FrancophonIA/ELRC3.0 huggingface dataset:
English: Systemic exposure of regorafenib at steady-state increases dose proportionally up to 60 mg and less than proportionally at doses greater than 60 mg. Accumulation of regorafenib at steady state results in about a 2-fold increase in plasma concentrations, which is consistent with the elimination half-life and dosing frequency.
Danish: Systemisk eksponering for regorafenib ved steady state stiger proportionalt med dosen op til 60 mg og mindre end proportionalt ved doser, der er større end 60 mg. Akkumulering af regorafenib ved steady state resulterer i en cirka 2 gange forhøjelse i plasmakoncentrationer, hvilket er overensstemmende med eliminationshalveringstiden og doseringsfrekvensen.
English: Metabolites M-2 and M-5 are weak substrates of P-gp.
Danish: Metabolitterne M-2 og M-5 er svage substrater for P-gb.
English: - an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections).
Danish: - en udvidelse og svækkelse af en blodårevæg eller en rift i en blodårevæg (aneurismer og arterielle dissektioner).
English: - if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall)
Danish: - Hvis du har eller har haft et aneurisme (udvidelse og svækkelse af en blodårevæg) eller en rift i en blodårevæg.
English: Inhibitors of P-glycoprotein and BCRP/Inducers of P-glycoprotein and BCRP In vitro studies indicate that the active metabolites M-2 and M-5 are substrates for P-glycoprotein and BCRP.
Danish: Inhibitorer af P-glykoprotein og BCRP/induktorer af P-glykoprotein og BCRP In vitro-studier indikerer, at de aktive metabolitter M-2 og M-5 er substrater for P-glykoprotein og BCRP.
English: The maximum daily dose is 160 mg.
Danish: Den maksimale daglige dosis er 160 mg.
English: Adverse drug reactions are grouped according to their frequencies.
Danish: Bivirkninger grupperes i henhold til hyppighed.
English: Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John's wort) may also increase metabolism of regorafenib.
Danish: Andre kraftige CYP3A4-induktorer (f.eks. phenytoin, carbamazepin, phenobarbital og prikbladet perikon) kan også øge regorafenibs metabolisme.
English: Swallow the tablet whole with water after a light meal that contains less than 30% fat.
Danish: Slug tabletten hel sammen med vand efter et let måltid med et fedtindhold på under 30 %.
English: Posterior reversible encephalopathy syndrome (PRES)
Danish: Posteriort reversibelt leukoence falopati syndrom (PRES)
English: If no improvement occurs despite dose reduction, interrupt therapy for a minimum of 7 days, until toxicity resolves to Grade 0-1.
Danish: Hvis der ikke ses forbedring på trods af dosisreduktion, afbrydes behandlingen i mindst 7 dage, indtil toksiciteten er reduceret til grad 0-1.
English: The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in Table 3.
Danish: Bivirkningerne rapporteret i kliniske studier hos patienter i behandling med Stivarga vises i tabel 3.
English: No studies on the effects of Stivarga on the ability to drive or use machines have been performed.
Danish: Der er ikke udført studier om Stivargas virkning på evnen til at føre motorkøretøj eller betjene maskiner.
English: Monitor liver function weekly until transaminases return to <3 times ULN (Grade 1) or baseline.
Danish: Kontrollér leverfunktionen ugentligt, indtil transaminaser vender tilbage til < 3 gange ULN (grad 1) eller baseline.
English: Parent compound found in faeces could be derived from intestinal degradation of glucuronides or reduction of metabolite M-2 (N-oxide), as well as unabsorbed regorafenib.
Danish: Moderforbindelsen fundet i fæces kan være afledt fra intestinal degradation af glucuronider eller reduktion af metabolit M-2 (N-oxid), samt ikke absorberet regorafenib.
English: Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding.
Danish: Blodtal og koagulationstal skal kontrolleres hos patienter med tilstande, der prædisponerer dem for blødning og hos patienter, der behandles med antikoagulantia (f.eks. warfarin eller phenprocoumon) eller andre samtidige lægemidler, der øger blødningsrisikoen.
English: Recommended measures and dose modification
Danish: Anbefalede foranstaltninger og dosismodifikation
English: - reduction in the number of blood platelets, characterised by easy bruising or bleeding
Danish: - reduktion i antallet af blodplader, der kan kendes ved, at du let får blå mærker eller bløder
English: Tell your doctor about any missed dose.
Danish: Fortæl din læge, hvis du glemmer en dosis.
English: The in vitro inhibitory potency towards CYP3A4 (Ki value of 11.1 micromolar) and CYP2C19 (Ki value of 16.4 micromolar) was less pronounced.
Danish: In vitro-inhibering af CYP3A4 (Ki-værdi på 11,1 mikromolær) og CYP2C19 (Ki-værdi på 16,4 mikromolær) var mindre udtalt.
English: Both metabolites, M-2 and M-5, exhibit non-linear accumulation, which might be caused by enterohepatic recycling or saturation of the UGT1A9 pathway.
Danish: Både metabolit M-2 og M-5 udviser ikke-lineær akkumulation, hvilket kan være forårsaget af entero-hepatisk genoptagelse eller mætning af UGT1A9-vejen.
English: No dosage adjustment is necessary if you have a mildly, moderately or severely impaired kidney function.
Danish: Det er ikke nødvendigt at justere dosis, hvis du har let, moderat eller svært nedsat nyrefunktion.
English: The safety and efficacy of regorafenib in patients below 18 years of age in the indication gastrointestinal stromal tumours (GIST) have not been established.
Danish: Regorafenibs sikkerhed og virkning hos patienter under 18 år for indikationen gastrointestinale stromale tumorer (GIST) er ikke klarlagt.
English: Gender The pharmacokinetics of regorafenib is not influenced by gender.
Danish: Køn Regorafenibs farmakokinetik påvirkes ikke af køn.
English: It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and to institute appropriate replacement therapy according to standard clinical practice if required.
Danish: Det anbefales at overvåge de biokemiske og metaboliske parameter under behandlingen med Stivarga og at indlede hensigtsmæssig substitutionsbehandling iht.
English: 28 film-coated tablets 84 (3 x 28) film-coated tablets
Danish: 28 filmovertrukne tabletter 84 (3 x 28) filmovertrukne tabletter
English: Biochemical and metabolic laboratory test abnormalities Stivarga has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase).
Danish: Biokemiske og metaboliske anomalier i laboratorieprøver Stivarga er blevet associeret med en øget forekomst af elektrolytforstyrrelser (inklusive hypofosfatæmi, hypokalcæmi, hyponatriæmi og hypokaliæmi) og metaboliske forstyrrelser (inklusive stigninger i tyroidea-stimulerende hormon, lipase og amylase).
English: There are no data for patients with Child-Pugh C (severe) hepatic impairment.
Danish: Der foreligger ikke data for patienter med Child-Pugh C (svært) nedsat leverfunktion.
English: The overall incidence of hand-foot skin reaction (74.8%, CRC, 88.2%, GIST and 67.1%, HCC) was higher in Stivarga-treated Asian patients, compared to other ethnicities.
Danish: Den samlede forekomst af hånd-fod-hudreaktion var (74,8 % (KRC), 88,2 % (GIST), og 67,1 % (HCC)) højere hos Stivargabehandlede patienter af asiatisk herkomst, sammenlignet med andre etniciteter.
English: It is recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied.
Danish: Det anbefales, at der undgås samtidig anvendelse af kraftige hæmmere af CYP3A4-aktivitet (f.eks. clarithromycin, grapefrugtjuice, itraconazol, ketoconazol, posaconazol, telithromycin og voriconazol), da deres indflydelse på steady state-eksponeringen over for regorafenib og metabolitter herfra ikke er blevet undersøgt.
English: Decrease dose by 40 mg (one tablet) and immediately institute supportive measures.
Danish: Reducer dosis med 40 mg (én tablet) og indled omgående afhjælpende behandling.
English: Monitor transaminases weekly until return to <3 times ULN or baseline.
Danish: Overvåg transaminaser ugentligt, indtil de vender tilbage til < 3 gange ULN eller baseline.
English: Cellulose microcrystalline Croscarmellose sodium Magnesium stearate Povidone (K-25) Silica, colloidal anhydrous
Danish: Mikrokrystallinsk cellulose Croscarmellosenatrium Magnesiumstearat Povidon (K-25) Kolloid vandfri silika
English: Whereas plasma concentrations of M-2 and M-5 after a single dose of regorafenib are much lower than those of parent compound, steady-state plasma concentrations of M-2 and M-5 are comparable to those of regorafenib.
Danish: Hvor plasmakoncentrationerne af M-2 og M-5 efter en enkelt dosis regorafenib er meget lavere end for moderforbindelsen, er plasmakoncentrationerne af M-2 og M-5 ved steady state sammenlignelige med koncentrationerne for regorafenib.
English: Across all clinical trials, cardiac disorder events (all grades) have been more often (13.7% vs. 6.5%) reported in Stivarga-treated patients aged 75 years or older (N=410), compared to Stivarga-treated patients below 75 years (N=4108).
Danish: I alle kliniske studier blev hjertesygdomme (alle grader) rapporteret hyppigere (13,7 % vs. 6,5 %) hos Stivargabehandlede patienter i alderen 75 år og derover (N=410) sammenlignet med patienter under 75 år (N=4108).
English: Patients receiving regorafenib who experienced disease progression and for whom in the investigator's opinion, treatment with regorafenib was providing clinical benefit, were offered the opportunity to continue open-label regorafenib.
Danish: Patienter, der fik regorafenib og oplevede sygdomsprogression, og som efter investigatorens skøn havde en klinisk fordel af behandlingen med regorafenib, blev tilbudt muligheden for at fortsætte med open-label regorafenib.
English: - liver cancer in adult patients who have been previously treated with another anticancer medicine (sorafenib).
Danish: - kræft i leveren hos voksne patienter, som tidligere er blevet behandlet med et andet lægemiddel mod kræft (sorafenib).
English: After repeated dosing to mice, rats and dogs, adverse effects were observed in a number of organs, primarily in the kidneys, liver, digestive tract, thyroid gland, lympho-/haematopoietic system, endocrine system, reproductive system and skin.
Danish: Efter gentagen dosering til mus, rotter og hunde blev der observeret bivirkninger i en række organer, primært i nyrerne, leveren, fordøjelseskanalen, tyreoidea, blod- og lymfesystemet, det endokrine system, det reproduktive system og huden.
English: Always take this medicine exactly as your doctor has told you to.
Danish: Tag altid lægemiddlet nøjagtigt efter lægens anvisning.
English: - if you get severe stomach and bowel problems (gastrointestinal perforation or fistula), your doctor should decide to discontinue treatment with Stivarga.
Danish: - Hvis du får alvorlige mave- og tarmproblemer (mave-tarm-perforation eller fistel), skal lægen beslutte, om behandlingen med Stivarga skal stoppes.
English: Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Table 4 and Table 4a (see also section 4.4).
Danish: Påvirkninger af laboratorieværdier opstået under behandlingen observeret i de placebokontrollerede fase III-studier vises i tabel 4 og tabel 4a (se også pkt.
English: - hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
Danish: - hepatocellulært karcinom (HCC), som tidligere er blevet behandlet med sorafenib.
English: In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation.
Danish: Især hæmmer regorafenib muteret KIT, en major onkogen driver i gastrointestinale stromale tumorer, og derved blokeres proliferationen af tumorcellerne.
English: A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone) CYP2C9 (S-warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam).
Danish: Et klinisk test-substrat-studie blev udført til evaluering af effekten af 14 dages dosering med 160 mg regorafenib på farmakokinetikken af probe-substraternes for CYP2C8 (rosiglitazon), CYP2C9 (S-warfarin), CYP2C19 (omeprazol) og CYP3A4 (midazolam).
English: This medicine contains 55.8 mg sodium (main component of cooking/table salt) in each daily dose (4 tablets).
Danish: Dette lægemiddel indeholder 55,8 mg natrium (hovedkomponent i madlavnings-/bordsalt) pr. daglige dosis (4 tabletter).
English: Metabolites may be reduced or hydrolysed in the gastrointestinal tract by microbial flora, allowing reabsorption of the unconjugated active substance and metabolites (enterohepatic circulation).
Danish: Metabolitter kan reduceres eller hydrolyseres i mave-tarm-kanalen af mikrobiel flora, hvilket tillader reabsorption af det ukonjugerede aktive stof og metabolitter (enterohepatisk cirkulation).
English: Regorafenib reaches mean peak plasma levels of about 2.5 mg/l at about 3 to 4 hours after a single oral dose of 160 mg given as 4 tablets each containing 40 mg.
Danish: Regorafenib når gennemsnitlige top-plasmaniveauer på ca. 2,5 mg/l 3 til 4 timer efter en enkelt oral dosis på 160 mg givet som 4 tabletter, der hver indeholder 40 mg.
English: - unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib
Danish: - inoperable eller metastaserende gastrointestinale stromale tumorer (GIST), som progredierede på eller var intolerante overfor tidligere behandling med imatinib og sunitinib
English: - if you have any liver problems including Gilbert's syndrome with signs such as: yellowish discolouration of the skin and the whites of the eyes, dark urine and confusion and/or disorientation.
Danish: - Hvis du har leverproblemer, herunder Gilberts syndrom, med tegn som: gullig misfarvning af huden og det hvide i øjnene, mørk urin og forvirring og/eller desorientering.
English: Increased Amylase a Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 b Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0
Danish: Øget amylase a Almindelige terminologikriterier for uønskede hændelser (Common Terminology Criteria for Adverse Events (CTCAE)), version 3.0 b Almindelige terminologikriterier for uønskede hændelser (Common Terminology Criteria for Adverse Events (CTCAE)), version 4.0 * International normaliseret ratio
English: Each film-coated tablet contains 40 mg regorafenib.
Danish: Hver filmovertrukket tablet indeholder 40 mg regorafenib.
English: Package Leaflet: Information for the user Stivarga 40 mg film-coated tablets regorafenib
Danish: Indlægsseddel: Information til brugeren Stivarga 40 mg filmovertrukne tabletter regorafenib
English: Occurrence Recommended dose modification and measures
Danish: Anbefalet dosismodifikation og foranstaltninger
English: The exposure of metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) is higher when regorafenib is given with a low fat breakfast, compared to fasting condition and lower when given with a high fat meal, compared to fasting condition.
Danish: Eksponeringen af metabolitterne M-2 (N-oxid) og M-5 (N-oxid og N-desmethyl) er højere, når regorafenib gives sammen med en fedtfattig morgenmad, sammenlignet med fastende tilstand, og lavere, når det gives sammen med et måltid med højt fedtindhold, sammenlignet med fastende tilstand.
English: Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug interaction (see also section 4.4).
Danish: Farmakokinetiske data indikerer, at regorafenib kan gives samtidigt med substrater for CYP2C8, CYP2C9, CYP3A4 og CYP2C19 uden en klinisk betydningsfuld lægemiddelinteraktion (se også pkt.
English: Regorafenib is eliminated mainly via the hepatic route.
Danish: Regorafenib elimineres primært via leveren.
English: In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibit glucuronidation mediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady state.
Danish: In vitro-data indikerer, at regorafenib og dets aktive metabolit M-2, hæmmer glucuronidering medieret af UGT1A1 og UGT1A9, hvorimod M-5 kun hæmmer UGT1A1 ved koncentrationer, der opnås in vivo ved steady state.
English: § Best Supportive Care * Hazard ratio < 1 favours Stivarga ** NR: not reached
Danish: § Bedste understøttende behandling * Hazard ratio <1: Stivarga er bedre end placebo ** NR: ikke nået
English: The primary efficacy endpoint was Overall Survival (OS).
Danish: Det primære endepunkt for virkning var overlevelse (OS).
English: <0.000001 1.9 months
Danish: <0,000001 1,9 måneder
English: It is not known whether Stivarga alters the ability to drive or use machines.
Danish: Det er uvist, om Stivarga påvirker evnen til at føre motorkøretøj eller betjene maskiner.
English: In rats, regorafenib or its metabolites are excreted in milk.
Danish: Hos rotter udskilles regorafenib eller metabolitter herfra i mælk.
English: Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 5.2).
Danish: Det anbefales at overvåge den samlede sikkerhed nøje hos disse patienter (se pkt.
English: In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki value of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2 micromolar) at concentrations which are achieved in vivo at steady state (peak plasma concentration of 8.1 micromolar).
Danish: In vitro-data indikerer, at regorafenib er en potent inhibitor af CYP2C8 (Ki-værdi på 0,6 mikromolær), CYP2C9 (Ki-værdi på 4,7 mikromolær), CYP2B6 (Ki-værdi på 5,2 mikromolær) ved koncentrationer, der opnås in vivo ved steady state (top-plasmakoncentration på 8,1 mikromolær).
English: Of the 199 randomised patients, the mean age was 58 years, 64% were male, 68% were Caucasian, and all patients had baseline ECOG Performance Status (PS of 0 or 1.
Danish: De 199 randomiserede patienter havde en gennemsnitsalder på 58 år, 64 % var mænd, 68 % var kaukasere, og alle patienterne havde baseline ECOG Performance Status (PS) på 0 eller 1.
English: Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (> 90%) East Asian patients enrolled.
Danish: Sammenlignet med det globale fase III-KRC-studie (CORRECT), hvor der primært indgik kaukasiske patienter (~80 %), blev der observeret en højere forekomst af forhøjede leverenzymer hos patienter, der blev behandlet med Stivarga i det asiatiske fase III-KRC-studie (CONCUR), hvor der primært indgik patienter fra Østasien (> 90 %).
English: Of the 760 randomised patients, the median age was 61 years, 61% were male, 78% were Caucasian, and all patients had baseline ECOG Performance Status (PS of 0 or 1.
Danish: Af de 760 randomiserede patienter var den gennemsnitlige alder 61 år, 61 % var mænd, 78 % var kaukasere, og alle patienter havde ECOG Performance Status (PS) ved baseline på 0 eller 1.
English: There is no relevant use of Stivarga in children and adolescents in the indication of liver cancer.
Danish: Der er ingen relevant brug af Stivarga hos børn og unge for indikationen kræft i leveren.
English: Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population and exposure might be increased in these patients.
Danish: Stivarga bør ikke anvendes til patienter med svært nedsat leverfunktion (Child-Pugh C), da Stivarga ikke er undersøgt hos denne population og eksponeringen kan være forhøjet hos disse patienter.
English: Table 1: Recommended dose modifications and measures for HFSR Skin toxicity grade
Danish: Tabel 1: Anbefalede dosismodifikationer og foranstaltninger for HFSR
English: ≤5 times upper limit of normal (ULN) (maximum Grade 2)
Danish: ≤ 5 gange den øvre normalgrænse (ULN) (maks.
English: Therapies included treatment with fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if the patient was KRAS wild type, an anti-EGFR therapy.
Danish: Tidligere behandlinger inkluderede fluorpyrimidinbaseret kemoterapi, en anti-VEGF-behandling og, hvis patienten havde en KRAS-vildtypetumor, en anti-EGFR-behandling.
English: Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor (see section 4.5).
Danish: Regorafenib er en uridin-diphosphat-glucuronosyltransferase (UGT)-1A1-inhibitor (se pkt.
English: Fatal outcomes associated with infection were observed more often in patients treated with Stivarga (1.0%), compared to patients receiving placebo (0.3%), and were mainly respiratory events.
Danish: Hændelser med dødeligt udfald forbundet med infektion blev oftere observeret hos patienter behandlet med Stivarga (1,0 %), sammenlignet med patienter, der fik placebo (0,3 %), og var hovedsageligt hændelser i luftvejene.
English: - The other ingredients are: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone (K-25) and silica colloidal anhydrous, iron oxide red (E172), iron oxide yellow (E172), lecithin (derived from soya), macrogol 3350, polyvinyl alcohol (partially hydrolysed), talc and titanium dioxide (E171) (see also section ‘Important information about some of the ingredients of Stivarga').
Danish: - Øvrige indholdsstoffer: Mikrokrystallinsk cellulose, croscarmellosenatrium, magnesiumstearat, povidon (K-25) og kolloid vandfri silika, rød jernoxid (E 172), gul jernoxid (E 172), lecithin (deriveret fra soja), macrogol 3350, polyvinylalkohol (delvist hydrolyseret), talcum og titandioxid (E 171) (se også punktet ”Stivarga indeholder natrium”).
English: No dose adjustment is necessary based on gender (see also section 5.2).
Danish: Der kræves ingen dosisjustering baseret på køn (se også pkt.
English: In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Stivarga, compared with nonJapanese patients (<0.1%).
Danish: I kliniske studier var der en højere forekomst af svær leverskade med dødeligt udfald hos japanske patienter (~1.5%), der blev behandlet med Stivaga, sammenlignet med ikke-japanske patienter (<0.1%).
English: The safety and efficacy of Stivarga in children and adolescents in the indication of gastrointestinal stromal tumours (GIST) have not been established.
Danish: Stivargas sikkerhed og virkning hos børn og unge for indikationen gastrointestinale stromale tumorer (GIST) er ikke klarlagt.
English: In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function.
Danish: I kliniske studier blev der ikke observeret relevante forskelle i eksponering, sikkerhed eller virkning mellem patienter med let nedsat leverfunktion (Child-Pugh A) og normal leverfunktion.
English: Table 2: Recommended measures and dose modifications in case of drug-related liver function test abnormalities
Danish: Tabel 2: Anbefalede foranstaltninger og dosismodifikationer i tilfælde af anomalier i leverfunktionsprøven relateret til lægemidlet
English: Any occurrence
Danish: Enhver forekomst