qanastek/EMEA-V3 huggingface dataset:
Because the number of patients with HPA is low, the disease is considered ‘ rare’, and Kuvan was designated an ‘ orphan medicine ’ (a medicine used in rare diseases) on 8 June 2004.
Minħabba li l- għadd ta ’ pazjenti bl- HPA huwa wieħed baxx, il- marda hija kkunsidrata bħala ‘ rari ’, u Kuvan ġie denominat bħala ‘ mediċina orfni ’ (mediċina użata fil- mardiet rari) fit- 8 ta ’ Ġunju 2004.
How is Kuvan used?
Kif jintuża Kuvan?
Treatment with Kuvan must be started and supervised by a doctor who has experience in the treatment of PKU and BH4 deficiency.
It- trattament b’ Kuvan għandu jinbeda u jiġi sorveljat minn tabib bl- esperjenza fit- trattament tal- PKU u tad- defiċjenza tal- BH4.
The amount of phenylalanine and protein in the patient ’ s diet needs to be monitored, to make sure that blood phenylalanine levels and nutritional balance are controlled.
L- ammont ta ’ fenilalanina u proteini fil- ħtiġijiet tad- dieta tal- pazjent irid jiġi sorveljat, biex ikun żgurat li l- livelli ta ’ fenilalanina fid- demm u l- bilanċ nutrittiv jiġu kkontrollati.
Kuvan is intended for long-term use.
Kuvan huwa intiż għal użu fit- tul.
The dose of Kuvan depends on the patient’ s weight.
Id- doża ta ’ Kuvan tiddependi mill- piż tal- pazjent.
Patients with PKU should start with 10 mg per kilogram body weight once a day and those with BH4 deficiency should start with 2 to 5 mg/ kg once a day.
Il- pazjenti bil- PKU għandhom jinbdew b’ 10 mg għal kull kilogramm li jiżen il- pazjent darba kuljum u dawk bid- defiċjenza tal- BH4 għandhom jibdew b’ bejn 2 u 5 mg/ kg darba kuljum.
After a week, the dose can be adjusted up to 20 mg/ kg once a day if the patient has not responded to treatment.
Wara ġimgħa, id- doża tkun tista ’ tiġi aġġustata sa 20 mg/ kg darba kuljum jekk il- pazjent ma jkunx irrisponda għat- trattament.
A satisfactory response is defined as a reduction in blood phenylalanine levels of at least 30% or to a level determined by the doctor.
Rispons sodisfaċenti huwa definit bħala tnaqqis fil- livelli tal- fenilalanina fid- demm ta ’ mill- inqas 30% jew għal livell determinat mit- tabib.
If this has been achieved after one month, the patient is classified as a ‘ responder’ and can continue taking Kuvan.
Jekk ikun intlaħaq wara xahar, il- pazjent jiġi klassifikat bħala ‘ responder ’ u jkun jista ’ jkompli jieħu Kuvan.
Kuvan should be used with caution in patients over 65 years of age, and in patients with liver or kidney problems.
Kuvan għandu jintuża b’ kawtela f’ pazjenti ta ’ iktar minn 65 sena, u f’ pazjenti bi problemi fil- fwied jew fil- kliewi.
How does Kuvan work?
Kif jaħdem Kuvan?
The high levels of phenylalanine in the blood are due to a problem with the conversion of phenylalanine into tyrosine by the enzyme ‘ phenylalanine hydroxylase’.
Il- livelli għoljin ta ’ fenilalanina fid- demm huma dovuti għal problema bil- konverżjoni tal- fenilalanina f’ tirosina bl- enzim ‘ fenilalanina idrossilażi (phenylalanine hydroxylase).
Patients with PKU have defective versions of the enzyme, and patients with BH4 deficiency have low levels of BH4, a ‘ cofactor ’ that this enzyme needs to work properly.
Il- pazjenti bil- PKU għandhom verżjonijiet difettużi ta ’ enzimi, u l- pazjenti bid- defiċjenza tal- BH4 ikollhom livelli baxxi ta ’ BH4, il - ‘ kofattur ’ li dan l- enzim ikollu bżonn biex jaħdem sew.
The active substance in Kuvan, sapropterin dihydrochloride, is a synthetic copy of BH4.
Is- sustanza attiva f’ Kuvan, sapropterin dihydrochloride, hija kopja sintetika ta ’ BH4.
In PKU, it works by enhancing the activity of the defective enzyme, and in BH4 deficiency it replaces the missing cofactor.
Fil- PKU, jaħdem billi jgħin l- attività tal - enzim difettuż, u fid- defiċjenza tal- BH4 jieħu post il- kofattur nieqes.
This helps to restore the ability of the enzyme to convert phenylalanine into tyrosine, reducing phenylalanine levels in the blood.
Dan jgħin biex jagħti lura l - abilità tal- enzim biex jikkonverti fenilalanina f’ tirosina, u b’ hekk inaqqas il- livelli tal- fenilalanina fid - demm.
How has Kuvan been studied?
Kif ġie studjat Kuvan?
The effects of Kuvan were first tested in experimental models before being studied in humans.
L- effetti ta ’ Kuvan għall- ewwel ġie ttestjat f’ mudelli sperimentali qabel ma ġew studjati fuq il - bnedmin.
For the treatment of patients with PKU, Kuvan has been studied in two main studies that compared Kuvan with placebo.
Għat- trattament ta ’ pazjenti bil- PKU, Kuvan ġie studjat f’ żewġ studji li qabblu Kuvan ma ’ plaċebo.
All of the patients included in the studies had shown a response to an initial eight-day course of Kuvan but had a period of at least one week without the medicine before the studies started.
Il - pazjenti kollha inklużi fl- istudji wrew rispons għal kors inizjali ta ’ tmint ijiem ta ’ Kuvan iżda kellhom perjodu ta ’ mill- inqas ġimgħa mingħajr il- mediċina qabel bdew l- istudji.
The first study involved 89 patients aged eight years or more who were not following a strict diet.
Fl- ewwel studju ħadu sehem 89 pazjent ta ’ tmien snin jew iktar li ma kinux qed isegwu dieta stretta.
The main measure of effectiveness was the reduction in blood phenylalanine levels over six weeks.
Il- kejl ewlieni tal- effikaċja kien it- tnaqqis fil- livelli tal- fenilalanina fid- demm matul perjodu ta ’ sitt ġimgħat.
The second study involved 46 children aged between four and 12 years, who were on a diet with a controlled level of phenylalanine.
Fit- tieni studju ħadu sehem 46 tifel u tifla ta ’ bejn erba ’ u 12- il sena, li kienu fuq dieta b’ livell ikkontrollat ta ’ fenilalanina.
From the third week of treatment, the diet was adjusted every two weeks based on blood phenylalanine levels.
Mit- tielet ġimgħa ta ’ trattament, id- dieta kienet aġġustata kull ġimagħtejn abbażi tal- livelli ta ’ fenilalanina fid- demm.
The main measure of effectiveness was the change in how much phenylalanine the children could eat while keeping blood phenylalanine at target levels.
Il- kejl ewlieni tal- effikaċja kien it- tibdil f’ kemm setgħu jieklu fenilalanina t- tfal waqt li jżommu l- livell tal- fenilalanina fid- demm fil- livelli fil- mira.
The study lasted for 10 weeks.
L- istudju dam 10 ġimgħat.
For the treatment of patients with BH4 deficiency, the company presented the results of three studies from the published literature with sapropterin dihydrochloride.
Għat- trattament tal- pazjenti bid- defiċjenza tal- BH4, il- kumpanija ppreżentat ir- riżultati ta ’ tliet studji mil- letteratura ppubblikata b’ sapropterin dihydrochloride.
One of these studies involved 16 patients who were treated for an average of 15.5 months.
F’ wieħed minn dawn l- istudji ħadu sehem 16- il pazjent li kienu qed jiġu ttrattati b’ medja ta ’ 15. 5 xhur.
What benefit has Kuvan shown during the studies?
X’ benefiċċju wera Kuvan waqt dawn l- istudji?
For the treatment of PKU, Kuvan was more effective than placebo.
Għat- trattament tal- PKU, Kuvan kien iktar effikaċi mill- plaċebo.
In the first study, blood phenylalanine levels were around 867 ‘ micromoles per litre ’ at the start of the study.
Fl- ewwel studju, il- livelli ta ’ fenilalanina kien madwar 867 ‘ mikromoli kull litru ’ fil- bidu tal- istudju.
Normal levels are around 60 micromoles per litre in people without PKU.
Il- livelli normali huma madwar 60 mikromoli kull litru fil- persuni mingħajr PKU.
After six weeks, phenylalanine levels had fallen by 236 micromoles per litre in the patients taking Kuvan and had risen by 3 micromoles per litre in the patients taking placebo.
Wara sitt ġimgħat, il- livelli ta ’ fenilalanina kienu naqsu b’ 236 mikromoli kull litru fil- pazjenti li kienu qed jieħdu Kuvan u kien żdied bi 3 mikromoli kull litru fil- pazjenti li jieħdu l- plaċebo.
In the second study, the children taking Kuvan could eat an average of 17.5 mg more phenylalanine per kilogram body weight every day after 10 weeks, compared to 3.3 mg more in the children taking placebo.
Fit- tieni studju, it- tfal li kienu qed jieħdu Kuvan setgħu jieklu medja ta ’ 17. 5 mg iktar fenilalanina għal kull kilogramma ta ’ piż korporju kuljum wara 10 ġimgħat, meta imqabbla ma ’ 3. 3 mg iktar fit- tfal li kienu qed jieħdu l- plaċebo.
In the studies of patients with BH4 deficiency, patients showed an improvement in blood phenylalanine levels and other markers of the disease when they were taking sapropterin dihydrochloride.
Fl- istudji tal- pazjenti b’ defiċjenza tal- BH4, il- pazjenti wrew titjib fil- livelli ta ’ fenilalanina fid- demm u markaturi oħrajn tal- marda meta kienu qed jieħdu sapropterin dihydrochloride.
What is the risk associated with Kuvan?
X’ inhu r- riskju assoċjat ma ’ Kuvan?
The most common side effects with Kuvan (seen in more than 1 patient in 10) are headache and rhinorrhoea (runny nose).
L- iktar effetti sekondarji komuni ma ’ Kuvan (li dehru f’ iktar minn pazjent wieħed minn kull 10) huma l- uġigħ ta ’ ras u l- flissjoni.
For the full list of all side effects reported with Kuvan, see the Package Leaflet.
Għal- lista sħiħa ta ’ effetti sekondarji rrappurtati ma ’ Kuvan, ara l- Fuljett ta ’ Tagħrif.
Kuvan should not be used in patients who may be hypersensitive (allergic) to sapropterin hydrochloride or any of the other ingredients.
Kuvan m’ għandux jintuża f’ pazjenti allerġiċi għal sapropterin hydrochloride jew għal kwalunkwe sustanza oħra tiegħu.
Why has Kuvan been approved?
Għaliex ġie approvat Kuvan?
The Committee for Medicinal Products for Human Use (CHMP) decided that Kuvan’ s benefits are greater than its risks for the treatment of HPA in adult and paediatric patients with PKU and with BH4 deficiency, who have been shown to be responsive to such treatment.
Il- Kumitat għall- Prodotti Mediċinali għall- Użu mill- Bniedem (CHMP) iddeċieda li l- benefiċċji ta ’ Kuvan huma ikbar mir- riskji tiegħu fit- trattament tal- HPA f’ pazjenti adulti u pedjatriċi b’ PKU u b’ defiċjenza tal- BH4, li ntwerew li rrispondew għal trattament bħal dan.
The Committee recommended that Kuvan be given marketing authorisation.
Il- Kumitat irrakkomanda li Kuvan jingħata l- awtorizzazzjoni għat- tqegħid fis- suq.
2/ 3 Other information about Kuvan:
2/ 3 Tagħrif ieħor dwar Kuvan:
The European Commission granted a marketing authorisation valid throughout the European Union for Kuvan to Merck KGaA on 2 December 2008.
Il- Kummissjoni Ewropea tat l- awtorizzazzjoni għat- tqegħid fis- suq għal Kuvan valida madwar l - Unjoni Ewropea kollha lil Merck KGaA fil - 2 ta ’ Diċembru 2008.
The summary of opinion of the Committee for Orphan Medicinal Products for Kuvan is available here.
Is- sommarju tal- opinjoni tal- Kumitat għall- Prodotti Mediċinali Orfni għal Kuvan jinstab hawn.
The full EPAR for Kuvan can be found here.
L- EPAR sħiħ għal Kuvan jista ’ jinstab hawn.
EU Numbers EU/ 1/ 08/ 481/ 001 EU/ 1/ 08/ 481/ 002 EU/ 1/ 08/ 481/ 003
Numru ta ’ l- EU EU/ 1/ 08/ 481/ 001 EU/ 1/ 08/ 481/ 002 EU/ 1/ 08/ 481/ 003
Invented name Kuvan Kuvan Kuvan
Isem inventat Kuvan Kuvan Kuvan
Strength 100 mg 100 mg 100 mg
Qawwa 100 mg 100 mg 100 mg
Pharmaceutical Form Soluble tablet Soluble tablet Soluble tablet
Għamla farmaċewtika Pillola li tinħall Pillola li tinħall Pillola li tinħall
Route of Administration Oral use Oral use Oral use
Mnejn jingħata Użu Orali Użu Orali Użu Orali
Packaging bottle (HDPE) bottle (HDPE) bottle (HDPE)
Il- pakkett flixkun (HDPE) flixkun (HDPE) flixkun (HDPE)
Package size 30 tablets 120 tablets 240 tablets
Daqs tal- pakkett 30 pilloli 120 pilloli 240 pilloli
SUMMARY OF PRODUCT CHARACTERISTICS
ANNESS I SOMMARJU TAL- KARATTERISTIĊI TAL- PRODOTT,
Kuvan 100 mg soluble tablets
Kuvan 100 mg pillola li tinħall
Each soluble tablet contains 100 mg of sapropterin dihydrochloride (equivalent to 77 mg of sapropterin).
Kull pillola li tinħall fiha 100 mg sapropterin dihydrochloride (ekwivalenti għal 77 mg ta ’ sapropterin).
Off-white to light yellow soluble tablet with “ 177 ” imprinted on one face.
Pillola li tinħall ta ’ kulur li jvarja minn abjad b’ xeħta ta ’ griż u isfar sa isfar ċar u għandha n- numru ‘ 177 ’ immarkat fuq naħa waħda.
Kuvan is indicated for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients of 4 years of age and over with phenylketonuria (PKU) who have been shown to be responsive to such treatment (see section 4.2).
Kuvan huwa indikat għal kura ta ’ hyperphenylalaninaemia (HPA) f’ persuni adulti u pazjenti tfal ta ’ 4 snin u aktar li jsofru mill- phenylketonuria (PKU) li jkunu ġa` urew rispons għal din il- kura (ara sezzjoni 4. 2).
Kuvan is also indicated for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment (see section 4.2).
Kuvan huwa indikat ukoll għal- kura ta ’ hyperphenylalaninaemia (HPA) f’ persuni adulti u pazjenti pedjatrici b’ defiċjenza ta ’ tetrahydrobiopterin (BH4) u li jkunu wrew rispons għal din il- kura (ara sezzjoni 4. 2).
Treatment with Kuvan must be initiated and supervised by a physician experienced in the treatment of PKU and BH4 deficiency.
Il- kura bil- Kuvan għandha tinbeda u titkompla bil- parir ta ’ tabib li għandu esperjenza fil- kura tal- PKU u tad- defiċjenza BH4.
Kuvan should be administered with a meal as a single daily dose, at the same time each day, preferably in the morning.
Kuvan għandu jingħata bħala doża waħda ma ’ l- ikel fl- istess ħin kuljum, preferibbilment filgħodu.
Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine levels and nutritional balance.
Sabiex wieħed jiżgura l- kontroll adegwat tal- livelli ta ’ phenylalanine fid- demm u bilanċ nutrizjonali waqt l- użu tal- Kuvan, hemm bżonn ta ’ kontroll sħiħ ta ’ l- ammont ta ’ phenylalanine kif ukoll ta ’ proteina fid- dieta.
As HPA due to either PKU or BH4 deficiency is a chronic condition, once responsiveness is demonstrated, Kuvan is intended for long-term use.
Peress li HPA dovuta għal jew PKU jew għad- defiċjenza BH4 hija kundizzjoni kronika, ladarba jidher li jkun hemm rispons, Kuvan għandu jitkompla fit- tul.
However, there are limited data regarding the long-term use of Kuvan.
Sadattant, l- informazzjoni disponibbli dwar l - użu ta ’ Kuvan fit- tul hija limitata.
Kuvan is provided as 100 mg tablets.
Kuvan huwa pprovdut f’ pilloli ta ’ 100 mg.
The calculated daily dose based on body weight should be rounded to the nearest multiple of 100.
Id- doża ta ’ kuljum ikkalkulata skond il- piż għandha tiġi korretta sal- iktar multiplu viċin tal- 100.
For instance, a calculated dose of 401 to 450 mg should be rounded down to 400 mg corresponding to 4 tablets.
Per eżempju, doża kkalkulata ta ’ 410 sa 450 mg għandha tiġi korretta l- isfel għal 400 mg li hija ekwivalenti għal 4 pilloli.
A calculated dose of 451 mg to 499 mg should be rounded up to 500 mg corresponding to 5 tablets.
Doża kkalkulata ta ’ 451 mg sa 499 mg għandha tiġi korretta l- fuq sa 500 mg, li hija ekwivalenti għal 5 pilloli.
The starting dose of Kuvan in adult and paediatric patients with PKU is 10 mg/ kg body weight once daily.
Id- doża tal- bidu ta ’ Kuvan f’ adulti u f’ pazjenti pedjatriċi li jsofru mill- PKU hija ta ’ 10 mg/ kg/ kuljum.
The dose is adjusted, usually between 5 and 20 mg/ kg/ day, to achieve and maintain adequate blood phenylalanine levels as defined by the physician.
Id- doża hija aġġustata normalment bejn 5 u 20 mg/ kg/ kuljum, sabiex wieħed jikseb u jżomm il- livelli adegwati ta ’ phenylalanine fid- demm, kif definiti mit- tabib.
2 BH4 deficiency
Defiċjenza BH4
The starting dose of Kuvan in adult and paediatric patients with BH4 deficiency is 2 to 5 mg/ kg body weight once daily.
Id- doża tal- bidu f’ adulti u f’ pazjenti pedjatriċi li jsofru mid- defiċjenza BH4, hija ta ’ minn 2 sa 5 mg / kg/ kuljum.
Doses may be adjusted up to 20 mg/ kg/ day.
Id- dożi jistgħu jiġu aġġustati sa 20 mg/ kg/ kuljum.
It may be necessary to divide the total daily dose into 2 or 3 administrations, distributed over the day, to optimise the therapeutic effect.
Sabiex wieħed jieħu l- aħjar effett terapewtiku, jista ’ jkun hemm il- bżonn li d- doża totali ta ’ kuljum tiġi maqsuma f’ żewġ jew 3 dożi mqassma matul il- ġurnata.
Determination of Response
Kif jiġi stabbilit ir- Rispons
It is of primary importance to initiate Kuvan treatment as early as possible to avoid the appearance of non-reversible clinical manifestations of neurological disorders in paediatric patients and cognitive deficits and psychiatric disorders in adults due to sustained elevations of blood phenylalanine.
Hu ta ’ importanza primarja li l- kura b’ Kuvan tinbeda kmieni kemm jista ’ jkun, sabiex minħabba livelli sostnuti ta ’ phenylananine fid- demm, jiġi evitat li jitfaċċaw manifestazzjonijiet kliniċi mhux reversibbli ta ’ disturbi newroloġiċi f’ pazjenti pedjatriċi, u defiċjenzi konjittivi u disturbi psikjatriċi fl - adulti.
Response to treatment is determined by a decrease in blood phenylalanine following treatment with Kuvan.
Ir- rispons wara l- kura b’ Kuvan huwa rifless bi tnaqqis ta ’ phenylalanine fid- demm.
Blood phenylalanine levels should be checked before initiating treatment and after 1 week of treatment with Kuvan at the recommended starting dose.
Il- livelli ta ’ phenylalanine fid- demm għandhom jiġu verifikati qabel ma tinbeda l- kura, kif ukoll wara ġimgħa ta ’ kura bid- doża tal- bidu rrakkomandata.
If an unsatisfactory reduction in blood phenylalanine levels is observed, then the dose of Kuvan can be increased weekly to a maximum of 20 mg/ kg/ day, with continued weekly monitoring of blood phenylalanine levels over a one month period.
Jekk jiġi osservat tnaqqis mhux sodisfaċenti fil- livelli ta ’ phenylalanine fid- demm, allura d- doża ta ’ Kuvan tista ’ kull ġimgħa tiġi miżjuda sa massimu ta ’ 20 mg/ kg / kuljum, b’ monitoraġġ kontinwu tal- livelli ta ’ phenylalanine fid- demm ta ’ kull ġimgħa għal perijodu ta ’ xahar.,.
The dietary phenylalanine intake should be maintained at a constant level during this period.
Phenylalanine għandu jingħata mad- dieta f’ livell kostanti tul dan il- perijodu.
A satisfactory response is defined as a ≥ 30 percent reduction in blood phenylalanine levels or attainment of the therapeutic blood phenylalanine goals defined for an individual patient by the treating physician.
Jista ’ wieħed jgħid li hemm rispons sodisfaċenti jekk il- livelli ta ’ phenylalanine fid- demm jilħqu ≥30 fil- mija jew kif il- miri terapewtiċi ta ’ phenylalanine fid- demm ġew milħuqa kif definit għal pazjent individwali mit- tabib kuranti.
Patients who fail to achieve this level of response within the described one month test period should be considered non-responsive and should not receive treatment with Kuvan.
Pazjenti li ma jilħqux dan il- livell ta ’ rispons matul il - perijodu ta ’ xahar prova, għandhom jiġu kkunsidrati li ma kienx hemm rispons, u għalhekk ma għandhomx jiġu kkurati b’ Kuvan.
Once responsiveness to Kuvan has been established, the dose may be adjusted within the range of 5 to 20 mg/ kg/ day according to response to therapy.
Meta r- rispons għal Kuvan ikun ġie stabbilit, d- doża tista ’ tiġi aġġustata skond ir- rispons għat - terapija, fil- medda ta ’ bejn 5 u 20 mg/ kg/ kuljum.
It is recommended that blood phenylalanine and tyrosine levels be tested one or two weeks after each dose adjustment and monitored frequently thereafter.
Huwa rrakkomandat li l- livelli ta ’ phenylalanine fid- demm u dawk ta ’ tyrosine jkunu kkonfermati ġimgħa jew ġimagħtejn wara kull aġġustament fid- doża, u wara jiġu osservati u segwiti frekwentement.
Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho-motor development).
Pazjenti kkurati b’ Kuvan għandhom ikomplu b’ dieta ristretta ta ’ phenylalaninine u jkollhom eżami kliniku regolarment (bħal monitoraġġ tal- livelli ta ’ phenylalanine fid- demm u tal - livelli ta ’ tyrosine, kemm jieħdu nutrijenti, u żviluppi psiko- motoreji).
The tablets should be administered as a single daily dose with a meal, to increase the absorption, and at the same time each day preferably in the morning.
Sabiex jiżdied l- assorbiment, il- pilloli għandhom jingħataw bħala doża waħda kuljum ma ’ l- ikel, fl - istess ħin tal- ġurnata u preferibbilment filgħodu.
Patients should be advised not to swallow the desiccant capsule found in the bottle.
Pazjenti għandhom jiġu avżati biex ma ’ jibilgħux il- kapsula ta ’ dessikant li tinsab fil- flixkun.
The prescribed number of tablets should be placed in a glass or cup of water and stirred until dissolved.
In- numru ta ’ pilloli preskritti għandhom jitpoġġew f’ tazza jew kikkra bl- ilma u għandhom jiġu imħawda sakemm jinħallu.
It may take a few minutes for the tablets to dissolve.
Il- pillolijdumu xi ftit minuti biex jinħallu.
To make the tablets dissolve faster they can be crushed.
Biex il- pilloli jinħallu aktar malajr jistgħu jiġu mitħuna.
Small particles may be visible in the solution and will not affect the effectiveness of the medicinal product.
Frak żgħir jista ’ jkun viżibbli fis- soluzzjoni u ma jnaqqasx l- effikaċja tal - prodott mediċinali.
The solution should be drunk within 15 to 20 minutes.
Is- soluzzjoni għandha tinxtorob mhux aktar tard minn 15 sa 20 minuta minn meta tkun ġiet ippreparata.
For doses below 100 mg, one tablet should be dissolved in 100 ml of water and the volume of solution corresponding to the prescribed dose administered.
3 Għal dożi taħt il- 100 mg pillola waħda għandha tiġi maħlula f’ 100 ml ilma u jingħata l- volum ta ’ soluzzjoni li jikkorrispondi għad- doża preskritta.
An accurate measuring device with suitable graduations should be used to ensure administration of the appropriate volume of solution.
Sabiex jiġi żgurat li jittieħed il- volum xieraq tas - soluzzjoni, għandu jintuża strument ta ’ kejl preċiż li jkollu l- marki jew diviżjonijiet kollha (ta 'kejl).
The prescribed number of tablets should be placed in a glass or cup with 120 to 240 ml of water and stirred until dissolved.
In- numru ta ’ pilloli preskritti għandhom jitpoġġew f’ tazza jew kikkra b’ 120 sa 240 ml ilma u jiġu mħawda sakemm jinħallu.
Paediatric patients
Pazjenti pedjatriċi
The prescribed number of tablets should be placed in a glass or cup with up to 120 ml of water and stirred until dissolved.
In- numru ta ’ pilloli preskritti għandhom jitpoġġew f’ tazza jew kikkra b’ 120 ml ilma u jiġu mħawda sakemm jinħallu.
3 Dose adjustment
Aġġustament tad- Doża
Treatment with Kuvan may decrease blood phenylalanine levels below the desired therapeutic level.
Il- kura b’ Kuvan tista ’ tnaqqas il- livelli ta ’ phenylalanine fid- demm taħt il- livell terapewtiku mixtieq.
Adjustment of the sapropterin dose or modification of dietary phenylalanine intake may be required to achieve and maintain blood phenylalanine levels within the desired therapeutic range.
Jista ’ jkun hemm bżonn aġġustament fid- doża ta ’ sapropterin jew modifikazzjoni tal- ammont ta ’ phenylalanine fid- dieta, sabiex il- livelli ta ’ phenylalanine fid- demm jinżammu fil- medda terapewtika mixtieqa.
Blood phenylalanine and tyrosine levels should be tested, particularly in children, one to two weeks after each dose adjustment and monitored frequently thereafter, under the direction of the treating physician.
Speċjalment fit- tfal, il- livell ta ’ phenylalanine fid- demm u l- livell ta ’ tyrosine, għandhom jiġu aġġustati u wara jiġu osservati u segwiti frekwentement, taħt id- direzzjoni tat- tabib kuranti.
If inadequate control of blood phenylalanine levels is observed during treatment with Kuvan, the patient ’ s adherence to the prescribed treatment, and diet, should be reviewed before considering an adjustment of the dose of Kuvan.
Jekk waqt il- kura b’ Kuvan, jiġi nnutat kontroll inadegwat fil- livelli ta ’ phenylalanine fid- demm, wieħed għandu jifli bir- reqqa kemm i t- trattament preskritt kif ukoll id- dieta, qabel jiġi kkunsidrat aġġustament fid- doża ta ’ Kuvan.
Discontinuation of Kuvan treatment should be done only under the supervision of a physician.
Il- kura b’ Kuvan għandha ssir u titwaqqaf biss taħt is- superviżjoni tat- tabib.
More frequent monitoring may be required, as blood phenylalanine levels may increase.
Jista ’ jkun hemm bżonn ta ’ monitoraġġ iżjed frekwenti għax il- livelli ta ’ phenylalanine fid- demm jistgħu jiżdiedu.
Dietary modification may be necessary to maintain blood phenylalanine levels within the desired therapeutic range.
Jista ’ jkun hemm bżonn ta ’ modifikazzjoni fid- dieta biex jinżammu l- livelli ta ’ phenylalanine fid- demm fil - medda terapewtika mixtieqa.
Special populations
Pazjenti speċjali
Kuvan has not been specifically studied in paediatric patients under 4 years of age (see section 5.1).
L- użu ta ’ Kuvan ma ’ ġiex speċifikament studjat f’ pazjenti pedjatriċi ta ’ taħt l- 4 snin fl- eta ’ (ara sezzjoni 5. 1).
Safety and efficacy of Kuvan in patients above 65 years of age have not been established.
Is- sigurta ’ u l- effikaċja ta ’ Kuvan f’ pazjenti ta ’ iktar minn 65 sena ma ’ ġietx stabbilita.
Caution must be exercised when prescribing to elderly patients.
Għaldaqstant, wieħed għandu jaħsibha sew qabel l- użu f’ pazjenti anzjani.
Safety and efficacy of Kuvan in patients with renal or hepatic insufficiency have not been established.
Is- sigurta ’ u l- effikaċja ta ’ Kuvan f’ pazjenti li jkunu qed ibatu b’ insuffiċjenza tal- kliewi jew tal- fwied, ma ’ ġietx stabbilita.
Caution must be exercised when prescribing to such patients.
Wieħed għandu joqgħod attent qabel jikteb riċetta għal dan it- tip ta ’ pazjent.
Patients treated with Kuvan must continue a restricted phenylalanine diet and undergo regular clinical assessment (such as monitoring of blood phenylalanine and tyrosine levels, nutrient intake, and psycho-motor development).
Pazjenti kkurati b’ Kuvan għandhom ikomplu b’ dieta ristretta ta ’ phenylalanine u regolarment għandhom jissottomettu ruħhom ghal- valutazzjoni klinika (eż. livelli ta ’ phenylalanine u tyrosine fid - demm jinżammu taħt osservazzjoni, l- itteħid ta ’ nutrijenti u żvilupp psiko- motoreju).
Sustained or recurrent dysfunction in the phenylalanine-tyrosine-dihydroxy-L-phenylalanine (DOPA) metabolic pathway can result in deficient body protein and neurotransmitter synthesis.
Disfunzjoni fit- tul u li tirrepeti ruħha fir- rotta metabolika tal- phenylalanine- tyrosine- dihydroxy – L – phenylalanine (DOPA), tista ’ tirriżulta f’ defiċjenza ta ’ proteini fil- ġisem u fis- sintesi ta ’ sustanzi
Prolonged exposure to low blood phenylalanine and tyrosine levels during infancy has been associated with impaired neurodevelopmental outcome.
Esponiment fit- tul għal livelli baxxi ta ’ phenylalanine u ta ’ tyrosine fid- demm waqt it- tfulija, ġiet assoċjata ma tfixkil fl- iżvilupp newroloġiku.
Active management of dietary phenylalanine and overall protein intake while taking Kuvan is required to ensure adequate control of blood phenylalanine and tyrosine levels and nutritional balance.
L- immaniġjar attiv tal- konsum ta ’ phenylalanine fid- dieta u kemm tittieħed proteina waqt l- użu ta ’ Kuvan, huwa neċessarju sabiex jiġi żġurat kontroll adegwat tal- livelli ta ’ phenylalanine u tyrosine fid- demm, kif ukoll ta ’ bilanċ ta ’ nutriment.
Consultation with a physician is recommended during illness as blood phenylalanine levels may increase.
Il- konsultazzjoni ma ’ tabib hija rrakkomandata waqt il- mard peress li l- livelli ta ’ phenylalanine fid - demm jistgħu jiżdiedu.
There are limited data regarding the long-term use of Kuvan.
L- informazzjoni dwar l- użu fit- tul ta ’ Kuvan hija limitata.
Caution is advised when sapropterin is used in patients with predisposition to convulsions.
Kawtela hija rrakkomandata fl- użu ta ’ sapropterin f’ pazjenti li huma predisposti għal konvulżjonijiet.
In clinical studies of patients with BH4 deficiency treated with a preparation of sapropterin, convulsions and exacerbation of convulsions was observed.
Fi studji kliniċi ta ’ pazjenti bid- defiċjenza BH4 li ġew ikkurati bi preparazzjoni ta ’ sapropterin, ġew innutati konvulżjonijiet u l- aggravazzjoni ta ’ konvulżjonijiet.
This was not observed in the clinical trials of Kuvan in patients with PKU.
Dawn l- effetti ma ’ ġewx osservati fi provi kliniċi ta ’ Kuvan f’ pazjenti li jsofru bil- PKU.
4 Sapropterin should be used with caution in patients who are receiving concomitant levodopa, as combined treatment with sapropterin may cause increased excitability and irritability.
Kawtela hija rrakkomandata fl- użu tal- sapropterin f’ pazjenti li qed jingħataw levodopa fl- istess ħin, għaliex l- użu flimkien ma ’ sapropterin, jista ’ jġib żieda fil- livell ta ’ eċċitament u irritabilita ’.
Kuvan has not been specifically studied in paediatric patients under 4 years of age (see section 5.1).
L- użu ta ’ Kuvan f’ pazjenti pedjatriċi ta ’ inqas minn 4 snin ma ’ ġiex speċifikatament studjat (ara sezzjoni 5. 1).
Safety and efficacy of Kuvan in patients above 65 years of age have not been established.
Is- sigurta ’ u l- effikaċja ta ’ Kuvan f’ pazjenti ta ’ aktar minn 65 sena ma ’ ġewx stabbiliti.
Safety and efficacy of Kuvan in patients with renal or hepatic insufficiency have not been established.
Is- sigurta ’ u l- effikaċja tal- Kuvan f’ pazjenti li jsofru b’ insuffiċjenza fil- kliewi u fil- fwied ma ’ ġewx stabbiliti.
No interaction studies have been performed.
Ma ’ sarux studji dwar l- effett ta ’ mediċini oħra jew ta ’ affarijiet oħra fuq l- effett farmaċewtiku tal - prodott.
Although concomitant administration of inhibitors of dihydrofolate reductase (e. g. methotrexate, trimethoprim) has not been studied, such medicinal products may interfere with BH4 metabolism.
Methotrexate, trimethoprim) ma ’ ġiex studjat, dawn il- prodotti mediċinali jistgħu jfixklu l- metaboliżmu BH4.
Caution is recommended when using such agents while taking Kuvan.
Trid tintuża kawtela meta jiġu użati aġenti simili waqt l- użu ta ’ Kuvan.
Caution is recommended during concomitant use of Kuvan with all agents that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e. g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil.
BH4 huwa ko- fattur għan- nitric oxide synthetase. Kawtela hija rrakkomandata waqt l- użu ta ’ Kuvan fl - istess ħin ma ’ l- aġenti kollha li jikkawżaw vażodilatazzjoni, inklużi dawk għal użu topikali, li jikkawżaw metaboliżmu tal- ossidu nitriku (NO), li jinkludu d- donaturi klassiċi NO (bħal glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP) u molsidomin), inibituri phosphodiesterase tat- tip 5 (PDE- 5) u minoxidil.
Caution should be exercised when prescribing Kuvan to patients receiving treatment with levodopa, as it may cause increased excitability and irritability.
Għandha tintuża kawtela meta Kuvan ikun se jingħata b’ riċetta lil- pazjenti li jkunu qed jiġu kkurati bil- levodopa u dan peress li jista ’ jikkawża żieda fil- livell ta ’ eċċitament u irritabilita ’.
For Kuvan, no clinical data on exposed pregnancies are available.
Fuq Kuvan 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.
Studji fuq l- annimali ma ’ jurux effetti ħżiena diretti jew indiretti fuq it- tqala, fuq l- iżvilupp tal- fetu, fuq il- ħlas jew fuq l- iżvilupp wara t - twelid.
Maternal blood phenylalanine levels must be strictly controlled before and during pregnancy.
5 Il- livelli ta ’ phenylalanine fid- demm tal- omm għandhom jiġu kkontrollati strettament qabel u waqt it - tqala.
If maternal phenylalanine levels are not strictly controlled before and during pregnancy, this could be harmful to the mother and the foetus.
Jekk il- livelli ta ’ phenylanine fid- demm tal- omm ma jkunux ikkontrollati strettament qabel u waqt it- tqala, dan jista ’ jkun ta ’ dannu kemm għall- omm u kemm għall- fetu.
Physician-supervised restriction of dietary phenylalanine intake prior to and throughout pregnancy is the first choice of treatment in this patient group.
It- tnaqqis ta ’ phenylalanine fid- dieta taħt sorveljanza tat- tabib, qabel u matul it- tqala, hija l- ewwel għażla tal- kura f’ dan it- tip ta ’ pazjent.
The use of Kuvan should be considered only if strict dietary management does not adequately reduce blood phenylalanine levels.
L- użu ta ’ Kuvan għandu jiġi kkunsidrat biss jekk l- immaniġjar strett fid- dieta mhux adegwat biex inaqqas il- livelli ta ’ phenylalanine fid- demm.
Caution must be exercised when prescribing to pregnant women.
Wieħed għandu joqgħod attent meta jikteb riċetta għal din il- mediċina għal nisa tqal.
It is not known whether sapropterin or its metabolites are excreted in human breast milk.
Mhux magħruf jekk sapropterin u l- metaboliti tiegħu fil- bniedem jgħaddux fil- ħalib tas- sider.
Kuvan should not be used during breast-feeding.
Kuvan m’ għandux jintuża waqt it- treddigħ.
No studies on the effects on the ability to drive and use machines have been performed.
Ma sarux studji dwar l- effetti fuq il- ħila biex issuq jew biex tħaddem magni.
Approximately 35% of the 579 patients who received treatment with sapropterin dihydrochloride (5 to 20 mg/ kg/ day) in the clinical trials for Kuvan experienced adverse reactions.
Approssimattivament 35% minn 579 pazjent li rċevew kura b’ sapropterin dihydrochloride (5 sa 20mg/ kg/ kuljum) fi provi kliniċi ta ’ Kuvan, esperjenzaw effetti mhux mixtieqa.
The most commonly reported events are headache and rhinorrhoea.
L- iżjed effetti komuni li ġew irrapurtati kienu l- uġigħ ta ’ ras u flissjoni.
In the pivotal clinical trials for Kuvan, the following undesirable effects have been identified.
Fil - provi kliniċi l- aktar importanti ta ’ Kuvan, ġew identifikati dawn l- effetti mhux mixtieqa.
5 Frequencies are defined as:
Il- frekwenzi huma definiti bħala:
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Komuni ħafna( ≥1/ 10) u Komuni (≥1/ 100 to < 1/ 10). F’ kull sezzjoni ta ’ frekwenza, l- effetti mhux mixtieqa huma mniżżla skond kemm huma serji, bl- aktar serji jitniżżlu l- ewwel.
System Organ Class
Sistema tal- klassifika tal - organi
Nervous system disorders Respiratory, thoracic and
Disturbi fis- sistema nervuża
Pharyngolaryngeal pain
Disturbi respiratorji, toraċiċi u medjastinali
mediastinal disorders
Flissjoni
Rhinorrhoea
Disturbi gastro- intestinali
Nasal congestion Cough Diarrhoea
Dijarea Rimettar Uġigħ addominali
Gastrointestinal disorders Metabolism and nutrition disorders
Disturbi fil- metaboliżmu u n - nutrizzjoni
Vomiting Abdominal pain Hypophenylalaninemia
Hypophenylalaninemia
Rebound, as defined by an increase in blood phenylalanine levels above pre-treatment levels, may occur upon cessation of treatment.
Jekk il- kura tieqaf, jista ’ jkun hemm żieda fil- livelli ta ’ phenylalanine fid- demm għal livelli ogħla minn dak ta ’ qabel il- kura.
Headache and dizziness have been reported after the administration of sapropterin dihydrochloride above the recommended maximum dose of 20 mg/ kg/ day.
Uġigħ ta ’ ras u sturdament ġew irrapurtati wara l- għoti ta ’ sapropterin dihydrochloride f’ doża iktar għolja minn dik irrakkomandata ta ’ 20 mg/ kg/ kuljum.
Treatment of overdose should be directed to symptoms.
Jekk tiittieħed doża eċċessiva il kura tikkonsisti li ttaffi s- sintomi.
Various alimentary tract and metabolism products, ATC code:
Kategorija farmakoterapewtika: prodotti relattivi għas- sistema alimentarja u l- metaboliżmu, Kodiċi ATC:
Hyperphenylalaninaemia (HPA) is diagnosed as an abnormal elevation in blood phenylalanine levels and is usually caused by autosomal recessive mutations in the genes encoding for phenylalanine hydroxylase enzyme (in the case of phenylketonuria, PKU) or for the enzymes involved in 6R-tetrahydrobiopterin (6R-BH4) biosynthesis or regeneration (in the case of BH4 deficiency).
F’ Hyperphenylalaninaemia (HPA) ikun hemm żieda anormali fil- livelli ta ’ phenylalanine fid- demm li hija normalment ikkawżata b’ mutazzjonijiet awtosomali reċessivi involuti fil- konverżjoni tal- ġeni għall- enżima phenylalanine hydroxylase (f’ kaz ta ’ phenylketonuria, PKU) jew għall- enżimi nvoluti fil- bijosintesi 6R- tetrahydrobiopterin jew fir- riġenerazzjoni (f’ każ ta ’ defiċjenza BH4).
BH4 deficiency is a group of disorders arising from mutations or deletions in the genes encoding for one of the five enzymes involved in the biosynthesis or recycling of BH4.
Id- defiċjenza BH4 tirriżulta minn grupp ta ’ devjazzjonijiet mis- sistema u ordni normali kawżati minn mutazzjonijiet jew tneħħija, fil- konverżjoni tal- ġeni f’ waħda mill- 5 enżimi nvoluti fil- bijosintesi jew ir- riċiklagg tal - BH4.
In both cases, phenylalanine cannot be effectively transformed into the amino acid tyrosine, leading to increased phenylalanine levels in the blood.
Fiż- żewġ każijiet phenylalanine qatt ma ’ jista ’ jiġi effettivament trasformat fl- amino aċidu tyrosine, li jwassal għal żieda fil- livelli ta ’ phenylalanine fid- demm.
Sapropterin is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan.
Sapropterin hija verzjoni sintetika ta ’ 6R- BH4 maħdum b’ mod naturali, li huwa ko- fattur tal - hydroxylases għal phenylalanine, tyrosine u tryptophan.
The rationale for administration of Kuvan in patients with BH4-responsive PKU is to enhance the activity of the defective phenylalanine hydroxylase and thereby increase or restore the oxidative metabolism of phenylalanine sufficient to reduce or maintain blood phenylalanine levels, prevent or decrease further phenylalanine accumulation, and increase tolerance to phenylalanine intake in the diet.
Ir- raġunament li jingħata Kuvan f’ pazjenti bi PKU li għandhom defiċjenza ta ’ BH4, huwa biex iżżid l - attivita ’ tal- phenylalanine hydroxylase difettuż u b’ dan il- mod iżżid jew tirrestawra l- metaboliżmu ossidattiv ta ’ phenylalanine, b’ riżultat li jkun suffiċjenti biex inaqqas jew iżomm il- livelli ta ’ phenylalanine fid- demm, kif ukoll jipprevjeni jew inaqqas aktar l- akkumulazzjoni ta ’ phenylalanine u żżid it- tolleranza meta jittieħed phenylalanine fid- dieta.
The rationale for administration of Kuvan in patients with BH4 Deficiency is to replace the deficient levels of BH4, thereby restoring the activity of phenylalanine hydroxylase.
Ir- raġunament fl- għoti ta ’ Kuvan f’ pazjenti li jbatu bid- defiċjenza BH4, hu sabiex dan jgħolli l- livelli defiċjenti ta ’ BH4, b’ mod li terġa tiġi rrestawrata l- attivita ’ ta ’ phenylalanine hydroxlase.
6 Clinical efficacy
Effikaċja klinika
The Phase III clinical development program for Kuvan included 2, randomised placebo-controlled studies in patients with PKU.
Il - Fażi III tal- programm ta ’ żvilupp kliniku ta ’ Kuvan kien jinkludi żewġ studji kkontrollati bil - plaċebo f’ pazjenti li jsofru bil- PKU magħżula kif ġie ġie.
The results of these studies demonstrate the efficacy of Kuvan to reduce blood phenylalanine levels and to increase dietary phenylalanine tolerance.
Ir- riżultati ta ’ dawn l- istudji juru l- effikaċja ta ’ Kuvan fit- tnaqqis tal- livelli ta ’ phenylalanine fid- demm u fiż- żieda tat- tolleranza ta ’ phenylalanine fid- dieta.
In 88 subjects with poorly controlled PKU who had elevated blood phenylalanine levels at screening, sapropterin dihydrochloride 10 mg/ kg/ day significantly reduced blood phenylalanine levels as compared to placebo.
Fi 88 suġġett b’ kontroll fqir tal- PKU li meta ġew eżaminati (screened) kellhom livelli għolja ta ’ phenylalanine fid- demm, 10 mg/ kg/ kuljum ta ’ sapropterin dihydrochloride naqqas b’ mod sinifikanti l - livelli ta ’ phenylalanine fid- demm meta mqabbel mal- plaċebo.
The baseline blood phenylalanine levels for the Kuvan-treated group and the placebo group were similar, with mean ± SD baseline blood phenylalanine levels of 842.7 ± 299.6 μ mol/ l and 888.3 ± 323.1 μ mol/ l, respectively.
Il- linja bażi tal- livelli ta ’ phenylalanine fid- demm tal- grupp ikkurat b’ Kuvan u l- grupp tal- plaċebo kienu simili, bil- medja ± SD mill- livelli ta ’ phenylalanine fid- demm kienet ta ’ 842. 7 ± 299. 6 µmol/ l u 888. 3 ± 323. 1 µmol/ l, rispettivament.
The mean ± SD decrease from baseline in blood phenylalanine levels at the end of the 6 week study period was 235.9 ± 257.0 μ mol/ l for the sapropterin treated group (n=47) as compared to an increase of 2.9 ± 239.5 μ mol/ l for the placebo group (n=41) (p < 0.001).
It - tnaqqis tal- medja ± SD fil- livelli ta ’ phenylalanine fid- demm mill- linja bażi fi tmiem il- perijodu ta ’ studju ta ’ 6 ġimgħat kien ta ’ 235. 9 ± 257. 0 µmol/ l għall- grupp ikkurat b’ sapropterin (n=47) meta mqabbel maż- żieda ta ’ 2. 9 ± 239. 5 µmol/ l għall- grupp ikkurat bil- plaċebo (n=41) (p < 0. 001).
For patients with baseline blood phenylalanine levels ≥ 600 µmol/ l, 41.9% (13/ 31) of those treated with sapropterin and 13.2% (5/ 38) of those treated with placebo had blood phenylalanine levels < 600 µmol/ l at the end of the 6-week study period (p=0.012).
Għall - pazjenti bil- livelli ta’ phenylalanine fid- demm fil- linja bażi ta ’ ≥600 µmol/ l, 41. 9% (13/ 31) ta ’ dawk ikkurati b’ sapropterin u 13. 2% (5/ 38) ta ’ dawk ikkurati bil- plaċebo kellhom livelli ta ’ phenylalanine fid- demm < 600 µmol/ l fit- tmiem tal- perijodu ta ’ studju ta ’ 6 ġimgħat (p=0. 012).
In a separate 10-week, placebo-controlled study, 45 PKU patients with blood phenylalanine levels controlled on a stable phenylalanine-restricted diet (blood phenylalanine ≤ 480 μ mol/ l on enrolment) were randomized 3:1 to treatment with sapropterin dihydrochloride 20 mg/ kg/ day (n=33) or placebo (n=12).
Fi studju separat ta ’ 10 ġimgħat ikkontrollat bil- plaċebo, 45 pazjenti bil- PKU b’ livelli ta ’ phenylalanine fid- demm ikkontrollati abbażi ta ’ dieta stabbli ristretta għal phenylalanine (phenylalanine fid- demm ta ’ ≤ 480 µmol/ l meta ġew irreġistrati) ġew magħżula mingħajr pjan definit jew ordni rranġata minn qabel fuq bażi 3: 1 għal kura b’ sapropterin dihydrochloride 20 mg/ kg/ kuljum (n=33) jew bil- plaċebo (n=12).
After 3 weeks of treatment with sapropterin dihydrochloride 20 mg/ kg/ day, blood phenylalanine levels were significantly reduced; the mean ± SD decrease from baseline in blood phenylalanine level within this group was 148.5 ±134.2 μ mol/ l (p < 0.001).
Wara 3 ġimgħat pazjenti kemm fil- grupp ikkurat b’ sapropterin u
After 3 weeks, subjects in both the sapropterin and placebo treatment groups were continued on their phenylalanine-restricted diets and dietary phenylalanine intake was increased or decreased using standardized phenylalanine supplements with a goal to maintain blood phenylalanine levels at < 360 μ mol/ l.
7 kemm f’ dak ikkurat bil- plaċebo baqgħu jiġu soġġetti għal dieti ristretti għal phenylalanine u biż- żieda jew tnaqqis ta ’ phenylalaline fid- dieta bl- użu ta ’ supplimenti standardizzati tal- phenylaline bl- iskop li l- phenylalanine fid- demm jiġi miżmum f’ livell ta ’ < 360 µmol/ l.
There was a significant difference in dietary phenylalanine tolerance in the sapropterin treatment group as compared to the placebo group.
Kien hemm differenza sinifikanti fit - tolleranza ta ’ phenylalanine fid- dieta fil- grupp ta ’ kura b’ sapropterin imqabbel mal- grupp tal- plaċebo.
The mean ± SD increase in dietary phenylalanine tolerance was 17.513 ±13.268 mg/ kg/ day for the group treated with sapropterin dihydrochloride 20 mg/ kg/ day, compared to 3.259 ± 5.291 mg/ kg/ day for the placebo group (p = 0.006).
Iż- żieda medja± SD fit- tolleranza ta ’ phenylalanine fid- dieta kienet 17. 513 ±13. 268 mg/ kg/ kuljum fil - grupp ikkurat b’ sapropetin dihydrochloride abbażi ta ’ 20mg/ kg/ kuljum, imqabbla ma ’ 3. 259 ± 5. 291 mg/ kg/ kuljum għall- grupp tal- plaċebo (p=0. 0006).
For the sapropterin treatment group, the mean ± SD total dietary phenylalanine tolerance was 38.406 ± 21.606 mg/ kg/ day during treatment with sapropterin dihydrochloride 20 mg/ kg/ day compared to 15.660 ± 7.159 mg/ kg/ day before treatment.
Għall- grupp ikkurat b’ sapropterin, il - medja± SD tat- tolleranza totali ta ’ phenylanine fid- dieta kienet 38. 406± 21. 606 mg/ kg/ kuljum waqt il - kura b’ sapropterin dihydrochloride ta ’ 20 mg/ kg/ kuljum komparat ma 15. 660 ± 7. 159 mg/ kg/ kuljum qabel il- kura.
Paediatric population
Pazjenti Pedjatriċi
Kuvan has not been specifically studied in children under 4 years of age, although the published literature indicates that more than 600 children of 0 to 4 years old with PKU, have been exposed to treatment with an un-registered preparation of BH4, including at least 35 who received therapy ≥ 2 months.
Kuvan ma ’ ġiex speċifikament studjat fi tfal ta ’ taħt l- 4 snin, għalkemm il- letteratura ppubblikata tindika li iktar minn 600 tifel u tifla ta ’ bejn 0 u 4 snin li jsofru bil- PKU, ġew sottoposti għal kura bi preparazzjoni mhux reġistrata ta ’ BH4 u li minnhom almenu 35 irċevew terapija għal ≥ xahrejn.
The maximum daily dose used was 20 mg/ kg body weight.
Id - doża massima użata ta ’ kuljum kienet 20 mg/ kg ta ’ piż.
Limited studies have been conducted in patients under 4 years of age with BH4 deficiency using another formulation of the same active substance (sapropterin) or an un-registered preparation of BH4.
Studji ristretti ġew imwettqa f’ pazjenti ta ’ inqas minn 4 snin li kellhom id- defiċjenza BH4, fejn ġiet użata formulazzjoni oħra tal- istess sustanza attiva (sapropterin) jew preparazzjoni mhux reġistrata ta ’ BH4.
Sapropterin is absorbed after oral administration of the dissolved tablet, and the maximum blood concentration (Cmax) is achieved 3 to 4 hours after dosing in the fasted state.
Sapropterin huwa assorbit wara li l- pillola maħlula tittieħed mill- ħalq u l- konċentrazzjoni massima fid- demm (Cmax) titla ’ bejn 3 u 4 sigħat wara li tittieħed id- doża wara sawma.
The rate and extent of absorption of sapropterin is influenced by food.
Ir- rata u l- entita ’ ta ’ assorbiment ta ’ sapropterin hija influwenzata mill- ikel.
The absorption of sapropterin is higher after a high-fat, high-calorie meal as compared to fasting, resulting, in average, in 40-85% higher maximum blood concentrations achieved 4 to 5 hours after administration.
L- assorbiment ta ’ sapropterin huwa ogħla wara ikla b’ kontenut għoli ta ’ xaħam u kaloriji imqabbel ma ’ stat ta ’ sawm, b’ riżultat fil- medja ta ’ 40 - 85% konċentrazzjonijiet massimi fid- demm ottenuti minn 4 sa 5 siegħat wara li jittieħed.
Absolute bioavailability or bioavailability for humans after oral administration is not known.
Bijodisponibilità assoluta jew bijodisponibilità fil- bniedem wara li tittieħed mil- ħalq mhuwiex magħruf.
7 Distribution
Distribuzzjoni
In non-clinical studies, sapropterin was primarily distributed to the kidneys, adrenal glands, and liver as assessed by levels of total and reduced biopterin concentrations.
Fi studji mhux kliniċi, sapropterin kien primarjament distribwit fil- kliewi, fil- glandoli adrenali u fil - fwied, kif valutati mill- livelli totali u dawk ridotti tal- konċentrazzjonijiet ta ’ biopterin.
In rats, following intravenous radiolabeled sapropterin administration, radioactivity was found to distribute in foetuses.
Fil- ġrieden, wara l- injezzjoni fil- vini ta ’ sapropterin immarkat bir- radioattivita`, instab li r- radjoattivita ’ xterdet fil- feti.
Excretion of total biopterin in milk was demonstrated in rats by intravenous route.
Il- ħruġ ta ’ biopterin totali fil- ħalib instabet fil- ġrieden permezz ta ’ injezzjoni fil- vini.
No increase in total biopterin concentrations in either foetuses or milk was observed in rats after oral administration of 10mg/ kg sapropterin dihydrochloride.
Fil - ġrieden, ma kienx hemm l- ebda żieda fil- konċentrazzjonijiet ta ’ biopterin totali la fil- feti u lanqas fil - ħalib wara l- għoti mill- ħalq ta ’ 10 mg/ kg ta ’ sapropterin dihydrochloride.
Sapropterin dihydrochloride is primarily metabolised in the liver to dihydrobiopterin and biopterin.
Sapropterin dihydrochloride fil- fwied huwa primarjament immetaboliżżat għal dihydrobiopterin u biopterin.
Since sapropterin dihydrochloride is a synthetic version of the naturally occurring 6R-BH4, it can be reasonably anticipated to undergo the same metabolism, including 6R-BH4 regeneration.
Peress li sapropterin dihydrochloride huwa verżjoni sintetika tal- prodott naturali 6R- BH4, wieħed jista ’ bir- raġun jistenna li jkollu l- istess metaboliżmu, nkluża r- riġenerazzjoni 6R- BH4.