natgillin/translations-raw huggingface dataset:
6 Der er blevet foretaget en farmakokinetisk undersøgelse blandt patienter med let nedsat leverfunktion.
6 A pharmacokinetic study has been performed in patients with mild hepatic impairment.
Det er dog ikke muligt at anbefale en endelig dosisreduktion på grund af betydelig variation i lægemiddeleksponeringen hos denne patientpopulation (se afsnit 5. 2).
However, a definitive recommendation on dose reduction is not possible due to substantial variability of drug exposure in this patient population (see section 5.2).
De tilgængelige kliniske sikkerhedsdata for abacavir hos patienter med nedsat leverfunktion er begrænsede.
The clinical safety data available with abacavir in hepatically impaired patients is very limited.
På grund af de potentielle stigninger i eksponering (AUC) hos visse patienter er tæt monitorering påkrævet.
Due to the potential increases in exposure (AUC) in some patients, close monitoring is required.
Der foreligger ingen data for patienter med moderat til svært nedsat leverfunktion.
No data are available in patients with moderate or severe hepatic impairment.
Plasmakoncentrationerne for abacavir forventes at stige betydeligt hos disse patienter.
Plasma concentrations of abacavir are expected to substantially increase in these patients.
Derfor anbefales abacavir ikke til patienter med moderat nedsat leverfunktion, medmindre det vurderes at være nødvendigt og der kræves tæt monitorering af disse patienter.
Therefore, the use of abacavir in patients with moderate hepatic impairment is not recommended unless judged necessary and requires close monitoring of these patients.
Ziagen er kontraindiceret hos patienter med svært nedsat leverfunktion (se afsnit 4. 3).
For patients with severe hepatic impairment, Ziagen is contraindicated (see section 4.3).
Ziagen bør ikke gives til patienter med nyresvigt (se afsnit 5. 2).
Ziagen should not be administered to patients with end-stage renal disease (see section 5.2).
Patienter, der får Ziagen eller anden antiretroviral behandling, kan fortsat få opportunistiske infektioner eller andre komplikationer af HIV- infektionen.
Opportunistic infections: patients receiving Ziagen or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection.
Patienter bør derfor følges tæt af læger med erfaring i behandling af disse sygdomme, som ledsager HIV.
Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.
Patienter bør orienteres om, at den nuværende antiretrovirale behandling, herunder Ziagen, ikke har vist sig at forebygge risikoen for at overføre HIV til andre gennem seksuel kontakt eller smittet blod.
Transmission: patients should be advised that current antiretroviral therapy, including Ziagen, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.
Det er desuden vist in vitro, at abacavir ikke hæmmer CYP 3A4, CYP2C9 eller CYP2D6 enzymerne i klinisk relevante koncentrationer.
Abacavir has also been shown in vitro not to inhibit CYP 3A4, CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations.
Der er ikke set induktion af levermetabolisme i kliniske undersøgelser.
Induction of hepatic metabolism has not been observed in clinical studies.
Derfor er der et lille potentiale for interaktioner med antiretrovirale PI’ er og andre lægemidler, som metaboliseres af betydende P450- enzymer.
Therefore, there is little potential for interactions with antiretroviral PIs and other medicinal products metabolised by major P450 enzymes.
Kliniske undersøgelser har vist, at der ikke er klinisk betydende interaktioner mellem abacavir, zidovudin og lamivudin.
Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.
41%.
Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%.
En farmakokinetisk undersøgelse viste, at samtidig administration af 600 mg abacavir 2 gange daglig og metadon reducerede Cmax for abacavir med 35% og udsatte tmax med en time, men
7 Methadone: in a pharmacokinetic study, coadministration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax but the AUC was unchanged.
I undersøgelsen øgede abacavir den gennemsnitlige systemiske clearance for metadon med 22%.
In this study abacavir increased the mean methadone systemic clearance by 22%.
Ziagen anbefales ikke under graviditet.
Ziagen is not recommended during pregnancy.
Det er ikke slået fast, om anvendelse af abacavir under graviditet er sikker.
The safe use of abacavir in human pregnancy has not been established.
Hos dyr er det vist, at abacavir og/ eller metabolitter heraf passerer placenta.
Placental transfer of abacavir and/ or its related metabolites has been shown to occur in animals.
Der forekom toksicitet over for embryoner og fostre hos rotter, men ikke hos kaniner (se afsnit 5. 3).
Toxicity to the developing embryo and foetus occurred in rats, but not in rabbits (see section 5.3).
Det teratogene potentiale for abacavir har ikke kunnet fastlægges på baggrund af dyreforsøg.
The teratogenic potential of abacavir could not be established from studies in animals.
Abacavir og metabolitter heraf udskilles i mælken hos diegivende rotter.
Abacavir and its metabolites are secreted into the milk of lactating rats.
Det forventes, at stofferne ligeledes vil udskilles i modermælk, skønt det ikke er påvist.
It is expected that these will also be secreted into human milk, although this has not been confirmed.
Det anbefales derfor, at mødre undlader at amme deres spædbørn, mens de er i behandling med Ziagen.
It is therefore recommended that mothers do not breast-feed their babies while receiving treatment with abacavir.
Overfølsomhed (se også afsnit 4. 4):
Hypersensitivity (see also section 4.4):
I kliniske studier med abacavir 600 mg én gang daglig forblev den rapporterede hyppighed af overfølsomhed indenfor det range der er registreret for abacavir 300 mg to gange daglig.
In clinical studies with abacavir 600 mg once daily the reported rate of hypersensitivity remained within the range recorded for abacavir 300 mg twice daily.
Åndenød, hoste, ondt i halsen, ARDS (adult respiratory distress syndrome), respirationssvigt
Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure
Andet Feber, svær udmatning, utilpashed, ødem, hævede lymfeknuder, hypotension, konjunktivitis, anafylaksi
8 hypotension, conjunctivitis, anaphylaxis
8 Neurologiske/ psykiatriske
Neurological/ Psychiatry
mod 54%) blev oftere rapporteret hos børn sammenlignet med voksne.
Rash (81% vs 67% respectively) and gastrointestinal manifestations (70% vs 54% respectively) were more frequently reported in children compared to adults.
Det blev først antaget, at nogle patienter med overfølsomhedsreaktioner havde gastroenteritis, respiratorisk sygdom (pneumoni, bronkitis, pharyngitis) eller influenzalignende sygdom.
Some patients with hypersensitivity reactions were initially thought to have gastroenteritis, respiratory disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness.
Denne forsinkede diagnosticering af overfølsomhed har bevirket, at Ziagen blev fortsat eller re- introduceret og har medført mere alvorlige overfølsomhedsreaktioner eller død.
This delay in diagnosis of hypersensitivity has resulted in Ziagen being continued or re-introduced, leading to more severe hypersensitivity reactions or death.
Symptomerne fremkom sædvanligvis inden for de første 6 uger efter start af behandlingen med abacavir (gennemsnitligt 11 dage til symptomdebut), skønt reaktionerne kan opstå på et hvilket som helst tidspunkt under behandlingen.
Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy.
Som konsekvens heraf bør patienter orienteres om vigtigheden af at tage Ziagen regelmæssigt.
Consequently, patients should be advised of the importance of taking Ziagen regularly.
Genoptages behandlingen med Ziagen efter en overfølsomhedsreaktion, vender symptomerne omgående tilbage inden for timer.
Restarting Ziagen following a hypersensitivity reaction results in a prompt return of symptoms within hours.
Denne tilbagevenden af overfølsomhedsreaktionen er som regel sværere end den initiale reaktion og kan eventuelt indebære livstruende hypotension og død.
This recurrence of the hypersensitivity reaction was usually more severe than on initial presentation, and may include life-threatening hypotension and death.
Patienter, der udvikler denne overfølsomhedsreaktion, skal stoppe brugen af Ziagen og aldrig genoptage behandlingen med Ziagen eller anden medicin, der indeholder abacavir (dvs.
Patients who develop this hypersensitivity reaction must discontinue Ziagen and must never be rechallenged with Ziagen, or any other medicinal product containing abacavir (i. e.
Overfølsomhedsreaktioner med hurtig indtræden, herunder livstruende reaktioner, er forekommet efter genoptagelse af Ziagen behandling hos patienter, der kun havde ét af de kendetegnende symptomer på overfølsomhedsreaktion (hududslæt, feber, symptomer fra mavetarmkanal, luftveje eller påvirket almentilstand, såsom svær udmatning og utilpashed) forud for ophør med Ziagen behandling.
Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting Ziagen in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping Ziagen.
9 For mange af de andre rapporterede bivirkninger er det uklart, om de skyldes Ziagen, den vide udstrækning af lægemidler, der bruges ved behandling af HIV infektion, eller er et resultat af sygdomsprocessen.
For many of the other adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide range of medicinal products used in the management of HIV infection or as a result of the disease process.
En del af de bivirkninger, der er nævnt nedenfor optræder almindeligvis (kvalme, opkastning, diarré, feber, svær udmatning, udslæt) hos patienter med overfølsomhed over for abacavir.
9 Many of those listed below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity.
Hvis behandling med Ziagen tidligere er blevet afbrudt hos patienter, der har oplevet nogen af disse symptomer, og det besluttes at starte patienten op igen på behandling med abacavir, skal dette foregå under omstændigheder, hvor muligheden for hurtig medicinsk indgriben er tilgængelig (se afsnit 4. 4).
If Ziagen has been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart a medicinal product containing abacavir, this must be done in a setting where medical assistance is readily available (see section 4.4.).
Der er meget sjældne rapporter om erythema multiforme, Stevens- Johnsons syndrom eller toksisk epidermal nekrolyse, hvor overfølsomhed over for abacavir ikke kunne udelukkes.
Very rarely cases of erythema multiforme, Stevens Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out.
Meget almindelig (> 1/ 10), almindelig (> 1/ 100, < 1/ 10), ikke almindelig (> 1/ 1. 000, < 1/ 100), sjælden (> 1/ 10. 000, < 1/ 1. 000) og meget sjælden (< 1/ 10. 000).
The following convention has been used for their classification: very common (> 1/ 10), common (> 1/ 100 ,< 1/10), uncommon (> 1/ 1,000 ,< 1/100), rare (> 1/ 10,000, < 1/ 1,000) very rare (< 1/ 10,000).
Anoreksi
Metabolism and nutrition disorders Common: anorexia
Hovedpine
Nervous system disorders Common: headache
Pancreatitis
Gastrointestinal disorders Common: nausea, vomiting, diarrhoea Rare: pancreatitis
Erythema multiforme, Stevens- Johnsons syndrom og toksisk epidermal nekrolyse
Skin and subcutaneous tissue disorders Common: rash (without systemic symptoms) Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
Feber, svær udmatning, træthed
General disorders and administration site conditions Common: fever, lethargy, fatigue
Hos HIV- inficerede patienter med svær immuninsufficiens kan der ved påbegyndelseaf antiretroviral kombinationsbehandling (CART) opstå en inflammatorisk reaktion på asymptomatiske eller residuale opportunistiske infektioner (se afsnit 4. 4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART) an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
Der var ingen forskel i forekomsten hos patienter, som fik Ziagen, og kontrolgrupperne.
Laboratory abnormalities In controlled clinical studies laboratory abnormalities related to Ziagen treatment were uncommon, with no differences in incidence observed between Ziagen treated patients and the control arms.
10 4. 9 Overdosering
10 4.9 Overdose
Der er givet enkeltdoser op til 1200 mg og døgndoser op til 1800 mg abacavir til patienter i kliniske undersøgelser.
Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered to patients in clinical studies.
Hvis overdosering finder sted, bør patienten overvåges for tegn på forgiftning (se afsnit 4. 8), og symptomatisk behandling iværksættes om nødvendigt.
If overdose occurs the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary.
Nukleosid revers transkriptasehæmmere, ATC- kode:
Pharmacotherapeutic group: nucleoside reverse transcriptase inhibitors, ATC Code:
Det er en potent selektiv hæmmer af HIV- 1 og HIV- 2.
It is a potent selective inhibitor of HIV-1 and HIV-2.
Abacavir bliver metaboliseret intracellulært til den aktive del, carbovir 5 ’ - triphosphat (TP).
Abacavir is metabolised intracellularly to the active moiety, carbovir 5’ - triphosphate (TP).
En virkning som medfører afslutning af kæden og afbrydelse af den virale replikationscyklus.
In vitro studies have demonstrated that its mechanism of action in relation to HIV is inhibition of the HIV reverse transcriptase enzyme, an event which results in chain termination and interruption of the viral replication cycle.
Det er vist at være additivt i kombination med didanosin, lamivudin og stavudin.
It has been shown to be additive in combination with didanosine, lamivudine and stavudine.
Der er påvist abacavirresistente isolater af HIV- 1 in vitro, som er forbundet med specifikke genotypeforandringer i revers transkriptase (RT) - codonregionen (codoner M184V, K65R, L74V og Y115F).
Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specific genotypic changes in the reverse transcriptase (RT) codon region (codons M184V, K65R, L74V and Y115F).
Isolater fra patienter, som har haft virologisk svigt under en behandling med abacavir i pivotale kliniske forsøg, viste i de fleste tilfælde enten ingen NRTI- relaterede ændringer i forhold til baseline (45%) eller kun M184V - eller M1841- mutationer (45%).
In vivo resistance (Therapy naïve patients) Isolates from most patients experiencing virological failure with a regimen containing abacavir in pivotal clinical trials showed either no NRTI-related changes from baseline (45%) or only M184V or M184I selection (45%).
Mindre almindelig var mutationerne L74V (5%), K65R (1%) og Y115F (1%).
The overall selection frequency for M184V or M184I was high (54%), and less common was the selection of L74V (5%), K65R (1%) and Y115F (1%).
Når zidovudin inkluderes i behandlingen med abacavir, reduceres forekomsten af L74V - og K65R- mutationerne (med zidovudin:
The inclusion of zidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in the presence of abacavir (with zidovudine:
Behandling
Abacavir + Abacavir +
Abacavir + lamivudin + NNRTI
lamivudine + NNRTI
Abacavir + lamivudin + PI (eller PI/ ritonavir)
PI (or PI/ ritonavir)
Antal virologiske svigt
Number of Virological Failures Number of
Antal genotyper i behandling
On-Therapy Genotypes
(100%)
232 (100%)
L74V Y115F
K65R L74V Y115F M184V/ I TAMs3
0 0
0 0 0 34 (85%) 3 (8%)
9 (18%) 2 (4%)
1 (2%) 9 (18%) 2 (4%) 22 (43%) 2 (4%)
70 (50%) 4 (3%)
2 (1%) 3 (2%) 0 70 (50%) 4 (3%)
126 (54%) 9 (4%)
3 (1%) 12 (5%) 2 (1%) 126 (54%) 9 (4%)
TAM’ er kan opstå, når thymidinanaloger anvendes sammen med abacavir.
11 TAMs might be selected when thymidine analogs are associated with abacavir.
11 der blev påvist TAM’ er i behandlingsregimerne indeholdende abacavir og thymidinanalogen zidovudin (22/ 86, 26%).
In a meta-analysis of six clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine (0/ 127), but were selected by regimens containing abacavir and the thymidine analogue zidovudine (22/ 86, 26%).
Den logistiske regressionsmodel for den prædiktive værdi af genotype (justeret for baseline - plasma HIV- 1- RNA [vRNA], CD4+- celletal, antal og varighed af tidligere antiretrovirale behandlinger) viste, at tilstedeværelsen af 3 eller flere NRTI- resistens- forbundne mutationer var forbundet med nedsat respons i uge 4 (p = 0, 015) eller 4 eller flere mutationer ved median uge 24 (p ≤ 0, 012).
Logistic regression modelling of the predictive value for genotype (adjusted for baseline plasma HIV-1 RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviral therapies), showed that the presence of 3 or more NRTI resistance-associated mutations was associated with reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 (p≤ 0.012).
Revers transkriptase -
Week 4 Baseline (n = 166) Reverse
mutation ved baseline
Percent with
(n = 166)
Mutation
Median ændring vRNA (log10 c/ ml)
Change vRNA
Procent med < 400 pr. ml vRNA
< 400 copies/ mL
Tre NRTI- forbundne mutationer
associated mutations
Tilstedeværelsen af M184V sammen med K65R giver mulighed for krydsresistens mellem abacavir, tenofovir, didanosin og lamivudin.
The presence of M184V with K65R does give rise to cross-resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V gives rise to cross-resistance between abacavir, didanosine and lamivudine.
Ligeledes kan tilstedeværelsen af M184V sammen med L74V være årsag til krydsresistens mellem abacavir, didanosin og lamivudin.
The presence of M184V with Y115F gives rise to cross-resistance between abacavir and lamivudine.
Gældende resistens - algoritmer kan vejlede om hensigtsmæssig brug af abacavir.
Appropriate use of abacavir can be guided using currently recommended resistance algorithms.
Der er sandsynligvis ingen krydsresistens mellem abacavir og antiretroviraler fra andre grupper (fx PI’ er eller NNRTI’ er).
PIs or NNRTIs) is unlikely.
Fordelen ved Ziagen er hovedsageligt baseret på resultater af studier med voksne behandlingsnaive patienter med et regime af Ziagen 300 mg to gange daglig i kombination med zidovudin og lamivudin.
The demonstration of the benefit of Ziagen is mainly based on results of studies performed in adult treatment-naïve patients using a regimen of Ziagen 300 mg twice daily in combination with zidovudine and lamivudine.
Administration to gange daglig (300 mg):
12 Twice daily (300 mg) administration:
• Terapinaive voksne
• Therapy naïve adults
70% (” intention to treat ” - analyse efter 48 uger) med et tilsvarende øget CD4- celletal.
In adults treated with abacavir in combination with lamivudine and zidovudine the proportion of patients with undetectable viral load (< 400 copies/ ml) was approximately 70% (intention to treat analysis at 48 weeks) with corresponding rise in CD4 cells.
12 Kombinationen af abacavir, lamivudin og zidovudin er i én randomiseret, dobbeltblind, placebokontrolleret klinisk undersøgelse hos voksne sammenlignet med kombinationen af indinavir, lamivudin og zidovudin.
One randomised, double blind, placebo controlled clinical study in adults has compared the combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and zidovudine.
På grund af den høje andel af tidligt ophør (42% af patienterne var stoppet med randomiseret behandling senest i uge 48) kan der ikke drages nogen definitiv konklusion med hensyn til ækvivalensen mellem behandlingsregimerne ved uge 48.
Due to the high proportion of premature discontinuation (42% of patients discontinued randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence between the treatment regimens at week 48.
Skønt en lignende antiviral effekt fandtes mellem regimerne med abacavir og indinavir, hvad angår andelen af patienter med udetekterbar virusbyrde (≤ 400 kopier/ ml; ” intention to treat ” - analyse (ITT) på 47% versus 49%; analyse af behandlede (AB) på 86% versus 94% for kombinationerne med henholdsvis abacavir og indinavir), var resultaterne til fordel for kombinationen med indinavir, særligt hos undergruppen af patienter med høj virusbyrde (udgangsværdi > 100. 000 kopier/ ml; ITT på 46% versus 55%; AB på 84% versus 93% for henholdsvis abacavir og indinavir).
Although a similar antiviral effect was observed between the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable viral load (≤ 400 copies/ ml; intention to treat analysis (ITT), 47% versus 49%; as treated analysis (AT), 86% versus 94% for abacavir and indinavir combinations respectively), results favoured the indinavir combination, particularly in the subset of patients with high viral load (> 100,000 copies/ ml at baseline; ITT, 46% versus 55%; AT, 84% versus 93% for abacavir and indinavir respectively).
I et multi- center, dobbelblindt, kontrolleret studie (CNA30024), blev 654 HIV- inficerede, antiretroviral terapinaive patienter randomiseret til at modtage enten abacavir 300 mg to gange daglig eller zidovudin 300 mg to gange daglig, begge i kombination med lamivudin 150 mg to gange daglig og efavirenz 600 mg én gang daglig.
In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine 300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg once daily.
Varigheden af dobbeltblind behandling var mindst 48 uger.
The duration of double-blind treatment was at least 48 weeks.
I ” intent- to- treat ” (ITT) populationen, opnåede 70% af patienterne i abacavirgruppen, sammenlignet med 69% af patienterne i zidovudingruppen, et virologisk respons af plasma HIV- 1 RNA ≤ 50 kopier/ ml ved uge 48 (point estimate for behandlingsforskel:
In the intent-to-treat (ITT) population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine group, achieved a virologic response of plasma HIV-1 RNA ≤ 50 copies/ ml by Week 48 (point estimate for treatment difference:
0, 8, 95% CI - 6, 3, 7, 9).
0.8, 95% CI -6.3, 7.9).
I ” as treated ” (AS) analysen var forskellen mellem begge behandlingsarme mere synlig (88% af patienterne i abacavirgruppen, sammenlignet med 95% af patienterne i zidovudingruppen (point estimate for behandlingsforskel: - 6, 8, 95% CI - 11, 8; - 1, 7).
In the as treated (AT) analysis the difference between both treatment arms was more noticeable (88% of patients in the abacavir group, compared to 95% of patients in the zidovudine group (point estimate for treatment difference: -6.8, 95% CI -11.8; - 1.7).
Begge analyser var dog sammenlignelige med en konklusion om ikke- inferioritet mellem begge behandlingsarme.
However, both analyses were compatible with a conclusion of non-inferiority between both treatment arms.