001/83/ES priporočil spremembo pogojev dovoljenj za promet z zdravili, ki vsebujejo metizergid in so navedena v Prilogi I.
For the indication “prophylaxis of migraine”, data were submitted from randomised, double-blind, placebo-controlled studies1,2,3,4.
Za indikacijo „preprečevanje migrene“ so bili predloženi podatki iz randomiziranih dvojno slepih študij, kontroliranih s placebom1,2,3,4.
The CHMP noted that the mechanistic basis for the fibrosis appears to be well-founded, and fits with the known association between methysergide use and fibrosis, which has been reported with respect of valvular heart disease since the mid-1960s.
Odbor CHMP je upošteval, da je osnovni mehanizem za fibrozo dobro utemeljen in se ujema z znano povezavo med uporabo metizergida in fibrozo, o kateri so poročali v povezavi z boleznijo srčne zaklopke od sredine 60. let prejšnjega stoletja.
Regarding the indication “treatment of diarrhoea caused by carcinoid disease”, the CHMP concluded that the benefit-risk balance is negative as there is a clearly demonstrated risk of fibrosis but no evidence of benefit.
V zvezi z indikacijo „zdravljenje driske, ki jo povzroča karcinoidna bolezen,“ je odbor CHMP zaključil, da je razmerje med tveganji in koristmi negativno, saj obstajajo nedvoumni dokazi o tveganju za fibrozo, dokazov o koristih pa ni.
Annex II Scientific conclusions and grounds for the variation of the marketing authorisations
Znanstveni zaključki in podlaga za spremembo dovoljenj za promet z zdravili
In 2011, a French national pharmacovigilance review reported serious cases of valvulopathy, pulmonary, pleural and retroperitoneal fibrosis associated with methysergide containing medicinal products.
Nacionalni farmakovigilančni pregled, opravljen leta 2011 v Franciji, je razkril resne primere valvulopatije ter pljučne, plevralne in retroperitonealne fibroze, povezane z uporabo zdravil, ki vsebujejo metizergid.
Methysergide is not effective for treating a migraine attack that is already present.
Metizergid ni učinkovit pri zdravljenju migrenskega napada, ki se je že pojavil.
The SAG also considered that patients should be monitored at baseline and every six months while on treatment (heart ultrasound, abdominal magnetic resonance imaging (MRI), pulmonary function tests) in order to be able to identify all fibrosis before severe and potentially irreversible reactions have occurred.
Znanstveno svetovalna skupina je menila tudi, da je treba bolnike pregledati ob začetku zdravljenja in nato še vsakih šest mesecev zdravljenja (ultrazvok srca, magnetno resonančno slikanje (MRS) trebuha, preiskave delovanja pljuč), da se odkrijejo vsi primeri fibroze, preden se pojavijo hude in možne ireverzibilne reakcije.
The CHMP noted that fibrosis can be a life-threatening event and that some of the retroperitoneal fibrotic reactions reported are very severe (ureter fibrosis, bilateral uretic stenting, bilateral nephrostomy etc.).
Odbor CHMP je upošteval, da je fibroza lahko smrtno nevaren dogodek in da so nekatere retroperitonealne fibrozne reakcije, o katerih poročajo, zelo hude (uretrna fibroza, vstavitev uretrnega stenta na obeh straneh, bilateralna nefrostomija itd.).
The minimal duration of treatment before concluding failure is 2 months.
Preden se zaključi, da je zdravljenje neuspešno, mora trajati najmanj 2 meseca.
The CHMP further took note of third party interventions received from patients and healthcare professionals during the assessment, highlighting the importance of maintaining availability of this product to a population that, albeit small, has few or no therapeutic alternatives for a debilitating condition.
Odbor CHMP je upošteval tudi pripombe tretjih oseb, tj. bolnikov in zdravstvenih delavcev, ki jih je prejel med postopkom ocenjevanja in ki so poudarili, da je pomembno zagotoviti, da bo to zdravilo še naprej na voljo populaciji, ki je sicer majhna, vendar ima malo drugih terapevtskih možnosti za izčrpavajočo bolezen ali pa sploh nobene.
• Therefore the CHMP was of the opinion that the benefit-risk balance of methysergide containing products:
• posledično je odbor CHMP menil, da razmerje med tveganji in koristmi zdravil, ki vsebujejo metizergid:
The results of these studies are suggestive of the efficacy of methysergide compared to placebo in the prophylaxis of migraine.
Rezultati teh študij kažejo na učinkovitost metizergida v primerjavi s placebom pri preprečevanju migrene.
The CHMP also recommended that methysergide treatment should be initiated and supervised by specialised physicians with experience in the treatment of migraine and cluster headache.
Odbor CHMP je priporočil tudi, da naj zdravljenje z metizergidom uvedejo in nadzorujejo zdravniki specialisti, ki imajo izkušnje z zdravljenjem migrene in glavobola v rafalih.
The CHMP has considered the totality of the available data on the safety and efficacy of methysergide.
Odbor CHMP je proučil vse razpoložljive podatke o varnosti in učinkovitosti metizergida.
No data was submitted in support of efficacy of methysergide in the “treatment of diarrhoea caused by carcinoid disease”, and it is therefore considered that efficacy in this indication has not been demonstrated.
V podporo učinkovitosti metizergida pri indikaciji „zdravljenje driske, ki jo povzroča karcinoidna bolezen,“ niso bili predloženi nobeni podatki, zato se šteje, da učinkovitost pri tej indikaciji ni bila dokazana.
In addition, risk minimisation measures can be put in place to minimise the risk of fibrosis.
Poleg tega se lahko sprejmejo ukrepi za zmanjšanje tveganja za fibrozo;
In particular, it binds to and is an antagonist of the 5HT2B receptor.
Še zlasti se veže na receptor 5-HT2B in je tudi njegov antagonist.
Considering the overall data available, the CHMP is of the opinion that there is some evidence of clinically significant efficacy of methysergide in the prophylactic treatment of severe and debilitating migraine.
Ob upoštevanju vseh razpoložljivih podatkov je odbor CHMP menil, da obstaja nekaj dokazov o klinično pomembni učinkovitosti metizergida pri profilaktičnem zdravljenju hude in izčrpavajoče migrene.
The real incidence rate might be under-estimated and the risk of fibrosis is probably higher.
Mogoče je, da je bila incidenca v resnici višja, tako da je tveganje za fibrozo verjetno večje.
In addition, the CHMP noted that methysergide is recommended by experts as a rescue treatment, reserved for patients in whom other treatments have failed.
Poleg tega je odbor CHMP upošteval, da strokovnjaki metizergid priporočajo za reševalno zdravljenje, ki se uporablja pri bolnikih, pri katerih druga zdravila niso bila učinkovita.
Having considered the overall data provided by the MAH in writing, the CHMP concluded that the benefit-risk balance of methysergide is favourable in:
Potem ko je proučil vse podatke, ki jih je v pisni obliki predložil imetnik dovoljenja za promet z zdravilom, je odbor CHMP zaključil, da je razmerje med tveganji in koristmi metizergida ugodno pri indikacijah:
• The Committee noted that there is no evidence of efficacy of methysergide in the treatment of diarrhoea caused by carcinoid disease, and therefore the potential benefit for patients in this indication is outweighed by the identified risk.
• odbor je upošteval, da ni dokazov o učinkovitosti metizergida pri zdravljenju driske, ki jo povzroča karcinoidna bolezen, zaradi česar je ugotovljeno tveganje večje od možne koristi za bolnike pri tej indikaciji;
Overall, the CHMP considered that methysergide seems to benefit a small patient population of migraine and cluster headache patients.
Na splošno je odbor CHMP menil, da je metizergid koristen za majhno populacijo bolnikov z migreno in glavobolom v rafalih.
Based on the clinical experience of headache experts, the SAG considered that there is a small proportion of the populations suffering from migraine and from cluster headache that seems to benefit from treatment with methysergide, when previous treatments have failed.
Na podlagi kliničnih izkušenj strokovnjakov za glavobole je znanstveno svetovalna skupina presodila, da obstaja majhen delež bolnikov, ki trpijo za migreno in glavobolom v rafalih, ki ima koristi od zdravljenja z metizergidom, potem ko predhodna zdravljenja niso bila uspešna.
The CHMP considered the view of the SAG which recommended some measures to be taken in order to minimise the risk of fibrotic reactions when prescribing methysergide.
Odbor CHMP je proučil mnenje znanstveno svetovalne skupine, ki je priporočila sprejetje nekaterih ukrepov za zmanjšanje tveganja za fibrozne reakcije, kadar se bolniku predpiše metizergid.
In a more recent review14, methysergide and verapamil were cited as the most useful treatments of the episodic form of cluster headache.
V enem od novejših pregledov14 so metizergid in verapamil navedli kot najučinkovitejši zdravili za epizodni glavobol v rafalih.
The CHMP noted that the clinical trial evidence for the efficacy of methysergide as a prophylactic treatment for cluster headache is less robust compared to the evidence for migraine prophylaxis and that the majority of studies have a number of limitations.
Odbor CHMP je upošteval, da dokazi o učinkovitosti metizergida pri profilaktičnem zdravljenju glavobola v rafalih, ki so jih pridobili v kliničnih preskušanjih, niso tako zanesljivi kot dokazi, povezani s preprečevanjem migrene, in da je večina študij imela številne pomanjkljivosti.
• The Committee considered that there is some evidence for clinically significant efficacy of methysergide in the prophylactic treatment of severe, debilitating migraine and cluster headache for which therapeutic alternatives are limited.
• odbor je menil, da obstaja nekaj dokazov o klinično pomembni učinkovitosti metizergida pri profilaktičnem zdravljenju hude izčrpavajoče migrene in glavobola v rafalih, za zdravljenje katerih obstaja malo drugih možnosti.
• the prophylactic treatment of severe intractable migraine (with or without aura) with functional disability in adults.
• profilaktično zdravljenje hude trdovratne migrene (z avro ali brez nje) s funkcionalno nezmožnostjo pri odraslih.
− Is favourable for the prophylactic treatment of severe intractable migraine (with or without aura) with functional disability in adults.
− je ugodno za profilaktično zdravljenje hude trdovratne migrene (z avro ali brez nje) s funkcionalno nezmožnostjo pri odraslih.
− Is favourable for the prophylactic treatment of episodic and chronic cluster headache in adults.
− je ugodno za profilaktično zdravljenje epizodnega in kroničnega glavobola v rafalih pri odraslih.
With regard to the indication “cluster headache”, the applicant referred to a review11 which suggested the prophylactic efficacy of methysergide, particularly for the episodic form of cluster headache and to a study12 where 69% of cluster headache patients reported to have good to excellent results.
Pri indikaciji „glavobol v rafalih“ se je predlagatelj skliceval na pregled11, ki je pokazal, da je metizergid učinkovit pri preprečevanju glavobola v rafalih, še zlasti epizodnega, in na študijo12, v kateri so pri
• The Committee considered that a causal association between methysergide and fibrotic reactions is likely based on available data (mainly relating to retroperitoneal fibrosis).
• odbor je menil, da razpoložljivi podatki (ki se v glavnem nanašajo na retroperitonealno fibrozo) kažejo, da verjetno obstaja vzročna povezava med metizergidom in fibroznimi reakcijami.
Grounds for variation to the terms of the marketing authorisations Whereas
Podlaga za spremembo pogojev dovoljenj za promet z zdravilom
• the prophylactic treatment of episodic and chronic cluster headache in adults.
• profilaktično zdravljenje epizodnega in kroničnega glavobola v rafalih pri odraslih.
There are a number of pharmacological pathways by which methysergide may be effective in preventing migraine, for instance some data support the role of antagonism of the 5-HT2B receptor in the prophylaxis of migraine.
Nekateri podatki na primer kažejo, da ima pri preprečevanju migrene vlogo antagonistično delovanje na receptor 5-HT2B.
23 Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fibrotic disorders associated with methysergide therapy for headache.
Respir Crit Care Med 2006;174(7):810-6. 23 Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fibrotic disorders associated with methysergide therapy for headache.
24 van Bommel EFH, Jansen I, Hendriksz TR, Aarnoudse ALHJ.
N Engl J Med 1966;274(7):359-68. 24 van Bommel EFH, Jansen I, Hendriksz TR, Aarnoudse ALHJ.
10 Lanteri-Minet M et al. Prise en charge diagnostique et thérapeutique de la migraine chez l'adulte et chez l'enfant.
2009 Sep;16(9):968-81. 10 Lanteri-Minet M et al. Prise en charge diagnostique et thérapeutique de la migraine chez l'adulte et chez l'enfant.
This should be taken into consideration.
To je treba upoštevati.
Date of first authorisation: 16 August 2016.
Datum prve odobritve: 16. avgust 2016
An updated RMP should be submitted: ● At the request of the European Medicines Agency;
Posodobljen RMP je treba predložiti: ● na zahtevo Evropske agencije za zdravila;
In this short period, a risk to the suckling child cannot be excluded.
V tem kratkem obdobju tveganja za dojenega otroka ni možno izključiti.
% reduction
% zmanjšanja
*** Patients weighing more than 188 kg were not studied.
*** Bolnikov, ki tehtajo več kot 188 kg, niso preučili.