qanastek/EMEA-V3 huggingface dataset:
Hence, the CHMP recommended that CIMZIA be refused marketing authorisation.
Għaldaqstant, is - CHMP irrakkomanda li CIMZIA ma jingħatax l- awtorizzazzjoni għat- tqegħid fis- suq.
The company informed the CHMP that there are no consequences for patients currently included in clinical trials or compassionate use programmes with CIMZIA.
X’ inhuma l- konsegwenzi tar- rifjut għal dawk il- pazjenti li jkunu qegħdin jagħmlu provi kliniċi jew programmi ta ’ użu b’ kumpassjoni bl- użu ta ’ CIMZIA Il- kumpanija għarrfet lis- CHMP li ma kienx hemm konsegwenzi għall- pazjenti li jkunu għaddejjin minn provi kliniċi jew programmi ta ’ użu b’ kumpassjoni b’ CIMZIA.
If you are in a clinical trial or compassionate use programme and need more information about your treatment, contact the doctor who is giving it to you.
Jekk inti qed tieħu sehem fi studju kliniku jew fi programm ta 'użu b’ kumpassjoni u trid iżjed tagħrif dwar it- trattament tiegħek, ikkuntattja lit- tabib li jkun qed jagħtik dan it- trattament.
Page 2/ 2
Paġna 2/ 2
EUROPEAN PUBLIC ASSESSMENT REPORT (EPAR) CIRCADIN EPAR summary for the public
RAPPORT TA ’ VALUTAZZJONI PUBBLIKA EWROPEA (EPAR)
It explains how the Committee for Medicinal products for Human Use (CHMP) assessed the studies performed, to reach their recommendations on how to use the medicine.
Huwa jispjega kif il- Kumitat għal Prodotti Mediċinali għall- Użu mill- Bniedem (CHMP) ivvaluta l- istudji mwettqin, biex jissodisfa ir- rakkomandazzjonijiet tagħhom dwar kif tintuża l- mediċina.
If you need more information about your medical condition or your treatment, read the Package Leaflet (also part of the EPAR) or contact your doctor or pharmacist.
Jekk teħtieġ iktar tagħrif dwar il- kundizzjoni medika jew it- trattament tiegħek, aqra l- Fuljett ta 'Tagħrif (li hu wkoll parti mill- EPAR) jew kellem lit- tabib jew spiżjar tiegħek.
What is Circadin?
X' inhu Circadin?
Circadin is a medicine containing the active substance melatonin.
Circadin hu mediċina li fiha s- sustanza attiva melatonin.
It is available as white prolonged- release tablets (2 mg).
Hija disponibbli bħala pilloli bojod li jerħu l - mediċina bil- mod (2 mg).
Prolonged-release means that melatonin is released slowly from the tablet over a few hours.
Li jerħu l- mediċina bil- mod ifisser li melatonin jintreħa bil- mod mill- pillola fuq perjodu ta 'ftit sigħat.
What is Circadin used for?
Għal x' hiex jintuża Circadin?
Circadin is used on its own for the short-term treatment of primary insomnia (poor quality of sleep) in patients aged 55 years or over. ‘ Primary ’ means that the insomnia does not have any identified cause, including other medical, mental or environmental causes.
'Primarja' tfisser li ma tkunx ġiet identifikata kawża medika, mentali jew ambjentali, għan- nuqqas ta ’ rqad.
How is Circadin used?
Kif jintuża Circadin?
The recommended dose of Circadin is one tablet a day, taken 1 to 2 hours before bedtime and after food.
Id- doża rakkomandata ta 'Circadin hi ta' pillola waħda kuljum, meħuda bejn siegħa u sagħtejn qabel l - irqad jew wara l- ikel.
This dose should be continued for three weeks.
Id- doża għandha titkompla għal tliet ġimgħat.
Circadin is not recommended for use in patients who have problems with their liver, and it should be used with caution in patients who have problems with their kidneys.
Circadin mhux rakkomandat għall- użu minn pazjenti li jkollhom problemi bil- fwied, u għandu jintuża b' kawtela f' pazjenti li jkollhom problemi fil- kliewi.
How does Circadin work?
Kif jaħdem Circadin?
The active substance in Circadin, melatonin, is a naturally occurring hormone, which is normally produced by a gland in the brain called the pineal gland.
Is- sustanza attiva f' Circadin, melatonin, hu ormon naturali, li normalment jiġi prodott minn glandola fil- moħħ magħrufa bħala l- pineal gland.
Melatonin is involved in co-ordinating the body’ s sleep cycle by acting on cells in specific areas of the brain.
Melatonin għandu x' jaqsam mal- ko- ordinazzjoni taċ- ċiklu ta 'l- irqad tal- ġisem billi jaġixxi fuq ċelloli f' partijiet speċifiċi tal- moħħ.
Its levels in the blood normally increase after the onset of darkness and peak in the middle of the night to promote sleep.
Il- livelli fid- demm normalment jiżdiedu wara li jidlam u jilħqu l- ogħla livelli fl- eqqel tal- lejl biex jippromwovu l- irqad.
Older people may produce less melatonin, leading to the development of insomnia.
L- anzjani ġieli jipproduċu inqas melatonin, u dan iwassal għall- insomnja.
By replacing the hormone, Circadin increases blood levels of melatonin, helping them to sleep.
Bis- sostituzzjoni ta 'l- ormon, Circadin iżid il- livelli ta' melatonin fid- demm, u dan jgħinhom jorqdu.
Circadin tablets release melatonin slowly over a few hours, to mimic the natural production of melatonin in the body.
Il- pilloli ta 'Circadin jerħu melatonin bil- mod fuq perjodu ta' ftit sigħat, b' mod li jimita l- produzzjoni naturali tal- melatonin fil- ġisem.
How has Circadin been studied?
Kif ġie studjat Circadin?
The effects of Circadin were first tested in experimental models before being studied in humans.
L- effetti ta 'Circadin għall- ewwel ġew ittestjati f' mudelli esperimentali qabel ma' ġew studjati fil - bnedmin.
The company also presented data from the scientific literature.
Il- kumpanija ppreżentat ukoll dejta mil- letteratura xjentifika.
The effects of Circadin have also been studied in three main studies involving a total of 681 patients aged over 55 years with primary insomnia.
L- effetti ta 'Circadin ġew studjati wkoll fi tliet studji ewlenin li fihom ħadu sehem total ta' 681 pazjent ta 'iktar minn 55 sena b' insomnja primarja.
The studies compared the effects of Circadin with those of placebo (a dummy treatment).
L- istudji qabblu l- effetti ta 'Circadin ma' dawk ta 'plaċebo (trattament finta).
7 Westferry Circus, Canary Wharf, London E14 4HB, UK Tel.
Il- mezz ewlieni ta 'l- effettività kien il- proporzjon ta' pazjenti li rrappurtaw titjib sinjifikanti fil- kwalità ta 'l- irqad u l- abilità li jirritornaw għall- funzjoni normali l- għada, wara tliet 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel.
(44-20) 74 18 84 00 Fax (44-20) 74 18 84 16 E-mail: mail@emea. europa. eu http: / /www. emea. europa. eu ©EMEA 2007 Reproduction and/ or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged What benefit has Circadin shown during the studies?
Il- pazjenti ivvalutaw is- severità tas- sintomi tagħhom bl- użu ta 'kwestjonarju standard.
Circadin was more effective than placebo at improving quality of sleep and the patients ’ ability to function normally on the following day.
Circadin kien iktar effettiv mill- plaċebo fit- titjib fil- kwalità ta 'l- irqad u l- ħila tal- pazjent li jiffunzjona b' mod normali.
When the results of all three studies were looked at together, 86 (32.4%) of the 265 patients taking Circadin reported a significant improvement in symptoms, compared with 51 (18.7%) of the 272 taking placebo.
Meta ngħatat ħarsa lejn ir- riżultati ta 'dawn it- tliet studji flimkien, 86 (32. 4%) tal- 265 pazjent li kienu qed jieħdu Circadin irrappurtaw titjib sinjifikanti fis- sintomi, meta mqabbla ma' 51 (18. 7%) minn 272 li kienu qed jieħdu l- plaċebo.
What is the risk associated with Circadin?
X' riskji huma assoċjati ma 'Circadin?
Side effects are uncommon in patients treated with Circadin, but the most common side effects (seen in between 1 and 10 patients in 1,000) are irritability, nervousness, restlessness, insomnia, abnormal dreams, migraine, psychomotor hyperactivity (restlessness with increased activity), dizziness, somnolence (drowsiness), abdominal (tummy) pain, constipation, dry mouth, hyperbilirubinaemia (raised blood levels of bilirubin, a breakdown product of red blood cells, which can cause yellowing of the skin and eyes), hyperhidrosis (excessive sweating), asthenia (weakness) and increased weight.
L- effetti sekondarji m' humiex komuni f' pazjenti ttrattati b' Circadin, iżda l- iktar effetti sekondarji komuni (li dehru f' bejn wieħed u 10 pazjenti minn kull 1, 000) huma l- irritabilità, n- nervi, l- insomnja, l- ħolm anormali, l- migranji, l- attività psikomotriċi żejda (żieda fl- attivita fiżika) sturdament, somnolenza, uġigħ ta 'żaqq, konstipazzjoni, inxif fil- ħalq, livelli għolja ta' bilirubin fid- demm (li jista 'jwassal għal suffejra fil- ġilda u fl- għajnejn), ħruġ eċċessiv ta' għaraq, astenja (dgħufija) u żieda fil- piż.
For the full list of all side effects reported with Circadin, see the Package Leaflet.
Għal- lista sħiħa ta 'effetti sekondarji rrappurtati ma' Circadin, ara l- Fuljett ta 'Tagħrif.
Circadin can cause drowsiness, so it should be used with caution in people in whom this could pose a risk to safety, including those who need to drive or use machines.
Circadin jista 'jwassal għal sturdament, u allura għandu jittieħed b' kawtela minn persuni li għalihom dan jista' jkun ta 'riskju għas- sigurtà, inkluż dawk li jkollhom bżonn isuqu jew jużaw magni.
Patients should avoid alcohol before, during and after taking Circadin.
Il - pazjenti għandhom jevitaw l- alkoħol qabel, waqt u wara li jieħdu Circadin.
Circadin should not be used in people who may be hypersensitive (allergic) to melatonin or any of the other ingredients.
Circadin m' għandux jintuża minn persuni li jkunu allerġiċi għal melatonin jew għal xi sustanza oħra tiegħu.
Why has Circadin been approved?
Għaliex ġie approvat Circadin?
The Committee for Medicinal Products for Human Use (CHMP) decided that, although Circadin has been shown to have a small effect size in a relatively small fraction of patients, its benefits are greater than its risks for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.
Il- Kumitat għall- Prodotti Mediċinali għall- Użu mill- Bniedem iddeċieda li, għalkemm intwera li Circadin ikollu effett żgħir fi frazzjoni żgħira ta 'pazjenti, il- benefiċċji tiegħu huma ikbar mir- riskji tiegħu meta jintuża fit- trattament għal perjodu qasir ta' l- insomnja primarja ikkaratterizzata minn nuqqas ta 'rqad f' pazjenti li jkollhom 55 sena jew iktar.
The Committee recommended that Circadin be given marketing authorisation.
Il- Kumitat irrakkomanda li Circadin jingħata awtorizzazzjoni għat- tqegħid fis- suq.
Other information about Circadin:
Tagħrif ieħor dwar Circadin:
The European Commission granted a marketing authorisation valid throughout the European Union for Circadin to Neurim Pharmaceuticals EEC Limited on 29 June 2007.
Il- Kummissjoni Ewropea tat awtorizzazzjoni għat- tqegħid fis- suq għal Circadin valida għall- Unjoni Ewropea kollha lil Neurim Pharmaceuticals EEC Limited fil- 29 ta 'Ġunju 2007.
The full EPAR for Circadin can be found here.
L- EPAR sħiħ għal Circadin jista 'jinkiseb minn hawn.
This summary was last updated in 05-2007
Dan is- sommarju ġie aġġornat l- aħħar f' Mejju ta 'l- 2007.
Invented name
Numru ta ’ Proċedura ta ’ l- EU
Pharmaceutical
Isem inventat
Route of
Qawwa
administration
Mnejn jingħata
Prolonged-release tablet
Pilloli li jerħu l - mediċina bil- mod
Oral use
Użu orali.
PVC/ PVDC blister/ alu
PVC/ PVDC folja/ alu
21 tablets
21 pillola
Circadin 2 mg prolonged-release tablets
Circadin 2 mg pilloli li jerħu l- mediċina bil- mod.
Each prolonged-release tablet contains 2 mg melatonin.
Kull pillola li terħi l- mediċina bil- mod fiha 2 mg melatonin.
Excipient: each prolonged-release tablet contains 80 mg lactose monohydrate.
Sustanza mhux attiva: kull pillola li terħi l- mediċina bil- mod fiha 80 mg lactose monohydrate.
Prolonged-release tablet.
Pillola li terħi l- mediċina bil- mod.
White to off-white, round, biconvex tablets
Pilloli bojod għal offwajt, tondi u ibbuzzati fuq iż- żewġ naħat
Circadin is indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.
Circadin huwa indikat bħala monoterapija għall- kura ta ’ perjodu qasir ta ’ insomnja primarja ikkaratterizzata minn kwalità ħażina ta ’ rqad f’ pażjenti b’ età ta ’ 55 sena jew aktar.
Tablets should be swallowed whole.
Il- pilloli għandhom jittieħdu sħaħ.
The recommended dose is 2 mg once daily, 1-2 hours before bedtime and after food.
Id- doża rakkomandata hi ta ’ 2 mg darba kuljum, siegħa sa ’ sagħtejn qabel il- ħin ta ’ l- irqad u wara l - ikel.
This dosage should be continued for three weeks.
Dan id- dożaġġ għandu jitkompla għal tliet ġimgħat.
Paediatric use Circadin is not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy.
Użu pedjatriku Circadin mhux irrakkomandat għall- użu fit- tfal u adoloxxenti taħt taħt l- età ta ’ 18- il sena peress li m’ hemmx biżżejjed informazzjoni dwar is- sigurtà u l- effikaċja.
Renal insufficiency The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied.
Insuffiċjenza renali L- effett ta ’ insuffiċjenza renali ta ’ kull stadju fuq il- farmakokinetika ta ’ melatonin ma ġiex studjat.
Caution should be used when melatonin is administered to such patients.
Għandu jkun hemm attenzjoni meta melatonin jingħata lil dawn il- pazjenti.
Hepatic impairment There is no experience of the use of Circadin in patients with liver impairment.
Indeboliment epatiku M’ hemmx esperjenza ta ’ użu ta ’ Circadin f’ pazjenti b’ indeboliment tal- fwied.
Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment.
Informazzjoni ippublikata turi b’ mod ċar livelli għolja ta ’ melatonin endoġenu matul is- siegħat ta ’ bi nhar minħabba tnaqqis fit- tneħħija f’ pazjenti b’ indeboliment epatiku.
Therefore, Circadin is not recommended for use in patients with hepatic impairment.
Għalhekk, Circadin mhux rakkomandat għall - użu f’ pazjenti b’ indeboliment epatiku.
Circadin may cause drowsiness.
Circadin jista jħeddel.
Therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety.
Għalhekk il- prodott għandu jintuża b’ attenzjoni jekk l- effetti tat- tħeddil jistgħu jiġu assoċjati ma ’ riskju għas- sikurtà.
2 No clinical data exist concerning the use of Circadin in individuals with autoimmune diseases.
2 M’ hemmx tagħrif disponnibli dwar l- użu ta ’ Circadin f’ individwi b’ mard awto- immun.
Therefore Circadin is not recommended for use in patients with autoimmune diseases.
Għalhekk Circadin mhux rakkomandat għall- użu f’ pazjenti b’ mard awto- immun.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pazjenti bi problemi ereditarji rari ta ’ intolleranza għal galattosju, defiċjenza LAPP lactase jew assorbiment ħażin ta ’ glukosju- galattosju m’ għandhomx jieħdu din il- mediċina.
Pharmacokinetic interactions
Interazzjonijiet farmakokinetiċi
• Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations.
• F’ konċentrazzjonijiet supra- terapewtiċi kien osservat li Melatonin jinduċi CYP3A.
The clinical relevance of the finding is unknown.
Ir - rilevanza klinika ta ’ dawn is- sejbiet m’ hix magħrufa.
If induction occurs, this can give rise to reduced plasma concentrations of concomitantly administered drugs. • Melatonin does not induce CYP1A enzymes in vitro at supra-therapeutic concentrations.
Jekk isseħħ induzzjoni, din tista ’ tirriżulta fi tnaqqis tal- konċentrazzjonijiet fil- plażma ta ’ mediċini mogħtija fl- istess waqt. • Melatonin ma jinduċix l- enżimi CYP1A in vitro f’ konċentrazzjonijiet supra- terapewtiċi.
Therefore, interactions between melatonin and other active substances as a consequence of melatonin’ s effect on CYP1A enzymes are not likely to be significant. • Melatonin’ s metabolism is mainly mediated by CYP1A enzymes.
Għalhekk, interazzjonijiet bejn melatonin u sustanzi attivi oħra bħala konsekwenza ta ’ l- effett ta ’ melatonin fuq l- enżimi CYP1A x’ aktarx ma jkunux sinifikanti. • Il- metaboliżmu ta ’ Melatonin huwa medjat l- aktar mill- enżimi CYP1A.
Therefore, interactions between melatonin and other active substances as a consequence of their effect on CYP1A enzymes is possible. • Caution should be exercised in patients on fluvoxamine, which increases melatonin levels (by 17-fold higher AUC and a 12-fold higher serum Cmax) by inhibiting its metabolism by hepatic cytochrome P450 (CYP) isozymes CYP1A2 and CYP2C19.
Għalhekk, interazzjonijiet bejn melatonin u sustanzi attivi oħra bħala konsekwenza ta ’ l- effett tagħhom fuq l- enżimi CYP1A huma possibli. • Għandha tintuża kawtela f’ pazjenti li qed jieħdu fluvoxamine, li jżid il- livelli ta ’ melatonin (l- AUC bi 17- il darba ogħla, u Cmax fis- serum bi 12- il darba ogħla) billi jinibixxi l- metaboliżmu tiegħu mill- isożimi epatiċi taċ- ċitokromju P450 (CYP), CYP1A2 u CYP2C19.
The combination should be avoided. • Caution should be exercised in patients on 5- or 8-methoxypsoralen (5 and 8-MOP), which increases melatonin levels by inhibiting its metabolism. • Caution should be exercised in patients on cimetidine a CYP2D inhibitor, which increases plasma melatonin levels, by inhibiting its metabolism. • Cigarette smoking may decrease melantonin levels due to induction of CYP1A2. • Caution should be exercised in patients on oestrogens (e. g. contraceptive or hormone replacement therapy), which increase melatonin levels by inhibiting its metabolism by CYP1A1 and CYP1A2. • CYP1A2 inhibitors such as quinolones may give rise to increased melatonin exposure. • CYP1A2 inducers such as carbamazepine and rifampicin may give rise to reduced plasma concentrations of melatonin. • There is a large amount of data in the literature regarding the effect of adrenergic agonists/ antagonists, opiate agonists/ antagonists, antidepressant medicinal products, prostaglandin inhibitors, benzodiazepines, tryptophan and alcohol, on endogenous melatonin secretion.
It- taħlita għandha tiġi evitata. • Għandha tintuża kawtela f’ pazjenti li qed jieħdu 5 - jew 8- methoxypsoralen (5 u 8 - MOP), li jżid il- livelli ta ’ melatonin billi jinibixxi l- metaboliżmu tiegħu. • Għandha tintuża kawtela f’ pazjenti li qed jieħdu cimetidine, inibitur ta ’ CYP2D, li jżid il- livelli ta ’ melatonin billi jinibixxi l- metaboliżmu tiegħu. • It- tipjip tas- sigaretti jista ’ jnaqqas il- livelli ta ’ melatonin peress li jinduċi CYP1A2. • Għandha tintuża kawtela f’ pazjenti li qed jieħdu oestrogens (eż. kontraċettivi jew terapija ta ’ sostituzzjoni ta ’ l- ormon), li jżidu il- livelli ta ’ melatonin billi jinibixxu l - metaboliżmu tiegħu minn CYP1A1 u CYP1A2. • Inibituri ta ’ CYP1A2 bħal quinolones jistgħu jżidu l- espożizzjoni għal melatonin. • Indutturi ta ’ CYP1A2 bħal carbamazepine u rifampicin jistgħu jirriżultaw fi tnaqqis tal - konċentrazzjonijiet fil- plażma ta ’ melatonin. • Hemm ammont kbir ta ’ tagħrif fil- letteratura dwar l- effett ta ’ agonisti/ antagonisti adrinerġiċi, agonisti/ antagonisti narkotiċi, prodotti mediċinali antidepressanti, inibituri ta ’ prostaglandin, benzodiazepines, tryptophan u alkoħol, fuq ir- reħa ta ’ melatonin endoġenu.
Whether or not these active substances interfere with the dynamic or kinetic effects of Circadin or vice versa has not been studied.
Ma ġiex studjat jekk dawn is- sustanzi attivi ifixklux l- effetti dinamiċi jew kinetiċi ta ’ Circadin jew vice versa.
Pharmacodynamic interactions
Interazzjonijiet farmakodinamiċi
• Alcohol should not be taken with Circadin, because it reduces the effectiveness of Circadin on sleep. • Circadin may enhance the sedative properties of benzodiazepines and non-benzodiazepine hypnotics, such as zalepon, zolpidem and zopiclone.
• L- alkoħol m’ għandux jittieħed flimkien ma ’ Circadin, għax inaqqas l- effettività ta ’ Circadin fuq l- irqad. • Circadin jista ’ jsaħħaħ l- proprjetajiet sedattivi ta ’ benzodiazepines u ipnotiċi mhux benzodiazepines, bħal zalepon, zolpidem u zopiclone.
In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between Circadin and zolpidem one hour following co-dosing.
Fi prova klinika, kien hemm evidenża ċara ta ’ interazzjoni farmakodinamika transitorja bejn Circadin u zolpidem siegħa wara li ngħataw flimkien.
Concomitant administration resulted in increased impairment of attention, memory and co-ordination compared to zolpidem alone. • Circadin has been co-administered in studies with thioridazine and imipramine, active substances which affect the central nervous system.
It- teħid flimkien wassal għal żieda fin- nuqqas ta ’ attenzjoni, memorja u ko- ordinazzjoni meta ’ mqabbel ma ’ zolpidem waħdu. • Fi studji Circadin ingħata flimkien ma ’ thioridazine u imipramine; sustanzi attivi li jaffettwaw is- sistema nervuża ċentrali.
No clinically significant pharmacokinetic interactions were found in each case.
Fl- ebda każ ma nstabu interazzjonijiet farmakokinetiċi ta ’ sinnifikat kliniku.
However, Circadin co-administration resulted in increased feelings of tranquility and difficulty in
Iżda, l- għotja ta ’ Circadin flimkien ma ’ dawn, irriżultat f’ sensazzjoni akbar ta ’ trankwillità u diffikultà biex jitwettqu azzjonijiet meta ’
3 performing tasks compared to imipramine alone, and increased feelings of “ muzzy- headedness” compared to thioridazine alone.
3 mqabbla ma ’ imipramine waħdu, u sensazzjoni akbar ta ’ konfużjoni tal- moħħ meta ’ mqabbla ma ’ thioridazine waħdu.
For melatonin, no clinical data on exposed pregnancies are available.
Għal melatonin m’ hemmx tagħrif kliniku dwar l- użu waqt it- tqala.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development (see section 5.3).
Studji fuq il- bhejjem ma jurux effetti ħżiena diretti jew indiretti fuq it- tqala, fuq l- iżvilupp ta ’ l- embriju/ fetu, ħlas jew żvilupp wara t - twelid (ara sezzjoni 5. 3).
In view of the lack of clinical data, use in pregnant women and by women intended to become pregnant is not recommended.
Minħabba n- nuqqas ta ’ tagħrif kliniku, l- użu f’ nisa tqal jew f’ nisa li jixtiequ joħorġu tqal mhux rakkomandat.
Endogenous melatonin was measured in human breast milk thus exogenous melatonin is probably secreted into human milk.
Melatonin endoġenu kien imkejjel fil- ħalib tas- sider tal- bniedem u għalhekk probabbilment melatonin exoġenu jintreħa fil- ħalib uman.
There are data in animal models including rodents, sheep, bovine and primates that indicate maternal transfer of melatonin to the foetus via the placenta or in the milk.
Hemm tagħrif f’ mudelli annimali inkluż rodentiċi, ngħaġ, baqar u primati li jindikaw trasferiment ta ’ melatonin mill- omm għall- fetu permezz tal- plaċenta jew fil- ħalib.
Therefore, breast-feeding is not recommended in women under treatment with melatonin.
Għalhekk, it- treddigħ mhux rakkomandat f’ nisa li qed jiġu kkurati b’ melatonin.
Circadin has moderate influence on the ability to drive and use machines.
Circadin għandu effett moderat fuq il- ħila biex issuq u tħaddem magni.
Circadin may cause drowsiness, therefore the product should be used with caution if the effects of drowsiness are likely to be associated with a risk to safety.
Circadin jista ’ jikkawża sturdament, għalhekk il- prodott għandu jintuża b’ attenzjoni jekk l- effetti ta ’ sturdament jistgħu jikkawżaw riskju għas- sigurtà.
In clinical trials (in which a total of 1361 patients were taking Circadin and 1247 patients were taking placebo), 37.0% of patients receiving Circadin reported an adverse reaction compared with 31.8% taking placebo.
Fi provi klinċi (fejn total ta ’ 1361 pazjent kienu qed jieħdu Circadin u 1247 pazjent kienu qed jieħdu plaċebo), 37. 0% tal- pazjenti li kienu qed jingħataw Circadin irrappurtaw reazzjoni avversa meta ’ mqabbla ma ’ 31. 8% li kienu qed jieħdu plaċebo.
3.17 – Circadin).
Meta tqabbel ir- rata ta ’ pazjenti reazzjoni avversa għal kull 100 ġimgħa ta ’ pazjent, ir- rata kienet ogħla għall- plaċebo milli b’ Circadin (8. 21 – plaċebo kontra 3. 17 Circadin).
The most common adverse reactions were headache, pharyngitis, back pain, and asthenia, which were common, by MedDRA definition, in both the Circadin and placebo treated groups.
L- aktar reazzjonijiet avversi komuni kienu uġigħ ta ’ ras, farinġite, uġigħ fid - dahar u astenija, li skond id- definizzjoni MedDRA, kienu komuni kemm fil- ġrupp ikkurat b’ Circadin kif wkoll fil- ġrupp ikkurat bil- plaċebo.
The following adverse reactions were reported in clinical trials and were defined as possibly, probably or definitely related to treatment.
Dawn ir- reazzjonijiet avversi li ġejjin kienu irrappurtati fi provi kliniċi u kienu definiti bħala possibilment, probabbilment jew definittivament relatati mal- kura.
A total of 6.9% of subjects receiving Circadin reported an adverse reaction compared with 5.9% of subjects taking placebo.
Total ta ’ 6. 9% ta ’ l- individwi li ngħataw Circadin irrappurtaw reazzjoni avversa meta mqabbel ma ’ 5. 9% ta ’ l- individwi li kienu qed jieħdu plaċebo.
Only those adverse events occurring in subjects at an equivalent or greater rate than placebo have been included below.
Taħt huma nklużi biss dawk ir- reazzjonijiet avversi li seħħew f’ individwi b’ rata ekwivalenti jew akbar milli bil- plaċebo.
Very common (≥ 1/ 10); Common (≥ 1/ 100 to < 1/ 10); Uncommon (≥ 1/ 1,000 to < 1/ 100); Rare (≥ 1/ 10,000 to < 1/ 1,000); Very rare (< 1/ 10,000), Not known (cannot be established from the available data).
Komuni ħafna (≥ 1/ 10); Komuni (≥ 1/ 100 sa < 1/ 10); Mhux komuni (≥ 1/ 1, 000 sa < 1/ 100); Rari (≥ 1/ 10, 000 sa < 1/ 1, 000); Rari ħafna (< 1/ 10, 000), Mhux magħruf (ma tistax tittieħed stima mid- data disponibbli).
System Organ
Sistema tal -
Common
Komuni Komuni
Uncommon
Mhux Komuni
Class
Klassifika tal - Organi
Common
Óħafna
Infections and Infestations
Infezzjonijiet u Infestazzjonijiet
Blood and Lymphatic System Disorders
Disturbi tad - Demm u tas - Sistema Limfatika
Leukopenia, Thrombocytopenia
Lewkopenja, Tromboċitopenja
Metabolism and Nutrition Disorders
Disturbi fil - Metaboliżmu u n - Nutrizzjoni
Hypertriglyceridaemia
Ipertrigliċeridimja
Psychiatric Disorders
4 Disturbi Psikjatriċi
Irritability, Nervousness, Restlessness, Insomnia, Abnormal dreams
Irritabilità, Nervi, Tħossok bla sabar, Nuqqas ta ’ rqad, Ħolm mhux normali
Mood altered, Aggression, Agitation, Crying, Early morning awakening, Libido increased
Bidla fil- burdata, Aggressjoni, Aġitazzjoni, Biki, Qawmien kmieni filgħodu, Żieda fil- libido
Nervous System Disorders
Disturbi fis - Sistema Nervuża
Migraine, Psychomotor hyperactivity, Dizziness, Somnolence
Emigranja, Iperattività psikomotorja, Sturdament, Ngħas
Memory impairment, Disturbance in attention, Poor quality sleep
Indeboliment tal - memorja, Disturbi fl - attenzjoni, Rqad ta ’ kwalità ħażina
Eye Disorders
Disturbi fl - Għajnejn
Visual acuity reduced, Vision blurred, Lacrimation increased
Akutezza tal- vista mnaqqsa, Vista mċajpra, Żieda fid- dmugħ
Ear and Labyrinth Disorders
Disturbi fil - Widnejn u fis - Sistema Labirintika
Vertigo positional
Vertigo pożizzjonali
Vascular Disorders
Disturbi Vaskulari
Gastrointestinal Disorders
Disturbi Gastro - intestinali
Abdominal pain, Constipation, Dry mouth
Uġigħ addominali, Stitikezza, Ħalq xott
Gastrointestinal disorder, Gastrointestinal upset, Vomiting, Bowel sounds abnormal, Flatulence, Salivary hypersecretion, Halitosis
Disturb gastro- intestinali, Taqlib gastro- intestinali, Rimettar, Ħsejjes tal - musrana mhux nornali, Gass, Żieda fit- tnixxija tal- bżieq, Alitosi
Hepatobiliary Disorders
Disturbi fil- Fwied u fil- Marrara
Hyperbilirubinaemia
Iperbilirubinimja
Hepatic enzyme increased, Liver function test abnormal, laboratory test abnormal
Żieda fl- enżimi epatiċi, Testijiet tal- funzjoni tal - fwied mhux normali, Testijiet tal- laboratorju mhux normali
Skin and Subcutaneous Tissue Disorders
Disturbi fil- Ġilda u fit- Tessuti ta ’ taħt il- Ġilda
Hyperhidrosis
Iperidrożi
Eczema, Erythema, Rash pruritic, Pruritus, Dry skin, Nail disorder, Night sweats,
Ekżema, Eritima, Raxx bil- ħakk, Ħakk, Ġilda xotta, Disturbi fid - dwiefer, Tegħreq ħafna matul il- lejl
Musculoskeletal and Connective Tissue Disorders
Disturbi Muskolu - Skeltrali u tal - Connective Tissue
Muscle cramp, Neck pain
Bugħawwieġ fil- muskuli, Uġigħ fl- għonq
Reproductive System and Breast Disorders
Disturbi fis - Sistema Riproduttiva u fis - Sider
Priapism
Priapismu
General Disorders and Administration Site Conditions
Disturbi Ġenerali u Kondizzjonijiet ta ’ Mnejn Jingħata
Fatigue
Għejja
Weight increased
Żieda fil- piż
Circadin has been administered at 5 mg daily doses in clinical trials over 12 months without significantly changing the nature of the adverse reactions reported.
Circadin ingħata f’ dożi ta ’ 5 mg kuljum fi provi kliniċi fuq perjodu ta ’ 12- il xahar mingħajr ma kien hemm tibdil sinifikanti fin- natura tar- reazzjonijiet avversi li ġew irrapurtati.
Administration of daily doses of up to 300 mg of melatonin without causing clinically significant adverse reactions have been reported in the literature.
L- għotja ta ’ dożi kuljum sa ’ 300 mg ta ’ melatonin mingħajr ma toħloq reazzjonijiet avversi ta ’ sinifikanza klinika ġew irrappurtati fil- letteratura.
If overdose occurs, drowsiness is to be expected.
5 Jekk isseħħ doża eċċessiva, hu mistenni li l- pazjent iħossu mħeddel.
Clearance of the active substance is expected within 12 hours after ingestion.
It- tneħħija tas- sustanza attiva hi mistennija fi żmien 12- il siegħa wara li tittieħed.
No special treatment is required.
M’ hix meħtieġa kura speċjali.
Melatonin Receptor Agonists, ATC code:
Riċetturi Agonisti ta ’ Melatonin, Kodiċi ATC:
Melatonin is a naturally occurring hormone produced by the pineal gland and is structurally related to serotonin.
Melatonin huwa ormon naturali li jiġi prodott mill- glandola pinejali u huwa relata strutturalment ma ’ serotonin.
Physiologically, melatonin secretion increases soon after the onset of darkness, peaks at 2-4 am and diminishes during the second half of the night.
Fiżjoloġikament, ir- reħa ta ’ melatonin tiżdied hekk kif jibda ’ jidlam, tilħaq il- quċċata ma ’ 2- 4 am u tonqos matul it- tieni nofs tal- lejl.
Melatonin is associated with the control of circadian rhythms and entrainment to the light-dark cycle.
Melatonin huwa assoċjat mal- kontroll tar- ritmi ċirkadjani u marbut maċ- ċiklu tad- dawl u tad- dlam.
It is also associated with a hypnotic effect and increased propensity for sleep.
Huwa assoċjat wkoll ma ’ effett ipnotiku u żieda fit- tendenza għall- irqad.
Mechanism of action The activity of melatonin at the MT1, MT2 and MT3 receptors is believed to contribute to its sleep- promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep regulation.
Mekkaniżmu ta ’ azzjoni L- attività ta ’ melatonin fir- riċetturi MT1, MT2 U MT3 hi maħsuba li tikkontribwixxi għall- kwalitajiet tiegħu li jippromwovi l- irqad, għax dawn ir- riċetturi (l- aktar MT1 u MT2) huma nvoluti fir - regolazzjoni tar- ritmi ċirkadjani u l- irqad.
Rationale for use Because of the role of melatonin in sleep and circadian rhythm regulation, and the age related decrease in endogenous melatonin production, melatonin may effectively improve sleep quality particularly in patients who are over 55 with primary insomnia.
Raġuni għall- użu Minħabba l- funzjoni ta ’ melatonin fir- regolazzjoni ta ’ l- irqad u tar- ritmi ċirkadjani, u t- tnaqqis fil - produzzjoni ta ’ melatonin endoġenu relatat ma ’ l- età, melatonin jista ’ jtejjeb il- kwalità ta ’ l- irqad b’ mod effettiv, speċjalment f’ pazjenti b’ età ta ’ aktar minn 55 sena li għandhom insomnja primarja.
Clinical efficacy In clinical trials, where patients suffering from primary insomnia received Circadin 2 mg every evening for 3 weeks, benefits were shown in treated patients compared to placebo in sleep latency (as measured by objective and subjective means) and in subjective quality of sleep and daytime functioning (restorative sleep) with no impairment of vigilance during the day.
Effikaċja klinika Fi provi kliniċi fejn pazjenti li jsofru minn insomnja primarja ngħataw Circadin 2 mg kull filgħaxija għal 3 ġimgħat, kienu osservati benefiċċji f’ pazjenti kkurati meta mqabbla ma ’ plaċebo fit- tul ta ’ l - irqad (kif imkejjel b’ mezzi oġġettivi u soġġettivi) u fil- kwalità soġġettiva ta ’ l- irqad u l- funżjoni tul il - ġurnata (irqad ristorattiv) bl- ebda nuqqas ta ’ viġilanza tul il- ġurnata.
In a polysomnographic (PSG) study with a run-in of 2 weeks (single-blind with placebo treatment), followed by a treatment period of 3 weeks (double-blind, placebo-controlled, parallel group design) and a 3-week withdrawal period, sleep latency (SL) was shortened by 9 minutes compared to placebo.
Fi studju polisomnografiku (PSG) b’ espożizzjoni ta ’ ġimagħtejn (single- blind b’ kura bil- plaċebo), segwit b’ perjodu ta ’ kura ta ’ 3 ġimgħat (disinn ta ’ grupp ta ’ paragun, double- blind, ikkontrollat bil - plaċebo) u perjodu ta ’ rtirar ta ’ 3 ġimgħat, il- ħin sa l- irqad (SL) kien imnaqqas b’ 9 minuti meta mqabbel mal- plaċebo.
There were no modifications of sleep architecture and no effect on REM sleep duration by Circadin.
Ma kienx hemm modifikazzjoni ta ’ l- istil tal- irqad u l- ebda effett fuq it- tul ta ’ l - irqad REM minn Circadin.
Modifications in diurnal functioning did not occur with Circadin 2 mg.
Ma kienx hemm modifikazzjonijiet fil- funzjoni tul il- ġurnata b’ Circadin 2 mg.
In an outpatient study with 2 week run-in baseline period with placebo, a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks and 2 week withdrawal period with placebo, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 47% in the Circadin group as compared to 27% in the placebo group.
Fi studju fuq pazjenti ta ’ barra b’ espożizzjoni ta ’ ġimagħtejn fil- perjodu tal- linja bażi bil- plaċebo, b’ perjodu ta ’ kura tal- grupp ta ’ paragun, randomised, double blind, u kkontrollat bil- plaċebo ta ’ 3 ġimgħat u perjodu ta ’ ġimagħtejn ta ’ rtirar bil- plaċebo, ir- rata ta ’ pazjenti li wrew titjib ta ’ sinifikanza klinika kemm fil- kwalità ta ’ l- irqad kif ukoll fil- viġilanza ta ’ filgħodu kienet ta ’ 47% fil- grupp ta ’ Circadin meta mqabbla ma ’ 27% fil- grupp bil- plaċebo.
In addition, quality of sleep and morning alertness significantly improved with Circadin compared to placebo.
Barra minn hekk, il- kwalità ta ’ l- irqad u l - viġilanza ta ’ filgħodu tjiebu b’ mod sinifikanti b’ Circadin meta mqabbel ma ’ plaċebo.
Sleep variables gradually returned to baseline with no rebound, no increase in adverse events and no increase in withdrawal symptoms.
Il- varjabbli ta ’ l - irqad reġgħu lura għal- linja bażi gradwalment mingħajr ma rritornaw lura għal ta ’ qabel, u mingħajr żieda fl- avvenimenti avversi u fis- sintomi ta ’ rtirar.
In a second outpatient study with two week run in baseline period with placebo and a randomised, double blind, placebo controlled, parallel group treatment period of 3 weeks, the rate of patients who showed a clinically significant improvement in both quality of sleep and morning alertness was 26% in the Circadin group as compared to 15% in the placebo group.
Fi studju ieħor fuq pazjenti ta ’ barra b’ espożizzjoni ta ’ ġimagħtejn fil- perjodu tal- linja bażi bil- plaċebo u b’ perjodu ta ’ kura tal- grupp ta ’ paragun, randomised, double blind, u kkontrollat bil- plaċebo ta ’ 3 ġimgħat, ir- rata ta ’ pazjenti li wrew titjib ta ’ sinifikanza klinika kemm fil- kwalità ta ’ l- irqad kif ukoll fil- viġilanza ta ’ filgħodu kienet ta ’ 26% fil- grupp ta ’ Circadin meta mqabbla ma ’ 15% fil- grupp bil - plaċebo.
Circadin shortened patients’ reported
Circadin qassar il- ħin irrappurtat li l- pazjenti jieħdu sakemm jorqdu b’ 24. 3 minuti vs 12. 9 minuti bil- plaċebo.
In addition, patients’ self-reported quality of sleep, number of awakenings and morning alertness significantly improved with Circadin compared to placebo.
Barra minn hekk, il- kwalità ta ’ l- irqad, in- numru ta ’ kemm il- darba qamu u l - viġilanza ta ’ filgħodu, hekk kif irrappurtati mill- pazjenti nfushom, tjiebu b’ mod sinifikattiv b’ Circadin meta mqabbla ma ’ plaċebo.
Quality of life was improved significantly with Circadin 2 mg compared to placebo.
Il- kwalità tal- ħajja tjiebet b’ mod sinifikattiv b’ Circadin 2 mg meta mqabbla ma ’ plaċebo.
5.2 Pharmacokinetic properties
6 5. 2 Tagħrif farmakokinetiku
Absorption The absorption of orally ingested melatonin is complete in adults and may be decreased by up to 50% in the elderly.
Assorbiment L- assorbiment ta ’ melatonin meħud mill- ħalq huwa komplut fl- adulti u jista ’ jonqos sa 50% fl - anzjani.
The kinetics of melatonin are linear over the range of 2-8 mg.
Il- kinetika ta ’ melatonin hija lineari tul il- firxa ta ’ 2- 8 mg.
Bioavailability is in the order of 15%.
Il- biodisponibiltà hija madwar 15%.
There is a significant first pass effect with an estimated first pass metabolism of 85%.
Hemm effett ta ’ l- ewwel mogħdija sinifikanti b’ metaboliżmu ta ’ l- ewwel mogħdija stmat għal 85%.
Tmax occurs after 3 hours in a fed state.
Tmax isseħħ wara 3 sigħat wara l- ikel.
The rate of melatonin absorption and Cmax following Circadin 2 mg oral administration is affected by food.
Ir- rata ta ’ assorbiment ta ’ melatonin u Cmax wara l- għotja ta ’ Circadin 2 mg mill- ħalq hija affetwata mill- ikel.
The presence of food delayed the absorption of the melatonin resulting in a later (Tmax=3.0 h versus Tmax=0.75 h) and lower peak plasma concentration in the fed state (Cmax=1020pg/ ml versus Cmax=1176 pg/ ml).
Il- preżenza ta ’ l - ikel ittawwal l- assorbiment ta ’ melatonin u twassal għal konċentrazzjoni massima fil- plażma aktar tard (Tmax=3. 0 h kontra Tmax=0. 75 h) u aktar baxxa wara l- ikel (Cmax = 1020 kontra Cmax = 1176 pg/ ml).
Distribution The in vitro plasma protein binding of melatonin is approximately 60%.
Distribuzzjoni Ir- rabta in vitro ta ’ melatonin mal- proteini fil- plażma hi madwar 60%.
Circadin is mainly bound to albumin, alpha1-acid glycoprotein and high density lipoprotein.
Circadin huwa l- aktar marbut ma ’ albumina, alpha1- acid glycoprotein u lipoproteina ta ’ densità għolja.
Biotransformation Experimental data suggest that isoenzymes CYP1A1, CYP1A2 and possibly CYP2C19 of the cytochrome P450 system are involved in melatonin metabolism.
Biotrasformazzjoni Tagħrif sperimentali jissuġġerixxi li l- isożimi CYP1A1, CYP1A2 u possibilment CYP2C19 tas - sistema taċ- ċitokromju P450 huma nvoluti fil- metaboliżmu ta ’ melatonin.
The principal metabolite is 6- sulphatoxy-melatonin (6-S-MT), which is inactive.
Il- metabolita prinċipali huwa 6- sulphatoxy- melatonin (6- S- MT), li huwa inattiv.
The site of biotransformation is the liver.
Il- lok ta ’ biotransformazzjoni huwa l- fwied.
The excretion of the metabolite is completed within 12 hours after ingestion.
It- tneħħija tal- metabolita hija kompluta wara 12- il siegħa wara li jittieħed mill- ħalq.
Elimination Terminal half life (t½) is 3.5-4 hours.
Eliminazzjoni Il- half- life terminali (t½) hi ta ’ 3. 5- 4 sigħat.
Elimination is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as melatonin (unchanged drug).
L- eliminazzjoni isseħħ permezz ta ’ tneħħija renali tal - metaboliti, 89% bħala konjugati b’ sulfat jew b’ glucoronide ta ’ 6- hydroxymeltonin u 2% jitneħħa bħala melatonin (mediċina m’ hix mibdula).
Gender A 3-4-fold increase in Cmax is apparent for women compared to men.
Sess Żieda ta ’ 3- 4 darbiet f’ Cmax hi evidenti fin- nisa meta ’ mqabbla ma ’ l- irġiel.
A five-fold variability in Cmax between different members of the same sex has also been observed.
Ġiet ukoll osservata varjazzjoni ta ’ 5 darbitet f’ Cmax bejn membri differenti ta ’ l- istess sess.
However, no pharmacodynamic differences between males and females were found despite differences in blood levels.
Madankollu, ma nstabux differenzi fil- farmakodinamika bejn irġiel u nisa minkejja differenzi fil- livelli fid- demm.
Elderly Melatonin metabolism is known to decline with age.
Anzjani Il- metaboliżmu ta ’ Melatonin huwa magħruf li jonqos bl- età.
Across a range of doses, higher AUC and Cmax levels have been reported in older subjects compared to younger subjects, reflecting the lower metabolism of melatonin in the elderly.
Tul firxa ta ’ dożi, kienu rrappurtati livelli ta ’ AUC u Cmax ogħla f’ individwi akbar fl- età meta mqabbla ma ’ individwi iżgħar, li jirriflettu metaboliżmu ta ’ melatonin fl- anzjani aktar baxx.
Cmax levels around 500 pg/ ml in adults (18-45) versus 1200 pg/ ml in elderly (55-69); AUC levels around 3,000 pg*h/ mL in adults versus 5,000 pg*h/ mL in the elderly.
Livelli ta ’ Cmax madwar 500 pg/ ml fl- adulti (18- 45) kontra 1200 pg/ ml fl- anzjani (55- 69); livelli ta ’ AUC madwar 3, 000 pg* h/ mL fl- adulti kontra 5, 000 pg* h/ mL fl- anzjani.
Renal impairment Company data indicates that there is no accumulation of melatonin after repeated dosing.
Indeboliment renali Tagħrif tal- kumpanija jindika li m’ hemmx akkumulazzjoni ta ’ melatonin wara dożi ripetuti.
This finding is compatible with the short half-life of melatonin in humans.
Din is - sejba hi kompatibbli mal- half- life qasira ta ’ melatonin fil- bniedem.
The levels assessed in the blood of the patients at 23:00 (2 hours after administration) following 1 and 3 weeks of daily administration were 411.4 ± 56.5 and 432.00 ± 83.2 pg/ ml respectively, and are similar to those found in in healthy volunteers following a single dose of Circadin 2 mg.
Il- livelli stmati fid- demm tal- pazjenti fil- 23: 00 (sagħtejn wara l- amministrazzjoni) wara ġimgħa u 3 ġimgħat ta ’ amministrazzjoni kuljum kienu ta ’ 411. 4 ± 56. 5 u 432. 00 ± 83. 2 pg/ ml rispettivament, u huma simili għal dawk li nstabu f’ voluntiera b’ saħħithom wara doża waħda ta ’ Circadin 2 mg.
Hepatic impairment The liver is the primary site of melatonin metabolism and therefore, hepatic impairment results in higher endogenous melatonin levels.
Indeboliment epatiku Il- fwied huwa l- post prinċipali għall- metaboliżmu ta ’ melatonin u għalhekk indeboliment epatiku jirriżulta f’ livelli ogħla ta ’ melatonin endoġenu.
7 Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours.
Il- livelli ta ’ melatonin fil- plażma f’ pazjenti b’ ċirrożi kienu miżjuda b’ mod sinifikattiv waqt is- sigħat ta ’ bi nhar.
Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin compared with controls.
Il- pazjenti kellhom tneħħija totali ta ’ 6- sulfatoxymelatonin imnaqqsa b’ mod sinifikattiv meta mqabbla mal- kontrolli.
5.3 Preclinical safety data
7 5. 3 Tagħrif ta 'qabel l- użu kliniku dwar is- sigurtà tal- mediċina
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Informazzjoni li mhiex klinika, ibbażata fuq studji konvenzjonali ta ’ sigurtà farmakoloġika, effett tossiku minn dożi ripetuti u effett tossiku fuq il- ġeni ma ’ turi l- ebda periklu speċjali għall- bnedmin.
The No Observed Adverse Effect Level (NOAEL) at 15 mg/ kg/ day in rats, is equivalent to an AUC which is considerably higher (x 15000) than the human exposure after ingestion of Circadin 2 mg.
Il- Livell ta ’ l- Ebda Effett Avvers Osservat (NOAEL) b’ 15 mg/ kg/ kuljum fil- firien huwa ekwivalenti għall- AUC li hija konsiderevolment ogħla (x 15000) mill- esponiment uman wara inġestjoni ta ’ Circadin 2 mg.
The carcinogenicity study in the rat did not reveal any effect which may be relevant for humans.
L- istudju dwar il- karċinoġeniċità fil- far ma wera ebda effett li jista jkun relevanti ghall- bniedem.
In reproductive toxicology, oral administration of melatonin in pregnant female mice, rats or rabbits did not result in adverse effects on their offspring, measured in terms of foetal viability, skeletal and visceral abnormalities, sex ratio, birthweight and subsequent physical, functional and sexual development.
Fit- tossikoloġija ripproduttiva, l- għotja mill- ħalq ta ’ melatonin lill- ġrieden, firien u fniek femminili tqal ma rriżulta fl- ebda effett avvers fuq il- frieħ tagħhom, meta mkejla f’ termini ta ’ vjabbiltà tal- fetu, anormalitajiet skeletrali u vixxerali, proporzjon ta ’ sess, piż tat- twelid u żvilupp fiżiku, funzjonali u sesswali sussegwenti.
A slight effect on post-natal growth and viability was found in rats only at very high doses, equivalent to approximately 2000 mg/ day in humans.
Fil- ġrieden effett ħafif fuq it- tkabbir ta ’ wara t- twelid u l- viabilità deher biss b’ dożi għolja ħafna, ekwivalenti għal madwar 2000mg/ kuljum fil- bnedmin.
Ammonio methacrylate copolymer type B Calcium hydrogen phosphate dihydrate Lactose monohydrate Silica, colloidal anhydrous Talc Magnesium stearate
Ammonio methacrylate copolymer type B Calcium hydrogen phosphate dihydrate Lactose monohydrate Silica, colloidal anhydrous Talkum Magnesium stearate
5 years
5 snin
The tablets are packed in PVC/ PVDC opaque blister strips with aluminium foil backing.
Il- pilloli huma ppakkjati ġo strixxi tal- folja opaki tal- PVC/ PVDC b’ rinforz ta ’ fojl ta ’ l- aluminju.
The pack consists of one blister strip containing 20 or 21 tablets.
Il - pakkett fih strixxa tal- folja waħda li fiha 20 jew 21 pillola.
The blisters are then packed in cardboard boxes.
Il- folji huma mbagħad ippakjati f’ kaxxi tal - kartun.
8 Medicines no longer required should not be disposed of via wastewater or the municipal sewage system.
Mediċini li m’ humiex meħtieġa aktar m’ għandhomx jintremew ma ’ l- ilma jew fis- sistema tad - drenaġġ.
Return them to a pharmacy or ask your pharmacist how to dispose of them in accordance with the national regulations.
Ħudhom lura fi spiżerija jew staqsi lill- ispiżjar tiegħek dwar kif għandek tarmihom skond il - liġijiet lokali.
RAD Neurim Pharmaceuticals EEC Limited One Forbury Square The Forbury Reading Berkshire RG1 3EB United Kingdom e-mail: neurim@neurim. com
RAD Neurim Pharmaceuticals EEC Limited One Forbury Square The Forbury Reading Berkshire RG1 3EB Ir- Renju Unit e- mail: neurim@ neurim. com
Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il- Mediċini (EMEA) http: // www. emea. europa. eu /.
9 ANNEX II
9 ANNESS II
Penn Pharmaceutical Services Ltd Units 23-24 Tafarnaubach Industrial Estate Tredegar Gwent NP22 3AA UK
Penn Pharmaceutical Services Ltd Units 23- 24 Tafarnaubach Industrial Estate Tredegar Gwent NP22 3AA Ir- Renju Unit
Catalent Germany Schorndorf GmbH Steinbeisstrasse 2 D-73614 Schorndorf Germany
Catalent Germany Schorndorf GmbH Steinbeisstrasse 2 D- 73614 Schorndorf Il- Ġermanja
The MAH must ensure that the system of pharmacovigilance is in place and functioning prior to placing the product on the market.
Id- Detentur ta ’ L- Awtorizzazzjoni għat- tqegħid fis- Suq għandu jiżgura li s- sistema ta ’ farmakoviġilanza hi implimentata u qed tiffunzjona qabel ma l- prodott jitqiegħed fis- suq.
Risk Management System
Sistema għall- Immaniġġjar ta ’ Riskji
The MAH commits to performing the study detailed in the Pharmacovigilance Plan.
Id- Detentur ta ’ L- Awtorizzazzjoni għat- tqegħid fis- Suq jobbliga ruħu li jwettaq l- istudju dettaljat fil - Pjan ta ’ Farmakoviġilanza.
An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk Management System for medicinal products for human use.
Skond il- Linji Gwida tas- CHMP dwar is- Sistema għall- Immanniġjar ta ’ Riskji għall- prodotti mediċinali għall- użu uman, għandu jiġi pprovdut Pjan għall- Immanniġjar ta ’ Riskji aġġornat.
11 ANNEX III
11 ANNESS III
13 PARTICULARS TO APPEAR ON THE OUTER PACKAGING
13 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA
CARTON
KARTUNA
Circadin 2 mg prolonged-release tablets melatonin
Circadin 2 mg pilloli li jerħu l- mediċina bil- mod melatonin
Each tablet contains 2 mg melatonin.
Kull pillola fiha 2 mg melatonin.
Contains lactose monohydrate See leaflet for further information
Fih lactose monohydrate Għal aktar informazzjoni ara l- fuljett ta ’ tagħrif
Prolonged-release tablets 20 tablets 21 tablets
Pilloli li jerħu l- mediċina bil- mod 20 pillola 21 pillola
Do not store above 25ºC.
Taħżinx f’ temperatura ’ l fuq minn 25°C.
EU/ 1/ 07/ 392/ 001 21 tablets EU/ 1/ 07/ 392/ 002 20 tablets
EU/ 1/ 07/ 392/ 001 21 pillola EU/ 1/ 07/ 392/ 002 20 pillola
15 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
15 TAGĦRIF MINIMU LI GĦANDU JIDHER FUQ IL- FOLJI JEW FUQ L- ISTRIXXI
BLISTER STRIP
STRIXXA TAL- FOLJA