qanastek/EMEA-V3 huggingface dataset:
Patients must be observed carefully for symptoms and signs of bleeding during treatment particularly if bivalirudin is combined with another anticoagulant (see section 4.5).
Il- pazjenti jridu jiġu osservati b’ attenzjoni għal sintomi u sinjali ta ’ fsada waqt it - trattament b’ mod partikolari jekk bivalirudin huwa kkombinat ma ’ antikoagulant ieħor (ara sezzjoni 4. 5).
Although most bleeding associated with bivalirudin occurs at the site of arterial puncture in patients undergoing PCI, haemorrhage can occur at any site during therapy.
Għalkemm il- biċċa l- kbira tal- fsada assoċjata ma ’ bivalirudin isseħħ fil- post ta ’ titqib ta ’ l- arterja f’ pazjenti sottoposti għal PCI, l- emorraġija tista ’ sseħħ fi kwalunkwe post matul it- terapija.
Unexplained decreases in haematocrit, haemoglobin or blood pressure may indicate haemorrhage.
Tnaqqis mhux spjegat fl- ematokrit, l- emaglobina jew il- pressjoni tad- demm jista ’ jindika emorraġija.
Treatment should be stopped if bleeding is observed or suspected.
It - trattament għandu jitwaqqaf jekk tkun osservata jew suspettata fsada.
There is no known antidote to bivalirudin but its effect wears off quickly (T½ is 35 to 40 minutes).
M’ hemmx antidotu magħruf għal bivalirudin iżda l- effett tiegħu jgħaddi malajr (T½ huwa ta ’ 35 sa 40 minuta).
Co-administration with platelet inhibitors or anti-coagulants:
L- għoti fl- istess ħin ma ’ inibituri tal- plejtlits jew ma ’ anti- koagulanti:
Combined use of anti-coagulant medicines can be expected to increase the risk of bleeding (see section 4.5).
Bl- użu kkombinat ta ’ mediċini anti- koagulanti jista ’ jkun mistenni li jiżdid ir- riskju ta ’ fsada (ara sezzjoni 4. 5).
When bivalirudin is combined with a platelet inhibitor or an anti-coagulant medicine, clinical and biological parameters of haemostatsis should be regularly monitored.
Meta bivalirudin jiġi kkombinat ma ’ inibitur tal- plejtlits jew ma ’ mediċina anti- koagulanti, il- parametri kliniċi u bijoloġiċi ta ’ emostażi għandhom jiġu mmonitorjati regolarment.
In patients taking warfarin who are treated with bivalirudin, International Normalised Ratio (INR) monitoring should be considered to ensure that it returns to pre-treatment levels following discontinuation of bivalirudin treatment.
4 F’ pazjenti li qegħdin jieħdu warfarin li huma kkurati b’ bivalirudin, għandu jiġi kkunsidrat il - monitoraġġ ta ’ l - International Normalised Ratio (INR) sabiex jiġi żgurat li dan imur lura għal- livelli ta ’ qabel il- kura wara l- waqfien tal- kura b’ bivalirudin.
Hypersensitivity:
Sensittività eċċessiva:
Allergic type hypersensitivity reactions were reported uncommonly in clinical trials.
Reazzjonijiet ta ’ sensittività eċċessiva li jixbhu allerġija ġew irrappurtati b’ mod mhux komuni fi provi kliniċi.
Necessary preparations should be made to deal with this.
Għandhom isiru l- preparazzjonijiet neċessarji biex dan jiġi indirizzat.
Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of chest, wheezing,
Il - pazjenti għandhom jiġu infurmati dwar is- sinjali bikrija tar- reazzjonijiet ta ’ sensittività eċċessiva fosthom ħorriqija, urtikarja ġeneralizzata, diqa fis- sider, tħarħir, pressjoni baxxa u anafilassi.
In the case of shock, the current medical standards for shock treatment should be applied.
Fil- każ ta ’ xokk, għandhom jiġu applikati l- istandards mediċi kurrenti għat- trattament ta ’ xokk.
Anaphylaxis, including anaphylactic shock with fatal outcome has been reported very rarely in post-marketing experience (see section 4.8).
Anafilassi, inkluż xokk anafilattiku b’ eżitu fatali ġiet irrapportata rari ħafna fl- esperjenza ta ’ wara t- tqegħid tal - prodott fis- suq (ara sezzjoni 4. 8).
Treatment-emergent positive bivalirudin antibodies are rare and have not been associated with clinical evidence of allergic or anaphylactic reactions.
L- antikorpi pożittivi ta ’ bivalirudin li joħorġu mit- trattament huma rari u ma ġewx assoċjati ma ’ evidenza klinika ta ’ reazzjonijiet allerġiċi jew anafilattiċi.
Caution should be exercised in patients previously treated with lepirudin who had developed lepirudin antibodies.
Għandha tintuża kawtela f’ pazjenti ttrattati preċedentement b’ lepirudin li jkunu żviluppaw antikorpi għal lepirudin.
Intra-procedural thrombus formation has been observed during gamma brachytherapy procedures with Angiox.
Kienet osservata formazzjoni ta ’ thrombus intra- proċedurali waqt proċeduri ta ’ gamma brakiterapija b’ Angiox.
Angiox should be used with caution during beta brachytherapy procedures.
Angiox għandu jintuża b’ kawtela waqt proċeduri ta ’ beta brakiterapija.
Drug-drug interaction studies have been conducted with platelet inhibitors, including acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, eptifibatide, or tirofiban.
Saru studji ta ’ l- interazzjoni bejn il- mediċini b’ inibituri tal- platelets, fosthom acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, eptifibatide, jew tirofiban.
The results do not suggest pharmacodynamic interactions with these medicinal products.
Ir- riżultati ma jissuġġerux interazzjonijiet farmakodinamiċi ma ’ dawn il- prodotti mediċinali.
From the knowledge of their mechanism of action, combined use of anti-coagulant medicinal products (heparin, warfarin, thrombolytics or antiplatelet agents) can be expected to increase the risk of bleeding.
Minn dak li huwa magħruf dwar il- mekkaniżmu ta ’ azzjoni tagħhom, l- użu kombinat ta ’ prodotti mediċinali antikoagulanti (eparina, warfarin, trombolitiċi jew sustanzi kontra l- plejtlits) jista ’ jkun mistenni li jżid ir- riskju ta ’ fsada.
In any case, when bivalirudin is combined with a platelet inhibitor or an anticoagulant drug, clinical and biological parameters of haemostasis should be regularly monitored.
F’ kull każ, meta bivalirudin jiġi kombinat ma ’ inibitur tal- plejtlits jew mediċina antikoagulanti, il - parametri kliniċi u bijoloġiċi ta ’ l- emostasi għandhom jiġu mmonitorjati b’ mod regolari.
There are no adequate data from the use of bivalirudin in pregnant women.
M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ bivalirudin waqt it- tqala.
Animal studies are insufficient with respect to effects on pregnancy, embryonal/ foetal development, parturition or post- natal development (see section 5.3).
Studji fuq bhejjem mhumiex biżżejjed rigward l- effetti fuq it- tqala, l- iżvilupp ta ’ l- embriju/ fetu, il- ħlas jew l- iżvilupp wara t- twelid (ara sezzjoni 5. 3).
The potential risk for humans is unknown.
Mhux magħruf ir- riskju potenzjali fuq il- bniedem.
Angiox should not be used during pregnancy unless clearly necessary.
Angiox m’ għandux jintuża waqt it- tqala sakemm ma jkunx hemm bżonn ċar.
It is not known whether bivalirudin is excreted in human milk.
Mhux magħruf jekk bivalirudin joħroġx fil- ħalib uman.
Angiox should be administered with caution in breast-feeding mothers.
Angiox għandu jingħata b’ kawtela f’ ommijiet li jkunu qegħdin ireddgħu.
The ACUITY Trial (ACS)
Il- Prova ta ’ ACUITY (ACS)
The following adverse reaction data are based on a clinical study of bivalirudin in 13,819 patients with ACS; 4612 were randomised to bivalirudin alone, 4604 were randomised to bivalirudin plus GPIIb/ IIIa inhibitor and 4603 were randomised to either unfractionated heparin or enoxaparin plus GPIIb/ IIIa inhibitor.
5 Din id- dejta dwar reazzjonijiet avversi li ġejja hija bbażata fuq studju kliniku ta ’ bivalirudin fi 13, 819 - il pazjent b’ ACS; 4612 ġew randomised għal bivalirudin biss u 4604 ġew randomised għal bivalirudin u inibitur GPIIb/ IIIa, u 4603 ġew randomised għal jew eparina mhux frazzjonata jew enoxaparin flimkien ma ’ inibitur GPIIb/ IIIa.
Adverse reactions were more frequent in females and in patients more than 65 years of age in both the bivalirudin and the heparin-treated comparator groups compared to male or younger patients.
Ir- reazzjonijiet avversi kienu iktar frekwenti fin- nisa u f’ pazjenti ta ’ aktar minn 65 sena kemm fil- grupp tal- bivalirudin kif ukoll f’ dak ta ’ kumparatur ikkurat bl- eparina meta mqabbla ma ’ pazjenti rġiel jew pazjenti iżgħar.
Approximately 23.3% of patients receiving bivalirudin experienced at least one adverse event and 2.1% experienced an adverse drug reaction.
Bejn wieħed u ieħor 23. 3% tal- pazjenti li rċievew bivalirudin esperjenzaw għallinqas episodju avvers wieħed u 2. 1% esperjenzaw reazzjoni avversa għall- mediċina.
Adverse event reactions are listed by system organ class in Table 1.
Reazzjonijiet ta ’ episodji avversi huma elenkati skond is- sistema ta ’ klassifika ta ’ l- organi fit- Tabella 1.
5 Platelets, bleeding and clotting
Pjastrini, fsada u għaqid tad- demm
In ACUITY, bleeding data were collected separately from adverse events.
F’ ACUITY, id- dejta dwar il- fsad inġabret separatament minn episodji avversi.
Major bleeding was measured by the ACUITY and TIMI major bleeding scales as defined in the footnotes to Table 2.
Fsada maġġuri ġiet imkejla bl- iskali ta ’ fsada maġġuri ACUITY u TIMI kif definit fin- noti ta ’ qiegħ il- paġna għat- Tabella 2.
Minor haemorrhage was defined as any observed bleeding event that did not meet the criteria for a major haemorrhage.
Emorraġija minuri ġiet definita bħala kull episodju ta ’ fsada osservat li ma ssodisfax il- kriterji għal emorraġija maġġuri.
Minor bleeding occurred very commonly (≥ 1/ 10) and major bleeding occurred commonly (≥ 1/ 100 and < 1/ 10).
Fsada minuri seħħet b’ mod komuni ħafna (≥ 1/ 10) u fsada maġġuri seħħet b’ mod komuni (≥1/ 100 and < 1/ 10).
Both major and minor bleeds were significantly less frequent with bivalirudin alone than the heparin plus GPIIb/ IIIa inhibitor and bivalirudin plus GPIIb/ IIIa inhibitor groups (see Table 2).
Kemm fsad minuri kif ukoll fsad maġġuri kienu ferm inqas frekwenti b’ bivalirudin waħdu milli l - eparina flimkien ma ’ Inibitur GPIIb/ IIIa u bivalirudin flimkien ma ’ gruppi ta ’ inibituri GPIIb/ IIIa (ara t- Tabella 2).
Similar reductions in bleeding were observed in patients who were switched to bivalirudin from heparin-based therapies (N = 2078).
Tnaqqis simili fil- fsad ġie osservat f’ pazjenti li nqelbu għal bivalirudin minn terapiji bbażati fuq l- eparina (N = 2078).
ACUITY trial; adverse drug reaction data
Prova ta ’ ACUITY; tagħrif dwar ir- reazzjoni avversa tal- mediċina
(≥ 1/ 1,000 to ≤ 1/ 100)
Sistema tal- klassifika ta ’ l - organi Disturbi tad- demm u tas - sistema limfatika
(≥ 1/ 10)
Komuni ħafna (≥1/ 10)
< 1/ 10)
Komuni (≥1/ 100 sa < 1/ 10)
Blood and the lymphatic system disorders
Mhux komuni (≥1/ 1, 000 sa ≤1/ 100) Żieda fl- INR, tromboċitopenja, anemija.
INR increased, Thrombocytopenia, anaemia.
Rari ≥1/ 10, 000 sa ≤1/ 1, 000
Immune system disorders Nervous system disorders Cardiac disorders
Disturbi fis- sistema immuni Disturbi fis- sistema nervuża Disturbi fil- qalb
Hypersensitivity Headache
Sensittività eċċessiva Uġigħ ta ’ ras
Bradycardia
Bradikardja
Minor bleeding
Fsada minuri
Major bleeding
Fsada maġġuri
Haematoma, hypotension
Ematoma, pressjoni baxxa
Haemorrhage, Vascular pseudoaneurysm
Emorraġija, Psewdoanewriżmu vaskulari
Gastrointestinal disorders Skin and subcutaneous tissue disorders
Disturbi gastro- intestinali Disturbi fil- ġilda u fit - tessuti ta ’ taħt il- ġilda
Nausea, vomiting
Nawseja, rimettar
Rash, urticaria
Raxx, urtikarja
Musculoskeletal and connective tissue disorders General disorders and administration site conditions
Disturbi muskolu- skeltrali u tal- connective tissue
Back pain, chest pain, Groin pain
Uġigħ fid- dahar, uġigħ fis- sider, uġigħ fil- groin
Injection site reactions
Reazzjonijiet fis - sit ta ’ l- injezzjoni
Table 2.
6 Tabella 2.
ACUITY trial; 30-day bleeding endpoints for
Prova ta ’ ACUITY; punti ta ’ tmiem il- fsada ta ’ 30 jum għall- popolazzjoni maħsuba li tiġi kkurata.
inhibitor +GPIIb/ IIIa (N= 4604) inhibitor (N=4603)%%
bivalirudin UFH/ enox + inibituri GP + inibitur bivalirudin IIb/ IIIa GPIIb/ IIIa (N= 4612) (N= 4604) (N=4603)%%%
ACUITY major bleeding TIMI major bleeding2 1
Fsada maġġuri ta ’ ACUITY1 Fsada maġġuri ta ’ TIMI 2
3.0 0.9
3. 0 0. 9
5.3 1.7
5. 3 1. 6
5.7 1.9
5. 7 1. 9
ACUITY major bleeding defined as any one of the following: intracranial, retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention, ≥ 5cm diameter haematoma at puncture site, reduction in haemoglobin concentration of ≥ 4g/ dL without an overt source of bleeding, reduction in haemaglobin concentration of ≥ 3g/ dL with an overt source of bleeding, re-operation for bleeding, use of any blood product transfusion.
Fsada maġġuri ta ’ ACUITY definita bħala waħda minn dawn li ġejjin: emorraġija intrakranjali, retroperitonjali, intraokulari, fis- sit ta ’ l- aċċess li teħtieġ intervent radjuloġiku jew kirurġiku, ematoma b’ dijametru ta ’ ≥5ċm fis - sit tat- titqiba, tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina ta ’ ≥ 4g/ dL mingħajr sors ovvju ta ’ fsada, tnaqqis fil - konċentrazzjoni ta ’ l- emoglobina ta ’ ≥3g/ dL b’ sors ovvju ta ’ fsada, operazzjoni mill- ġdid għall- fsada, użu ta ’ kwalunkwe trasfużjoni bi prodott tad- demm.
2 TIMI major bleeding defined as intracranial bleeding or a decrease in haemoglobin concentration ≥ 5g/ dL
2 Fsada maġġuri ta ’ TIMI definite bħala fsada intrakranjali jew tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina ≥5g/ dL
6 Major bleeding occurred most frequently at the sheath puncture site (see Table 3).
Fsada maġġuri seħħet l- aktar frekwenti fis- sit tat- titqiba tal- għant (ara Tabella 3).
Other less frequently observed bleeding sites with greater than 0.1% (uncommon) bleeding included “ other” puncture site, retroperitoneal, gastrointestinal, ear, nose or throat.
Siti oħrajn ta ’ fsada osservati b’ mod inqas frekwenti bi fsada ta ’ aktar minn 0. 1% (mhux komuni) inkludew siti ta ’ titqib “ oħrajn ”, retroperitonali, gastrointestinali, widnejn, imnieħer jew gerżuma.
ACUITY trial; 30-day population.
ta ’ fsada ta ’ 30 jum (għall -
bleeding site frequency data for the
eparina Bivalirudin +inibitur
bivalirudin bivalirudin +GPIIb/ IIIa
+inibitur GPI bivalirudin Ib/ IIIa
UFH/ enox
Sit ta ’ fsada
+GPIIb/ IIIa inhibitor
(N=4612)
Bleeding site
GPIIb/ IIIa
inhibitor (N=4604)%
(N=9025)%
(N=4603)%
(N=4697)%
Puncture site haematoma < 5 cm
Ematoma fis- sit ta ’ l -
3.8 3.7 0.7
3. 7 0. 7 0. 7
cm Gingival Bleeding Genitourinary Gastrointestinal Sheath puncture site Retroperitoneal Hemoptysis Melena Ear, Nose or Throat Cardio/ pulmonary Intracranial Other
Fsada ġinġivali Ġeniturinarja Gastrointestinali Sit ta ’ titqib tal- għant Retroperitonali Emoptissi Melena Widnejn, imnieħer jew
0.7 0.3 0.3 0.5 0.4 0.2 0.1 0.3 0.1 < 0.1 < 0.1 3.5
0. 3 0. 3 0. 5 0. 4 0. 2 0. 1 0. 3
2.2 1.5 1.1 0.7 0.7 0.6 0.5 0.3 0.2 0.1 < 0.1 4.4
1. 5 1. 1 0. 7 0. 7 0. 6 0. 5 0. 3
2.2 0.6 0.9 0.9 0.5 0.5 0.3 0.4 0.1 0.1 0.1 5.4
0. 6 0. 9 0. 9 0. 5 0. 5 0. 3 0. 4
Thrombocytopenia was reported in 10 bivalirudin-treated patients participating in the ACUITY study (0.1%).
7 Tromboċitopenja ġiet irrapportata f’ 10 pazjenti ttrattati b’ bivalirudin fl- istudju ta ’ ACUITY (0. 1%).
The majority of these patients received concomitant acetylsalicylic acid and clopidogrel, and 6 out of the 10 patients also received a GPIIb/ IIIa inhibitor.
Il- maġġoranza ta ’ dawn il- pazjenti rċevew acetylsalicylic acid u clopidogrel fl- istess ħin, u 6 minn 10 pazjenti irċievew ukoll inibitur GPIIb/ IIIa.
Mortality among these patients was nil.
Il- mortalità fost dawn il- pazjenti kienet xejn.
The REPLACE-2 Trial (PCI)
Il- Prova REPLACE- 2 (PCI)
The following adverse reaction data is based on a clinical study of bivalirudin in 6000 patients undergoing PCI, half of whom were treated with bivalirudin (REPLACE-2).
Id- dejta li ġejja dwar ir- reazzjonijiet avversi hija bbażata fuq studju kliniku ta ’ bivalirudin f’ 6000 pazjent sottoposti għal PCI, li nofshom ġew ikkurati b’ bivalirudin (REPLACE- 2).
Adverse events were more frequent in females and in patients more than 65 years of age in both the bivalirudin and the heparin-treated comparator groups compared to male or younger patients.
L- episodji avversi kienu aktar frekwenti fin- nisa u f’ pazjenti ta ’ ’ l fuq minn 65 sena kemm fil- grupp ta ’ tqabbil fuq bivalirudin kif ukoll f’ dak ittrattat bl- eparina meta mqabbel ma ’ pazjenti rġiel jew aktar żagħżugħa.
Approximately 30% of patients receiving bivalirudin experienced at least one adverse event and 3% experienced an adverse drug reaction.
Madwar 30% tal- pazjenti li rċevew bivalirudin esperjenzaw mill- anqas episodju avvers wieħed u 3% esperjenzaw reazzjoni avversa għall- mediċina.
Adverse event reactions are listed by system organ class in Table 4.
L- episodji avversi huma elenkati skond is- sistema tal - klassifika ta ’ l- organi f’ Tabella 4.
7 Table 4.
8 Tabella 4.
REPLACE-2 trial; adverse drug reaction data
Dejta dwar ir- reazzjonijiet avversi għall- mediċina
Common
Sistema tal- klassifika ta ’ l -
System organ class
Komuni
(≥ 1/ 100 to
Mhux komuni (≥1/ 1, 000 sa ≤1/ 100)
Uncommon
organi Disturbi tad- demm u tas- sistema limfatika Disturbi fis- sistema immuni Disturbi fis- sistema nervuża Disturbi fil- qalb
(≥ 1/ 10)
ħafna (≥1/ 10)
(≥ 1/ 1,000 to ≤ 1/ 100)
(≥1/ 100 sa < 1/ 10)
Thrombocytopenia, anaemia Allergic reaction Headache Ventricular tachycardia, angina pectoris, bradycardia
Tromboċitopenija, anemija Reazzjoni allerġika Uġigħ ta ’ ras Takikardija ventrikulari, anġina pectoris, bradikardija
Thrombosis, hypotension, haemorrhage, vascular disorder, vascular anomaly
Trombożi, pressjoni baxxa, emorraġija, disturb vaskulari, anomalija vaskulari
Gastrointestinal disorders Skin and subcutaneous tissue disorders
Disturbi gastro- intestinali Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Nausea, vomiting Rash
Dardir, rimettar Raxx
Injection site haemorrhage, injection site pain, chest pain
Emorraġija fis- sit ta ’ l - injezzjoni, uġigħ fis - sit ta ’ l- injezzjoni, uġigħ fis- sider
Platelets, bleeding and clotting
Plejtlits, fsada u koagulazzjoni
In REPLACE-2, bleeding data were collected separately from adverse events.
F’ REPLACE- 2, id- dejta dwar fsada nġabret separatament mill- episodji avversi.
Major bleeding was defined as the occurrence of any of the following: intracranial haemorrhage, retroperitoneal haemorrhage, blood loss leading to a transfusion of at least two units of whole blood or packed red blood cells, or bleeding resulting in a haemoglobin drop of more than 3 g/ dl, or a fall in haemoglobin greater than 4 g/ dl (or 12% of haematocrit) with no bleeding site identified.
Fsada maġġuri ġiet definita bħala s- seħħ ta ’ xi waħda minn dawn li ġejjin: emorraġija intrakranjali, emorraġija retroperitonali, telf ta ’ demm li jwassal għal trasfużjoni ta ’ mill- anqas żewġ unitajiet ta ’ demm sħiħ jew ċelloli ħomor tad- demm ippakkjati, jew fsada li tirriżulta fi tnaqqis fl- emoglobina ta ’ aktar minn 3 g/ dl, jew tnaqqis fl- emoglobina ta ’ aktar minn 4 g/ dl (jew 12% ta ’ l- ematokrit) mingħajr ma jkun identifikat l- ebda sit ta ’ fsada.
Minor haemorrhage was defined as any observed bleeding event that did not meet the criteria for a major haemorrhage.
Fsada minuri ġiet definita bħala kwalunkwe episodju osservat ta ’ fsada li ma jissodisfax il- kriterji għal emorraġija maġġuri.
Minor bleeding occurred very commonly (≥ 1/ 10) and major bleeding occurred commonly (≥ 1/ 100 and < 1/ 10).
Fsada minuri seħħet b’ mod komuni ħafna (≥ 1/ 10) u fsada maġġuri seħħet b’ mod komuni (≥1/ 100 u < 1/ 10).
Both minor and major bleeds were significantly less frequent with bivalirudin than the heparin plus GPIIb/ IIIa inhibitor comparator group.
Kemm il- fsad minuri kif ukoll dak maġġuri kienu sinifikattivament anqas frekwenti b’ bivalirudin milli fil- grupp ta ’ tqabbil fuq l- eparina u l- inibitur tal- GPIIb/ IIIa.
Major bleeding occurred most frequently at the sheath puncture site (see Table 5).
Fsada maġġuri seħħet bl- aktar mod frekwenti fis- sit tat- titqib ta ’ l- għant (ara Tabella 5).
Other less frequently observed bleeding sites with greater than 0.1% (uncommon) bleeding included “ other” puncture site, retroperitoneal, gastrointestinal, ear, nose or throat.
Siti oħra ta ’ fsada osservati b’ mod anqas frekwenti b’ aktar minn 0. 1% (mhux komuni) ta ’ fsada kienu jinkludu sit “ ieħor ” ta ’ titqib, retroperitonali, gastro- intestinali, il- widnejn, l- imnieħer, jew il- gerżuma.
8 Table 5.
9 Tabella 5.
REPLACE-2; bleeding site frequency data (bivalirudin versus heparin + GPIIb/ IIIa inhibitor).
REPLACE- 2; Tagħrif tal- frekwenza tas- siti ta ’ fsada (bivalirudin + inibitur tal- GPIIb/ IIIa).
heparin bivalirudin +GPIIb/ IIIa
eparina +inibitur tal - bivalirudin
Bleeding site
0. 8 0. 2 0. 2 0. 1 0. 1 < 0. 1
(N=2994)%
2. 5 0. 2 0. 5 0. 6 0. 3
inhibitor (N=3008)%
Ġenitourinarji
p-value
0. 125
Sheath puncture site Other puncture site Retroperitoneal Gastrointestinal Ear, Nose or Throat
1. 000
0.8 0.2 0.2 0.1 0.1
Kardjo/ pulmonari Oħrajn
2.5 0.2 0.5 0.6 0.3
0. 1 0. 4
< 0.1 < 0.1 0.1 0.4
0. 3 0. 5
0.2 0.1 0.3 0.5
0. 035 0. 556
Post-marketing experience
Esperjenza ta ’ wara t- tqegħid fis- suq tal- prodott
Adverse reactions that have been reported from extensive post-marketing experience and that have not been reported above are summarised by system organ class in Table 6.
Ir- reazzjonijiet avversi li ġew irrappurtati mill- esperjenza estensiva ta ’ wara t- tqegħid fis- suq tal - prodott u li ma ġewx irrappurtati fuq huma miġburin bis- sistema tal- klassifika ta ’ l- organi f’ Tabella 6.
Serious bleeding, including bleeding with a fatal outcome has been reported in post-marketing experience for bivalirudin.
Fsada serja, inkluż fsada b’ riżultat fatali ġiet irrapportata f’ esperjenza ta ’ wara t- tqegħid fis- suq għal bivalirudin.
Post-marketing adverse reactions reported for bivalirudin
Reazzjonijiet avversi ta ’ wara t- tqegħid fis- suq tal- prodott irrappurtati għal bivalirudin
System organ class
Sistema tal- klassifika ta ’ l - organi
Frequency not known
Frekwenza mhux magħrufa
Anaphylactic reaction, anaphylactic shock including fatal shock, hypersensitivity, urticaria
Reazzjoni anafilattika, xokk anafilattiku inkluż xokk fatali, sensittività eċċessiva, urtikarja
Thrombus including fatal thrombus, haematoma
Għoqda tad- demm li tinkludi għoqda tad - demm fatali, ematoma
Intracranial haemorrhage
Emorraġija intrakranjali
Cases of overdose of up to 10 times the recommended dose have been reported in clinical trials.
Każijiet ta ’ doża eċċessiva ta ’ mhux aktar minn 10 darbiet id- doża rakkomandata ġew irrapportati fi provi kliniċi.
Single bolus doses of bivalirudin up to 7.5mg/ kg have also been reported.
Dożi bolus waħdanin sa 7. 5mg/ kg ġew irrapportati wkoll.
None of these cases were associated with bleeding or other adverse events.
Ebda każ minn dawn ma kien assoċjat ma ’ fsada jew ma ’ episodji avversi oħrajn.
In cases of overdose, treatment with bivalirudin should be immediately discontinued and the patient monitored closely for signs of bleeding.
F’ każi ta ’ doża eċċessiva, it- trattament b’ bivalirudin għandu jitwaqqaf immedjatament u l- pazjent jiġi mmonitorjat mill- qrib għal sinjali ta ’ fsada.
In the event of major bleeding, treatment with bivalirudin should be immediately discontinued.
10 F’ każ ta ’ fsada maġġuri, il- kura b’ bivalirudin għandu jitwaqqaf immedjatament.
There is no known antidote to bivalirudin, however, bivalirudin is haemo-dialysable.
M’ hemmx antidotu magħruf għal bivalirudin, madankollu, bivalirudin huwa emodijalizzabbli.
Direct thrombin inhibitors ATC code B01AE06.
Inibituri ta ’ trombin diretti, Kodiċi ATC B01AE06.
Angiox contains bivalirudin, a direct and specific thrombin inhibitor that binds both to the catalytic site and the anion-binding exosite of fluid-phase and clot-bound thrombin.
Angiox fih bivalirudin, inibitur dirett u speċifiku tat- thrombin li jeħel kemm mas- sit katalittiku kif ukoll ma ’ l- anion- binding exosite tat- thrombin fil- fażi fluwida u clot- bound.
Thrombin plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross- linked framework that stabilises the thrombus.
It- thrombin għandu rwol ċentrali fil- proċess trombotiku, billi jaqsam il- fibrinoġen f’ monomeri tal - fibrin u jattiva l- Fattur XIII għall- Fattur XIIIa, u hekk jippermetti l- fibrin jiżviluppa qafas cross- linked b’ mod kovalenti li jistabbilizza t- thrombus.
Thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release.
It- thrombin jattiva wkoll il- Fatturi V u VIII, li jippromwovi aktar ġenerazzjoni ta ’ thrombin, u jattiva l- plejtlits, biex jistimula l- aggregazzjoni u r - rilaxx tal- granijiet.
Bivalirudin inhibits each of these thrombin effects.
Bivalirudin jimpedixxi dawn l- effetti kollha tat- thrombin.
The binding of bivalirudin to thrombin, and therefore its activity, is reversible as thrombin slowly cleaves the bivalirudin, Arg3-Pro4, bond, resulting in recovery of thrombin active site function.
It- twaħħil ta ’ bivalirudin mat- thrombin, u għalhekk l- attività tiegħu, huwa riversibbli billi t- thrombin jaqsam bil- mod ir- rabta Arg3- Pro4 ta ’ bivalirudin, li jwassal għall- irkupru tal- funzjoni tas- sit attiv tat - thrombin.
Thus, bivalirudin initially acts as a complete non-competitive inhibitor of thrombin, but transitions over time to become a competitive inhibitor enabling initially inhibited thrombin molecules to interact with other clotting substrates and to coagulation if required.
Għalhekk, bivalirudin għall- ewwel jaġixxi kompletament bħala inibitur mhux kompetittiv tat- thrombin, iżda maż- żmien jinbidel biex isir inibitur kompetittiv li jippermetti molekuli inizjalment inibiti tat- thrombin li jinteraġixxu ma ’ sottostrati oħra ta ’ koagulazzjoni u jikkoagulaw jekk ikun meħtieġ.
In vitro studies have indicated that bivalirudin inhibits both soluble (free) and clot-bound thrombin.
Studji in vitro indikaw li bivalirudin jimpedixxi kemm thrombin solubbli (liberu) kif ukoll clot- bound.
Bivalirudin remains active and is not neutralised by products of the platelet release reaction.
Bivalirudin jibqa ’ attiv u ma jiġix newtralizzat minn prodotti tar- reazzjoni tar- rilaxx tal- plejtlits.
In vitro studies have also shown that bivalirudin prolongs the activated partial thromboplastin time (aPTT) thrombin time (TT) and pro-thrombin time (PT) of normal human plasma in a concentration- dependent manner and that bivalirudin does not induce a platelet aggregation response against sera from patients with a history of Heparin-Induced Thrombocytopenia/ Thrombosis Syndrome (HIT/ HITTS).
Studji in vitro wrew ukoll li bivalirudin itawwal it- thromboplastin time parzjali attivat (aPTT), it - thrombin time (TT) u l- pro- thrombin time (PT) ta ’ plażma umana normali b’ mod dipendenti fuq il - konċentrazzjoni u li bivalirudin ma jinduċix rispons ta ’ aggregazzjoni tal- plejtlits kontra sera minn pazjenti bi preċedent tas- Sindrome tat- Tromboċitopenija/ Trombożi Indotta mill- Eparina (HIT/ HITTS).
In healthy volunteers and patients, bivalirudin exhibits dose- and concentration dependent anticoagulant activity as evidenced as prolongation of the ACT, aPTT, PT, INR and TT.
F’ voluntiera u pazjenti b’ saħħithom, bivalirudin juri attività antikoagulanti dipendenti fuq id- doża u l - konċentrazzjoni kif jidher mit- titwil ta ’ l- ACT, l- aPTT, il- PT, l- INR u TT.
Intravenous administration of bivalirudin produces measurable anticoagulation within minutes.
L- għoti minn ġol- vini ta ’ bivalirudin jipproduċi antikoagulazzjoni miżurabbli fi ftit minuti.
The pharmacodynamic effects of bivalirudin may be assessed using measures of anticoagulation including the ACT.
L- effetti farmakodinamiċi ta ’ bivalirudin jistgħu jiġu evalwati billi jintużaw miżurazzjonijiet ta ’ l - antikoagulazzjoni fosthom l- ACT.
The ACT value is positively correlated with the dose and plasma concentration of bivalirudin administered.
Il- valur ta ’ l- ACT huwa korrelatat pożittivament mad- doża u l - konċentrazzjoni fil- plażma ta ’ bivalirudin mogħti.
Data from 366 patients indicates that the ACT is unaffected by concomitant treatment with a GPIIb/ IIIa inhibitor.
Id- dejta minn 366 pazjent tindika li l- ACT mhux affettwat minn kura simultanju b’ inibitur tal- GPIIb/ IIIa.
In clinical studies bivalirudin has been shown to provide adequate anticoagulation during PCI procedures.
Fi studji kliniċi, bivalirudin intwera li jipprovdi antikoagulazzjoni adegwata matul proċeduri ta ’ PCI.
ACUITY Trial
Il- Prova ta ’ ACUITY
The ACUITY trial was a prospective, randomised open-label, trial of bivalirudin with or without GPIIb/ IIIa inhibitor (Arms B and C respectively) versus unfractionated heparin or enoxaparin with GPIIb/ IIIa inhibitor (Arm A) in 13,819 high risk ACS patients.
Il- prova ta ’ ACUITY kienet prova prospettiva, randomised open- label ta ’ bivalirudin bi jew mingħajr inibitur GPIIb/ IIIa (Fergħat B u Ċ rispettivament) meta mqabbla ma ’ eparina jew enoxaparina mhux frazzjonata b’ inibitur GPIIb/ IIIa (Fergħa A) fi 13, 819- il pazjent ta ’ ACS b’ riskju għoli.
In Arms B and C of the ACUITY trial, the recommended dose of bivalirudin was an initial post- randomisation IV bolus of 0.1mg/ kg followed by a continuous IV infusion of 0.25 mg/ kg/ h during angiography or as clinically warranted.
Fil- fergħat B u Ċ tal- prova ta ’ ACUITY, id- doża rakkomandata ta ’ bivalirudin kienet bolus IV inizjali ta ’ wara r- randomizzazzjoni ta ’ 0. 1mg/ kg segwita minn infużjoni IV kontinwa ta ’ 0. 25 mg/ kg/ h matul anġjografija jew kif klinikament garantit.
For patients undergoing PCI, an additional IV bolus of 0.5mg/ kg bivalirudin was administered and the rate of IV infusion increased to 1.75 mg/ kg/ h.
11 Pazjenti li kienu qegħdin jagħmlu PCI, ingħataw bolus IV addizzjonali ta ’ 0. 5mg/ kg ta ’ bivalirudin u r- rata ta ’ infużjoni IV żdiedet għal 1. 75 mg/ kg/ h.
10 In Arm A of the ACUITY trial, UFH or enoxaparin was administered in accordance with the relevant guidelines for the management of ACS in patients with UA and NSTEMI.
F’ Fergħa A tal- prova ta ’ ACUITY, ingħataw UFH jew enoxaparin skond il- linji gwida relevanti għall - ġestjoni ta ’ ACS f’ pazjenti b’ UA u b’ NSTEMI.
Patients in Arms A and B were also randomised to receive a GPIIb/ IIIa inhibitor either upfront at the time of randomization (prior to angiography) or at the time of PCI.
Pazjenti fil- Fergħat A u B ġew randomised wkoll sabiex jirċievu inibitur GPIIb/ IIIa jew bil- quddiem fil- ħin tar- randomizzazzjoni (qabel anġjografika) jew fil- ħin ta ’ PCI.
A total of 356 (7.7%) of patients randomised to Arm C also received a GPIIb/ IIIa inhibitor.
Total ta ’ 356 (7. 7%) tal- pazjenti randomizzati għal Fergħa Ċ irċevew ukoll inibitur GPIIb/ IIIa.
High risk patient characteristics of the ACUITY population that mandated angiography within 72 hours were balanced across the three treatment arms.
Il- karatteristiċi tal- pazjenti ta ’ riskju għoli tal- popolazzjoni ta ’ ACUITY li ħtieġu anġjografija fi żmien 72 siegħa kienu bilanċjati fuq it- tliet fergħat ta ’ kura.
Approximately 77% of patients had recurrent ischaemia, approximately 70% had dynamic ECG changes or elevated cardiac biomarkers, approximately 28% had diabetes and approximately 99% of patients underwent angiography within 72 hours.
Madwar 77% tal- pazjenti kellhom iskemja rikorrenti, madwar 70% kellhom tibdil dinamiku fl- ECG jew bijomarkaturi kardijaċi għoljin, bejn wieħed u ieħor 28% kellhom id- dijabete u bejn wieħed u ieħor 99% tal- pazjenti kellhom jgħaddu minn anġjografika fi żmien 72 siegħa.
Following angiographic assessment, patients were triaged to either medical management (33%), PCI (56%) or CABG (11%).
Wara valutazzjoni anġjografika, il- pazjenti ġew soġġetti jew għal amministrazzjoni medika (33%), PCI (56%) jew għal CABG (11%).
Additional anti-platelet therapy utilised in the study included aspirin and clopidogrel.
Kura addizzjonali kontra- plejtlits wżata fl- istudju inkludiet aspirina u klopidogrel.
The primary analysis and results for ACUITY at 30-days and 1 year for the overall (ITT) population and for the patients that received aspirin and clopidogrel as per protocol (pre-angiography or pre-PCI) are shown in Tables 7 and 8.
L- analiżi primarja u r- riżultati għal ACUITY wara 30 jum u wara sena għall- popolazzjoni totali (ITT) u għall- pazjenti li rċevew aspirina u klopidogrel skond il- protokoll (pre- anġjografija jew pre- PCI) huma murija fit- Tabelli 7 u 8.
ACUITY trial; 30-day and 1-year risk differences for the composite endpoint and its components for the overall population (ITT)
Prova ta ’ ACUITY; differenzi fir- riskju wara 30 jum u sena għal punt ta ’ tmiem iskemiku kompost u l- komponenti tiegħu għall- popolazzjoni totali (ITT)
ischaemic
30- jum
Overall population (ITT) Arm A Arm B UFH/ e bival nox +GPII Arm C
Popolazzjoni totali (ITT) Fergħa A Fergħa B Fergħa C UFH/ enox bival + B– A C– A bival +inibitur inibitur Diff. fir- risk Diff. fir- risk. waħdu GPIIb/ IIIa GPIIb/ IIIa (95% CI) (95% CI) (N=4612) (N=4603) (N=4604)%%%
+GPII b/ IIIa B– A bival
Fergħa B
C– A
Fergħa C
b/ IIIa
bival +
inhibit
bival
Risk diff.
C– A
alone
inibitur inibitur
Risk diff.
Diff. fir- risk
inhibit
waħdu
or
30- jum
(N=46
Iskemja
30-day
7. 4 7. 4
(N=46 03)%
0. 03
7.8
7. 0
0.55
- 0. 35
ischae mia
komposta
(-0.60, 1.55)
(- 1. 32, 1. 38)
(-0.53, 1.63)
(- 1. 68, 0. 99)
Death
Mewt
1.3
1. 4
1.5
1. 4
0.17
- 0. 00 (- 0. 60, 0. 60)
1.6
1. 2
(-0.23, 0.75)
- 0. 14 (- 0. 72, 0. 45)
4.9
4. 8
5.0
4. 9
0.04 (-0.84, 0.93)
0. 04 (- 1. 07, 1. 14)
5.4
4. 7
0.45 (-0.46, 1.35)
- 0. 08 (- 1. 18, 1. 02)
Unplanned revasc.
Rivask.
2.7
2. 6
2.4
2. 8
15.9
0. 23
0.65
2. 2
16.0
- 0. 41
0.71
mhux ippjanata sena
ischae mia
(- 0. 61, 1. 08)
(-0.83, 2.13)
(- 1. 20, 0. 39)
(-0.77, 2.19)
Iskemja
Death
16. 1
3.9
16. 8
3.8
0. 68
0.04
15. 8
3.7
- 0. 35
-0.18
komposta
MI
Mewt
6.8
3. 7
7.0
3. 9
0.19 (-0.84, 1.23)
0. 20 (- 0. 78, 1. 19)
7.6
3. 3
0.83 (-0.22, 1.89)
- 0. 36 (- 1. 31, 0. 59)
8.1
MI
8.8
6. 7
8.4
7. 3
0.37 (-0.75, 1.50)
0. 60 (- 0. 71, 1. 91)
12 Table 8.
6. 8
Composite ischae mia
0. 19 (- 1. 11, 1. 48)
Death
Rivask.
MI
9. 4
1-year
10. 0
Death
0. 59
3.7 3.9 0.20 3.3 -0.36 (-0.78, 1.19) (-1.31, 0.59)
8. 9
MI
- 0. 53
6.7 7.3 0.60 6.8 0.19 (-0.71, 1.91) (-1.11, 1.48)
mhux ippjanata
Unplanned revasc.
(- 0. 94, 2. 12)
9.4 10.0 0.59 8.9 -0.53 (-0.94, 2.12) (-2.02, 0.96)
(- 2. 02, 0. 96)
*clopidogrel pre-angiography or pre-PCI
* klopidogrel pre- anġjografija jew pre- PCI
The incidence of both ACUITY-scale and TIMI-scale bleeding events up to day 30 is presented in Table 9 for the overall (ITT) population and for patients that received aspirin and clopidogrel as per protocol.
L- inċidenza ta ’ episodji ta ’ fsada kemm ta ’ skala ta ’ ACUITY kif ukoll ta ’ skala ta ’ TIMI sa jum 30 hija ppreżentata f’ Tabella 9 għall- popolazzjoni totali (ITT) u għall- pazjenti li rċevew aspirina u klopidogrel skond il- protokoll.
ACUITY trial; bleeding events up to day 30 for the overall (ITT) population and the population of patients who received aspirin and clopidogrel as per protocol*
Prova ta ’ ACUITY; episodji ta ’ fsada sa jum 30 għall- popolazzjoni totali (ITT) u għall- popolazzjoni ta ’ pazjenti li rċevew aspirina u klopidogrel skond il- protokoll *
Patients receiving aspirin & clopidogrel Overall population (ITT) as per protocol UFH/ enox bival bival UFH/ enox bival bival + + alone + + GPIIb/ IIIa alone GPIIb/ IIIa GPIIb/ IIIa (N=4612) GPIIb/ IIIa inhibitor (N=2911) inhibitor inhibitor% inhibitor (N=2924)% (N=4603) (N=4604) (N=2842)%%%%
Pazjenti li rċevew aspirina u Popolazzjoni totali (ITT) klopidogrel skond il- protokoll UFH/ enox bival bival UFH/ enox bival bival + inibitur + inibitur waħdu + inibitur + inibitur waħdu GPIIb/ IIIa GPIIb/ IIIa (N=4612) GPIIb/ IIIa GPIIb/ IIIa (N=2911) (N=4603) (N=4604)% (N=2842) (N=2924)%%%%% 5. 3 3. 0
ACUITY
ACUITY skala maġġuri1
5.7 5.3 3.0 5.9 5.4 3.1
5. 9 5. 4 3. 1 5. 7 1. 7 0. 9
1 scale major TIMI scale major2
TIMI skala maġġuri2
0.9 1.9 1.9
1. 9 1. 9 0. 8 1. 9
0.8
* klopidogrel pre- anġjografija jew pre- PCI1
*clopidogrel pre-angiography or pre-PCI1 ACUITY major bleeding defined as any one of the following: intracranial, retroperitoneal, intraocular, access site haemorrhage requiring radiological or surgical intervention, ≥ 5cm diameter haematoma at puncture site, reduction in haemoglobin concentration of ≥ 4g/ dL without an overt source of bleeding, reduction in haemaglobin concentration of ≥ 3g/ dL with an overt source of bleeding, re-operation for bleeding, use of any blood product transfusion.
13 ACUITY fsada maġġura definita bħala kwalunkwe minn dawn li ġejjin: emorraġija ġewwa l- kranju, wara l - peritonijum, ġewwa l- għajn, fis- sit ta ’ l- aċċess li teħtieġ intervent radjoloġiku jew kirurġiku, ematoma dijametru ta ’ ≥ 5ċm fis- sit tat- titqiba, tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina ta ’ ≥ 4g/ dL mingħajr sors fid- dieher ta ’ fsada, tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina ta ’ ≥3g/ dL b’ sors fid- dieher ta ’ fsada, operazzjoni mill- ġdid għal fsada, użu ta ’ trażfużjoni ta ’ kwalunkwe prodott tad- demm.
2 TIMI major bleeding defined as intracranial bleeding or a decrease in haemoglobin concentration ≥ 5g/ dL
2 TIMI fsada maġġura definita bħala fsada ġewwa l- kranju jew tnaqqis fil- konċentrazzjoni ta ’ l- emoglobina ≥5g/ dL
The advantage of bivalirudin over UFH/ enoxaparin plus GPIIb/ IIIa inhibitor in terms of bleeding events was only observed in the bivalirudin monotherapy arm.
Il- vantaġġ ta ’ bivalirudin fuq UFH/ enoxaparin flimkien ma ’ inibitur GPIIb/ IIIa f’ termini ta ’ episodji ta ’ fsada ġie osservat biss fil- fergħa tal- monoterapija ta ’ bivalirudin.
The 30-day results based on quadruple and triple endpoints from a randomized, double-blind trial of over 6,000 patients undergoing PCI (REPLACE-2), are shown in Table 10.
Ir- riżultati ta ’ 30 ġurnata msejsa fuq punti finali kwadrupli u tripli minn prova double- blind, randomised, ta ’ ’ l fuq minn 6, 000 pazjent sottoposti għal PCI (REPLACE- 2), huma murija f’ Tabella 10.
Major bleeding in REPLACE-2 was defined by non-TIMI criteria.
Fsada maġġuri f’ REPLACE- 2 ġiet definita bi kriterji mhux- TIMI.
Table 10.
Tabella 10.
30-day endpoints (intent-to-treat and per-protocol
Riżultati ta ’ l- istudju REPLACE- 2: punti finali ta ’ 30 ħsieb ta ’ kura u skond il- protokoll)
Intent-to-treat Per-protocol heparin heparin
jum (popolazzjonijiet bil -
Endpoint
Punt finali
bivalirudin + GPIIb/ IIIa bivalirudin + GPIIb/ IIIa (N=2994) inhibitor (N=2902) inhibitor% (N=3008)% (N=2882)%%
Ħsieb ta ’ trattament bivalirudin eparina + inibitur tal - (N=2994)% GPIIb/ IIIa (N=3008)%
Quadruple
Skond il- protokoll eparina bivalirudin + inibitur tal - (N=2902) GPIIb/ IIIa% (N=2882)%
Triple endpoint* Components:
Punt finali kwadruplu Punt finali triplu * Komponenti:
7.6
9. 2 7. 6
7.1
10. 0 7. 1
7.8
9. 2 7. 8
Death Myocardial Infarction Major bleeding**
Mewt Infart Mijokardijaku Fsada maġġuri **
0.2 7.0 2.4
0. 2 7. 0 2. 4
0.4 6.2 4.1
0. 4 6. 2 4. 1
0.2 7.1 2.2
0. 2 7. 1 2. 2
0.4 6.4 4.0
0. 4 6. 4 4. 0
(based on non-TIMI criteria - see section 4.8)
(ibbażata fuq kriterji mhux- TIMI – ara sezzjoni 4. 8)
Urgent
Rivaskularizzazzjoni
1.2 1.4 1.2
1. 2 1. 4 1. 2
**p < 0.001
1. 3
14 Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia-thrombosis syndrome (HIT/ HITTS):
Tromboċitopenija indotta mill- eparina (HIT) u s- sindrome tat- tromboċitopenija- trombożi indotta mill - eparina (HIT/ HITTS):
Clinical trials in a small number of patients have provided limited information about the use of Angiox in patients with HIT/ HITTS.
Provi kliniċi f’ numru żgħir ta ’ pazjenti pprovdew tagħrif limitat dwar l- użu ta ’ Angiox f’ pazjenti b’ HIT/ HITTS.
The pharmacokinetic properties of bivalirudin have been evaluated and found to be linear in patients undergoing Percutaneous Coronary Intervention and in patients with ACS.
Il- kwalitajiet farmakokinetiċi ta ’ bivalirudin ġew evalwati u nstabu li huma lineari f’ pazjenti sottoposti għal Intervent Koronarju Perkutanju u f’ pazjenti b’ ACS
The bioavailability of bivalirudin for intravenous use is complete and immediate.
Il- bijodisponibilità ta ’ bivalirudin għall- użu fil- vini hija sħiħa u immedjata.
The mean steady-state concentration of bivalirudin following a constant intravenous infusion of 2.5 mg/ kg/ h is 12.4 µg/ ml.
Il - konċentrazzjoni fissa medja ta ’ bivalirudin wara infużjoni kostanti fil- vini ta ’ 2. 5 mg/ kg/ siegħa hija ta ’ 12. 4 µg/ ml.
Bivalirudin is rapidly distributed between plasma and extracellular fluid.
Bivalirudin jiġi assorbit malajr bejn il- plażma u l- fluwidu extra- ċellulari.
The steady-state volume of distribution is 0.1 litre/ kg.
Il- volum tad - distribuzzjoni fiss huwa ta ’ 0. 1 litru/ kg.
Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells.
Bivalirudin ma jeħilx mal- proteini tal- plażma (għajr it - thrombin) jew maċ- ċelloli ħomor tad- demm.
Biotransformation:
14 Bijotrasformazzjoni:
As a peptide, bivalirudin is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acid in the body pool.
Bħala peptide, bivalirudin huwa mistenni li jgħaddi minn kataboliżmu għall- aċidi amminiċi kostitwenti tiegħu, bir- riċiklaġġ sussegwenti ta ’ l- aċidu amminiku fl- għadira tal- ġisem.
Bivalirudin is metabolized by proteases, including thrombin.
Bivalirudin huwa metabolizzat minn proteases, fosthom it- thrombin.
The primary metabolite resulting from the cleavage of Arg3-Pro4 bond of the N-terminal sequence by thrombin is not active because of the loss of affinity to the catalytic active site of thrombin.
Il- metabolit primarju li jirriżulta mill- qasma tar- rabta Arg3- Pro4 tas- sekwenza N- terminali mit- thrombin mhuwiex attiv minħabba t- telf ta ’ l- affinità għas- sit katalittiku attiv tat- thrombin.
About 20% of bivalirudin is excreted unchanged in the urine.
Madwar 20% ta ’ bivalirudin jitneħħa mhux mibdul fl- awrina.
The concentration-time profile following intravenous administration is well described by a two-compartment model.
Il- profil tal- konċentrazzjoni mal- ħin wara għoti fil- vini huwa deskritt tajjeb b’ mudell ta ’ żewġ kompartimenti.
Elimination follows a first order process with a terminal half-life of 25 ± 12 minutes in patients with normal renal function.
L- eliminazzjoni ssegwi proċess ta ’ l- ewwel ordni b’ half- life terminali ta ’ 25 ± 12- il minuta f’ pazjenti b’ funzjoni tal- kliewi normali.
The corresponding clearance is about 3.4 ± 0.5 ml/ min/ kg.
It- tneħħija korrispondenti hija ta ’ madwar 3. 4 ± 0. 5 ml/ min/ kg.
Hepatic Insufficiency:
Insuffiċjenza tal- fwied:
The pharmacokinetics of bivalirudin have not been studied in patients with hepatic impairment but are not expected to be altered because bivalirudin is not metabolized by liver enzymes such as cytochrome P-450 isozymes.
Il- farmakokinetiċi ta ’ bivalirudin ma ġewx studjati f’ pazjenti b’ indeboliment tal- fwied iżda mhumiex mistennija li jinbidlu minħabba li bivalirudin ma jiġix metabolizzat minn enzimi tal- fwied bħall- isoenzimi taċ- ċitokromu P- 450.
The systemic clearance of bivalirudin decreases with glomerular filtration rate (GFR).
It- tneħħija sistemika ta ’ bivalirudin tonqos bir- rata tal- filtrazzjoni glomerulari (GFR).
The clearance of bivalirudin is similar in patients with normal renal function and those with mild renal impairment.
It- tneħħija ta ’ bivalirudin hija simili f’ pazjenti li għandhom funzjoni tal- kliewi normali u dawk b’ indeboliment ħafif tal- kliewi.
Clearance is reduced by approximately 20% in patients with moderate or severe renal impairment, and 80% in dialysis-dependent patients (Table 11).
It- tneħħija tonqos b’ madwar 20% f’ pazjenti b’ indeboliment moderat jew sever tal- kliewi, u bi 80% fil- pazjenti dipendenti fuq id- dijalisi (Tabella 12).
Table 11.
Tabella 12.
Pharmacokinetic parameters for bivalirudin in patients with normal and impaired renal function.
Parametri farmakokinetiċi għal bivalirudin f’ pazjenti b’ funzjoni tal- kliewi normali u indebolita.
Renal function (GFR)
Funzjoni tal- kliewi (GFR)
Clearance
Tneħħija
Half-life (minutes)
Half- life (minuti)
(ml/ min/ kg) Normal renal function (≥ 90ml/ min) Mild renal impairment (60-89 ml/ min) Moderate renal impairment (30-59 ml/ min) Severe renal impairment (10-29 ml/ min)
(ml/ min/ kg) Funzjoni tal- kliewi normali (≥ 90ml/ min) Indeboliment ħafif tal- kliewi (60- 89 ml/ min) Indeboliment moderat tal- kliewi (30- 59 ml/ min) Indeboliment sever tal- kliewi (10- 29 ml/ min)
3.4 3.4 2.7 2.8
3. 4 3. 4 2. 7 2. 8
Dialysis dependent patients (off-dialysis)
Pazjenti dipendenti fuq dijalisi (barra d- dijalisi)
1.0
3. 5
3.5 hours
sigħat
In patients with renal insufficiency, coagulation parameters such as the ACT should be monitored during Angiox therapy.
F’ pazjenti b’ insuffiċjenza tal- kliewi, il- parametri ta ’ koagulazzjoni bħall- ACT għandhom jiġu mmonitorjati waqt terapija b’ Angiox.
Pharmacokinetics have been evaluated in elderly patients as part of a renal pharmacokinetic study.
Il- farmakokinetiċi ġew evalwati f’ pazjenti anzjani bħala parti minn studju farmakokinetiku renali.
Dose adjustments for this age group should be on the basis of renal function, see section 4.2.
L- aġġustamenti fid- doża għal dan il- grupp ta ’ età għandhom ikunu bbażati fuq il- funzjoni renali, ara sezzjoni 4. 2.
There are no gender effects in the pharmacokinetics of bivalirudin.
M’ hemmx effetti skond is- sess tal- persuna fil- farmakokinetiċi ta ’ bivalirudin.
15 Weight:
Piż tal- persuna:
Bivalirudin dose is body weight adjusted in mg/ kg.
Id- doża ta ’ bivalirudin tiġi aġġustata skond il- piż tal- ġisem f’ mg/ kg.
5.3 Pre-clinical safety data
5. 3 Tagħrif ta ’ qabel l- użu kliniku dwar is- sigurtà tal- mediċina
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction.
Dejta mhux klinika ma turi ebda periklu speċjali għall- bniedem u dan abbażi ta ’ studji konvenzjonali tas- sigurtà, farmakoloġija, tossiċità ta ’ doża ripetuta, ġenotossiċità jew tossiċità għar- riproduzzjoni.
Toxicity in animals upon repeated or continuous exposure (1 day to 4 weeks at exposure levels of up to 10 times the clinical steady state plasma concentration) was limited to exaggerated pharmacological effects.
It- tossiċità fl- annimali wara esponiment ripetut jew kontinwu (ġurnata sa 4 ġimgħat f’ livelli ta ’ esponiment sa 10 darbiet il- konċentrazzjoni klinika fissa fil- plażma) kienet limitata għal effetti farmakoloġiċi esaġerati.
Comparison of the single and repeated dose studies revealed that toxicity was related primarily to duration of exposure.
Tqabbil ta ’ l- istudji b’ doża waħda u b’ doża ripetuta wera li t- tossiċità kienet relatata primarjament mat- tul ta ’ l- esponiment.
All the undesirable effects, primary and secondary, resulting from excessive pharmacological activity were reversible.
L- effetti mhux mixtieqa kollha, primarji u sekondarji, li rriżultaw minn attività farmakoloġika eċċessiva kienu riversibbli.
Undesirable effects that resulted from prolonged physiological stress in response to a non-homeostatic state of coagulation were not seen after short exposure comparable to that in clinical use, even at much higher doses.
L- effetti mhux mixtieqa li rriżultaw minn stress fiżjoloġiku prolungat b’ rispons għal stat mhux omeostatiku ta ’ koagulazzjoni ma dehrux wara esponiment qasir komparabbli ma ’ dak fl- użu kliniku, anki f’ dożi ferm aktar għoljin.
Bivalirudin is intended for short-term administration and therefore no data on the long-term carcinogenic potential of bivalirudin are available.
15 Bivalirudin huwa maħsub biex jingħata għal żmien qasir u għalhekk mhix disponibbli dejta dwar il - potenzjal karċinoġeniku fuq perjodu fit- tul ta ’ bivalirudin.
However, bivalirudin was not mutagenic or clastogenic in standard assays for such effects.
Madankollu, bivalirudin ma kienx mutaġeniku jew klastoġeniku f’ assays standard għal effetti simili.
Mannitol Sodium hydroxide solution 2% (for pH adjustment).
6. 2 Inkompatibilitajiet
The following medicinal products should not be administered in the same intravenous line as bivalirudin since they result in haze formation, micro-particulate formation or gross precipitation; alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase and vancomycin HCl.
Il- prodotti mediċinali li ġejjin m’ għandhomx jingħataw fl- istess linja intravenuża ma ’ bivalirudin billi jwasslu għal formazzjoni ta ’ ċpar, formazzjoni ta ’ partikuli żgħar ħafna jew preċipitazzjoni qawwija; alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase u vancomycin HCl.