qanastek/EMEA-V3 huggingface dataset:
This recurrence of the hypersensitivity reaction was usually more severe than on initial presentation, and may include life-threatening hypotension and death.
Din ir- rikkorrenza ta` reazzjonijiet ta` sensittività eċċessiva ħafna drabi kienet aktar severa mill- ewwel waħda, u tista tinkludi pressjoni baxxa ħafna ta ’ periklu għall- ħajja u mewt.
Patients who develop this hypersensitivity reaction must discontinue Kivexa and must never be rechallenged with Kivexa, or any other medicinal product containing abacavir (Ziagen or Trizivir).
Ziagen jew Trizivir).
To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, abacavir must be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicinal products).
Sabiex id- dijanjożi issir mill- ewwel u biex jitnaqqas ir- riskju ta` reazzjoni ta` sensittività eċċessiva ta` periklu għall- ħajja, abacavir għandu jitwaqqaf għal dejjem hekk kif ikun hemm suspett ta ’ sensittività eċċessiva anki meta jkun hemm possibiltà ta` dijanjożi oħra (mard respiratorju, mard simili għal dak ta` l- influwenza, gastroenterite jew reazzjonijiet għal mediċini oħra).
Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting abacavir 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 abacavir.
Kien hemm reazzjonijiet ta ’ sensittività eċċessiva li bdew malajr, li kienu jinkludu reazzjonijiet ta` periklu għall- ħajja wara li reġa ’ ngħata abacavir lill- pazjenti li kellhom biss wieħed mis- sintomi ewlenin magħrufa ta` sensittività eċċessiva (raxx tal- ġilda, deni, sintomi gastrointestinali, sintomi respiratorji jew kostituzzjonali bħal letarġija u ħass ħażin) qabel ma abacavir twaqqaf.
The most common isolated symptom of a hypersensitivity reaction was a skin rash.
L- aktar sintomu komuni iżolat ta` sensittività eċċessiva kien raxx tal - ġilda.
Moreover, on very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction.
Barra hekk, f`okkażjonijiet rari ħafna reazzjonijiet ta` sensittività eċċessiva ġew rappurtati f`pazjenti li reġgħu bdew it- terapija, u li ma kellhom l- ebda sintomi preċedenti ta ’ xi reazzjoni ta` sensittività eċċessiva.
In both cases, if a decision is made to restart abacavir this must be done in a setting where medical assistance is readily available.
Fiż- żewġ każijiet jekk tittieħed deċiżjoni sabiex jerġa ’ jinbeda abacavir, dan għandu jingħata fejn hemm assistenza medika disponibbli.
Each patient must be warned about this hypersensitivity reaction to abacavir.
Kull pazjent għandu jiġi mwissi dwar ir- reazzjonijiet ta` sensittività eċċessiva għal abacavir.
Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity.
Ħafna mill- effetti avversi mniżżla fit- tabella t’ hawn taħt huma komuni (nawżeja, rimettar, dijarrea, deni, letarġija, raxx) f` pazjenti b`sensittività eċċessiva għal abacavir.
Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction.
Għalhekk, pazjenti li jkollhom wieħed minn dawn is- sintomi għandhom jiġu eżaminati sewwa għal xi reazzjonijiet ta` sensittività eċċessiva li jista jkollhom.
If Kivexa 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).
Jekk Kivexa kien twaqqaf f’ xi pazjenti minħabba li kien instab li kellhom xi wieħed minn dawn is- sintomi u reġgħet ttieħdet id- deċiżjoni sabiex jerġa jibda jingħata prodott medicinali li fih abacavir, dan għandu jingħata fejn ikun hemm assistenza medika disponibbli (see section 4. 4.).
Very rarely cases of erythema multiforme, Stevens- Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out.
Rari ħafna każijiet ta ’ erythema multiforme, sindromu ta ’ Stevens Johnson jew nekroliżi epidermali tossika dehru meta reazzjoni ta ’ sensittività eċċessiva għal abacavir ma setgħetx tiġi eskluża.
In such cases medicinal products containing abacavir should be permanently discontinued.
F`dawn il- każijiet prodotti medicinali li fihom abacavir għandhom jitwaqqfu għal dejjem.
The adverse reactions considered at least possibly related to abacavir or lamivudine are listed by body system, organ class and absolute frequency.
L- effetti avversi kkunsidrati li huma għallinqas possibilment relatati ma ’ abacavir jew lamivudine huma elenkati skond is- sistema tal- ġisem, klassi ta ’ l- organi u l- frekwenza assoluta.
Frequencies are defined as very common (> 1/ 10), common (> 1/ 100 ,< 1/10), uncommon (> 1/ 1000 ,< 1/100), rare (> 1/ 10,000, < 1/ 1000), very rare (< 1/ 10,000).
Il- frekwenzi 10 huma mfissra bħala komuni ħafna (> 1/ 10), komuni (> 1/ 100, < 1/ 10), mhux komuni (> 1/ 1, 000, < 1/ 100), rari (> 1/ 10, 000, < 1/ 1, 000) rari ħafna (< 1/ 10, 000).
Body system
Sistema tal- ġisem
lymphatic systems
Disturbi fid- demm u fis- sistema limfatika
anaemia (both occasionally severe), thrombocytopenia Very rare:
Newtropenja u anemija( it- tnejn kultant qawwijin ħafna), tromboċitopenja Rari ħafn:
Pure red cell aplasia
Aplażja ta ’ ċelluli ħomor biss
Common: hypersensitivity
Komuni: sensittivita` eċċessiva
Metabolism and nutrition disorders
Disturbi fil- metaboliżmu u fin - nutrizzjoni
Common: anorexia
Komuni: anoressja
Headache, insomnia.
Uġigħ ta’ ras, insomnja.
Cases of peripheral neuropathy (or paraesthesia) have been reported
Każi ta ’ newropatija periferali (jew paraesteżija) ġew rappurtati
10 Respiratory, thoracic and mediastinal disorders
Disturbi respiratorji, toraċiċi, u medjastinali
Cough, nasal symptoms
Sogħla, sintomi fl - imnieħer
Common: nausea, vomiting, diarrhoea Rare: pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain
Komuni: nawżeja, remettar, dijarrea Rari: dehret pankreatite, iżda mhux ċert jekk kinetx kawżata minn abacavir
Nausea, vomiting, abdominal pain or cramps, diarrhoea Rare:
Nawżeja, rimettar, uġigħ addominali jew bugħawwieġ, dijarreja Rari:
Rises in serum amylase.
Żjieda ta ’ amylase fis - serum.
Cases of pancreatitis have been reported
Kien hemm każi ta ’ pankreatite
Transient rises in liver enzymes (AST, ALT), Rare:
Żjieda ta ’ enzimi tal- fwied( AST, ALT) Rari:
Skin and subcutaneous tissue disorders
Disturbi fil- ġilda u fit- tessuti ta` taħt il- ġilda
Common: rash (without systemic symptoms) Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
Komuni: raxx, (mingħajr sintomi sistemiċi) Rari ħafna: eritema multiformi, sindromu ta ’ Stevens- Johnson u nekroliżi tossika epidermali
Arthralgia, muscle disorders Rare:
Artralġja, mard tal - muskoli Rari:
Rhabdomyolysis
Rabdomijolożi
Common: fever, lethargy, fatigue.
Komuni: deni, letarġija, għeja
Common: fatigue, malaise, fever.
Għeja, telqa, deni
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4).
Każijiet ta` aċidożi lattika, ġieli fatali, normalment assoċjati ma 'epatomegalija qawwija u stejatożi epatika, ġew rappurtati waqt l- użu ta` analogi tan- nukleosidi (ara sezzjoni 4. 4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Terapija antiretrovirali kombinata, ġiet assoċjata ma ’ ridistribuzzjoni tax- xaħam fil- ġisem (lipodistrofija) f`pazjenti bl- HIV li jinkludi t- telf ta ’ xaħam ta ’ taħt il- ġilda f’ żoni periferali u fil- wiċċ, żieda fix- xaħam intra- addominali u vixxerali, tkabbir tas- sider u akkumulazzjoni ta ’ xaħam
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Terapija antiretrovirali kombinata ġiet assoċjata ma ’ anormalitajiet metaboliċi bħal ipertrajgliseridimja, iperkolesterolimja, reżistenza għall- insulina, ipergliċemija u iperlaktejtimja (ara sezzjoni 4. 4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).
F’ pazjenti nfettati bl- HIV b’ defiċjenza qawwija fl- immunita ’ meta tibda tingħatalhom terapija antiretrovirali kombinata, tista ’ titfaċċa reazzjoni infjammatorja għal infezzjonijiet opportunistiċi asintomatiċi jew residwali.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
Dehru xi każi ta ’ osteonekrożi, partikolarment f’ pazjenti b’ fatturi ta ’ riskju ġeneralment magħrufa, b’ mard ta ’ HIV li daħal ’ il ġewwa, jew b’ esponiment fit- tul għal terapija antiretrovirali kombinata( TARK).
The frequency of this is unknown (see section 4.4).
Mhux magħruf kemm din tiġri spiss (ara sezzjoni 4. 4).
No specific symptoms or signs have been identified following acute overdose with abacavir or lamivudine, apart from those listed as undesirable effects.
Ebda sintomi jew sinjali speċifiċi ma ġew identifikati wara t- teħid ta ’ doża eċċessiva ta ’ abacavir jew lamivudine, minbarra dawk imniżżlin bħala effetti mhux mixtieqa.
If overdose occurs the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary.
Jekk ikun hemm każ ta` doża eċċessiva l- pazjent għandu jibqa ’ taħt osservzzjoni għall- evidenza ta` tossiċità (ara sezzjoni 4. 8), u għandha tingħata kura bażika ta ’ sapport kif ikun hemm bżonn.
Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied.
Billi lamivudine jista ’ jiġi dijalisizzat, tista ’ tintuża emodijaliżi kontinwa fit- trattament ta ’ doża eċċessiva, għalkemm m’ hemmx studji dwar dan.
It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.
Għadu mhux magħruf jekk abacavir jistax jitneħħa b`dijaliżi peritonali jew b' emodijaliżi.
Antivirals for treatment of HIV infections, combinations.
Mediċini kontra l- vajrus għall- kura ta ’ infezzjonijiet b’ HIV, kombinazzjonijiet.
ATC code:
Kodiċi ATC code:
Mechanism of action:
Mekkaniżmu ta ’ kif taħdem:
Abacavir and lamivudine are NRTIs, and are potent selective inhibitors of HIV- 1 and HIV-2.
Abacavir u lamivudine huma NRTIs, u huma inibituri potenti selettivi kontra l- HIV- 1 u l- HIV- 2.
Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective 5'-triphosphate (TP) which are the active moieties.
Kemm Abacavir, kif ukoll lamavudine jiġu metabolizzati sekwenzjalment b’ kinases ta ’ ġoċ- ċelloli, għall- 5 ’ - triphosphate rispettivi (TP) li huma l- parti attiva.
Lamivudine-TP and carbovir-TP (the active triphosphate form of abacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT).
Lamivudine- TP u carbovir- TP( il- forma tat- triphosphate attiva ta ’ abacavir) huma substrati u inibituri kompetittivi ta ’ l - HIV reverse transcriptase (RT).
However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination.
Madankollu, l- attivita` anti- virali ewlenija tagħhom hi permezz ta ’ l - inkorporazzjoni tal- forma monofosfata fil- katina virali tad- DNA, li tirriżulta fid- distruzzjoni tal - katina.
Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.
Abacavir u lamivudine triphosphates juru affinita` sostanzjalment inqas għal polymerases tad - DNA taċ- ċellula reċipjenta.
Lamivudine has been shown to be highly synergistic with zidovudine, inhibiting the replication of HIV in cell culture.
Ġie ppruvat li lamivudine joħloq ħafna sinerġija ma ’ zidovudine, u dan jimpedixxi r- replikazzjoni ta ’ l- HIV fis- cell culture.
Abacavir shows synergy in vitro in combination with amprenavir, nevirapine and zidovudine.
Abacavir juri effett sinerġistiku in vitro meta jingħata ma` amprenavir, nevirapine u zidovudine.
It has been shown to be additive in combination with didanosine, stavudine and lamivudine.
Intwera li jkun hemm effett addittiv meta jingħata ma` didanosine, stavudine u lamivudine.
In-vitro resistance:
Reżistenza in vitro:
HIV-1 resistance to lamivudine involves the development of a M184I or, more commonly, M184V amino acid change close to the active site of the viral RT.
Reżistenza ta ’ HIV- 1 għal lamivudine tinvolvi l- iżvilupp ta ’ M184I jew, aktar komuni, l- aċidu amino M184V viċin tas- sit attiv ta ’ l- RT virali.
Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F).
Iżolati ta` l- HIV- 1 reżistenti għal abacavir intgħażlu in vitro u dawn huma assoċjati ma 'tibdiliet ġenotipiċi speċifiċi ta ’ (RT) codon region (codons M184V, K65R, L74V u Y115F).
Viral resistance to abacavir develops relatively slowly in vitro, requiring multiple mutations for a clinically relevant increase in EC50 over wild-type virus.
Reżistenza virali għal abacavir tiżviluppa relattivament bil- mod in vitro li jirrikjedu bosta mutazzjonijiet sabiex tintlaħaq żieda ta ’ livell klinikament rilevanti fl- EC50 fuq dak tal- virus li jinsab fin- natura.
In vivo resistance (Therapy-naïve patients):
Resistenza in vivo( Pazjenti li qatt ma ngħatalhom kura):
The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy.
Il- varjanti ta ’ M184V u M184I issibhom f’ pazjenti nfettati bl- HIV- 1 li jingħataw trattament antiretrovirali li fih lamivudine.
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%).
12 Iżolati mill- biċċa l- kbira tal - pazjenti li jkunu għaddejin minn insuffiċjenza viroloġika b’ sistema ta ’ kura b’ abacavir, urew jew li ma kien hemm l- ebda bdil mill- livell bażiku( 45%) relatat ma ’ NRTI jew M184V biss jew għażla ta ’ M184I (45%) fi studji kliniċi prinċipali.
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%) (see Table).
Il- frekwenza ta ’ selezzjoni totali għal M184V jew M184I kienet għolja (54%), u s- selezzjoni ta ’ L74V (5%), K65R (1%) u Y115F (1%) kienet anqas komuni (Ara t- tabella).
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:
Sar magħruf li ż- żieda ta ’ zidovudine fis- sistema ta ’ kura tnaqqas il- frekwenza ta ’ selezzjoni ta ’ L74V u K65R fil- preżenza ta ’ abacavir (ma ’ zidovudine:
0/ 40, without zidovudine:
0/ 40, mingħajr zidovudine:
Abacavir + Abacavir + lamivudine +
Abacavir + Abacavir + lamivudine + PI Abacavir + Totali
Abacavir +
Combivir1
lamivudine +
lamivudine + NNRTI
PI (or
(jew
PI/ ritonavir) Number of
PI/ ritonavir) Numru ta ’
Subjects
Individwi Numru ta ’
Number of Virological Failures Number of On-
Fallimenti Viroloġiċi Numru ta ’
22 (43%) 2 (4%)
1 (2%) 9 (18%) 2 (4%) 22 (43%) 2 (4%)
1. Combivir is a fixed dose combination of lamivudine and zidovudine 2. Includes three non-virological failures and four unconfirmed virological failures.
1. Combivir fih doża fissa ta ’ taħlita ta ’ lamivudine u zidovudine 2.
3.
Jinkludi tlett fallimenti mhux viroloġiċi u erba ’ fallimenti viroloġiċi mhux konfermati 3.
Number of subjects with ≥ 1 Thymidine Analogue Mutations (TAMs).
Numru ta ’ individwi b’ ≥1 Mutazzjonijiet ta ’ l- Analogu ta ’ Thymidine (TAMs).
TAMs might be selected when thymidine analogs are associated with abacavir.
TAMs jistgħu ikunu magħżula meta analogi ta ’ thymidine ikunu assoċjati ma ’ abacavir.
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%).
F’ meta - analiżi ta ’ sitt studji kliniċi, it- TAMs ma kienux magħżula minn sistemi ta ’ kura li fihom abacavir mingħajr zidovudine (0/ 127), imma kienu magħżula minn sistemi ta ’ kura li fihom abacavir u l - analogu ta ’ thymidine zidovudine (22/ 86, 26%).
In vivo resistance (Therapy experienced patients):
Reżistenza in vivo (Pazjenti b’ esperjenza ta ’ kura):
The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy and confer high-level resistance to lamivudine.
Il- varjanti ta ’ M184V jew M184I issibhom f’ pazjenti nfettati bl- HIV- 1 li jingħataw trattament antiretrovirali li fih lamivudine u jkollhom reżistenza ta ’ livell għoli għal lamivudine.
In vitro data tend to suggest that the continuation of lamivudine in anti- retroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness).
Data in vitro għandha t- tendenza li turi li l- kontinwazzjoni ta 'lamivudine f’ sistema ta ’ kura antiretrovirali minkejja l- iżvilupp ta ’ M184V tista ’ tipprovdi attivita ’ antiretrovirali residwa (li tista ’ tiġri minħabba li l- virus ma jibqax jiffunzjona sewwa).
Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field.
Ċertament, id- data klinika disponibbli hija limitata ħafna u ma tippermettix li ssir konkluzzjoni ta ’ min joqgħod fuqha fil- qasam.
In any case, initiation of susceptible NRTIs should always be preferred to maintenance of lamivudine therapy.
F’ kull ċirkostanza, huwa dejjem preferit li jinbdew NRTIs suxxettibli minflok terapija kontinwa b' lamivudine.
Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTIs are available.
Għalhekk, għandha tiġi kkunsidrata biss terapija regolari b’ lamivudine, minkejja li titfaċċa mutazzjoni ta ’ M184V fejn l- ebda NRTI attiv ieħor ma ’ jkun disponibbli.
Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to other nucleoside inhibitors.
Tnaqqis klinikament sinifikanti fis- suxxettibilita ’ għal abacavir deher f’ iżolati kliniċi ta ’ pazjenti, b’ replikazzjoni mingħajr kontroll tal- virus, li kienu ttrattati minn qabel b’ inibituri tan- nukleosidi oħra u huma resistenti għalihom.
In a meta-analysis of five clinical trials where ABC was added to intensify therapy, of 166 subjects, 123 (74%) had M184V/ I, 50 (30%) had T215Y/ F, 45 (27%) had M41L, 30 (18%) had K70R and 25 (15%) had D67N.
F’ meta- analiżi ta ’ ħames studji kliniċi fejn żdied ABC biex iqawwi t - terapija, ta ’ 166 individwu, 123 (74%) kellhom M184V/ I, 50( 30%) kellhom T215Y/ F, 45 (27%) kellhom M41L, 30 (18%) kellhom K70R u 25 (15%) kellhom D67N.
K65R was absent and L74V and Y115F were uncommon (≤ 3%).
Ma kienx hemm K65R u L74V u Y115F ma kienux komuni (≤3%).
Logistic regression modelling of the predictive value for genotype (adjusted for baseline plasma HIV-1RNA [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).
Rigressjoni fl- immudellar loġistiku tal- figuri predikattivi tal - ġenotip (aġġustat għall- livell bażiku fil- plażma ta ’ HIV- 1 RNA [VRNA], l- għadd ta ’ ċelloli CD4+, in - 13 numru u t- tul ta ’ terapiji antiretrovirali ta ’ qabel), wera li l- preżenza ta ’ 3 jew aktar mutazzjonijiet assoċċjati ma ’ resistenza b’ NRTI, kellhom x’ jaqsmu ma ’ respons mnaqqas fir- 4 Ġimgħa (p=0. 015) jew 4 jew aktar mutazzjonijiet fil- medja ta ’ 24 Ġimgħa (p≤0. 012).
In addition, the 69 insertion complex or the Q151M mutation, usually found in combination with A62V, V75I, F77L and F116Y, cause a high level of resistance to abacavir.
Barra minn hekk, id- dħul ta ’ kumpless fil- pożizzjoni 69 jew il- mutazzjoni Q151M, li ssoltu ssibhom ma ’ A62V, V751, F77L u F116Y, jikkawżaw reżistenza kbira għal abacavir.
Week 4
4 Ġimgħa Mutazzjoni tal - (n = 166) lina bażi ta ’ Bidla Medja
Baseline Reverse Transcriptase
Reverse
(n = 166) Percent with
vRNA (log10
Mutatio
Persentaġġ b ’
n n
Transcriptase
Change vRNA (log10 c/ mL)
c/ mL)
< 400 copies/ mL vRNA
< 400 kopji/ mL vRNA
Any one NRTI
M184V waħdu Kull mutazzjoni
mutation
ta ’ NRTI waħda Kull żewg
Any two NRTI-
mutazzjonijiet
associated mutations Any three NRTI-
assoċjati ma ’ NRTI Kull tlett
associated mutations Four or more NRTI-
assoċjati ma ’ NRTI 4 jew aktar
associated mutations
assoċjati ma ’ NRTI
Phenotypic resistance and cross-resistance:
Reżistenza Finotipika u cross resistance:
Phenotypic resistance to abacavir requires M184V with at least one other abacavir-selected mutation, or M184V with multiple TAMs.
Reżistenza finotipika għal abacavir għanda bżonn M184V b’ almenu mutazzjoni waħda oħra magħżula għal abacavir, jew M184V b’ ħafna TAMs.
Phenotypic cross- resistance to other NRTIs with M184V or M184I mutation alone is limited.
Cross - resistance finotipika għal NRTI oħra bil- mutazzjoni M184V jew M184I waħidha hija limitata.
The
Zidovudine, didanosine, stavudine u tenofovir iżommu l- attivita ’ antiretrovirali tagħhom kontra dawn it- tipi ta ’ varjanti ta ’ HIV- 1.
13 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.
Il- preżenza ta ’ M184V ma ’ K65R tikkawża cross- resistance bejn abacavir, tenofovir, didanosine u lamivudine.
The presence of M184V with Y115F gives rise to cross-resistance between abacavir and lamivudine.
Il- preżenza ta ’ M184V ma ’ Y115F tikkawża cross - resistance bejn abacavir u lamivudine.
Appropriate use of abacavir can be guided using currently recommended resistance algorithms.
L- użu xieraq ta ’ abacavir jista ’ jkun iggwidat bl- użu ta ’ algoritmi ta ’ reżistenza li huma rakkomandati bħal issa.
Cross-resistance between abacavir or lamivudine and antiretrovirals from other classes e. g.
Cross- resistance bejn abacavir jew lamivudine u antiretrovirali ta ’ klassijiet oħra e. g.
PIs or NNRTIs is unlikely.
PIs jew NNRTIs mhix probabbli.
Clinical experience
Studji kliniċi f` pazjenti li qatt ma kienu fuq kura antiretrovirali
Therapy-naïve patients The combination of abacavir and lamivudine as a once daily regimen is supported by a 48 weeks multi-centre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults.
Il- kombinazzjoni ta ’ abacavir u lamivudine mgħotija b’ doża ta ’ darba kuljum ġiet studjata f ’ istudju kontrollat (CNA30021), double blind, f’ ħafna ċentri, mifrux fuq 48 ġimgħa, ta’ 770 adulti nfettati bl - HIV li qatt ma kienu fuq it- terapija qabel.
These were primarily asymptomatic HIV infected patients (CDC stage A).
Dawn kienu primarjament pazjenti nfettati bl- HIV asintomatika (CDC stadju A).
They were randomised to receive either abacavir (ABC) 600 mg once daily or 300 mg twice daily, in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily.
Kienu magħżula bl- addoċċ biex jingħataw jew 600 mg abacavir (ABC) darba kuljum jew 300 mg darbtejn kuljum, kombinati ma 300 mg lamivudine darba kuljum u 600 mg efavirenz darba kuljum.
The results are summarised in the table below:
Ir- riżultati jidhru fil- qosor fit- tabella t’ hawn taħt:
Virological Response Based on Plasma HIV-1 RNA < 50 copies/ ml at Week 48 ITT-Exposed Population
14 Rispons Viroloġiku Bażat fuq l- HIV- 1 fil- plażma RNA < 50 kopji/ ml fit- 48 Ġimgħa Popolazzjoni Esposta Għal ITT
ABC twice/ day
ABC darbtejn kuljum ABC darba kuljum Sistema ta ’ trattament
Virological response
Rispons viroloġiku
Similar clinical success (point estimate for treatment difference: -1.7, 95% CI – 8.4, 4.9) was observed for both regimens.
L- istess suċċess kliniku (point estimate għad- differenza fit- trattament: - 1. 7, 95% CI – 8. 4, 4. 9) ġie osservat fiż- żewġ sistemi.
From these results, it can be concluded with 95% confidence that the true difference is no greater than 8.4% in favour of the twice daily regimen.
Minn dawn ir- riżultati, jista ’ jiġi konkluż b’ ċertezza ta ’ 95% li d- differenza vera mhix aktar minn 8. 4% favur is- sistema ta ’ darbtejn kuljum.
This potential difference is sufficiently small to draw an overall conclusion of non-inferiority of abacavir once daily over abacavir twice daily.
Din id- differenza potenzjali hi żgħira biżżejjed biex twassal għall- konklużjoni li abacavir darba kuljum m’ huwiex inqas effettiv minn abacavir darbtejn kuljum.
There was a low, similar overall incidence of virologic failure (viral load > 50 copies/ ml) in both the once and twice daily treatment groups (10% and 8% respectively).
Kien hemm inċidenza ġenerali simili ta ’ indeboliment viroloġiku, li kienet baxxa, (viral load > 50 kopji/ ml) fiż- żewġ gruppi ta ’ trattament b’ darba u darbtejn kuljum (10% u 8% rispettivament).
In the small sample size for genotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the once daily versus the twice daily abacavir regimens.
Fil - kejl b’ kampjun żgħir għal analiżi ġenotipika, kien hemm xejra lejn rata ogħla ta ’ mutazzjonijiet assoċjati ma NRTI fis- sistemi ta ’ abacavir mgħoti darba kuljum meta mqabbel ma ’ abacavir mgħoti darbtejn kuljum.
No firm conclusion could be drawn due to the limited data derived from this study.
Ma tistax tinġibed konklużjoni preċiża minħabba l- informazzjoni limitata li ħarġet minn dan l- istudju.
Long term data with abacavir used as a once daily regimen (beyond 48 weeks) are currently limited.
Tagħrif dwar użu fit- tul ta ’ abacavir darba kuljum (aktar minn 48 ġimgħa) huwa limitat fil- preżent.
Therapy-experienced patients In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and received treatment with either Kivexa once daily or abacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovir and a PI or an NNRTI for 48 weeks.
Studji kliniċi fuq pazjenti b’ esperjenza tat- terapija Fl- istudju CAL30001, 182 pazjent b’ esperjenza tat- terapija u li kellhom indeboliment viroloġiku ntgħażlu kif ġie ġie u bdew trattament b’ Kivexa darba kuljum jew bi 300 mg abacavir darbtejn kuljum u 300 mg lamivudine darba kuljum, it- tnejn mgħotija flimkien ma ’ tenovir u PI jew NNRTI għal 48 ġimgħa.
Results indicate that the Kivexa group was non-inferior to the abacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average area under the curve minus baseline (AAUCMB, - 1.65 log10 copies/ ml versus -1.83 log10 copies/ ml respectively, 95% CI -0.13, 0.38).
Ir- riżultati indikaw li l- grupp li ħadu Kivexa ma kienux inferjuri għall- grupp li ħadu abacavir darbtejn kuljum, bażati fuq tnaqqis simili fl- HIV- 1 RNA kif imkejjel b’ żona medja taħt il- curve minus baseline (AAUCMB, - 1. 65 log10 kopji/ ml kontra - 1. 83 log10kopji/ ml rispettivament, 95% CI - 0. 13, 0. 38).
Proportions with HIV-1 RNA < 50 copies/ ml (50% versus 47%) and < 400 copies/ ml (54% versus 57%) were also similar in each group (ITT population).
Il- proporzjonijiet b ’ HIV- 1 RNA < 50 kopja/ ml (50% kontra 47%) u < 400 kopja/ ml (54% kontra 57%) kienu simili wkoll f’ kull grupp (popolazzjoni ITT).
However, as there were only moderately experienced patients included in this study with an imbalance in baseline viral load between the arms, these results should be interpreted with caution.
Madankollu, billi kien hemm biss pazjenti b’ esperjenza moderata inklużi f’ dan l- istudju bi żbilanċ fil- baseline viral load bejn id - dirgħajn, dawn ir- riżultati għandhom ikun interpretati b’ ċerta kawtela.
Results
Fl- istudju ESS30008, 260 pazjent b’ soppressjoni viroloġika fuq sistema ta ’ terapija first line bi 300 mg abacavir u 150 mg lamivudine, it- tnejn meħudin darbtejn kuljum flimkien ma ’ PI jew NNRTI, intgħażlu kif ġie ġie biex ikomplu b’ din is- sistema jew jaqilbu għal Kivexa flimkien ma ’ PI jew NNRTI għal 48 ġimgħa.
14 indicate that the Kivexa group was associated with a similar virologic outcome (non-inferior) compared to the abacavir plus lamivudine group, based on proportions of subjects with HIV-1 RNA < 50 copies/ ml (90% and 85% respectively, 95% CI -2.7, 13.5).
Ir- riżultati indikaw li l- grupp ta ’ Kivexa kien assoċjat ma ’ riżultat viroloġiku simili mhux inferjuri, paragunat mall- grupp ta ’ abacavir u lamivudine, bażati fuq proporzjonijiet ta ’ individwi b ’ HIV- 1 RNA < 50 kopji/ ml (90% u 85% rispettivament, 95% CI - 2. 7, 13. 5).
The fixed-dose combination tablet of abacavir/ lamivudine (FDC) has been shown to be bioequivalent to lamivudine and abacavir administered separately.
Il- pillola kombinata b’ doża fissa ta ’ abacavir/ lamivudine (FDC) ġiet ppruvat li hi bijoekwivalenti għal lamivudine u abacavir meħudin separatament.
This was demonstrated in a single dose, 3-way crossover bioequivalence study of FDC (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg lamivudine tablets (fasted) versus FDC administered with a high fat meal, in healthy volunteers (n = 30).
Dan ħareġ minn studju b’ doża waħda u bijoekwivalenza 3- way crossover ta ’ FDC( b’ sawm) kontra żewġ pilloli ta ’ 300 mg abacavir flimkien ma ’ żewġ pilloli ta ’ 150 mg lamivudine (b’ sawm) kontra FDC meħud ma ’ ikla b’ ħafna xaħam f’ voluntieri f’ saħħithom (n- 30).
In the fasted state there was no significant difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component.
Fl- istat sajjem ma kienx hemm differenza sinifikanti fl- ammont ta ’ assorbiment, imkejjel biż- żona ta ’ taħt l- concentration- time curve (AUC) tal- plażma u l - konċentrazzjoni massima( Cmax), ta ’ kull komponent.
There was also no clinically significant food effect observed between administration of FDC in the fasted or fed state.
Barra hekk ma ġie osservat ebda effett klinikament sinifikanti mill- ikel meta FDC ittieħed fi stat sajjem jew ma ’ l- ikel.
These results indicate that FDC can be taken with or without food.
Dawn ir- riżultati juru li FDC jista ’ jittieħed ma ’ l- ikel jew fuq stonku vojt.
The pharmacokinetic properties of lamivudine and abacavir are described below.
Il- kwalitajiet farmakokinetiċi ta ’ lamivudine u abacavir huma deskritti hawn taħt.
Absorption
15 Assorbiment
Abacavir and lamivudine are rapidly and well absorbed from the gastro-intestinal tract following oral administration.
Abacavir u lamivudine jiġu assorbiti malajr u tajjeb mir- rotta gastro- intestinali wara li jittieħdu mill - ħalq.
The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and 80-85% respectively.
Il- bijodisponibbiltà assoluta ta ’ abacavir u lamivudine orali fl- adulti hija ta` madwar 83% u 80 - 85% rispettivament.
The mean time to maximal serum concentrations (tmax) is about 1.5 hours and 1.0 hour for abacavir and lamivudine, respectively.
Il- ħin medju biex jintlaħqu konċentrazzjonijiet massimi tas- serum( tmax) hu ta ’ madwar 1. 5 sigħat u siegħa għal abacavir u lamivudine, rispettivament.
Following a single dose of 600 mg of abacavir, the mean (CV) Cmax is 4.26 µg/ ml (28%) and the mean (CV) AUC∞ is 11.95 µg. h/ ml (21%).
Wara doża waħda ta ’ 600 mg abacavir il- medja (CV) (Cmax) hi 4. 26 µg/ ml (28%) u l- medja (CV) AUC∞ hi 11. 95 µg. h/ ml (21%).
Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 µg/ ml (26%) and the mean (CV) AUC24 is 8.87 µg. h/ ml (21%).
Wara t- teħid mill- ħalq ta ’ doża multipla ta ’ 300 mg lamivudine darba kuljum għal sebat ijiem, il - medja (CV) fi stat stabbli ta ’ Cmax hi 2. 04 µg/ ml (26%) u l- medja (CV) ta ’ l- AUC24 hi 8. 87 µg. h/ ml (21%).
Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 l/ kg respectively.
Studji dwar l- għoti fil- vina ta ’ abacavir u lamivudine juru li l- medja tal- volum ta` distribuzzjoni apparenti kien ta` madwar 0. 8 u 1. 3 l/ kg rispettivament.
Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations.
Studji in vitro dwar kemm jeħlu mal- proteini tal- plażma juru li abacavir jeħel ftit jew moderatament (~49%) ma ’ proteini tal- plażma umani f’ konċentrazzjonijiet terapewtiċi.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (< 36%).
Lamivudine juri farmakokinetiċi lineari fuq il- firxa ta ’ dożi terapewtiċi u juri li jeħel b’ mod limitat mal- proteini tal- plażma in vitro (< 36%). possibiltà baxxa ta ’ interazzjonijiet ma ’ prodotti mediċinali oħra permezz ta ’ spostament li teħel mal- proteini tal- plażma.
This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.
Dan jindika tas- sustanza
Data show that abacavir and lamivudine penetrate the central nervous system (CNS) and reach the cerebrospinal fluid (CSF).
Informazzjoni disponibbli turi li abacavir u lamivudine jidħlu sew fis- sistema nervuża ċentrali (CNS) u jilħqu l- fluwidu ċerebro- spinali (CSF).
Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%.
Studji dwar abacavir juru l- proporzjon tas- CSF ma ’ l- AUC fil- plażma ta ’ bejn 30 sa 44%.
The observed values of the peak concentrations are 9 fold greater than the IC50 of abacavir of 0.08 µg/ ml or 0.26 µM when abacavir is given at 600 mg twice daily.
L- ammonti osservati ta ’ l- ogħla konċentrazzjonijiet huma 9 darbiet akbar mill - IC50 ta ’ abacavir ta ’ 0. 08 µg/ ml jew 0. 26 µM meta tingħata doża ta ’ 600 mg abacavir darbtejn kuljum.
The mean ratio of CSF/ serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%.
Il- proporzjon medju ta ’ konċentrazzjonijiet ta ’ lamivudine fis- CSF/ serum 2- 4 sigħat wara li jittieħed mill- ħalq hu bejn wieħed u ieħor 12%.
The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
M’ huwiex magħruf sa fejn tasal il - penetrazzjoni ta ’ lamivudine fis- CNS u r- relazzjoni tagħha ma ’ xi effikaċja klinika.
Metabolism
Metaboliżmu:
Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound.
Abacavir huwa primarjament metabolizzat mill- fwied u bejn wieħed u ieħor 2% tad- doża li tingħata titneħħa mill- ġisem permezz tal- kliewi, bħala sustanza mhux mibdula.
The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5’ -carboxylic acid and 5’ -glucuronide which account for about 66% of the administered dose.
Ir- rotot ewlenin tal - metaboliżmu fil- bniedem huma bl- alkohol dehydrogenase u bi glukoronidazzjoni sabiex jiproduċu 5 ’ - carboxylic acid u 5 ’ - glucuronide li jirrappreżentaw 66% tad- doża li tingħata.
These metabolites are excreted in the urine.
Dawn il- metaboliti joħorġu ma ’ l- awrina.
Metabolism of lamivudine is a minor route of elimination.
Metaboliżmu ta ’ lamivudine hu rotta minuri ta ’ eliminazzjoni.
Lamivudine is predominately cleared by renal excretion of unchanged lamivudine.
Lamivudine jitneħħa prinċipalment bħala lamivudine mhux mibdul permezz tal- kliewi.
The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%).
Il- probabbilta` ta ’ interazzjonijiet metaboliċi ta ’ mediċini ma ’ lamivudine hi baxxa minħabba l- metaboliżmu limitat tal- fwied (5- 10%)
15 The mean half-life of abacavir is about 1.5 hours.
Il- medja tal- half- life ta ’ abacavir hija madwar 1. 5 sigħat.
Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir.
Wara diversi dożi ta ’ 300 mg abacavir mill - ħalq mgħoti darbtejn kuljum ma` jkunx hemm akkumulazzjoni sinifikanti ta ’ abacavir.
Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine.
It- tneħħija ta ’ abacavir mill- ġisem issir permezz ta ’ metaboliżmu fil- fwied u s- sustanzi li jiffurmaw jitneħħew primarjament fl- awrina.
The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine.
Is- sustanzi ffurmati mill- metaboliżmu u l- abacavir mhux mibdul fl- awrina jilħqu it- 83% tad- doża li tingħata.
The remainder is eliminated in the faeces.
Il- bqija jitneħħew fl- ippurgar.
The observed lamivudine half-life of elimination is 5 to 7 hours.
Il- half life ta ’ l- eliminazzjoni ta ’ lamivudine osservata hi minn 5 sa 7 sigħat.
The mean systemic clearance of lamivudine is approximately 0.32 l/ h/ kg, predominantly by renal clearance (> 70%) via the organic cationic transport system.
It- tneħħija sistemika medja ta ’ lamivudine hi bejn wieħed u ieħor 0. 32 l/ h/ kg, prinċipalment bi tneħħija mill- kliewi (> 70%) permezz tas- sistema tat- trasport organika u katjonika.
Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction.
Studji fuq pazjenti b’ indeboliment tal- kliewi juru li disfunzjoni tal- kliewi teffettwa t- tneħħija ta ’ lamivudine.
Dose reduction is required for patients with creatinine clearance < 50 ml/ min (see section 4.2).
Tnaqqis ta ’ doża hu meħtieġ f’ pazjenti bi tneħħija ta ’ kreatinina ta ’ < 50 ml/ min (ara sezzjoni 4. 2)
Intracellular pharmacokinetics
16 Farmakokinetiċi intraċellulari
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours.
Fi studju ta ’ 20 pazjent infettati bl- HIV li kienu qed jieħdu 300 mg abacavir darbtejn kuljum, b’ doża waħda ta ’ 300 mg meħuda qabel il- perijodu ta ’ 24 siegħa li fihom ittieħdu il- kampjuni, il- half- life terminali, medja, ġeometrika ta ’ carbovir- TP intra- ċellulari fi stat stabbli kienet ta ’ 20. 6 sigħat, meta mqabbla mal- half- life medja ġeometrika ta ’ abacavir fil- plażma f’ dan l- istudju ta ’ 2. 6 sigħat.
For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, compared to the plasma lamivudine half-life of 5-7 hours.
Fi studju crossover f’ 27 pazjent infettat bl- HIV, l- espożizzjonijiet għal carbovir- TP ġewwa ċ- ċellola kienu aktar għoljin għas- sistema ta ’ kura b’ abacavir 600mg darba kuljum (AUC24, ss + 32%, Cmax 24, ss + 99% u C trough + 18%) meta mqabbla mas- sistema ta ’ kura ta ’ 300mg darbtejn kuljum. F’ pazjenti li jkunu qed jieħdu 300 mg lamivudine darba kuljum, il- half- life intraċellulari terminali ta ’ lamivudine- TP ġiet imtawla għal 16- 19- il siegħa, meta mqabbla mal- half- life ta ’ lamivudine fil- plażma ta ’ 5- 7 sigħat.
In a crossover study in 60 healthy volunteers, intracellular lamivudine-TP pharmacokinetic parameters were similar (AUC24, ss and Cmax24, ss) or lower (Ctrough – 24%) for the lamivudine 300 mg once daily regimen compared to the lamivudine 150 mg twice daily regimen.
Fi studju crossover f’ 60 voluntier b’ saħħithom, il- parametri farmakokinetiċi ta ’ lamivudine- TP fiċ- ċelluli kienu simili (AUC24, ss u Cmax, ss) jew aktar baxxi (Ctrough – 24%) għas- sistema ta ’ kura ta ’ lamivudine 300mg darba kuljum meta mqabbla mas- sistema ta ’ kura ta ’ lamivudine 150mg darbtejn kuljum.
Overall, these data support the use of lamivudine 300 mg and abacavir 600 mg once daily for the treatment of HIV-infected patients.
Kollox ma ’ kollox dan it- tagħrif jiffavorixxi l- użu ta ’ 300 mg lamivudine u 600 mg abacavir darba kuljum għall- kura ta ’ pazjenti nfettati bl- HIV.
Additionally, the efficacy and safety of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021- See Clinical experience).
Barra dan, l- effikaċja u s- sigurtà ta ’ din il - kombinazzjoni ta ’ darba kuljum intweriet fi studju kliniku ta ’ importanza kbira (CNA30021 – Ara Esperjenza klinika).
Hepatically impaired:
Indeboliment tal- fwied:
There are no data available on the use of Kivexa in hepatically impaired patients.
M’ hemmx tagħrif disponibbli dwar l- użu ta ’ Kivexa f’ pazjenti b’ indeboliment epatiku.
Pharmacokinetic data has been obtained for abacavir and lamivudine alone.
Tagħrif farmakokinetiku nkiseb dwar abacavir u lamivudine weħidhom.
Abacavir is metabolised primarily by the liver.
Abacavir huwa primarjament metabolizzat mill- fwied.
The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose.
Il- farmakokinetika ta ’ abacavir ġiet studjata f’ pazjenti b’ indeboliment epatiku ħafif (punteġġ Child- Pugh 5- 6) li kienu qed jirċievu doża waħda ta` 600 mg.
The results showed that there was a mean increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life.
Ir- riżultati wrew li kien hemm żieda medja ta` 1. 89 drabi [1. 32; 2. 70] f' l- AUC ta ’ abacavir, u ta ’ 1. 58 drabi [1. 22; 2. 04] fil- half- life ta ’ l- eliminazzjoni mill- ġisem.
No recommendation on dosage reduction is possible in patients with mild hepatic impairment due to substantial variability of abacavir exposure.
Ma tistax tingħata rakkomandazzjoni għal tnaqqis fid- doża f`pazjenti li jbatu minn indeboliment epatiku ħafif minħabba l- varjazzjoni sostanzjali fl- esponiment għal abacavir.
Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.
Tagħrif li nkiseb minn pazjenti b’ indeboliment epatiku sever juri li funzjoni epatika ħażina m’ għandhiex effett sinifikanti fuq farmakokinetiċi ta ’ lamivudine
Renally impaired:
Indeboliment renali:
Pharmacokinetic data have been obtained for lamivudine and abacavir alone.
Tagħrif farmakokinetiku inkiseb dwar lamivudine u abacavir weħidhom.
Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged in the urine.
Abacavir huwa primarjament metabolizzat mill- fwied u bejn wieħed u ieħor 2% ta ’ abacavir jitneħħa mingħajr ma jinbidel fl- awrina.
The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function.
Il- farmakokinetika ta ’ abacavir f`pazjenti fl- aħħar stadju ta ’ mard renali hija simili għal dik ta ’ pazjenti b`funzjoni normali tal- kliewi.
Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance.
Studji dwar lamivudine juru li konċentrazzjonijiet fil- plażma (AUC) jiżdiedu f’ pazjenti b’ funzjoni ħażina tal- kliewi minħabba tnaqqis ta ’ eliminazzjoni.
Dose reduction is required for patients with creatinine clearance of < 50 ml/ min.
Tnaqqis tad- doża hu meħtieġ għal pazjenti li għandhom eliminazzjoni ta ’ kreatinina ta ’ < 50 ml/ min.
No pharmacokinetic data are available in patients over 65 years of age.
M’ hemmx tagħrif farmakokinetiku dwar pazjenti li għandhom ‘ l fuq minn 65 sena.
With the exception of a negative in vivo rat micronucleus test, there are no data available on the effects of the combination of abacavir and lamivudine in animals.
Bl- eċċezzjoni ta ’ test negattiv mikronukleu in vivo fuq ġrieden, ma hawnx tagħrif disponibbli dwar l - effetti tal- kombinazzjoni ta ’ abacavir u lamivudine fuq l- annimali.
Mutagenicity and carcinogenicity
Mutaġeniċita` u karċinoġeniċita`
Neither abacavir nor lamivudine were mutagenic in bacterial tests, but like many nucleoside analogues they show activity in the in vitro mammalian tests such as the mouse lymphoma assay.
La abacavir u lanqas lamivudine ma kienu mutaġeniċi f`testijiet batteriċi, iżda bħal ħafna analogi tan - nukleosidi dawn juru attivita` fit- testijiet in vitro fuq mammali bħall- analiżi tal- limfoma fil- ġrieden.
This is consistent with the known activity of other nucleoside analogues.
Dan juri konsistenza ma l- attivita` magħrufa ta ’ analogi tan- nukleosidi.
The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were negative.
Ir- riżultati ta ’ test mikronukleu in vivo fuq ġrieden b’ abacavir u lamivudine flimkien kienu negattivi.
Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasma concentrations up to 30-40 times higher than clinical plasma concentrations.
17 Lamivudine ma were ebda attivita` ġenotossika fl- istudji in vivo fejn ingħataw dożi li wasslu għal konċentrazzjonijiet fil- plażma sa 30- 40 darba ogħla minn konċentrazzjonijet fil- plażma kliniċi.
Abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high tested concentrations.
Abacavir għandu potenzjal dgħajjef li jikkawża ħsara fil- kromożomi kemm in vitro kif ukoll in vivo b’ konċentrazzjonijiet għolja li ġew studjati.
The carcinogenic potential of a combination of abacavir and lamivudine has not been tested.
Il- potenzjal karċinoġeniku ta ’ kombinazzjoni ta ’ abacavir u lamivudine ma ġiex ittestjat.
In long- term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.
Fi studji orali dwar karċinoġenita` li saru fit- tul fi ġrieden u firien, lamivudine ma wera ebda potenzjal karċinoġeniku.
Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours.
Studji dwar il- karċinoġeniċità ta ’ abacavir mill- ħalq fi ġrieden u firien urew żieda ta ’ inċidenza ta` tumuri malinni kif ukoll mhux malinni.
Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in rats in the thyroid gland of males and in the liver, urinary bladder, lymph nodes and the subcutis of females.
Tumuri malinni ħarġu fil- glandola prepuzzjali fl - annimali tas- sess maskili u fil- glandola klitorali fl- annimali tas- sess femminili taż- żewġ speċi, u fil - firien maskili ħarġu fil- glandola tat- tirojde, u fil- fwied, fil- bużżieqa ta ’ l- awrina, fil- glandoli żgħar limfatiċi u fis- subkute tal- firien femminili.
The majority of these tumours occurred at the highest abacavir dose of 330 mg/ kg/ day in mice and 600 mg/ kg/ day in rats.
Il- parti l- kbira ta` dawn it- tumuri ħarġu waqt li kienet qed tingħata l- aktar doża għolja ta ’ abacavir ta` 330 mg/ kg kuljum fil- ġrieden u 600 mg/ kg kuljum fil- firien.
The exception was the preputial gland tumour which occurred at a dose of 110 mg/ kg in mice.
L- eċċezzjoni kienet fil- każ tat- tumur tal - glandola prepuzzjali li deher f`doża ta` 110 mg/ kg fil- ġrieden.
The systemic exposure at the no effect level in mice and rats was equivalent to 3 and 7 times the human systemic exposure during therapy.
L- esponiment sistemiku għall- livell ta ’ bla effett fil- ġrieden u fil- firien kienet ekwivalenti għal minn 3 u 7 darbiet aktar mill- esponiment sistemiku uman li jkun hemm waqt it- terapija.
While the carcinogenic potential in humans is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.
Filwaqt li l- potenzjal karċinoġeniku fil- bniedem mhux magħruf, dan it- tagħrif jindika li r- riskju ta` karċinoġeniċità fil- bniedem huwa anqas mill- potenzjal tal - benefiċċju kliniku.
Repeat-dose toxicity
Tossiċita` minn dożi ripetuti