natgillin/translations-raw huggingface dataset:
Da alendronat og D3- vitamin allerede anvendes særskilt i godkendte lægemidler i Den Europæiske Union, fremlagde firmaet data, som var indsamlet i tidligere undersøgelser, og data fra den offentliggjorte faglitteratur.
Because alendronate and vitamin D3 are already used separately in authorised medicines in the European Union, the company presented data obtained in earlier studies and from the published literature.
Firmaet gennemførte også en undersøgelse hos 35 mænd og 682 postmenopausale kvinder med osteoporose for at dokumentere, at ADROVANCE effektivt øger D - vitaminniveauerne.
The company also carried out a study in 35 men and 682 post-menopausal women with osteoporosis to show ADROVANCE’ s effectiveness in increasing vitamin D levels.
Patienterne fik enten ADROVANCE eller alendronat én gang om ugen.
Patients received either ADROVANCE or alendronate only once a week.
Det primære mål for virkningen var procentdelen af patienter med lave D- vitaminniveauer.
The main measure of effectiveness was the percentage of patients with low vitamin D levels.
Hvilken fordel viser undersøgelserne, at der er ved ADROVANCE?
What benefit has ADROVANCE shown during the studies?
Efter 15 ugers behandling var andelen af patienter med lave D- vitaminniveauer lavere blandt de patienter, som blev behandlet med ADROVANCE (11%), end blandt de patienter, som kun blev behandlet med alendronat (32%).
After 15 weeks of treatment, the proportion of patients with low vitamin D levels was lower among the patients treated with ADROVANCE (11%) than those taking alendronate only (32%).
Firmaet fremlagde også videnskabelige beviser for, at den dosis alendronat, som ADROVANCE indeholdt, svarede til den dosis, der var nødvendig for at forhindre tab af knoglemasse.
The company also presented evidence that the dose of alendronate included in ADROVANCE was the same as the dose needed to prevent bone loss.
Hvilken risiko er der forbundet med ADROVANCE?
What is the risk associated with ADROVANCE?
De mest almindelige bivirkninger (set hos 1 til 10 patienter ud af 100) er hovedpine, muskuloskeletale smerter (i knogler, muskler eller led), gastrointestinale symptomer såsom mavesmerter, dyspepsi (fordøjelsesbesvær), forstoppelse, diarré, flatulens (luft i maven), øsofagus- ulcus (ulcus i spiserøret), dysfagi (synkebesvær), udspilet mave og syreregurgitation (sure opstød).
The most common side effects (seen in between 1 and 10 patients in 100) are headache, musculoskeletal (bone, muscle or joint) pain and gastro-intestinal symptoms such as abdominal (tummy) pain, dyspepsia (indigestion), constipation, diarrhoea, flatulence (wind), oesophageal (gullet) ulcers, dysphagia (difficulty swallowing), abdominal distension (swollen tummy) and acid regurgitation.
Den fuldstændige liste over de indberettede bivirkninger ved ADROVANCE fremgår af indlægssedlen.
For the full list of all side effects reported with ADROVANCE, see the Package Leaflet.
ADROVANCE må ikke anvendes til personer, som kan være overfølsomme (allergiske) over for alendronat, D3- vitamin eller et eller flere af de øvrige indholdsstoffer.
ADROVANCE should not be used in people who may be hypersensitive (allergic) to alendronate, vitamin D3 or any of the other ingredients.
Det må ikke anvendes til patienter med abnormiteter i spiserøret (øsofagus), patienter med hypocalcæmi (for lavt calciumniveau) eller patienter, som ikke kan stå eller sidde op i mindst 30 minutter.
It should not be used where there are abnormalities of the oesophagus (gullet), in patients who have hypocalcaemia (low calcium levels), or in patients who cannot stand or sit upright for at least 30 minutes.
Hvorfor er ADROVANCE blevet godkendt?
Why has ADROVANCE been approved?
Udvalget for Humanmedicinske Lægemidler (CHMP) har konkluderet, at fordelene ved ADROVANCE er større end risiciene ved behandling af osteoporose hos postmenopausale kvinder, som har risiko for D- vitaminmangel.
The Committee for Medicinal products for Human Use (CHMP) decided that ADROVANCE’ s benefits are greater than its risks for the treatment of osteoporosis in postmenopausal women at risk of vitamin D insufficiency.
Udvalget anbefalede udstedelse af markedsføringstilladelse for ADROVANCE.
The Committee recommended that ADROVANCE be given marketing authorisation.
Andre oplysninger om ADROVANCE:
Other information about ADROVANCE:
Europa- Kommissionen udstedte en markedsføringstilladelse med gyldighed i hele Den Europæiske Union for ADROVANCE til Merck Sharp & Dohme Ltd. den 7. januar 2007.
The European Commission granted a marketing authorisation valid throughout the European Union for ADROVANCE to Merck Sharp & Dohme Ltd. on 4 January 2007.
Den europæiske offentlige vurderingsrapport (EPAR) for ADROVANCE kan ses i sin helhed her.
The full EPAR for ADROVANCE is available here.
Dette sammendrag blev sidst ajourført i 11- 2006.
This summary was last updated in 11-2006.
EU- nummer EU/ 1/ 06/ 364/ 001 EÚ/ 1/ 06/ 364/ 002 EU/ 1/ 06/ 364/ 003 EU/ 1/ 06/ 364/ 004 EU/ 1/ 06/ 364/ 005 EU/ 1/ 06/ 364/ 006 EU/ 1/ 06/ 364/ 007 EU/ 1/ 06/ 364/ 008 EU/ 1/ 06/ 364/ 009
EU Number EU/ 1/ 06/ 364/ 001 EU/ 1/ 06/ 364/ 002 EU/ 1/ 06/ 364/ 003 EU/ 1/ 06/ 364/ 004 EU/ 1/ 06/ 364/ 005 EU/ 1/ 06/ 364/ 006 EU/ 1/ 06/ 364/ 007 EU/ 1/ 06/ 364/ 008 EU/ 1/ 06/ 364/ 009
Navn Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance
Invented name Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance Adrovance
Styrke 70 mg/ 2800 IE 70 mg/ 2800 IE 70 mg/ 2800 IE 70 mg/ 2800 IE 70 mg/ 2800 IE 70 mg / 5600 IE 70 mg / 5600 IE 70 mg / 5600 IE 70 mg / 5600 IE
Strength 70 mg/ 2800 IU 70 mg/ 2800 IU 70 mg/ 2800 IU 70 mg/ 2800 IU 70 mg/ 2800 IU 70 mg/ 5600 IU 70 mg/ 5600 IU 70 mg/ 5600 IU 70 mg/ 5600 IU
Lægemiddelform Tabletter Tabletter Tabletter Tabletter Tabletter Tabletter Tabletter Tabletter Tabletter
Pharmaceutical Form Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet
Administrationsvej Til oral anvendelse Til oral anvendelse Til oral anvendelse Til oral anvendelse Til oral anvendelse Til oral anvendelse Til oral anvendelse Til oral anvendelse Til oral anvendelse
Route of Administration Oral use Oral use Oral use Oral use Oral use Oral use Oral use Oral use Oral use
Emballage blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu)
Packaging blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu) blister (alu/ alu)
Pakningsstørrelse 2 4 6 12 40 2 4 12 40
Package size 2 tablets 4 tablets 6 tablets 12 tablets 40 tablets 2 tablets 4 tablets 12 tablets 40 tablets
ADROVANCE 70 mg/ 2800 IE tabletter
ADROVANCE 70 mg/ 2800 IU tablets
Hver tablet indeholder 70 mg alendronsyre som alendronatnatriumtrihydrat og 70 mikrogram (2800 IE) colecalciferol (D3- vitamin).
Each tablet contains 70 mg alendronic acid as alendronate sodium trihydrate, and 70 micrograms (2800 IU) colecalciferol (vitamin D3).
Hver tablet indeholder 62 mg vandfrit lactose og 8 mg saccharose.
Each tablet contains 62 mg lactose anhydrous and 8 mg sucrose.
Kapselformede, hvide/ beige tabletter, mærket med et omrids af en knogle på den ene side og ” 710 ” på den anden.
Capsule-shaped, white to off-white tablets, marked with an outline of a bone image on one side, and '710 'on the other.
Behandling af postmenopausal osteoporose hos patienter med risiko for D- vitaminmangel.
Treatment of postmenopausal osteoporosis in patients at risk of vitamin D insufficiency.
ADROVANCE reducerer risikoen for vertebrale frakturer og hoftefrakturer.
ADROVANCE reduces the risk of vertebral and hip fractures.
Den anbefalede dosis er én ADROVANCE tablet, én gang ugentligt.
The recommended dosage is one ADROVANCE tablet once weekly.
4. 5).
Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate (see section 4.5).
4. 4):
The following instructions should be followed exactly in order to minimize the risk of oesophageal irritation and related adverse reactions (see section 4.4):
• ADROVANCE skal først tages, efter patienten er stået op, og skal tages sammen med et helt glas postevand (mindst 200 ml).
• ADROVANCE should only be swallowed after getting up for the day with a full glass of water (not less than 200ml or 7fl. oz.).
• Patienten må ikke tygge eller opløse tabletten i munden, på grund af risiko for oropharyngeale ulcerationer.
• Patients should not chew the tablet or allow the tablet to dissolve in their mouths because of a potential for oropharyngeal ulceration.
• Patienten må ikke ligge ned, før dagens første måltid er indtaget, hvilket bør være mindst 30 minutter efter indtagelse af tabletten.
• Patients should not lie down until after their first food of the day which should be at least 30 minutes after taking the tablet.
2 • Patienten må ikke ligge ned de første 30 minutter efter indtagelsen af ADROVANCE.
• Patients should not lie down for at least 30 minutes after taking ADROVANCE.
• ADROVANCE må ikke tages ved sengetid eller før patienten står op.
2 • ADROVANCE should not be taken at bedtime or before arising for the day.
Patienterne skal have supplerende kalcium, hvis indtagelsen fra kosten ikke er tilstrækkelig (se pkt.
Patients should receive supplemental calcium if intake from diet is inadequate (see section 4.4).
Yderligere tilskud af D- vitamin bør overvejes på individuel basis, idet der tages hensyn til indtagelsen af D- vitamin fra vitaminer og kosttilskud.
Additional supplementation with vitamin D should be considered on an individual basis taking into account any vitamin D intake from vitamins and dietary supplements.
Ækvivalensen mellem indtagelse af 2800 IE D3 - vitamin ugentligt i ADROVANCE og daglig dosering af D- vitamin 400 IE er ikke undersøgt.
The equivalence of intake of 2800 IU of vitamin D3 weekly in ADROVANCE to daily dosing of vitamin D 400 IU has not been studied.
Brug til ældre:
Use in the elderly:
Der er i kliniske forsøg ikke vist aldersrelateret forskel i alendronats effekt eller sikkerhedsprofil.
In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate.
Dosisjustering er derfor ikke nødvendig til ældre patienter.
Therefore no dosage adjustment is necessary for the elderly.
Brug ved nyreinsufficiens:
Use in renal impairment:
Dosisjustering er ikke nødvendig hos patienter med en kreatinin- clearance > 35 ml/ min.
No dosage adjustment is necessary for patients with a glomerular filtration rate (GFR) greater than 35ml/ min.
På grund af manglende erfaring anbefales ADROVANCE ikke til patienter med nyreinsufficiens, hvor kreatinin - clearance er < 35 ml/ min.
ADROVANCE is not recommended for patients with renal impairment where GFR is less than 35ml/ min, due to lack of experience.
Brug til børn og unge:
Use in children and adolescents:
ADROVANCE er ikke undersøgt hos børn og unge og bør derfor ikke anvendes til dem.
ADROVANCE has not been studied in children and adolescents and therefore should not be given to them.
• Overfølsomhed over for de aktive indholdsstoffer eller over for et eller flere af hjælpestofferne.
• Hypersensitivity to the active substances or to any of the excipients.
• Esophagusabnormaliteter og andre faktorer, som forsinker esophagustømning, såsom striktur eller akalasi.
• Abnormalities of the oesophagus and other factors which delay oesophageal emptying such as stricture or achalasia.
Alendronat Alendronat kan forårsage lokal irritation af slimhinderne i den øvre del af gastrointestinalkanalen.
Alendronate Alendronate can cause local irritation of the upper gastrointestinal mucosa.
4. 3).
Because there is a potential for worsening of the underlying disease, caution should be used when alendronate is given to patients with active upper gastrointestinal problems, such as dysphagia, oesophageal disease, gastritis, duodenitis, ulcers, or with a recent history (within the previous year) of major gastrointestinal disease such as peptic ulcer, or active gastrointestinal bleeding, or surgery of the upper gastrointestinal tract other than pyloroplasty (see section 4.3).
Der er rapporteret om esophageale reaktioner (nogle gange alvorlige og indlæggelseskrævende), såsom esophagitis, esophageale ulcera samt esophaguserosioner, i sjældne tilfælde efterfulgt af esophagusstriktur, hos patienter i behandling med alendronat.
Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture, have been reported in patients receiving alendronate.
4. 8).
Physicians should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue alendronate and seek medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing or retrosternal pain or new or worsening heartburn (see section 4.8).
Risikoen for alvorlige, esophageale bivirkninger synes større hos patienter, der ikke tager alendronat som foreskrevet, og/ eller som fortsætter med at tage alendronat efter at have udviklet symptomer, der tyder på esophageal irritation.
The risk of severe oesophageal adverse reactions appears to be greater in patients who fail to take alendronate properly and/ or who continue to take alendronate after developing symptoms suggestive of oesophageal irritation.
4. 2).
It is very important that the full dosing instructions are provided to, and are understood by the patient (see section 4.2).
Patienterne skal informeres om, at risikoen for esophagusproblemer kan øges, hvis disse instruktioner ikke følges.
Patients should be informed that failure to follow these instructions may increase their risk of oesophageal problems.
4. 8).
3 While no increased risk was observed in extensive clinical trials with alendronate, there have been rare (post-marketing) reports of gastric and duodenal ulcers, some of which were severe and with complications (see section 4.8).
Kæbeosteonekrose, som normalt er associeret med tandudtrækning og/ eller lokal infektion (inklusive osteomyelitis), er rapporteret hos cancerpatienter, som modtager behandlingsregimer, inklusive primært intravenøst administrerede bisphosphonater.
Osteonecrosis of the jaw, generally associated with tooth extraction and/ or local infection (including osteomyelitis) has been reported in patients with cancer who are receiving treatment regimens including primarily intravenously administered bisphosphonates.
En dental undersøgelse med hensigtsmæssig præventiv tandlægebehandling bør overvejes før behandling med bisphosphonater hos patienter med samtidige risikofaktorer (f. eks. cancer, kemoterapi, strålebehandling, kortikosteroider, dårlig oral hygiejne, paradentose).
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e. g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene, periodontal disease).
Den behandlende læges kliniske vurdering bør være vejledende for den enkelte patients behandlingsplan og være baseret på individuel vurdering af fordele/ risici.
Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/ risk assessment.
Knogle -, led - og/ eller muskelsmerter er rapporteret hos patienter, der tager bisphosphonater.
Bone, joint, and/ or muscle pain has been reported in patients taking bisphosphonates.
4. 8).
In post-marketing experience, these symptoms have rarely been severe and/ or incapacitating (see section 4.8).
De må ikke tage 2 tabletter samme dag, men skal fortsætte med at tage 1 tablet, 1 gang ugentligt, på den oprindeligt valgte ugedag.
They should not take two tablets on the same day but should return to taking one tablet once a week, as originally scheduled on their chosen day.
4. 2).
ADROVANCE is not recommended for patients with renal impairment where GFR is less than 35ml/ min (see section 4.2).
Andre årsager til osteoporosis end østrogenmangel og aldring bør overvejes.
Causes of osteoporosis other than oestrogen deficiency and ageing should be considered.
4. 3).
Hypocalcaemia must be corrected before initiating therapy with ADROVANCE (see section 4.3).
Andre lidelser, som påvirker mineralmetabolismen (såsom D- vitaminmangel og hypoparathyroidisme), skal også behandles effektivt, før behandling med ADROVANCE initieres.
Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated before starting ADROVANCE.
Indholdet af D- vitamin i ADROVANCE er ikke velegnet til opretning af D- vitaminmangel.
The content of vitamin D in ADROVANCE is not suitable for correction of vitamin D deficiency.
Hos patienter med disse lidelser bør serumkalcium og symptomer på hypokalcæmi monitoreres under behandling med ADROVANCE.
In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with ADROVANCE.
På grund af alendronats positive effekt på øgning i knoglemineraltætheden, kan der opstå fald i serumkalcium og serumfosfat.
Due to the positive effects of alendronate in increasing bone mineral, decreases in serum calcium and phosphate may occur.
4. 8).
However, there have been rare reports of symptomatic hypocalcaemia, which have occasionally been severe and often occurred in patients with predisposing conditions (e. g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption) (see section 4.8).
Colecalciferol D3- vitamin kan øge sværhedsgraden af hyperkalcæmi og/ eller hyperkalciuri, når det gives til patienter med sygdomme, der er forbundet med ureguleret overproduktion af calcitriol (f. eks. leukæmi, lymphoma, sarcoidosis).
Colecalciferol Vitamin D3 may increase the magnitude of hypercalcaemia and/ or hypercalciuria when administered to patients with disease associated with unregulated overproduction of calcitriol (e. g. leukaemia, lymphoma, sarcoidosis).
Urin og serumkalcium bør monitoreres hos disse patienter.
Urine and serum calcium should be monitored in these patients.
Patienter med malabsorption kan måske ikke optage tilstrækkeligt D3- vitamin.
Patients with malabsorption may not adequately absorb vitamin D3.
4 Hjælpestoffer Dette lægemiddel indeholder lactose og saccharose.
4 Excipients This medicinal product contains lactose and sucrose.
Patienter med sjældne arvelige problemer med fructoseintolerance, galactoseintolerance, Lapp lactasemangel, glucose- galactose malabsorption eller sucrase- isomaltasemangel bør ikke tage dette lægemiddel.
Patients with rare hereditary problems of fructose intolerance, galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.
Alendronat Ved samtidig administration kan mad og drikkevarer (inklusive mineralvand), kalciumtilskud, antacida samt visse peroralt administrerede lægemidler påvirke absorptionen af alendronat.
Alendronate If taken at the same time, it is likely that food and beverages (including mineral water), calcium supplements, antacids, and some oral medicinal products will interfere with absorption of alendronate.
4. 2 og 5. 2).
Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product (see sections 4.2 and 5.2).
Der forventes ingen andre klinisk signifikante interaktioner.
No other clinically significant interactions with medicinal products are anticipated.
Flere patienter i de kliniske undersøgelser fik østrogen (intravaginalt, transdermalt eller peroralt) samtidig med alendronat.
A number of patients in the clinical trials received oestrogen (intravaginal, transdermal, or oral) while taking alendronate.
Der sås ingen uønskede reaktioner, der kunne tilskrives den samtidige administration.
No adverse reactions attributable to their concomitant use were identified.
Selvom der ikke er udført specifikke interaktionsundersøgelser, er alendronat i kliniske undersøgelser anvendt sammen med en lang række almindeligt anvendte lægemidler uden tegn på interaktioner af klinisk relevans.
Although specific interaction studies were not performed, in clinical studies alendronate was used concomitantly with a wide range of commonly prescribed medicinal products without evidence of interactions of clinical relevance.
Colecalciferol Olestra, mineralske olier, orlistat og galdesyremidler (cholestyramin, colestipol) kan svække optagelsen af D- vitamin.
Colecalciferol Olestra, mineral oils, orlistat, and bile acid sequestrants (e. g. cholestyramine, colestipol) may impair the absorption of vitamin D.
Antiepileptika, cimetidin og thiazider kan øge katabolismen af D- vitamin.
Anticonvulsants, cimetidine and thiazides may increase the catabolism of vitamin D.
Yderligere D- vitamintilskud kan overvejes på individuel basis.
Additional vitamin D supplements may be considered on an individual basis.
ADROVANCE er kun beregnet til anvendelse for postmenopausale kvinder, og bør derfor ikke anvendes under graviditet eller af ammende kvinder.
ADROVANCE is only intended for use in postmenopausal women and therefore it should not be used during pregnancy or in breast-feeding women.
Der er ikke tilstrækkelige data fra brug af ADROVANCE til gravide kvinder.
There are no adequate data from the use of ADROVANCE in pregnant women.
Dyreundersøgelser med alendronat tyder ikke direkte på skadelig virkning med hensyn til graviditet, embryo/ føtal- udvikling eller postnatal udvikling.
Animal studies with alendronate do not indicate direct harmful effects with respect to pregnancy, embryonal/ foetal development, or postnatal development.
5. 3).
Alendronate given during pregnancy in rats caused dystocia related to hypocalcaemia (see section 5.3).
5. 3).
Studies in animals have shown hypercalcaemia and reproductive toxicity with high doses of vitamin D (see section 5.3).
Det vides ikke, om alendronat udskilles i modermælk.
It is not known whether alendronate is excreted into human breast milk.
Colecalciferol og nogle af dets aktive metabolitter udskilles i modermælk.
Colecalciferol and some of its active metabolites pass into breast milk.
Der er ikke udført undersøgelser med henblik på indvirkningen på evnen til at køre bil eller betjene maskiner.
No studies on the effects on the ability to drive and use machines have been performed.
Der er imidlertid ingen information, der indikerer, at ADROVANCE påvirker patientens evne til at køre bil eller betjene maskiner.
However, there is no information to indicate that ADROVANCE affects a patient’ s ability to drive or operate machines.
Følgende bivirkninger er indberettet i forbindelse med kliniske undersøgelser med alendronat og/ eller efter markedsføring.
The following adverse reactions have been reported during clinical studies and/ or post-marketing use with alendronate.
Der er ikke identificeret nye bivirkninger for ADROVANCE.
No additional adverse reactions have been identified for ADROVANCE.
Mave- tarmkanalen:
[Common (≥ 1/ 100, < 1/ 10), uncommon (≥ 1/ 1000, < 1/ 100), rare (≥ 1/ 10,000, < 1/ 1000), very rare (< 1/ 10,000)]
Sjælden:
5 Nervous system disorders:
Almindelig:
Common: headache
Ikke almindelig:
Eye disorders:
Kvalme, opkastning, gastritis, esophagitis *, esophageal erosion *, melaena.
Gastrointestinal disorders:
4. 2 og 4. 4.
Rare: uveitis, scleritis, episcleritis Common: abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation Uncommon: nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melena Rare: oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding)(see section 4.4). *See sections 4.2 and 4.4
Ikke almindelig:
Metabolism and nutrition disorders:
Udslæt, kløe, erythema.
General disorders and administration site conditions:
Sjælden:
Immune system disorders: